CA1106837A - Androstadiene-17-carboxylic acids - Google Patents
Androstadiene-17-carboxylic acidsInfo
- Publication number
- CA1106837A CA1106837A CA353,029A CA353029A CA1106837A CA 1106837 A CA1106837 A CA 1106837A CA 353029 A CA353029 A CA 353029A CA 1106837 A CA1106837 A CA 1106837A
- Authority
- CA
- Canada
- Prior art keywords
- hydroxyl group
- formula
- chlorine
- group
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Landscapes
- Steroid Compounds (AREA)
Abstract
ABSTRACT
Novel androstadiene-17-carboxylic acids are disclosed of the formula:
(I) wherein R1 is H or Cl, each of R2 and R3 represents hydrogen, chlorine or fluorine with the proviso that at least one of these substituents is chlorine or fluorine when R1 is Cl and that R2 is only Cl or F ant R3 is H or Cl when R1 is H, R4 is Oh, whilst R3 and R4 together can also represent a further 9,11 C-C-bond or -O-, R5 represents a methyl group in the .alpha.- or .beta.-position, the ethylene group, a free hydroxyl group or a hydroxyl group which is esteri-fied with a lower alkanoic acid, R6 represents a free hydroxyl group or a hydroxyl group which is esterified with a carboxylic acid having not more than 7 carbon atoms, whilst R5 and R6 together represent the 16.alpha.,17.alpha.-dihydroxy-acetonide group
Novel androstadiene-17-carboxylic acids are disclosed of the formula:
(I) wherein R1 is H or Cl, each of R2 and R3 represents hydrogen, chlorine or fluorine with the proviso that at least one of these substituents is chlorine or fluorine when R1 is Cl and that R2 is only Cl or F ant R3 is H or Cl when R1 is H, R4 is Oh, whilst R3 and R4 together can also represent a further 9,11 C-C-bond or -O-, R5 represents a methyl group in the .alpha.- or .beta.-position, the ethylene group, a free hydroxyl group or a hydroxyl group which is esteri-fied with a lower alkanoic acid, R6 represents a free hydroxyl group or a hydroxyl group which is esterified with a carboxylic acid having not more than 7 carbon atoms, whilst R5 and R6 together represent the 16.alpha.,17.alpha.-dihydroxy-acetonide group
Description
3~3'~
This is a divisional application of the Canadian Patent application ser. no. 272,291.
The invention relates to novel androstadiene-17-carboxylic acids of the formula R ~ l l ~ 1 ; CQOH
Rl ~ ~ ~ R5 o RZ
wherein Rl is H or Cl, each of R and R3 represents hydro-gen, chlorine or fluorine, with the proviso that at least one of these substituents is chlorine or fluorine when Rl ~ ,,, is Cl and that R is only Cl or F and R3 is H or Cl when Rl is H, R is OH, whilst R and R4 together can also represent a further 9,11 C-C-bond or -O-, R represents a methyl group in the a- or ~-position, the methylene group, a free hydroxyl group or a hydroxyl group which is esteri-fied with a lower alkanoic acid, R6 represents a free hydroxyl group or a hydroxyl group whlch is esterified with a carboxylic acid having not~ore than 7 carbon atoms, whilst R5 and R together represent the 16a,17a-dihydroxy-acetonide group 3~
~ / \ CH
as well as to a process for the manufacture thereof and to their use.
The term "lower" used throughout this specification in connection with the number of carbon- atoms of organic groups denotes groups having 1 to 7 carbon atoms, unless othexwise expressly defined.
An esterified hydroxyl group R is derived from a saturated or unsaturated carboxylic acid of 1 to 7 carbon atoms which is unsubstituted or substituted by halogen ato~s, hydroxyl or lower alkoxy groups and is for example the formyloxy, acetoxy, propionyloxy, butyryloxy, ~aleryloxy, trimethylacetoxy, diethylacetoxy, capronyloxy, chloro~cetoxy, chloropropionyloxy, oxypropionyloxy or ace~oxypropionylox~
group.
The novel steroid-17-carboxylic acids of the present invention can be prepared in a manner which is known per se. In particular, they can be obtained by a) treating the corresponding 21-hydroxy-pregna-1,4-dien-20-ones wherein R6 represents an esterified hydroxyl group with sodium bismuthate or by b) treating the corresponding 21-hydroxy-pregna-1,4-dien-33~
20-ones wherein R6 represents a free hydroxyl group and 3~~ represents an esterified hydroxyl group or a methyl or methylene group with periodic acid or periodate and, if desired, esterifying the 17~-hydroxyl group of the resultant steroid-17-carboxylic acids of the formula tI) wherein R6 represents OH whilst optionally protecting the ll-hydroxyl group temporarily, or converting esterifled or ketalised hydroxyl groups R and/or R into free hydro-xyl groups, and/or adding chlorine to the 1,2-dou~le bond of a compound of the formula (I) wherein Rl represents hydrogen whils~ optionally protecting the ll-hydroxyl group temporarily, and dehydrochlorinating the resultant 1,2-di-chloro compound, and/or, if desired, converting the resul-tant acids of the formula (I) into the salts.
