CA1047510A - Benzopyrans - Google Patents
BenzopyransInfo
- Publication number
- CA1047510A CA1047510A CA205,977A CA205977A CA1047510A CA 1047510 A CA1047510 A CA 1047510A CA 205977 A CA205977 A CA 205977A CA 1047510 A CA1047510 A CA 1047510A
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- Prior art keywords
- hydrolysis
- compound
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- reaction
- followed
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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
- C07D311/22—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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
ABSTRACT
There are described compounds of formula VII, VII
in which X represents an alkylene chain which is optionally substituted by a hydroxy group, or a pharmaceutically acceptable salt, ester or amide thereof. Processes for the production of the compounds are also described. The compounds of formula VII are useful as anti-asthmatics.
There are described compounds of formula VII, VII
in which X represents an alkylene chain which is optionally substituted by a hydroxy group, or a pharmaceutically acceptable salt, ester or amide thereof. Processes for the production of the compounds are also described. The compounds of formula VII are useful as anti-asthmatics.
Description
~0475~l) This invention relates to new compounds, processes for their production and processes using them.
According to our invention we provide compounds of formula I, OXO ~ E
in which E represents a carboxylic acid, a carbohydroxamic acid or a lH-tetrazol-5-yl group, or a derivative thereof, and X represents an alkylene chain which is optionally substituted by a hydroxy group, and pharmaceutically acceptable derivatives thereof.
According to our invention we also provide a process for the production of a compound of fornula I, or a pharmaceutically acceptable derivative thereof, which oomprises, (a) reacting a compound of formLla II, Hal Hal Hal ~Hal zO E ~ OXO ~ E
in which E and X are as defined above, and Hal represents a halogen atom, with a sulphur nucleophile, or Cb) reac~ing a compound of fornLla r~ or V,
According to our invention we provide compounds of formula I, OXO ~ E
in which E represents a carboxylic acid, a carbohydroxamic acid or a lH-tetrazol-5-yl group, or a derivative thereof, and X represents an alkylene chain which is optionally substituted by a hydroxy group, and pharmaceutically acceptable derivatives thereof.
According to our invention we also provide a process for the production of a compound of fornula I, or a pharmaceutically acceptable derivative thereof, which oomprises, (a) reacting a compound of formLla II, Hal Hal Hal ~Hal zO E ~ OXO ~ E
in which E and X are as defined above, and Hal represents a halogen atom, with a sulphur nucleophile, or Cb) reac~ing a compound of fornLla r~ or V,
- 2 -~0~75iO
o o E ~ OXO ~ E IV
0 0 o O
E ~ OXO ~ Z EV
in which E and X are as defined above, and Z represents hydrogen or an alkali metal cation, with phosphorus pentasulphide, boron sulphide or silieon disulphide, and i desired or necessary converting the compound of fo~mula I to a pha~maceutically acceptable derivative thereof or vice versa.
Process (a) may be carried out in a solvent which is inert under the reaction c~nditions, for example benzene. The reaction is preferably carried out at a temperature of from about O to 20 100Co When the group X represents an alkylene chain substituted by a hydroxy group it may be desirable to protect the hydroxy group, for example by formylation, before the reaction and to remove the protecting group after the reaction. The sulphur nu d eophile may be, for exampIe a bisulphide ion, an alkali metal bisulphide in an alkanol, hydrogen sulphide and hydrochloric acid in an alkanol 1047S~(J
thiourea, a thiosulphate, an alkali metal xanthate in petroleum ether or a compound of formula III, RCOSH j III
S in which R represents an alkyl te.g. C 1 to 6), or an aryl (e.g.
a phenyl) group.
Process (b) may be carried out in a solvent which is inert under the reaction conditions, e.g. benzene or chloroforn. The reaction is conveniently carried out at an elevated temperature, e.g. the re1ux temperature of the reaction mLxture.
The compounds of folmula I may be isolated from reaction mixtures containing them using conventional techniques known E~! se-The compounds of fo~mula II, and protected derivatives thereof, may be made by reaction of a compound of formula IV or V, or a protected derivative thereof, with a thionyl halide.
It is usual not to isolate the compound of formula II, but to convert it directly to the compound of formula I.
The compounds of formulae IV and V are known compounds or may be made from known compounds using conventional techniques.