The conversion of a free hydroxyl group in the 17-position into an esterified hydroxyl group is effected in a manner known per se by reaction with therespective acid or a functional derivative, such as a halide or the anhy-dride, advantageously in thepresence of an acid catalyst, or example p-toluenesulphonic acid, perchloric acid, or~ith anacid ion exchan~ex,such as ~Ambexlite IR120 ~Tra~e mar3;), or qulphosalicylic acid and, with partlcular ad~antage, in the presence of trifluoroacetic anhydride. The reaction is advantageously carried out in a chlorinated hydrocar3~on, such as benzene or toluene, or in a chlorinated aliphatic hydrocarbon, such as methylene chloride or chloroform, or ~..~, 6~3!7 an excess of the acid itself is used as solvent. The reactions are advantageously carried out in the tempera-ture range between 20 and 100C. When using acid halides, the esterification can also be carried out in the presence of a base, such as pyridine, and at low temperature, for ex-ample at 0C.
If desired, the ll~-h~7droxyl group can be protected temporarily during the esterification of a 17-hydroxyl group, for example in accordance with the p.ocess describcd above.
The esterification with trifluoroacetic acid can be employed for this purpose. The trifluoroacetates are ob~ained by reacting the starting materials with trifluoroacetic chloride or anhydride in a manner known per se. It is known that tnis ester group can be easily split off again by hydrolysis or solvolysis, for e~ample by treatment with hydroxides, carbonates, bicarbonates or acetates of alkali metals or alkaline eart~ metals, for example in alcoholic or aqueous-alcoholic solution, for example in methanolic solution, or with alcohols alone. A particular method of carrying out the solvolysis of the ll~-trifluoroacetate group is that desoribed in German patent specification 1,593,519. This method comprises treating the ll^ester in a lo;~er alcohol with a salt of an acid ~hose pK value is iTI the range between about 2.3 and about 7.3, such as sodium or potassium azide or sodium or potassium formiate. If appropr-iate, this salt can also only be used in catalytic amounts. Furthermore, the hydrolysis of the ll-trifluoroacetate group can also be ef-fected by treat~ent with other basic reagents, for example with amines, in particular heterocyclic bases, such as ~yri-dine or collidine. Finally, the saponification by treatmellt with silica gel according to the process described in DT-CS
This is a divisional application of the Canadian Patent application ser. no. 272,291.
The invention relates to novel androstadiene-17-carboxylic acids of the formula R ~ l l ~ 1 ; CQOH
Rl ~ ~ ~ R5 o RZ
wherein Rl is H or Cl, each of R and R3 represents hydro-gen, chlorine or fluorine, with the proviso that at least one of these substituents is chlorine or fluorine when Rl ~ ,,, is Cl and that R is only Cl or F and R3 is H or Cl when Rl is H, R is OH, whilst R and R4 together can also represent a further 9,11 C-C-bond or -O-, R represents a methyl group in the a- or ~-position, the methylene group, a free hydroxyl group or a hydroxyl group which is esteri-fied with a lower alkanoic acid, R6 represents a free hydroxyl group or a hydroxyl group whlch is esterified with a carboxylic acid having not~ore than 7 carbon atoms, whilst R5 and R together represent the 16a,17a-dihydroxy-acetonide group 3~
~ / \ CH
as well as to a process for the manufacture thereof and to their use.
The term "lower" used throughout this specification in connection with the number of carbon- atoms of organic groups denotes groups having 1 to 7 carbon atoms, unless othexwise expressly defined.
An esterified hydroxyl group R is derived from a saturated or unsaturated carboxylic acid of 1 to 7 carbon atoms which is unsubstituted or substituted by halogen ato~s, hydroxyl or lower alkoxy groups and is for example the formyloxy, acetoxy, propionyloxy, butyryloxy, ~aleryloxy, trimethylacetoxy, diethylacetoxy, capronyloxy, chloro~cetoxy, chloropropionyloxy, oxypropionyloxy or ace~oxypropionylox~
group.
The novel steroid-17-carboxylic acids of the present invention can be prepared in a manner which is known per se. In particular, they can be obtained by a) treating the corresponding 21-hydroxy-pregna-1,4-dien-20-ones wherein R6 represents an esterified hydroxyl group with sodium bismuthate or by b) treating the corresponding 21-hydroxy-pregna-1,4-dien-33~
20-ones wherein R6 represents a free hydroxyl group and 3~~ represents an esterified hydroxyl group or a methyl or methylene group with periodic acid or periodate and, if desired, esterifying the 17~-hydroxyl group of the resultant steroid-17-carboxylic acids of the formula tI) wherein R6 represents OH whilst optionally protecting the ll-hydroxyl group temporarily, or converting esterifled or ketalised hydroxyl groups R and/or R into free hydro-xyl groups, and/or adding chlorine to the 1,2-dou~le bond of a compound of the formula (I) wherein Rl represents hydrogen whils~ optionally protecting the ll-hydroxyl group temporarily, and dehydrochlorinating the resultant 1,2-di-chloro compound, and/or, if desired, converting the resul-tant acids of the formula (I) into the salts.