Pharmaceutically acceptable derivatives of the compounds of formula I include pharmaceutically acceptable salts, and whero E
is a -COOH group, esters and amides thereof. Suitable salts include water soluble salts~ for example ammonium, alkali metal (eOgO sodium and potassium) and alkaline earth metal (e.g. calcium 1~4'~510 and magnesium) salts and salts with suitable organic bases, e~g.
salts with lower (C 1 to 6) alkyl amines, eOg. methylamine or ethylamine, with hydroxy substituted C 1 to 6 alkylamines, or with simple nocyclic nitrogen heterocyclic compounds, e,g~
piperid me and morpholineO Suitable esters include C 1 to 10, and preferably C 1 to 6, alkyl esters, and C 1 to 6 alkyl amino-C 1 to 6 alkyl esters, e.g. the diethylaminoethyl ester, and the acid addition salts thereof.
The pharmaceutically acceptable derivatives of the compound of formula I may be made and interconverted by conventional techniques known ~ se.
The compounds of formulae I and IV, and pharmaceutically acceptable deri~atives thereof, are useful because they possess pharmacological activity in animals; in particular they are useful because they inhibit the release and/or action of phaTmacological mediators which result from the in vivo combination of certain types of antibody and specific antigen, e.g. the combination of reaginic antibody with specific antigen~ (See Example 15 of British Patent Specification No 1,230,087).
In man, both subjective and objective changes which result from the inhalation of specific antigen by sensitised subjects are inhibited by pTior administration of the new compounds.
Thus the new compounds are indicated for use in the treatment of asthma, e~g. allergic asthmaO The new compounds are also indicated for use in the treatment of so-called 'intrinsic' asthma ~04'75i'~
(in which no sensitivity to extrinsic antigen can be demonstrated).
The new compounds may also be of value in the treatment of other conditions in which antigen-antibody reactions are responsible for disease, for example, allergic rhinitis; certain eye conditions, S e.g. trachoma; urticaria; and gastrointestinal allergy, especially in children, eOgO milk allergy.
For the above mentioned uses the dosage administered will, of course, vary with the com~ound employed, the mode of administration and the treatment desired~ However, in general satisfactory results are obtained when the compounds are adminîstered at a dosage of from 0.1 to 50 mg per kg of animal body weight in the test set out in Example 15 of British Patent Specification No 1,230,087. For man the total daily dosage is in the range of from about 1 mg to 3,5C0 mg which may be adm m istered in divided doses from 1 to 6 times a day or in sustained release fonm. Thus dosage forms suitable for administration (by inhalation or oesophageally) comprise from about 0.17 mg to 600 mg of the compound admixed with a solid or liquid pharmaceutically acceptable diluent or carrierO
According to our invention we also provide a pharmaceutical composition co~prising (preferably a minor proportion of) a compound of formula I, or a pharmaceutically acceptable derivative thereo~, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier~ Examples of suitable adjuvants, diluents or carrier are:- for tablets and dragées;
10~'7SiO
lactose, starch, talc or stearic acid; for capsules, tartaric acid or lactose; for suppositories, natural or hardened oils or waxes; for inhalation compositions, coarse lactose. For use in inhalation compositions, the compound of formLla I, or the pharmaceutically acceptable derivative thereof, preferably has a mass median diameter of from 0.01 to 10 microns. The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, sweetening and colouring agents and flavourings. The compositions may, if desired, be formLlated in sustained release form.
According to the invention there is also provided a process for the production of a pharmaceutically acceptable salt of a compound of formula I, which comprises treating a compound of foTmula Ix, 1S s oxo_ J L G
in which X is as defined above, and G is a group E, or another salt thereof, or when E in the compound of formula I is a carboxylic acid group, G may be a carboxylic ester group, a nitrile group, an acid halide group or an amide group, with a compound containing an available pharmaceutically acceptable cation and capable of converting the group G to a ln47510 p~larmaceutically acceptable salt of an E gTOUp.
Com~ounds capable of converting the group G to a p]larmaceutically acceptable salt of E include compounds, e.g.
bases and ion exchange resins, containing pharmaceutically acceptable cations, e.g. sodium, potassium, calcium, ammonium and appropriate nitrogen containing organic cations. In general we prefer to form the pharmaceutically acceptable salt by treating the free acid of formula I with an appropriate base, e.g. with an alkaline-earth or alkali metal hydroxide, carbonate or bicarbonate in aqueous solution, or by treating another salt of a compound of foxmula I with an appropriate salt by a metathetical process. When a strongly basic compound is used care should be taken, e.g. by keeping the temperature sufficiently low, to ensure that the compound of formula I is not hydrolysed or otherwise degraded.
The pharmaceutically acceptable salt may be recovered from the reaction mixture by, for example, solvent precipitation and/or removal of the solvent by evaporation, e.g. by freeze drying.
According to a further feature of our invention we provide a process for the production of a compound of foTmula rv, which comprises hydrolysis; or alkylation followed by hydrolysis or oxidation followed by hydrolysis, of a compound of formula I, or a derivative thereof.
When simple hydrolysis is used the reaction may be carried out in the presence of a heavy metal compound, e.g. a compound of group Ib, IIb or IIIb of the Periodic Table as catalyst.
ln~slo Suitable compounds include mercury, thallium and silver compounds, eOg. mercury (11) acetate or chloride, thallium (111) trifluoroacetate, and silver oxide. The reaction may be carried out in the presence of water and an organic solvent system such as acetone-acetic acid, alkanols, tetrahydrofuran/methanol, or tetrahydrofuran. Alternatively the hydrolysis may be carried out in the presence of an acid, e.g. sulphuric acid, hydrochloric acid, trifluoroacetic acid, P-toluenesulphonic acid or a Lewis acid such as boron trifluoride, preferably in the presence of a polar solvent such as dimethylsulphoxide.
When the reaction involves alkylation followed by hydrolysis the reaction may be effected by (i) an alkyl halide or sulphonate (e.g. methyl iodide) in a moist solvent, e.g. acetone, (ii) an alkylfluorosulphonate and water in sulphur dioxide, or tiii) a trialkyl oxonium fluoroborate followed by aqueous sodium hydroxide.
When the reaction involves oxidation followed by hydrolysis the reactlon may involve l-chlorobenzotriazole in methylene chloride followed by hydrolysis with sodium hydroxide, chlora~ine-T in water or an aqueous alkanol, ceric amnonium nitrate in aqueous acetonitrile, or N-halosuccinimide opti ally in conjunctian with silver nitrate in aqueous acetonitrile.
It is preferred that X should contain from 2 to 10 and more preferably from 3 to 7 carbon atoms, eOg. a group -GH2CHoHCH2-, and that the -OX0- group should link the 5,5' positions on the benzopyran Z5 nuclei~
_ g _ - 1047S~0 The invention is found to be particularly useful in providing a process for the preparation of a compound of formula VII, O O
HOOC_ ~ J ; ~ COOH
in which X represents an alkylene chain which is optionally substituted by a hydroxy group, or a pharmaceutically acceptable salt, ester or amide thereof, which comprises, hydrolysis: or alkylation followed by hydrolysis; or oxidation followed by hydrolysis, of a compound of formula Vl, ~ ~ + OXO ~ ~ COOH
in which X is as defined above; or a corresponding salt, e~ter or amide thereof.
, .. .
.
1~47S10 The invention is illustrated but in no way limited by the following Examples.
Example 1 D thyl 5,5'(2-hydroxytrimethylenedioxy)bis(4-oxo-4H-l-benzopyran -2-carboxylate) Diethyl 5,5'(2-hydroxytrimethylenedioxy)bis(4-thioxo-4H
-l-benzopyran-2-carboxylate) (41 mgs, 0.074 m mole) in lOml Analar acetone + 4 drops water was mixed with an excess of mercury (11) acetate (302 mgs, 0.95 m mole) in 6ml glacial acetic acid. A red colour was immediately observed and the resulting mixture was stirred at room temperature for 5 minutes and then warmed for 2 minutes on a hot plate. The colour had by this time faded to orange. The reaction mixture was filtered through a diatomaceous earth (kieselguhr) filter aid known by the trade mark 'Hiflo-supercel' and the residue washed thoroughly with acetone. The filtrate was poured into water and extracted three times with dichloromethane. The combined organic layers were shaken with aqueous sodium bicarbonate solution, washed with water, dried (anhydrous sodium sulphate) and concentrated affording a solid/gum mixture. This crude product was recrystallised from ethanol affording 6 mgs of solid product, mp 172-180, whose rf value on TLC, using ethyl acetate as eluent, was identical to that of an authentic sample of diethyl 5,5'-(2-hydroxy-trimethylene)bis (4-oxo-4H-l-benzopyran-2-carboxylate).
Example 2 Diethyl 5,5'-(2-Hydroxytrimethylenedioxy)bis(4-oxo-4H-l-benzopyran-2-carboxylate) 104'~51V
A mixture of 25 mgs (00045 mmole of diethyl 5,5'-t2-hydroxy-trimethylenedioxy)bis~4-thioxo-4H-l-benzopyran-2-carboxylate) and 3 drops methyl iodide in 10 ml analar acetone containing 4 drops of water was stirred in the dark at room temperature for 2 days.