The conversion of a free hydroxyl group in the 17-position into an esterified hydroxyl group is effected in a manner known per se by reaction with therespective acid or a functional derivative, such as a halide or the anhy-dride, advantageously in thepresence of an acid catalyst, or example p-toluenesulphonic acid, perchloric acid, or~ith anacid ion exchan~ex,such as ~Ambexlite IR120 ~Tra~e mar3;), or qulphosalicylic acid and, with partlcular ad~antage, in the presence of trifluoroacetic anhydride. The reaction is advantageously carried out in a chlorinated hydrocar3~on, such as benzene or toluene, or in a chlorinated aliphatic hydrocarbon, such as methylene chloride or chloroform, or ~..~, 6~3!7 an excess of the acid itself is used as solvent. The reactions are advantageously carried out in the tempera-ture range between 20 and 100C. When using acid halides, the esterification can also be carried out in the presence of a base, such as pyridine, and at low temperature, for ex-ample at 0C.
If desired, the ll~-h~7droxyl group can be protected temporarily during the esterification of a 17-hydroxyl group, for example in accordance with the p.ocess describcd above.
The esterification with trifluoroacetic acid can be employed for this purpose. The trifluoroacetates are ob~ained by reacting the starting materials with trifluoroacetic chloride or anhydride in a manner known per se. It is known that tnis ester group can be easily split off again by hydrolysis or solvolysis, for e~ample by treatment with hydroxides, carbonates, bicarbonates or acetates of alkali metals or alkaline eart~ metals, for example in alcoholic or aqueous-alcoholic solution, for example in methanolic solution, or with alcohols alone. A particular method of carrying out the solvolysis of the ll~-trifluoroacetate group is that desoribed in German patent specification 1,593,519. This method comprises treating the ll^ester in a lo;~er alcohol with a salt of an acid ~hose pK value is iTI the range between about 2.3 and about 7.3, such as sodium or potassium azide or sodium or potassium formiate. If appropr-iate, this salt can also only be used in catalytic amounts. Furthermore, the hydrolysis of the ll-trifluoroacetate group can also be ef-fected by treat~ent with other basic reagents, for example with amines, in particular heterocyclic bases, such as ~yri-dine or collidine. Finally, the saponification by treatmellt with silica gel according to the process described in DT-CS
2,144,405 is also possible.
In order to prepare the starting materials wherein R5 and R together represent the 16~,17a-dihydroxyacetonide group the corresponding compounds, in which each of R and R represents a free hydroxyl group, are reacted with acetone in a manner known per se. The reaction with acetone is ef-fected preferably in the presence of an acid catalyst. Strong mineraL acids are use~ as acid catalysts, such as hydrochloric acid, sulphuric acids, phosphoric acids and especially per-chloric acid, or organic sulphonic acids, such as camphor-sulphonic acid, or in particular monocyclic aromatic sul-phonic acids, such as p-toluenesulphonic acid or sulpho-salicylic acid Preferably an excess of acetone is used, so that it can also be used as solvent. However, the reaction with acetone can also be carried out in another organic solvent, for example a halogenated aliphatic hydrocarbon, such as chloroform or methylene chloride, or in an amide, such as dimethyl for~amide, or in a cyclic ether, such as tetrahydrofurane or dioxane. The 16a,17a-diols used as start-ing materials can also be formed in situ, for example by using a 16-ester of these diols and reacting it in their stecld in the indicated manner with acetone when the fr e dioLs are formed as intermediates. Instead of acetone, i~ is also possible to use a reactive derivative, for example a ket:al, such as one derived from a lower aliphatic alcohol, or an enol acylate, for example enol acetate.
The introduction of the 2-chlorine atom into steroid-17-carboxylic acids of the formula (I) wherein R is H is accomplished by the addition of chlorine to the 1,2-double bond in a manner knGwn Der se and dehydrochlorination of the resultant 1,2-~ichloro compound also in a manncr known per se.
Preferably elementary chlorine is used for the addi-tion of chlorine and the chlorination is carried out in an inert solvent, for example an ether, such as dioxane or tetrahydrofurane, a halogenated hydrocarbon, for example metkylene chloride, or a carboxylic acid, for example a lower aliphatic carboxylic acid, such as acetic acid or propionic acid. Instead of using carboxylic acids it is also possible to use derivatives thereo~, such as acid amides, for example dimethyl ~ormamide, or nitriles, such as lower alkylnitriles, for example acetonitrile. Advantageously, mixtures o~ these solvents can also be used, in particular a mixture of an ether, such as dioxane, with one of the above mentioned lower aiiphatic carboxylic acids. The process can be carried out ~ith chlorine in an amount substantially in excess of the theoretical amount; but preferably the stoichiometric amount of chlorine is used. The chlorination is advantageously 6 ~ ~
carried out at low temperature, approx between -50 and +30''C, for example between -20 and +10C, and in the dark.