Concentration of the reaction mixture afforded a light brown solid which was recrystallised from aqueous ethanol to yield an off-yellow solid, mp 178-180Co The ir spectru~ and tlc rf value ~ethyl acetate as eluent) of this solid were identical to that of an authentic sample of diethyl 5,5'-~2-hydroxy-trimethylenedioxy)bis~4-oxo-4H-l-benzopyran-2-carboxylate)O
Exampls 3 Diethyl 5,5'-t2-Hydroxytrimethylenedioxn bist4-thioxo-4H-l-benzopyran-2-carboxylate~
ta) Diethyl 5,5'-(2-Formyl~ytrimethylenedioxy)bis(4-thioxo-4H-l-benzopyran-2-carboxylate) A stirred mixture of 2.0g (3.62 mmole) of diethyl 5,5'-~2-fo~myloxytrimethylenedioxy)bis~4-oxo-4H-l-benzopyran-2-carboxylate) in lS ml thionyl chloride was refluxed for 18 hoursO The orange zO solution was evaporated to dryness and the glassy residue dissolved in benzeneO This solution was treated with 2 ml (28.2 le) of thioacetic acid and the resulting mixture refluxed for 4 hours.
Evaporation of the solution afforded a green gum which was crystallised from ethanol affording 1.37 g of a green solid, mp 137-140o m4 7sio Cb) Diethyl 5,5'-(2-Hydroxytrimethylenedioxy)bist4-thioxo-4H-l-benzopyran-2-carboxylate) A stirred m~xture of 005g (0086 mmole) of diethyl 5,5'-(2-formyloxytrimethylenedioxy)bis(4-thioxo-4H-l-benzopyran-2-carboxylate) S in 15 ml ethanol containing 3 drops of concentrated hydrochloric acid was refluxed for 5 hours and then left stirring overnight at room temperatureO The reaction mixture was diluted with chloroform and washed twice with waterO The organic layer was ~ried (anhydrous sodium sulphate) and concentrated affording a dark green solid, 0046g, mp 150-155.
The diethyl ester may be hydrolysed to the correspo.nding dicarboxylic acid 5,5'-(2-Hydroxytrimethylenedioxy)bis(4-thioxo-4H-l-benzopyran-2-carboxylic acid).
ln47si(~
Example 4 Diethyl 5,5'(2-hydroxytrimethylenedioxy)bis(4-oxo-4H-l-benzo-E~-an-2-carboxylate) A mixture of diethyl 5,5'(2-hydroxytrimethylenedioxy) bis(4-thioxo-4H-l-benzopyran-2-carboxylate) (27mg, 0.05 m mole) in acetonitrile (lOml) was added with stirring to a solution of N-chlorosuccinimide (27 mg, 0.2 m mole) and silver nitrate (38.3mg, 0.225 m mole) in 80% aqueous acetonitrile (lOml) at 25.
The mixture was heated to 50 stirred at that temperature for 2 hours and then treated with saturated aqueous sodium sulphite, aqueous sodium bicarbonate and brine. Dichloromethane was adde~
and mixture filtered through a diatomaceous earth (kieselguhr) filter aid known by the trade mark 'Celite'. The aqueous layer was extracted with dichloromethane and the combined organic layers dried and concentrated affording a solid which was recrystallised from aqueous ethanol to yield an off-yellow solid m.p., 174-180C
whose RF value on thin layer chromatography using ethyl acetate as eluent was identical to that of an authentic sample of the title compound.
o o E ~ OXO ~ E IV
0 0 o O
E ~ OXO ~ Z EV
in which E and X are as defined above, and Z represents hydrogen or an alkali metal cation, with phosphorus pentasulphide, boron sulphide or silieon disulphide, and i desired or necessary converting the compound of fo~mula I to a pha~maceutically acceptable derivative thereof or vice versa.
Process (a) may be carried out in a solvent which is inert under the reaction c~nditions, for example benzene. The reaction is preferably carried out at a temperature of from about O to 20 100Co When the group X represents an alkylene chain substituted by a hydroxy group it may be desirable to protect the hydroxy group, for example by formylation, before the reaction and to remove the protecting group after the reaction. The sulphur nu d eophile may be, for exampIe a bisulphide ion, an alkali metal bisulphide in an alkanol, hydrogen sulphide and hydrochloric acid in an alkanol 1047S~(J
thiourea, a thiosulphate, an alkali metal xanthate in petroleum ether or a compound of formula III, RCOSH j III
S in which R represents an alkyl te.g. C 1 to 6), or an aryl (e.g.
a phenyl) group.