The reaction ti~e is normally several hours or days, for example up to 7 days. In a particularly preferred embodi~ent of the process, the starting steroid is dissolved in one of the solvents mentioned above, for example dioxane, and treated with a solution of the chlorinating agent, for example chlorine, in a lower aliphatic carboxylic acid, for example propionic acid, and this solution is then allo~1ed to stand at the given temperature for several days.
However, the chlorination of the 1,2-double bond can also be effected with mixtures of two different chlorine-containing compounds one of which yields positive and the other negative chlorine. Examples of suitable reagents which are able to set free positive chlorine are chlorinated acid amides or acid imides, such as chlorosuccinimide or chlo~o-acetamide, and reagents which yield negative chlorine are, for example, hydrogen chloride and alkali metal chlorides.
The above mentioned solvents can also be used for the addi-tion of chlorine with these reagents.
If desired, the ll~-hydroxyl group can be protected before the chlorination This can be effected as described above in connection with the esterification of a 17~-hydroxyl group. The ll-hydroxyl protective group can be removed immediately after the addition of chlorine to the l,2-double bond or, if appropriate, simultaneously with dehydrochlorina-g tion by treatment with a base to be carried out, accordingto the process, after the chlorination. However, if desired, it is possible not to remcve the pxotective group until after the dehydrochlorination by treatment wîth a base.
The dehydrochlorination of the 1,2-dichloro compounds obtained by the addition of chlorine to the 1,2-double bond can advantageously be carried out with a base. Suitable bases are, for example, tertiary organic nitrogen bases, such as the lower aliphatic amines, for example triethylamine, or heterocyclic bases, such as pyridine and homologues thereof, for example collidine, or aromatic bases, such as N,N-dialkyl-aniline However, it is also possible to use inorganic bases, such as in particular the alkali metal and alkaliné earth metal salts also used for removing the above mentioned 11~-hydroxyl protective group, for example potassiu~ or sodium acetate or potassium or sodium bicarbonate, in aqueous-alcoholic solution, and the corresponding hydroxides, in which connect on care must be taken that no saponification of the 17-ester group takes place. This is possible by keeping ~he reaction condition~ as mild as possible,` such as choice of suitable temperature and concentration of the hydrolysing agent. The dehydrohalogenation is preferably carried o~t in the temperature range between approx. 20 and 100C and over the course of half an hour up to approx. 30 hours, depending on whether the reaction is carried out at elevated or low temperature. Preferably~ an excess of the dehydrohalogenating ~ J3 agent is used.
The salts of the steroid-17-carboxylic acids are pre-pared by treating for ~xample a solution or a suspension o~
the aci~ in water, or in a mixture ~f w3ter and an slcohol, with the calculated amount of the respective ~ase, for 2X-ample an alkali metal hydr~xide, or with a carbona~e or bi-carbonate~ and isolatin~ the salt in a manner ~nown p~- se, for example by precipitation with a suitable solvent ~r ~y crystallisation during the concentration of the resul~nt salt solution, or by lyophilisatio~, 17~-Esters can especially be prepared from 17a-hydroxy-steroid-17~-carboxylic acids of the formula (I) by reacting them initially with the anhydride corresponding to-the ester group to be introduced, whereupon the 17-ester of the mixed anhydride of the respective acid and the steroid-17-carboxylic acid are formed. The reaction is preferably carried out at elevated temperature. The mixed anhydride can be resolved by solvolysis, for example by treatment with basic or alkaline media, for example with aqueous acetic acid or aqueous pyri-dine or diethylamine in acetone.
The starting materials are known or can be prepared in known manner.
The compounds of the formula (I) are useful as inter-mediates for the preparation of the 17-carboxylic acid esters which are disclosed in the Canadian patent application ser.
no. 272 t 291.
.. , .. . . . .. . ... . .. . . ... . . . . . . .. . ~
The following Examples describe the invention in more detail.
Example 1 A solution of S g of 2-chloro-6a~9-difluoro~ ,17a-21-trihydroxy-1 6a - methyl-pregna-1,4-diene-3,20-dione in 200 ml of dioxane is treated with 12.5 g of periodic acid in 100 ml of water and the reaction mixture is stirred for 1 hour at room temperature. After addition of 150 ml of water, dioxane is evaporated in a water jet vacuum and the pre-cipitate which has formed is taken up in chloroform and washed with ice-cold dilute sodium hydroxide solution. The sodi~m hydroxide extract is acidified with ice-cold dilute hydrochloric acid and extracted with chloroform. The dried organic phase is concentrated in a water jet vacuum to yield the free 2-chloro-6a,9a-difluoro-11~,17a-dihydroxy-16-methyl-
In order to prepare the starting materials wherein R5 and R together represent the 16~,17a-dihydroxyacetonide group the corresponding compounds, in which each of R and R represents a free hydroxyl group, are reacted with acetone in a manner known per se. The reaction with acetone is ef-fected preferably in the presence of an acid catalyst. Strong mineraL acids are use~ as acid catalysts, such as hydrochloric acid, sulphuric acids, phosphoric acids and especially per-chloric acid, or organic sulphonic acids, such as camphor-sulphonic acid, or in particular monocyclic aromatic sul-phonic acids, such as p-toluenesulphonic acid or sulpho-salicylic acid Preferably an excess of acetone is used, so that it can also be used as solvent. However, the reaction with acetone can also be carried out in another organic solvent, for example a halogenated aliphatic hydrocarbon, such as chloroform or methylene chloride, or in an amide, such as dimethyl for~amide, or in a cyclic ether, such as tetrahydrofurane or dioxane. The 16a,17a-diols used as start-ing materials can also be formed in situ, for example by using a 16-ester of these diols and reacting it in their stecld in the indicated manner with acetone when the fr e dioLs are formed as intermediates. Instead of acetone, i~ is also possible to use a reactive derivative, for example a ket:al, such as one derived from a lower aliphatic alcohol, or an enol acylate, for example enol acetate.
The introduction of the 2-chlorine atom into steroid-17-carboxylic acids of the formula (I) wherein R is H is accomplished by the addition of chlorine to the 1,2-double bond in a manner knGwn Der se and dehydrochlorination of the resultant 1,2-~ichloro compound also in a manncr known per se.
Preferably elementary chlorine is used for the addi-tion of chlorine and the chlorination is carried out in an inert solvent, for example an ether, such as dioxane or tetrahydrofurane, a halogenated hydrocarbon, for example metkylene chloride, or a carboxylic acid, for example a lower aliphatic carboxylic acid, such as acetic acid or propionic acid. Instead of using carboxylic acids it is also possible to use derivatives thereo~, such as acid amides, for example dimethyl ~ormamide, or nitriles, such as lower alkylnitriles, for example acetonitrile. Advantageously, mixtures o~ these solvents can also be used, in particular a mixture of an ether, such as dioxane, with one of the above mentioned lower aiiphatic carboxylic acids. The process can be carried out ~ith chlorine in an amount substantially in excess of the theoretical amount; but preferably the stoichiometric amount of chlorine is used. The chlorination is advantageously 6 ~ ~
carried out at low temperature, approx between -50 and +30''C, for example between -20 and +10C, and in the dark.
The reaction ti~e is normally several hours or days, for example up to 7 days. In a particularly preferred embodi~ent of the process, the starting steroid is dissolved in one of the solvents mentioned above, for example dioxane, and treated with a solution of the chlorinating agent, for example chlorine, in a lower aliphatic carboxylic acid, for example propionic acid, and this solution is then allo~1ed to stand at the given temperature for several days.
However, the chlorination of the 1,2-double bond can also be effected with mixtures of two different chlorine-containing compounds one of which yields positive and the other negative chlorine. Examples of suitable reagents which are able to set free positive chlorine are chlorinated acid amides or acid imides, such as chlorosuccinimide or chlo~o-acetamide, and reagents which yield negative chlorine are, for example, hydrogen chloride and alkali metal chlorides.
The above mentioned solvents can also be used for the addi-tion of chlorine with these reagents.
If desired, the ll~-hydroxyl group can be protected before the chlorination This can be effected as described above in connection with the esterification of a 17~-hydroxyl group. The ll-hydroxyl protective group can be removed immediately after the addition of chlorine to the l,2-double bond or, if appropriate, simultaneously with dehydrochlorina-g tion by treatment with a base to be carried out, accordingto the process, after the chlorination. However, if desired, it is possible not to remcve the pxotective group until after the dehydrochlorination by treatment wîth a base.
The dehydrochlorination of the 1,2-dichloro compounds obtained by the addition of chlorine to the 1,2-double bond can advantageously be carried out with a base. Suitable bases are, for example, tertiary organic nitrogen bases, such as the lower aliphatic amines, for example triethylamine, or heterocyclic bases, such as pyridine and homologues thereof, for example collidine, or aromatic bases, such as N,N-dialkyl-aniline However, it is also possible to use inorganic bases, such as in particular the alkali metal and alkaliné earth metal salts also used for removing the above mentioned 11~-hydroxyl protective group, for example potassiu~ or sodium acetate or potassium or sodium bicarbonate, in aqueous-alcoholic solution, and the corresponding hydroxides, in which connect on care must be taken that no saponification of the 17-ester group takes place. This is possible by keeping ~he reaction condition~ as mild as possible,` such as choice of suitable temperature and concentration of the hydrolysing agent. The dehydrohalogenation is preferably carried o~t in the temperature range between approx. 20 and 100C and over the course of half an hour up to approx. 30 hours, depending on whether the reaction is carried out at elevated or low temperature. Preferably~ an excess of the dehydrohalogenating ~ J3 agent is used.