Process (b) may be carried out in a solvent which is inert under the reaction conditions, e.g. benzene or chloroforn. The reaction is conveniently carried out at an elevated temperature, e.g. the re1ux temperature of the reaction mLxture.
The compounds of folmula I may be isolated from reaction mixtures containing them using conventional techniques known E~! se-The compounds of fo~mula II, and protected derivatives thereof, may be made by reaction of a compound of formula IV or V, or a protected derivative thereof, with a thionyl halide.
It is usual not to isolate the compound of formula II, but to convert it directly to the compound of formula I.
The compounds of formulae IV and V are known compounds or may be made from known compounds using conventional techniques.
Pharmaceutically acceptable derivatives of the compounds of formula I include pharmaceutically acceptable salts, and whero E
is a -COOH group, esters and amides thereof. Suitable salts include water soluble salts~ for example ammonium, alkali metal (eOgO sodium and potassium) and alkaline earth metal (e.g. calcium 1~4'~510 and magnesium) salts and salts with suitable organic bases, e~g.
salts with lower (C 1 to 6) alkyl amines, eOg. methylamine or ethylamine, with hydroxy substituted C 1 to 6 alkylamines, or with simple nocyclic nitrogen heterocyclic compounds, e,g~
piperid me and morpholineO Suitable esters include C 1 to 10, and preferably C 1 to 6, alkyl esters, and C 1 to 6 alkyl amino-C 1 to 6 alkyl esters, e.g. the diethylaminoethyl ester, and the acid addition salts thereof.
The pharmaceutically acceptable derivatives of the compound of formula I may be made and interconverted by conventional techniques known ~ se.
The compounds of formulae I and IV, and pharmaceutically acceptable deri~atives thereof, are useful because they possess pharmacological activity in animals; in particular they are useful because they inhibit the release and/or action of phaTmacological mediators which result from the in vivo combination of certain types of antibody and specific antigen, e.g. the combination of reaginic antibody with specific antigen~ (See Example 15 of British Patent Specification No 1,230,087).
In man, both subjective and objective changes which result from the inhalation of specific antigen by sensitised subjects are inhibited by pTior administration of the new compounds.
Thus the new compounds are indicated for use in the treatment of asthma, e~g. allergic asthmaO The new compounds are also indicated for use in the treatment of so-called 'intrinsic' asthma ~04'75i'~
(in which no sensitivity to extrinsic antigen can be demonstrated).
The new compounds may also be of value in the treatment of other conditions in which antigen-antibody reactions are responsible for disease, for example, allergic rhinitis; certain eye conditions, S e.g. trachoma; urticaria; and gastrointestinal allergy, especially in children, eOgO milk allergy.
For the above mentioned uses the dosage administered will, of course, vary with the com~ound employed, the mode of administration and the treatment desired~ However, in general satisfactory results are obtained when the compounds are adminîstered at a dosage of from 0.1 to 50 mg per kg of animal body weight in the test set out in Example 15 of British Patent Specification No 1,230,087. For man the total daily dosage is in the range of from about 1 mg to 3,5C0 mg which may be adm m istered in divided doses from 1 to 6 times a day or in sustained release fonm. Thus dosage forms suitable for administration (by inhalation or oesophageally) comprise from about 0.17 mg to 600 mg of the compound admixed with a solid or liquid pharmaceutically acceptable diluent or carrierO
According to our invention we also provide a pharmaceutical composition co~prising (preferably a minor proportion of) a compound of formula I, or a pharmaceutically acceptable derivative thereo~, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier~ Examples of suitable adjuvants, diluents or carrier are:- for tablets and dragées;
10~'7SiO
lactose, starch, talc or stearic acid; for capsules, tartaric acid or lactose; for suppositories, natural or hardened oils or waxes; for inhalation compositions, coarse lactose. For use in inhalation compositions, the compound of formLla I, or the pharmaceutically acceptable derivative thereof, preferably has a mass median diameter of from 0.01 to 10 microns. The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, sweetening and colouring agents and flavourings. The compositions may, if desired, be formLlated in sustained release form.