The salts of the steroid-17-carboxylic acids are pre-pared by treating for ~xample a solution or a suspension o~
the aci~ in water, or in a mixture ~f w3ter and an slcohol, with the calculated amount of the respective ~ase, for 2X-ample an alkali metal hydr~xide, or with a carbona~e or bi-carbonate~ and isolatin~ the salt in a manner ~nown p~- se, for example by precipitation with a suitable solvent ~r ~y crystallisation during the concentration of the resul~nt salt solution, or by lyophilisatio~, 17~-Esters can especially be prepared from 17a-hydroxy-steroid-17~-carboxylic acids of the formula (I) by reacting them initially with the anhydride corresponding to-the ester group to be introduced, whereupon the 17-ester of the mixed anhydride of the respective acid and the steroid-17-carboxylic acid are formed. The reaction is preferably carried out at elevated temperature. The mixed anhydride can be resolved by solvolysis, for example by treatment with basic or alkaline media, for example with aqueous acetic acid or aqueous pyri-dine or diethylamine in acetone.
The starting materials are known or can be prepared in known manner.
The compounds of the formula (I) are useful as inter-mediates for the preparation of the 17-carboxylic acid esters which are disclosed in the Canadian patent application ser.
no. 272 t 291.
.. , .. . . . .. . ... . .. . . ... . . . . . . .. . ~
The following Examples describe the invention in more detail.
Example 1 A solution of S g of 2-chloro-6a~9-difluoro~ ,17a-21-trihydroxy-1 6a - methyl-pregna-1,4-diene-3,20-dione in 200 ml of dioxane is treated with 12.5 g of periodic acid in 100 ml of water and the reaction mixture is stirred for 1 hour at room temperature. After addition of 150 ml of water, dioxane is evaporated in a water jet vacuum and the pre-cipitate which has formed is taken up in chloroform and washed with ice-cold dilute sodium hydroxide solution. The sodi~m hydroxide extract is acidified with ice-cold dilute hydrochloric acid and extracted with chloroform. The dried organic phase is concentrated in a water jet vacuum to yield the free 2-chloro-6a,9a-difluoro-11~,17a-dihydroxy-16-methyl-
3~oxo-androsta-1,4-diene-17-carboxylic acid, which is dis-solved in 20 ml of methanol and 40 ml of methylene chloride and esterified ~ith an ethereal diazomethane solution. The solvent is evaporated to yield the methyl 2-chloro-6a,9a-difluoro-11~,17~-dihydroxy-16 methyl-3-oxo-androsta-1,4-diene-17-carboxylate, which melts at 275-277C after re-erystallisation from chloroform/methanol/ether.
6~3~
Example 2 A solution of 2 g of 2 chloro-9~-fluoro-11~,17~-21-trihydroxy-lS~-methyl-pregna-1,4-diene-3,20-dione (prepared by chlorination of betamethasone-21-acetate with chlorine in propionic aci.d, splitting off 1 mole of hydrochloric acid with pyridine and subsequent mild saponification with potas-sium carbonate) in 80 ml of dioxane is treated with 5 g of periodic acid in 40 ml of water and the reaction mixture is stirred for 1.5 hours at room temperature. Ater addition of 60 ml of water, the dioxane is evaporated in a water Jet vacuum and the precipitated 2-chloro-9~-fluoro-11~,17~-di-hydroxy-16~-methyl-3-oxo-androsta-1~4-diene-17-carboxylic acid is filtered off, thoroughly dried, thereafter dissolved in 32 ~l of pyridine and the solution is treated at -10C with 8 ml of an ice-cold solution consisting of 25 ml of abs.
toluene and 1.9 ml of propionyl chloride. The reaction mixture is allowed .o stand for 18 hours at -10C, then poured into 200 ml of ice/water, acidified with dilute hydrochloric acid and extracted with chloroform. The dried organic phase is con-centrated in a water jet vacuum to yield the amorphous 2-chloro-9~-fluoro-11~-hydroxy-16~-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carboxylic acid.
Example 3 A solution of 5 g of 2,9-dichloro-6-fluoro-11~-17, 21-trihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione (which can be obtained for example by chlorinating the corresponding derivative which is not chlorinated in 2-position and de-hydrochlorination, e.g. with pyridine, in known manner) in 200 ml of dioxane is treated with a solution of 12.S g of periodic acid ln 100 ml of water and the reaction mixture is stirred for 1.5 hours at room temperature. After addition of 150 ml of water, the dioxane is evaporated in a water jet vacuu~. The 2,9-dichloro-6a fluoro-11~,17-dihydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17-carboxylic acid, which is filtered off and well dried, is dissolved in 85 ml of pyridine.
The solution is treated at -10C wi.h 20 ml of an ice-cold solution consis~ing of 25 ml of abs. toluene and 1.9 ml of propionyl chloride and the mixture is allowed to stand for 18 hours at -10C. The batch is then poured into 500 ml of ice/
water, acidified with dilute hydrochloric acid and extracted witll chloroform. The dried organic phase is concentrated in a water jet vacuum to yield the amorphous 2,9-dichloro-6~-fluoro-ll~-hydroxy-16-methyl-3-oxo-17~-propionyloxy-androsta-1,4-diene-17-carboxylic acid.
Example 4 6a,9a-difluoro-11~-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17-carboxylic acid is prepared in known manner by bismuthate degradation of flumethasone-17-propionate.
. .
6~3~
Example 2 A solution of 2 g of 2 chloro-9~-fluoro-11~,17~-21-trihydroxy-lS~-methyl-pregna-1,4-diene-3,20-dione (prepared by chlorination of betamethasone-21-acetate with chlorine in propionic aci.d, splitting off 1 mole of hydrochloric acid with pyridine and subsequent mild saponification with potas-sium carbonate) in 80 ml of dioxane is treated with 5 g of periodic acid in 40 ml of water and the reaction mixture is stirred for 1.5 hours at room temperature. Ater addition of 60 ml of water, the dioxane is evaporated in a water Jet vacuum and the precipitated 2-chloro-9~-fluoro-11~,17~-di-hydroxy-16~-methyl-3-oxo-androsta-1~4-diene-17-carboxylic acid is filtered off, thoroughly dried, thereafter dissolved in 32 ~l of pyridine and the solution is treated at -10C with 8 ml of an ice-cold solution consisting of 25 ml of abs.
toluene and 1.9 ml of propionyl chloride. The reaction mixture is allowed .o stand for 18 hours at -10C, then poured into 200 ml of ice/water, acidified with dilute hydrochloric acid and extracted with chloroform. The dried organic phase is con-centrated in a water jet vacuum to yield the amorphous 2-chloro-9~-fluoro-11~-hydroxy-16~-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carboxylic acid.
Example 3 A solution of 5 g of 2,9-dichloro-6-fluoro-11~-17, 21-trihydroxy-16~-methyl-pregna-1,4-diene-3,20-dione (which can be obtained for example by chlorinating the corresponding derivative which is not chlorinated in 2-position and de-hydrochlorination, e.g. with pyridine, in known manner) in 200 ml of dioxane is treated with a solution of 12.S g of periodic acid ln 100 ml of water and the reaction mixture is stirred for 1.5 hours at room temperature. After addition of 150 ml of water, the dioxane is evaporated in a water jet vacuu~. The 2,9-dichloro-6a fluoro-11~,17-dihydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17-carboxylic acid, which is filtered off and well dried, is dissolved in 85 ml of pyridine.
The solution is treated at -10C wi.h 20 ml of an ice-cold solution consis~ing of 25 ml of abs. toluene and 1.9 ml of propionyl chloride and the mixture is allowed to stand for 18 hours at -10C. The batch is then poured into 500 ml of ice/
water, acidified with dilute hydrochloric acid and extracted witll chloroform. The dried organic phase is concentrated in a water jet vacuum to yield the amorphous 2,9-dichloro-6~-fluoro-ll~-hydroxy-16-methyl-3-oxo-17~-propionyloxy-androsta-1,4-diene-17-carboxylic acid.
Example 4 6a,9a-difluoro-11~-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17-carboxylic acid is prepared in known manner by bismuthate degradation of flumethasone-17-propionate.
. .
Claims (10)
1. A process for the manufacture of androstadiene-17-carboxylic acids of the formula (I) wherein R1 is H or Cl, each of R2 and R3 represents hydro-gen, chlorine or fluorine, with the proviso that at least one of these substituents is chlorine or fluorine when R1 is Cl and that R2 is only Cl or F and R3 is H or Cl when R1 is H, R4 is OH, whilst R3 and R4 together can also represent a further 9,11 C-C-bond or -O-, R5 represents a methyl group in the .alpha.- or .beta.-position, the methylene group, a free hydroxyl group or a hydroxyl group which is esteri-fied with a lower alkanoic acid, R6 represents a free hydroxyl group or a hydroxyl group which is esterified with a carboxylic acid having not more than 7 carbon atoms, whilst R5 and R6 together represents the 16.alpha.,17.alpha.-dihydroxy-acetonide group which process comprises a) treating the corresponding 21-hydroxy-pregna-1,4-dien-20-ones wherein R6 represents an esterified hydroxyl group with sodium bismuthate or by b) treating the corresponding 21-hydroxy-pregna-1,4-dien-20-ones wherein R6 represents a free hydroxyl group and R5 represents an esterified hydroxyl group or a methyl or methylene group with periodic acid or periodate and, if desired, esterifying the 17.alpha.-hydroxyl group of the resultant steroid-17-carboxylic acids of the formula (I) wherein R6 represents OH whilst optionally protecting the 11-hydroxyl group temporarily, or converting esterified or ketalised hydroxyl groups R5 and/or R6 into free hydro-xyl groups, and/or adding chlorine to the 1,2-double bond of a compound of the formula (I) wherein R1 represents hydrogen whilst optionally protecting the 11-hydroxyl group temporarily, and dehydrochlorinating the resultant 1,2-di-chloro compound, and/or, if desired, converting the resul-tant acids of the formula (I) into the salts.
2. A process according to claim 1 which is process variant a).
3. A process according to claim 1 which is process variant b).
4. A process according to anyone of claims 1-3 wherein starting compounds are used so as to produce a compound of the formula (I) wherein R1 is hydrogen.