According to the invention there is also provided a process for the production of a pharmaceutically acceptable salt of a compound of formula I, which comprises treating a compound of foTmula Ix, 1S s oxo_ J L G
in which X is as defined above, and G is a group E, or another salt thereof, or when E in the compound of formula I is a carboxylic acid group, G may be a carboxylic ester group, a nitrile group, an acid halide group or an amide group, with a compound containing an available pharmaceutically acceptable cation and capable of converting the group G to a ln47510 p~larmaceutically acceptable salt of an E gTOUp.
Com~ounds capable of converting the group G to a p]larmaceutically acceptable salt of E include compounds, e.g.
bases and ion exchange resins, containing pharmaceutically acceptable cations, e.g. sodium, potassium, calcium, ammonium and appropriate nitrogen containing organic cations. In general we prefer to form the pharmaceutically acceptable salt by treating the free acid of formula I with an appropriate base, e.g. with an alkaline-earth or alkali metal hydroxide, carbonate or bicarbonate in aqueous solution, or by treating another salt of a compound of foxmula I with an appropriate salt by a metathetical process. When a strongly basic compound is used care should be taken, e.g. by keeping the temperature sufficiently low, to ensure that the compound of formula I is not hydrolysed or otherwise degraded.
The pharmaceutically acceptable salt may be recovered from the reaction mixture by, for example, solvent precipitation and/or removal of the solvent by evaporation, e.g. by freeze drying.
According to a further feature of our invention we provide a process for the production of a compound of foTmula rv, which comprises hydrolysis; or alkylation followed by hydrolysis or oxidation followed by hydrolysis, of a compound of formula I, or a derivative thereof.
When simple hydrolysis is used the reaction may be carried out in the presence of a heavy metal compound, e.g. a compound of group Ib, IIb or IIIb of the Periodic Table as catalyst.
ln~slo Suitable compounds include mercury, thallium and silver compounds, eOg. mercury (11) acetate or chloride, thallium (111) trifluoroacetate, and silver oxide. The reaction may be carried out in the presence of water and an organic solvent system such as acetone-acetic acid, alkanols, tetrahydrofuran/methanol, or tetrahydrofuran. Alternatively the hydrolysis may be carried out in the presence of an acid, e.g. sulphuric acid, hydrochloric acid, trifluoroacetic acid, P-toluenesulphonic acid or a Lewis acid such as boron trifluoride, preferably in the presence of a polar solvent such as dimethylsulphoxide.
When the reaction involves alkylation followed by hydrolysis the reaction may be effected by (i) an alkyl halide or sulphonate (e.g. methyl iodide) in a moist solvent, e.g. acetone, (ii) an alkylfluorosulphonate and water in sulphur dioxide, or tiii) a trialkyl oxonium fluoroborate followed by aqueous sodium hydroxide.
When the reaction involves oxidation followed by hydrolysis the reactlon may involve l-chlorobenzotriazole in methylene chloride followed by hydrolysis with sodium hydroxide, chlora~ine-T in water or an aqueous alkanol, ceric amnonium nitrate in aqueous acetonitrile, or N-halosuccinimide opti ally in conjunctian with silver nitrate in aqueous acetonitrile.
It is preferred that X should contain from 2 to 10 and more preferably from 3 to 7 carbon atoms, eOg. a group -GH2CHoHCH2-, and that the -OX0- group should link the 5,5' positions on the benzopyran Z5 nuclei~
_ g _ - 1047S~0 The invention is found to be particularly useful in providing a process for the preparation of a compound of formula VII, O O
HOOC_ ~ J ; ~ COOH
in which X represents an alkylene chain which is optionally substituted by a hydroxy group, or a pharmaceutically acceptable salt, ester or amide thereof, which comprises, hydrolysis: or alkylation followed by hydrolysis; or oxidation followed by hydrolysis, of a compound of formula Vl, ~ ~ + OXO ~ ~ COOH
in which X is as defined above; or a corresponding salt, e~ter or amide thereof.
, .. .
.
1~47S10 The invention is illustrated but in no way limited by the following Examples.
Example 1 D thyl 5,5'(2-hydroxytrimethylenedioxy)bis(4-oxo-4H-l-benzopyran -2-carboxylate) Diethyl 5,5'(2-hydroxytrimethylenedioxy)bis(4-thioxo-4H
-l-benzopyran-2-carboxylate) (41 mgs, 0.074 m mole) in lOml Analar acetone + 4 drops water was mixed with an excess of mercury (11) acetate (302 mgs, 0.95 m mole) in 6ml glacial acetic acid. A red colour was immediately observed and the resulting mixture was stirred at room temperature for 5 minutes and then warmed for 2 minutes on a hot plate. The colour had by this time faded to orange. The reaction mixture was filtered through a diatomaceous earth (kieselguhr) filter aid known by the trade mark 'Hiflo-supercel' and the residue washed thoroughly with acetone. The filtrate was poured into water and extracted three times with dichloromethane. The combined organic layers were shaken with aqueous sodium bicarbonate solution, washed with water, dried (anhydrous sodium sulphate) and concentrated affording a solid/gum mixture. This crude product was recrystallised from ethanol affording 6 mgs of solid product, mp 172-180, whose rf value on TLC, using ethyl acetate as eluent, was identical to that of an authentic sample of diethyl 5,5'-(2-hydroxy-trimethylene)bis (4-oxo-4H-l-benzopyran-2-carboxylate).
Example 2 Diethyl 5,5'-(2-Hydroxytrimethylenedioxy)bis(4-oxo-4H-l-benzopyran-2-carboxylate) 104'~51V
A mixture of 25 mgs (00045 mmole of diethyl 5,5'-t2-hydroxy-trimethylenedioxy)bis~4-thioxo-4H-l-benzopyran-2-carboxylate) and 3 drops methyl iodide in 10 ml analar acetone containing 4 drops of water was stirred in the dark at room temperature for 2 days.
Concentration of the reaction mixture afforded a light brown solid which was recrystallised from aqueous ethanol to yield an off-yellow solid, mp 178-180Co The ir spectru~ and tlc rf value ~ethyl acetate as eluent) of this solid were identical to that of an authentic sample of diethyl 5,5'-~2-hydroxy-trimethylenedioxy)bis~4-oxo-4H-l-benzopyran-2-carboxylate)O
Exampls 3 Diethyl 5,5'-t2-Hydroxytrimethylenedioxn bist4-thioxo-4H-l-benzopyran-2-carboxylate~
ta) Diethyl 5,5'-(2-Formyl~ytrimethylenedioxy)bis(4-thioxo-4H-l-benzopyran-2-carboxylate) A stirred mixture of 2.0g (3.62 mmole) of diethyl 5,5'-~2-fo~myloxytrimethylenedioxy)bis~4-oxo-4H-l-benzopyran-2-carboxylate) in lS ml thionyl chloride was refluxed for 18 hoursO The orange zO solution was evaporated to dryness and the glassy residue dissolved in benzeneO This solution was treated with 2 ml (28.2 le) of thioacetic acid and the resulting mixture refluxed for 4 hours.
Evaporation of the solution afforded a green gum which was crystallised from ethanol affording 1.37 g of a green solid, mp 137-140o m4 7sio Cb) Diethyl 5,5'-(2-Hydroxytrimethylenedioxy)bist4-thioxo-4H-l-benzopyran-2-carboxylate) A stirred m~xture of 005g (0086 mmole) of diethyl 5,5'-(2-formyloxytrimethylenedioxy)bis(4-thioxo-4H-l-benzopyran-2-carboxylate) S in 15 ml ethanol containing 3 drops of concentrated hydrochloric acid was refluxed for 5 hours and then left stirring overnight at room temperatureO The reaction mixture was diluted with chloroform and washed twice with waterO The organic layer was ~ried (anhydrous sodium sulphate) and concentrated affording a dark green solid, 0046g, mp 150-155.
The diethyl ester may be hydrolysed to the correspo.nding dicarboxylic acid 5,5'-(2-Hydroxytrimethylenedioxy)bis(4-thioxo-4H-l-benzopyran-2-carboxylic acid).
ln47si(~
Example 4 Diethyl 5,5'(2-hydroxytrimethylenedioxy)bis(4-oxo-4H-l-benzo-E~-an-2-carboxylate) A mixture of diethyl 5,5'(2-hydroxytrimethylenedioxy) bis(4-thioxo-4H-l-benzopyran-2-carboxylate) (27mg, 0.05 m mole) in acetonitrile (lOml) was added with stirring to a solution of N-chlorosuccinimide (27 mg, 0.2 m mole) and silver nitrate (38.3mg, 0.225 m mole) in 80% aqueous acetonitrile (lOml) at 25.
The mixture was heated to 50 stirred at that temperature for 2 hours and then treated with saturated aqueous sodium sulphite, aqueous sodium bicarbonate and brine. Dichloromethane was adde~
and mixture filtered through a diatomaceous earth (kieselguhr) filter aid known by the trade mark 'Celite'. The aqueous layer was extracted with dichloromethane and the combined organic layers dried and concentrated affording a solid which was recrystallised from aqueous ethanol to yield an off-yellow solid m.p., 174-180C
whose RF value on thin layer chromatography using ethyl acetate as eluent was identical to that of an authentic sample of the title compound.
Claims (7)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:-
1. A process for the preparation of a compound of formula VII, VII
in which X represents an alkylene chain which is optionally substituted by a hydroxy group, or a pharmaceutically acceptable salt, ester or amide thereof, which comprises, hydrolysis; or alkylation followed by hydrolysis; or oxidation followed by hydrolysis, of a compound of formula VI, VI
in which X is as defined above, or a corresponding salt, ester or amide thereof.
in which X represents an alkylene chain which is optionally substituted by a hydroxy group, or a pharmaceutically acceptable salt, ester or amide thereof, which comprises, hydrolysis; or alkylation followed by hydrolysis; or oxidation followed by hydrolysis, of a compound of formula VI, VI
in which X is as defined above, or a corresponding salt, ester or amide thereof.
2. A process according to Claim 1, wherein, when simple hydrolysis is used, the reaction is carried out in the presence of a heavy metal compound as catalyst.
3. A process according to Claim 2, wherein the catalyst is a compound of group Ib, IIb or IIIb of the Periodic Table.
4. A process according to Claim 1, wherein, when simple hydrolysis is used, the reaction is carried out in the presence of an acid or a Lewis acid.
5. A process according to Claim 1, wherein, when the reaction involves alkylation, the reaction is effected by an alkyl halide or an alkyl sulphonate and water, an alkylfluoro-sulphonate and water in sulphur dioxide, or a trialkyl oxonium fluoroborate followed by aqueous sodium hydroxide.
6. A process according to Claim 1, wherein, when the reaction involves oxidation followed by hydrolysis, it comprises treatment with 1-chlorobenzotriazole in methylene chloride followed by hydrolysis with sodium hydroxide, treatment with chloramine-T in water or an aqueous alkanol, treatment with ceric ammonium nitrate in aqueous acetonitrile, and N- halosuccinimide optionally in conjunction with silver nitrate in aqueous acetonitrile.
7. A process according to Claim 1, wherein the compound of formula VII is diethyl 5,5'(2-hydroxytrimethylenedioxy)bis(4-oxo-4H-1-benzopyran-2-carboxylate.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3655573 | 1973-08-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1047510A true CA1047510A (en) | 1979-01-30 |
Family
ID=10389217
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA205,977A Expired CA1047510A (en) | 1973-08-01 | 1974-07-30 | Benzopyrans |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5082069A (en) |
| CA (1) | CA1047510A (en) |
| CH (1) | CH610896A5 (en) |
| DE (1) | DE2436552A1 (en) |
| DK (1) | DK408974A (en) |
| FI (1) | FI217474A (en) |
| FR (1) | FR2239244A1 (en) |
| NO (1) | NO142960C (en) |
| SE (1) | SE415256B (en) |
-
1974
- 1974-07-16 FI FI2174/74A patent/FI217474A/fi unknown
- 1974-07-30 DE DE2436552A patent/DE2436552A1/en active Pending
- 1974-07-30 FR FR7426369A patent/FR2239244A1/fr not_active Withdrawn
- 1974-07-30 CA CA205,977A patent/CA1047510A/en not_active Expired
- 1974-07-31 NO NO742774A patent/NO142960C/en unknown
- 1974-07-31 DK DK408974*A patent/DK408974A/da not_active Application Discontinuation
- 1974-07-31 CH CH1052474A patent/CH610896A5/en not_active IP Right Cessation
- 1974-07-31 SE SE7409901A patent/SE415256B/en unknown
- 1974-08-01 JP JP49087579A patent/JPS5082069A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DK408974A (en) | 1975-04-01 |
| FR2239244A1 (en) | 1975-02-28 |
| CH610896A5 (en) | 1979-05-15 |
| SE415256B (en) | 1980-09-22 |
| NO142960B (en) | 1980-08-11 |
| NO742774L (en) | 1975-03-03 |
| DE2436552A1 (en) | 1975-02-27 |
| FI217474A (en) | 1975-02-02 |
| SE7409901L (en) | 1975-02-03 |
| JPS5082069A (en) | 1975-07-03 |
| NO142960C (en) | 1980-11-19 |
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