5. A process according to anyone of claims 1-3 wherein starting compounds are used so as to produce a compound of the formula (I) wherein R1 is chlorine.
6. A process according to claim 2 wherein starting compounds are used so as to produce a compound of the formula (I) wherein R5 is a methyl group in the a-position and R6 is propionyloxy.
7. A process according to anyone of claims 1-3 wherein starting compounds are used so as to produce a compound of the formula (I) wherein R2 is fluorine and R3 is chlorine.
8. A process according to anyone of claims 1-3 wherein starting compounds are used so as to produce a compound of the formula (I) wherein R3 and R4 together represent a further C-C-bond.
9. A process according to anyone of claims 1-3 wherein starting compounds are used so as to produce a compound of the formula (I) wherein R3 and R4 together represent -O-.
10. A process according to anyone of claims 1-2 wherein starting compounds are used so as to produce a compound of the formula (I) wherein R1 is hydrogen, R2 is fluorine, R3 is chlorine, R5 is a methyl group in the .alpha.-position and R6 represents a hydroxyl group which is esterified with a linear and unsubstituted lower alkanoic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA353,029A CA1106837A (en) | 1976-02-24 | 1980-05-29 | Androstadiene-17-carboxylic acids |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH2253/76 | 1976-02-24 | ||
| CH225376A CH628355A5 (en) | 1976-02-24 | 1976-02-24 | METHOD FOR PRODUCING NEW ANDROSTADIEN-17BETA-CARBONIC ACIDS AND THEIR ESTERS AND SALTS. |
| CA272,291A CA1084483A (en) | 1976-02-24 | 1977-02-22 | Androstadiene-17-carboxylic acid esters |
| CA353,029A CA1106837A (en) | 1976-02-24 | 1980-05-29 | Androstadiene-17-carboxylic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1106837A true CA1106837A (en) | 1981-08-11 |
Family
ID=27164923
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA353,029A Expired CA1106837A (en) | 1976-02-24 | 1980-05-29 | Androstadiene-17-carboxylic acids |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1106837A (en) |
-
1980
- 1980-05-29 CA CA353,029A patent/CA1106837A/en not_active Expired
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK153493B (en) | METHOD OF ANALOGY FOR THE PREPARATION OF ANDROSTADIA-17-CARBOXYLIC ACID ESTERS AND ANDROSTADIA-17-CARBOXYLY ACIDS FOR USE AS AN INTERMEDIATE PRODUCT BY THE PROCEDURE | |
| KR100787293B1 (en) | Oxidation process for preparing the intermediate 6.alpha.,9.alpha.-difluoro-11.beta.,17.alpha.-dihydroxy-16.alpha.-methyl-androst-1,4-dien-3-one 17.beta.-carboxylic acid | |
| US4650610A (en) | Androstane carbothioic acids | |
| US5434258A (en) | δ1,4 -pregnadiene-3,20-diones | |
| US5478957A (en) | Preparation of 6α, 9α-difluoro steroids | |
| CA1106837A (en) | Androstadiene-17-carboxylic acids | |
| US4525303A (en) | Process for preparation of steroids | |
| KR100312268B1 (en) | Novel 17,20-epoxide derivatives, processes for their preparation, their use in the preparation of cortisone derivatives and intermediates | |
| KR920005830B1 (en) | Process for preparing amino-hydroxy cepham carboxylates | |
| US20030181742A1 (en) | Process for the preparation of pregnane derivatives | |
| KR100284824B1 (en) | How to prepare 16 alpha-methylated steroids | |
| EP1526139A1 (en) | A process for preparing highly pure androstane 17-beta-carboxylic acids and androstane 17-beta-carbothioic acid fluoromethyl esters | |
| CS250695B2 (en) | Method of pregnane derivatives production | |
| HU221970B1 (en) | 3-protected oxo-delta5 (10), 9(11)-steroids and process for producing them | |
| CZ191398A3 (en) | Process for preparing 9,11{beta}epoxy-steroids | |
| NO137994B (en) | PROCEDURES FOR PROCESSING A BAR-OBJECT OBJECTIVE TO PROTECT ITS OUTER SURFACE | |
| FI77445B (en) | FOERFARANDE FOER FRAMSTAELLNING AV ETT INDOLDERIVAT. | |
| US4031080A (en) | 16-Alpha-methyl-17 alpha-bromo-1,4-pregnadiene-21-ol-3,20-dione-derivatives | |
| EP0948491B1 (en) | Aminothiazole derivatives useful in the preparation of beta-lactam antibiotics | |
| US4323512A (en) | Process for the preparation of steroidal 17α-arylcarboxylates | |
| KR100394203B1 (en) | 17Beta-carboxysteroid derivatives manufacturing method and new intermediates | |
| AU2004324237B2 (en) | Process for the esterification of a carbothioic acid | |
| KR900001854B1 (en) | Process for preparing cephem derivatives | |
| KR820001643B1 (en) | Process for the preparation of 6-halo-pregrnanes | |
| CA2231185C (en) | Preparation of ester derivatives of steroids |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |