CA1065849A - Process for the manufacture of steroid carboxylic acid lactones - Google Patents
Process for the manufacture of steroid carboxylic acid lactonesInfo
- Publication number
- CA1065849A CA1065849A CA254,684A CA254684A CA1065849A CA 1065849 A CA1065849 A CA 1065849A CA 254684 A CA254684 A CA 254684A CA 1065849 A CA1065849 A CA 1065849A
- Authority
- CA
- Canada
- Prior art keywords
- acid
- process according
- compound
- carbon atoms
- formula
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/001—Lactones
- C07J21/003—Lactones at position 17
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/003—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring the S atom directly linked to a ring carbon atom of the cyclopenta(a)hydrophenanthrene skeleton
Abstract
PROCESS FOR THE MANUFACTURE OF STEROID
CARBOXYLIC ACID LACTONES
Abstract of the Disclosure An advantageous method for the manufacture of steroidal lactones of the spironolactone and canrenone type involves the following reactions sequence : bromination of a 3.beta.,17=
dihydroxy- 17.alpha.-pregn-5-en-21-aldehyde in basic or neutral medium, oxidation of the 5,6-dibromo compound with hexavalent chromium compounds under basic or neutral conditions, dehydro-bromination with inorganic basic agents, such as lithium halides in the presence of lithium carbonate, or with organic bases, such as pyridine, oxidation of the steroid-4,6-diene compound so obtained having in the 17-position the same substituents as the starting material mentioned, with compounds of hexavalent chromium in acid solution, optionally after pretreatment with an acid or, in particular, with a thiocarboxylic acid (to introduce the 7.alpha.-acylthio group, e.g.
if spironolactone is to be manufactured). The new process gives better yields than those hitherto described.
CARBOXYLIC ACID LACTONES
Abstract of the Disclosure An advantageous method for the manufacture of steroidal lactones of the spironolactone and canrenone type involves the following reactions sequence : bromination of a 3.beta.,17=
dihydroxy- 17.alpha.-pregn-5-en-21-aldehyde in basic or neutral medium, oxidation of the 5,6-dibromo compound with hexavalent chromium compounds under basic or neutral conditions, dehydro-bromination with inorganic basic agents, such as lithium halides in the presence of lithium carbonate, or with organic bases, such as pyridine, oxidation of the steroid-4,6-diene compound so obtained having in the 17-position the same substituents as the starting material mentioned, with compounds of hexavalent chromium in acid solution, optionally after pretreatment with an acid or, in particular, with a thiocarboxylic acid (to introduce the 7.alpha.-acylthio group, e.g.
if spironolactone is to be manufactured). The new process gives better yields than those hitherto described.
Description
The present invention provides a process for the manufacture of steroid carboxylic acid lactones, in particular of 3-oxo-17~-pregn-4-ene-21, 17-carboxylic acid lactones of the formula ,~0 ~f~,~J (I) O `R
wherein Rl represents an ~-acylthio group and R2 represents hydrogen or R
and R2 together represent a further 6,7-carbon-carbon bond. The acylthio group is in particular a lower acylthio group, primarily the acetylthio group.
The compounds are known aldosterone antagonists, such as spironolactone, the compound of formula I, wherein Rl represents the acetyl-thio group, which is commercially obtainable under the registered tradename Aldacton ~. The 17-hydroxy-21-carboxylic acids and salts thereof which are derived from the ~ 4~6 compounds of the above formula also have the same anti-aldosterone effects and are likewise used as aldosterone antagonists.
Numerous processes for obtaining compounds of the formula (I) have been proposed in the literature and patent literature. For example, the Journal of the American Chemical Society, 79, pa~e 480~ and United States patent 2,705,712 describe a process for obtaining a compound oE the formula (~), wherein Rl and R2 to~ether represent a Eurthor 6,7-carbon-carbon bond, which process can be illustrated as follows tprocess A):
f~
~ - 1 -;.. . ~ . ~ . . ;
. .~.. ` .:
~ 6~
C -CH
-o CH--CH?~ 0~1 C2H5MgBr C--C-COOH
~` ~, potassaum I t ~ co ,~ OH
~ ~ amylate> ~ ~ ~" 2>~,~ ~ ~"
HO ~II) ~,'~,~ I
HO HO
Pd + C/H ~
chloranil ~ ~ ,H 2 ~ ~ .
O ~ ~ ~,C~J Oppenauer ~ 7 HO
.
To obtain the corresponding compounds, wherein R represents an acylthîo group, especially the acetylthio group, the abo~e compound ~III) is reactedwath athiocarboxylic acid, in particular thioacetic acid, according ;
to the process described in German patent 1,121,610. .
The above process for obtaining the 4,6-diene compound of ; ;
formula tIII~ must be regarded as redundant at present because of the unsatisfactory yields. A better alternative is for example, the process o ::
United States patents 3,738,983 and 3,270,008 ~process B):
~ 2 -.
.. , ' ,, ,, ' ,',. ' ',' . , ', .; ' ',, . ,' '.. ,,, ,' ' . ~ ', ,, ' ' " ,, " ', ".' , C--CH R= alkyl C- CH
HC-OR
RO - CH
CH3 a) CH3Mg Br b) Co2 c) H
d) N(Et)3 ~:
~Lt)-NH COO
H ~ ~J o ~ a) H2-Pd/CaCO3 ~ DH
HO Br2 Li2C3/LiBr Gorman O:EEenlogungsschrift 2,237J143 doscrlbos a method o:E
obtaining the spironolactone according to the :~ollowing roaction schomo ~procoss C):
3.~651~4L9 CH~ 0/\ CH~
CH30H / HCl OC~13 HO
VII VI
chloranil ~ SCOC113 O . SCOCH
CrO3 I X
ac~ ~0 ` SCOCH3 ,~ .
~ ~65~4~
An alternative thereof is claimed in German Offenlegungsschrift
wherein Rl represents an ~-acylthio group and R2 represents hydrogen or R
and R2 together represent a further 6,7-carbon-carbon bond. The acylthio group is in particular a lower acylthio group, primarily the acetylthio group.
The compounds are known aldosterone antagonists, such as spironolactone, the compound of formula I, wherein Rl represents the acetyl-thio group, which is commercially obtainable under the registered tradename Aldacton ~. The 17-hydroxy-21-carboxylic acids and salts thereof which are derived from the ~ 4~6 compounds of the above formula also have the same anti-aldosterone effects and are likewise used as aldosterone antagonists.
Numerous processes for obtaining compounds of the formula (I) have been proposed in the literature and patent literature. For example, the Journal of the American Chemical Society, 79, pa~e 480~ and United States patent 2,705,712 describe a process for obtaining a compound oE the formula (~), wherein Rl and R2 to~ether represent a Eurthor 6,7-carbon-carbon bond, which process can be illustrated as follows tprocess A):
f~
~ - 1 -;.. . ~ . ~ . . ;
. .~.. ` .:
~ 6~
C -CH
-o CH--CH?~ 0~1 C2H5MgBr C--C-COOH
~` ~, potassaum I t ~ co ,~ OH
~ ~ amylate> ~ ~ ~" 2>~,~ ~ ~"
HO ~II) ~,'~,~ I
HO HO
Pd + C/H ~
chloranil ~ ~ ,H 2 ~ ~ .
O ~ ~ ~,C~J Oppenauer ~ 7 HO
.
To obtain the corresponding compounds, wherein R represents an acylthîo group, especially the acetylthio group, the abo~e compound ~III) is reactedwath athiocarboxylic acid, in particular thioacetic acid, according ;
to the process described in German patent 1,121,610. .
The above process for obtaining the 4,6-diene compound of ; ;
formula tIII~ must be regarded as redundant at present because of the unsatisfactory yields. A better alternative is for example, the process o ::
United States patents 3,738,983 and 3,270,008 ~process B):
~ 2 -.
.. , ' ,, ,, ' ,',. ' ',' . , ', .; ' ',, . ,' '.. ,,, ,' ' . ~ ', ,, ' ' " ,, " ', ".' , C--CH R= alkyl C- CH
HC-OR
RO - CH
CH3 a) CH3Mg Br b) Co2 c) H
d) N(Et)3 ~:
~Lt)-NH COO
H ~ ~J o ~ a) H2-Pd/CaCO3 ~ DH
HO Br2 Li2C3/LiBr Gorman O:EEenlogungsschrift 2,237J143 doscrlbos a method o:E
obtaining the spironolactone according to the :~ollowing roaction schomo ~procoss C):
3.~651~4L9 CH~ 0/\ CH~
CH30H / HCl OC~13 HO
VII VI
chloranil ~ SCOC113 O . SCOCH
CrO3 I X
ac~ ~0 ` SCOCH3 ,~ .
~ ~65~4~
An alternative thereof is claimed in German Offenlegungsschrift
2,24~,834 ~process D) and another in German Offenlegungsschrift 2,248,835 (process E).
Finally, German Offenlegungsschrit 2,251,476 claims yet another alternative method according to which a start is made from the 3-oxo-4,6-diene derivatives which correspond to the above compounds of the formula V, thioacetic acid is added to these, and the resultant corresponding 3-oxo-7~- .
acetyl-thîo-4-ene derivatives with intact 17~-hydroxy-17a-propionaldehyde-acetal side-chain are oxidised in acid solution to give spironolactone.
The addition of thioacetic acid to the 6,7-double bond while preserving intact the substituents contained in the starting material in 17-position is described in this patent specification as surpri5ing, since acyclisation of the following kind / \ / O~ ~ S-CO-CH3 ~f\ , 1 ;~:, 0~1 ~ .
was to be expected in the acid medium of the thioacetic acid.
Experimental verification of this process has now revealed that the 3-oxo-4,6-di.enes ~i.th 17~-hydroxy-l7~-propionaldehyde-acetal side-chain referred to above as starting materials are not known at all and also cannot be obtained according to the particulars of DOS 2,251,476. For i:~ the 3-o~o-4-enes with 17~-hydroxy-17~-propionaldehyde-acetal side-chain initially obtainablo according to DOS 2,237,143 and 2,248,834 re:Eorrod to abov~ (citod on page 4 o~ DOS 2,251,476) are dehydrogenated with chloranil ~as also, for example, in United States patent 3,137,690, also referred to on page 4 of DOS 2,251,476 and on page 12 in the experimental part), then the 4,6-dienes of th0 cyclic deri~atives formed in the above reaction scheme are obtained and not the corresponding 4,6-dienes, and the ether group which derives 5 _ ~J
", ' .
., , . ' , ~ . .
,.
.
~()65~4~1 ~rom the alcohol used as ~olv~nt may be present instead of the ac~tylthio group. The process described and claimed in DOS 2,251,476 therefore cannot be performed.
From the operational point of view, all the processes referred to hereinabove for obtaining carboxylic acid lactones of the formula (I) are unsatisfactory. In the first published process A, reactions are used which are lit~le suited to the exigencies of practice, for example the protracted carbon dioxide treatment in the second step and the catalytic hydrogenation in the second.
Process B affords in the subsequent working up a yield of app.
20 percent, referred to the dehydro-epi-androsterone used as starting material for obtaining the 17 d~ethinyl-androst-5-en-3~,17~-diol indicated as first step in the reaction scheme.
According to the experimental part of the respective patent appli-cations, the yields of processes C to E are between 10 and 23 percent by weight again referred to the dehydro-epi-androsterone used as starting material.
The present invention provides a process for the manu~acture of compounds of the above formula I which affords higher yields than those of the prior art and which from the operational point of view is also simpler, more convenient, and easier to reproduce.
The process of the present invention for the manufacture of com-pounds of the formula I comprises treating an acetal of 3~,17-dihydroxy-17~-pregn-5-en-21-carbaldehyde in basic or neutral medium with a brominating agent which is suitable ~or adding bromine to the double bond, oxidisin~ the 3-hydroxy-5J6-dibromo der~vative so ormed with a hexavalent chromium compound under basic or neutral conditions to conYert the 3-hydroxy group to a 3-oxo group, dehydrobrominating ~he 3-one compound to obtain a ~,6-dien-3-one com-pound, reacting the ~,6-dien-3-one with a compound of hexavalent chromium in ~ i - 6 -J
.
.. .
~ 0~i5849 acid solution and, if a compound in which Rl represents an acylthio group and R2 is hydrogen is required, reacting the 4,6-dien-3-one compound, either be-fore or after reaction with the hexavalent chromium compound in acid solution, with a thiocarboxylic acid to introduce an acylthio group at the 7-position.
The addition of bromine to the 5,6-double bond of the cited start-ing materials according to the process of this invention can be effected with -a brominating agent which is generally able to add bromine to double bonds, while ensuring tha~ the reaction is carried out in basic ~r neutral medium.
This addition can therefore be accomplished in known manner, for example by using bromine in an inert neutral solvent, for example a halogenated hydro-carbon, such as ethylene chloride or chloroform, or in a di-lower alkyl-lower alkanoic amide, for example dimethyl formamide, with or without a buffer, such as an organic or inorganic baseJ or in an excess of an organic nitrogen base, for example bromine in a tertiary organic aromatic base, such as pyridine or the C-methyl homologs thereof, such as the picolines, in particular collidine.
Bromine forms perbromides as intermediates with those nitrogen bases, for example the perbromides of hydrohalogen salts o the bases, for example the perbromides of salts of hydrobromic acid. Such perbromides can also be used with advantage for the bromination according to the invention. In particular, pyridine hydrobromide perbromide is used. It is advantageous to use a small excess over the amount of bromine required in theory or brominating a double bond.
Besides the perbromides of th~ clted nitrogen bases or of other bascsl lt is nlso possiblo to u9e tho adducts of bromine to ethers, ln parti-cular cyclic ethers, such as dioxan. A tertiary aromatic base, such as one .
- . ~
.: , ~ . , .
.. ..
of those referred to above, is also advantageously added in these cases.
The perbromides or bromine addu~ts are reacted in an inert organic solvent, such as one of those referred to above, or also in an ether, a hydro-carbon, in alcohols, in particular lower aliphatic univalent or bivalent alcohols, such as methyl or ethyl alcohol, or n-butanol, or ethylene glycol.
Other bromine addition complexes, besides those mentioned, can also effect the addition, for example the addition complex of bromine and tetramethylammonium bromide.
It is very advantageous to use pyridine hydrobromide perbromide, which is reacted in pyridine solution and at room temperature or at lower or elevated temperature~ for example from -10 to +100C, preferably from 0 to ~20C.
The oxidation of the 5,6-dibromo adduct with a compound of hexa-valent chromium, for example chromium trioxide or chromic acid, will take place in basic or neutral medium. If appropriate, a suf~icient amount of the base used beforehand in the bromination is again added during the oxida-tion, for example pyridine, so as to avoid overstepping the neutral point, or the bromination reaction mixture obtained in the previous step is treated with a pyridine chromate solution. This operation is advantageously carried out at tsmperatures of app, -10 to app, ~30C.
The debromination of thc chromic acid oxidation product to be then carried out according to the invention can also be accomplished in known mannor. ~or this purposc thoro are used, for example, inorganic basic agents, such as lithium salts, in particular lithium halides, primarily lithium bromide, in the presence of a basic salt of an alkali metal or alkaliTIe earth metal, such as the carbonates or basic carbonates, for example oE lithium sodium, calcium or magnesium. The solvent used in this method is advantageously a dialkylamide of a lower aliphatic carboxylic acid, in ~ - 8 -.. , ~ , : . . ..
.,, :
, ~ -5~49 particular a di-lo~er alkyl derivative, for example dimethyl formamide, at temperatures between 0 and app. 180C, advantageously a~ temperatures bet~een 80 and 150C. It is also possible to use nitrogen-containing bases of aromatic character for the dehydrobromination, for example those cited hereinabove, especially pyridine or collidine.
After hydrogen bromide has been removed in the manner described, the 4,6 dien-3-one derivative containing the 17~-propionaldehyde-acetal sidechain is obtained as reaction product. This compound can then be pro-cessed direct to give the corresponding lactone of the formula ~I), wherein Rl and R2 represent a further carbon-carbon bond bet~een position 6 and 7 or indirectly to give compounds of the same type with the 7~-acylthio group, In the first case, the product is oxidised with a compound of hexa-valent chromium in acid solution, especially in a mineral acid solution.
In doing so, the aldehyde-acetal group is simultaneously deacetalysed, whereupon cyclisation of the propionaldehyde side-chain with the 17~-hydroxyl group to give the cyclic hemi-acetal and oxidation thereof to give the corresponding lactone group take place. The oxidation can be carried out with chromium trioxide in acid solution, in particular in sulphuric acid, hydrochloric acid or one of the phosphoric acids, or in a lower carboxylic acid, such as an alkanecarboxylic acid of 1 to 7 carbon atoms, for example formic acid, acetic acid or propionic acid or one of the butyric acids or valeric acids, or in mixtures of these acids, also with or without the addition of water. The oxidation can also be carried out in organic solvents, such as ketones or ethers, for example in acetono, dioxan or tetrahydro~uran, ~ith or without the addition o~ water.
It is advantageously to carry out a preliminary treatment with one of the cited acids before the oxidation, when the cyclic hemi-acetal is obtained ~irst, and to e~ect the oxidation in a second step under the condi-tions just stated.
.~,1 9 In the second case, a thioalkane acid is added in known manner to the 4,6-diene derivative obtained in the dehydrobromination step, i.e. as is known for compounds of the formula I, wherein Rl and R2 represent a further carbon-carbon bond between 6- and 7-position, and subsequently as described above, ~reated in acid solution with a compound of hexavalent chromium.
The above addition of a thiocarboxylic acid to the 4,6-diene deri-vative can be carried out in known manner as defined herein, for example by treating the steroid with an excess of thiocarboxylic acid without a solvent a~ ele~ated temperature. However, the reaction of the 4,6-steroid diene in a polar solvent, in particular an alcohol, preferably a lower alkanol contain~
ing 1 to 7 carbon atoms, with app. 1.5 to 3.5 moles of thiocarboxylic acid, if desired with the addition o~ water, gives better yields. The best yields are obtained at temperatures between O and app. 120C, for example by carry-ing out the reaction at the boiling point of the cited alcohols, for example methanol, ethanol, propyl alcohol, isopropyl alcohol, the butanols or penta-nols, in the absence of water, The most preferred temperatur0 range is that between 50 and 100C. In this way very good yields o~ the desired 7~acyl-~hio derivative are obtained without any appreciable formation of the 7~-isomer, In particular, lower thioalkanoic acids containing 1 to 7 carbon atoms, such as thioacetic acid, thiopropionic acid or thiovaleric acid, are used as thiocarboxylic acids.
The acetals to be used as starting materials are derived from any aliphatic, alicyclic, araliphatic or mixed aliphatic-alicyclic alcoholJ
pr~marily ~rom lower alkanols containing 1 to 7 carbon atoms or lower nlkane-diols containing 1 to 7 carbon atoms. In particular the ethylene glycol ace-tal o 3~,17~- dihydroxy-17~pregn-5-en-21-carbaldehyde is used as starting material.
The process can be illustrated by the following example of the r^-~ ' ~' ~ , ' .
'' . ' ''" '' :.',, ' ' ' ' .
.
.
~;S8~9 manufacture of spiron~lactone or canrenOne C3-oxo-17~-pregna-4,6-diene-21, 17-carbolactone~, ~herein the theoretical yields, referred to the starting material I', are indicated. As is evident, the total yield of spironolacton0 IV', referred to the starting material I', is 47% of theory, and of canrenone V', 61% of thcory:
ICH3 !;~~
1~ pyridineperbromide 2~ chromium trioxyde-pyridine 74,7% 3) Li2CO3 ~ dimethyl of theory ` formamide hioa~ tic acid ~J
III ~n. me ~anol IT' q~ ~ :~ < ~ -~--6~ ~ ..
SCOC~13 ;:
chromic acid 1) H2SO~ .
64% of theory referred to ~ . .
; compound II' 2) chromlc ac d IV' ~ V' ;
canrenone SCOChl3 ~aldadiene) spironolactone 61% of theory referred to 1' 47% of theory referred to l' . .
" r -1l-.Y ~ .
; ' ' ~ ' ' `' ' . . . . , ,,.. ... . : . , :. . ., ~ . .
8~
To make a comparison ~ith earlier processes, for example those of the German Offenlegung~schriften cited hereinbefore, the manufacture of I' from dehydro-epi-androsterone by the method used in the~e patent speci~ica-tions of reacting dehydro-epi-androsterone with a chloropropionaldehyde-acetal, for example the ethylene acetal, in the presence of lithium, must be included. This reaction affords a yield of app. 60~ of the theoretical amount. By converting all yields into percentages by weight, referred to dehydro-epi-androsterone, then in the manufacture of spironolactone by the process of the present invention, for example in Examples 2 and 7, the yield is app. 41 percent by weight, and in the manufacture of canrenone, for example according to Examples 2 and ~, the yield is app. ~3 percent by weight. On the other hand, as stated hereinbefore, the yields of the processes C to E are app. 10 to 23 percent by weight of spironolactone, referred to dehydro-epi-androsterone.
The process of the present invention can be carried out with a still higher yield of the desired end products, provided compound I' is obtained from dehydro-epi-androsterone by addition of chloropropionaldehyde-ethylsne acetal/Li, by choosing the following novel and invent~ve modifica-tion which, as particular embodiment of the process of the present inven-tion, also forms an object thereof. It has been found that, when reactingthe dehydro-epi-androsterone with the chloropropionaldehyde-acetal in the presence of lithium, a substantial amount of dehydro-epi-androsterone can be recovered by reacting the reaction product with steam following the roaction in known manner. Both dehydro-epi-androsterone ~nd the reaction product, for example the 17~-(3'-ethylenedioxy-propyl)-androst-5-en-3~,17-diol, can be readily separated from each other from the component which is not volatile in steam, by means of conventional purification operations, such as chromatography, for example through aluminium oxideJ and/or ; - 12 -.~1 1 1 ~i .
" . ~ .. ~: , , .
~o~
crystallisation. On account of this improvement in obtaining the starting material of the present invention, as illustrated for example in Example 8, it is possible to increase the yield or example of spironolactone, among other things as a consequence of the recovery of starting material, `
i.e. of dehydro-epi-androsterone to 50%, and of canrenone to 52%, of the ~eight of reacted dehydro-epi-androsterone.
A particular advantage of the present process also resides in the fact that in the steps of the reaction of the starting material with the brominating agent, and of the oxidation thereof and the dehydrobromination, l~ the 4,6-dien-3-one intermediate is formed as a unitary compound which can be ;~ -readily obtained pure, for example by mere crystallisation, As against this, in the processes C to E discussed at the outset, which all proceed via the 4,6-dien-3-one step according to formula VIII, it is difficult to obtain pure preparations of this constitution, since the products are invariably mixtures of alkoxy compounds which are epimeric at the 21a-carbon atom.
A consequence thereof is, among other things, that the puriication in the final step, for example of the spironolactone, is very tedi~us and compli-cated. In contradistinction thereto, products of such quality are obtained in the final steps of the present process that normally a simple purifica-tion, for example crystallisation, suffices to obtain entirely pure products.
T~e advantage o the present proce~s compared wlth that of process B of United States patents 3,738,983 and 3,270,008, besides ~he ad-vantages alreacly mentioned regarding the yields, also resides in the fact that it involves only a eew and technically simple oporations.
If desired, the compounds of the formula I, wherein Rl and R2 represent a further carbon-carbon bond between position 6 and 7, can be converted in kno~n manner into the salts, in particular the metal salts, of the corresponding 17~-hydroxy-21-carbox~lic acids, for example b~ treatment with metal hydroxides, such as potassium or sodium hydroxide, in a~ueous ~.... - . . . . .................. . . , . .:: . , : .... .
. . . . . .
- ~0~ 9 or alcoholic solution.
If desired, the compounds of the formula I obtained by the process o the present invention, wherein Rl and R2 represent a further carbon-carbon bond in 6,7-position, can be converted in known manner with a thiocarboxylic acid, in particular with a lower thioalkanoic acid, for example one of those referred to hereinbefore, into the compounds of the formula 1, in which Rl represent~ an acylthio group and R2 represents hydrogen.
The invention also comprises those embodiments of the process in which a compound obtained in any intermediate stage is used as starting material and the missing process steps are carried out, or the process is interrupted in any stage, or in which the starting materials are obtained in situ. The invention also has for its object the special embodiment described hereinabove in which the starting material is prepared by reacting dehydro-epi-androsterone with a chloropropionaldehyde-acetal in the presence of lithium~ and, following the reaction, the unreacted dehydro-epi-androsterone is recovered after treating the reaction mixture beforehand uith steam.
The invention also has for its object the embodiment of the present process in which compounds of the formula I, wherein R1 and R2 represent a further 6,7-carbon-carbon bond, are obtained first and then converted in known manner into the compounds of the formula I, wherein R
represents an acylthio group and R2 represents hydrogen.
The Eollowing ~xamples serve to illustrate the invention without restricting it to what is described thercin.
Example 1 2~ g of dehydro-epi-androsterone are dissolved in 500 ml of abs.
tetrahydr~uran, Then 5.2 g of lithium wire~ cut into small pieces, are added, ~fter cooling ~ith an ice bath to 0C, 38 g of ~-chloropropionalde-hyde ethylene acetal in 50 ml of abs, tetrahydrofuran are added dropwise ~,^?`.¦
. .
,.,' . ~
with stirring in an atmosphere of nitrogen in the course of 15 minutes.
During thi~ addition, the mixture is so intensively cooled ~ice/sodium chloride mixture) that the reaction temperature does not exceed 10C.
Stirring is subsequently continued for a further 2 1/2 hours at 0 C and `
overnight at room temperature ~under nitrogen). Excess pieces of lithium are then separated off and the reaction solution is poured into ice water.
Extraction is then performed with ethyl acetate and the extract is washed with saturated aqueous soaium chloride solution until neutral. The crude product obtained after drying the organic phase over Na2SO4 and evaporating it is filtered through 300 g of neutral A1203 of activity IIl unreacted reagent and nonsteroid impurities being eluted with 3 litres of petroleum ether/toluene ~1:1) mixture. With CH2C12 as eluant, 19.9 g of 17~-~3'-ethylenedioxy-propyl)-androst-5-en-3~,17~-diol are obtained in m.p. 181-182C after one recrystallisation from acetone/petroleum ether. Yield:
16.4 g ~60.6% of theory). IR. 3600, 3~50 cm 1~CH2C12). - NMR.: 0.87, s, CH3tl8); 1,02, s~, CH3(19); 3.50, m, CH~3); 3.92, m, -OC~l2C~120-; ~.91,t, J = ~, C~1(3'); 5.34, m, CH~6) ~CDC13).
Example 2 To 6 g of 17~-~3'-ethylenedioxy-propyl)-androst-5-en-3~,17~-diol in 60 ml of pyridine are added at 0C 5.~ g of solid pyridine hydrobromide perbromide. The mixture is then stirred for 3 hours at 0C under anhydrous conditions. One hour ater the start of this reaction, ~1.5 g of Cr03 in 6 ml o~ H20 are added dropwise, with stirring, to ~5 ml of ice-cold pyridine, the rate of addition be:Lng so chosen that the temperature in ~he flask does not exceed 10C. The pyridine chromate solution obtained is then stirred until completion of the parallel bromination reaction at 0C. The pyridine chromate solution is then poured into the bromination solution and the reaction mixture is stirred initially for a further 3 hours at ~C and then .~ .
. , .
l~S~
additionally overnight at room temperature. The batch is then diluted with a substantial amount of C~IC13 and washed 4 times in succession with saturated aqueous NaCl solution ten times with water. The organic phase is subsequent-ly dried over NA2S04 and evaporated to dryness ln vacuo.
The crude oxidation product is dissolved repeatedly in toluene to remove residual pyridine as an azeotrope and evaporated to dryness in vacuo.
The product is dissolved in 108 ml of abs. dimethyl formamide, treated with 10.8 g of LiBr and Li2C03 respectively, and heated, with stirring, in an atmosphere of nitrogen to 1~0C in the course of 15 minutes and kept at this temperature for a further 1 1/4 hours. The batch is afterwards allowed to cool, diluted ~ith ethyl acetate, and washed ten times with water and once with saturated sodium chloride solution. The organic phase is dried over Na2S0~, then concentrated in vacuo, and the residue is filtered through 100 g of neutral A1203 ~activity II). The apolar impurities are first eluted with 500 ml of toluene. The subsequent ethyl acetate eluates consist of 4.56 g of ll@-hydroxy-17~-t3~-ethylenedioxy-propyl)-androsta-4,6-dien-3-one, and melt at 132C after one recrystallisation from acetone/petroleum ether. Yield after recrystallisation: 4.44 g (74.7% of theory). IR.: 3570, 3450, 1655, 1620, 1585 cm (CH2C12). - UV.: 287 ~19700~ in C2H50H. - NMR.: 0.95, SJ
CH3(18); 1.10, s, CH3(19), ca. 3.95~ m, -OCH2CH~0-; 4,89, t, J = 4, CH(3');
5.65, s, CH~4~; 6.08, s (2H), CH(6) ~ CH~7) (CDC13). - ~D ~ ~ 6 ~ in CHC13~.
5 g o~ 17~-hydroxy-17~-~3'-ethylenediox~-prop~l~-androsta-~,6-dien_3 one are dIssolved at room temperature in 50 ml of methanol. Then 7.5 ml of water and 2.5 ml of thioacetic acid are added in succession and the mixture is stirred for 3 hours at room temperature. The batch is thereafter poured into ice-cold 2 normal a~ueous Na~lC03 solution and extrac-tion is performed with ethyl acetate. The extract is washed neutral with saturated aqueous NaCl so~ution, dried over sodium sulphate and concentrated q~ ~
,J ~ 1~ ~
.. ... . .. . . . .
-'~ ' . ' : , ' 65~34~
in vacuo, to yield 5.86 ~ of 7c~-acetrlthio-17~-hydroxy-17-C3'-ethylene-dioxy-propyl)-androst-4-en-3-one ~IR. 3450 ~wide) 1685, 1670, 1620 cm 1 (CH2C12); NMR. 0.92, s, CH3(18~; 1.22, s, CH3(19); 2.33, s, SCOCH3;
Finally, German Offenlegungsschrit 2,251,476 claims yet another alternative method according to which a start is made from the 3-oxo-4,6-diene derivatives which correspond to the above compounds of the formula V, thioacetic acid is added to these, and the resultant corresponding 3-oxo-7~- .
acetyl-thîo-4-ene derivatives with intact 17~-hydroxy-17a-propionaldehyde-acetal side-chain are oxidised in acid solution to give spironolactone.
The addition of thioacetic acid to the 6,7-double bond while preserving intact the substituents contained in the starting material in 17-position is described in this patent specification as surpri5ing, since acyclisation of the following kind / \ / O~ ~ S-CO-CH3 ~f\ , 1 ;~:, 0~1 ~ .
was to be expected in the acid medium of the thioacetic acid.
Experimental verification of this process has now revealed that the 3-oxo-4,6-di.enes ~i.th 17~-hydroxy-l7~-propionaldehyde-acetal side-chain referred to above as starting materials are not known at all and also cannot be obtained according to the particulars of DOS 2,251,476. For i:~ the 3-o~o-4-enes with 17~-hydroxy-17~-propionaldehyde-acetal side-chain initially obtainablo according to DOS 2,237,143 and 2,248,834 re:Eorrod to abov~ (citod on page 4 o~ DOS 2,251,476) are dehydrogenated with chloranil ~as also, for example, in United States patent 3,137,690, also referred to on page 4 of DOS 2,251,476 and on page 12 in the experimental part), then the 4,6-dienes of th0 cyclic deri~atives formed in the above reaction scheme are obtained and not the corresponding 4,6-dienes, and the ether group which derives 5 _ ~J
", ' .
., , . ' , ~ . .
,.
.
~()65~4~1 ~rom the alcohol used as ~olv~nt may be present instead of the ac~tylthio group. The process described and claimed in DOS 2,251,476 therefore cannot be performed.
From the operational point of view, all the processes referred to hereinabove for obtaining carboxylic acid lactones of the formula (I) are unsatisfactory. In the first published process A, reactions are used which are lit~le suited to the exigencies of practice, for example the protracted carbon dioxide treatment in the second step and the catalytic hydrogenation in the second.
Process B affords in the subsequent working up a yield of app.
20 percent, referred to the dehydro-epi-androsterone used as starting material for obtaining the 17 d~ethinyl-androst-5-en-3~,17~-diol indicated as first step in the reaction scheme.
According to the experimental part of the respective patent appli-cations, the yields of processes C to E are between 10 and 23 percent by weight again referred to the dehydro-epi-androsterone used as starting material.
The present invention provides a process for the manu~acture of compounds of the above formula I which affords higher yields than those of the prior art and which from the operational point of view is also simpler, more convenient, and easier to reproduce.
The process of the present invention for the manufacture of com-pounds of the formula I comprises treating an acetal of 3~,17-dihydroxy-17~-pregn-5-en-21-carbaldehyde in basic or neutral medium with a brominating agent which is suitable ~or adding bromine to the double bond, oxidisin~ the 3-hydroxy-5J6-dibromo der~vative so ormed with a hexavalent chromium compound under basic or neutral conditions to conYert the 3-hydroxy group to a 3-oxo group, dehydrobrominating ~he 3-one compound to obtain a ~,6-dien-3-one com-pound, reacting the ~,6-dien-3-one with a compound of hexavalent chromium in ~ i - 6 -J
.
.. .
~ 0~i5849 acid solution and, if a compound in which Rl represents an acylthio group and R2 is hydrogen is required, reacting the 4,6-dien-3-one compound, either be-fore or after reaction with the hexavalent chromium compound in acid solution, with a thiocarboxylic acid to introduce an acylthio group at the 7-position.
The addition of bromine to the 5,6-double bond of the cited start-ing materials according to the process of this invention can be effected with -a brominating agent which is generally able to add bromine to double bonds, while ensuring tha~ the reaction is carried out in basic ~r neutral medium.
This addition can therefore be accomplished in known manner, for example by using bromine in an inert neutral solvent, for example a halogenated hydro-carbon, such as ethylene chloride or chloroform, or in a di-lower alkyl-lower alkanoic amide, for example dimethyl formamide, with or without a buffer, such as an organic or inorganic baseJ or in an excess of an organic nitrogen base, for example bromine in a tertiary organic aromatic base, such as pyridine or the C-methyl homologs thereof, such as the picolines, in particular collidine.
Bromine forms perbromides as intermediates with those nitrogen bases, for example the perbromides of hydrohalogen salts o the bases, for example the perbromides of salts of hydrobromic acid. Such perbromides can also be used with advantage for the bromination according to the invention. In particular, pyridine hydrobromide perbromide is used. It is advantageous to use a small excess over the amount of bromine required in theory or brominating a double bond.
Besides the perbromides of th~ clted nitrogen bases or of other bascsl lt is nlso possiblo to u9e tho adducts of bromine to ethers, ln parti-cular cyclic ethers, such as dioxan. A tertiary aromatic base, such as one .
- . ~
.: , ~ . , .
.. ..
of those referred to above, is also advantageously added in these cases.
The perbromides or bromine addu~ts are reacted in an inert organic solvent, such as one of those referred to above, or also in an ether, a hydro-carbon, in alcohols, in particular lower aliphatic univalent or bivalent alcohols, such as methyl or ethyl alcohol, or n-butanol, or ethylene glycol.
Other bromine addition complexes, besides those mentioned, can also effect the addition, for example the addition complex of bromine and tetramethylammonium bromide.
It is very advantageous to use pyridine hydrobromide perbromide, which is reacted in pyridine solution and at room temperature or at lower or elevated temperature~ for example from -10 to +100C, preferably from 0 to ~20C.
The oxidation of the 5,6-dibromo adduct with a compound of hexa-valent chromium, for example chromium trioxide or chromic acid, will take place in basic or neutral medium. If appropriate, a suf~icient amount of the base used beforehand in the bromination is again added during the oxida-tion, for example pyridine, so as to avoid overstepping the neutral point, or the bromination reaction mixture obtained in the previous step is treated with a pyridine chromate solution. This operation is advantageously carried out at tsmperatures of app, -10 to app, ~30C.
The debromination of thc chromic acid oxidation product to be then carried out according to the invention can also be accomplished in known mannor. ~or this purposc thoro are used, for example, inorganic basic agents, such as lithium salts, in particular lithium halides, primarily lithium bromide, in the presence of a basic salt of an alkali metal or alkaliTIe earth metal, such as the carbonates or basic carbonates, for example oE lithium sodium, calcium or magnesium. The solvent used in this method is advantageously a dialkylamide of a lower aliphatic carboxylic acid, in ~ - 8 -.. , ~ , : . . ..
.,, :
, ~ -5~49 particular a di-lo~er alkyl derivative, for example dimethyl formamide, at temperatures between 0 and app. 180C, advantageously a~ temperatures bet~een 80 and 150C. It is also possible to use nitrogen-containing bases of aromatic character for the dehydrobromination, for example those cited hereinabove, especially pyridine or collidine.
After hydrogen bromide has been removed in the manner described, the 4,6 dien-3-one derivative containing the 17~-propionaldehyde-acetal sidechain is obtained as reaction product. This compound can then be pro-cessed direct to give the corresponding lactone of the formula ~I), wherein Rl and R2 represent a further carbon-carbon bond bet~een position 6 and 7 or indirectly to give compounds of the same type with the 7~-acylthio group, In the first case, the product is oxidised with a compound of hexa-valent chromium in acid solution, especially in a mineral acid solution.
In doing so, the aldehyde-acetal group is simultaneously deacetalysed, whereupon cyclisation of the propionaldehyde side-chain with the 17~-hydroxyl group to give the cyclic hemi-acetal and oxidation thereof to give the corresponding lactone group take place. The oxidation can be carried out with chromium trioxide in acid solution, in particular in sulphuric acid, hydrochloric acid or one of the phosphoric acids, or in a lower carboxylic acid, such as an alkanecarboxylic acid of 1 to 7 carbon atoms, for example formic acid, acetic acid or propionic acid or one of the butyric acids or valeric acids, or in mixtures of these acids, also with or without the addition of water. The oxidation can also be carried out in organic solvents, such as ketones or ethers, for example in acetono, dioxan or tetrahydro~uran, ~ith or without the addition o~ water.
It is advantageously to carry out a preliminary treatment with one of the cited acids before the oxidation, when the cyclic hemi-acetal is obtained ~irst, and to e~ect the oxidation in a second step under the condi-tions just stated.
.~,1 9 In the second case, a thioalkane acid is added in known manner to the 4,6-diene derivative obtained in the dehydrobromination step, i.e. as is known for compounds of the formula I, wherein Rl and R2 represent a further carbon-carbon bond between 6- and 7-position, and subsequently as described above, ~reated in acid solution with a compound of hexavalent chromium.
The above addition of a thiocarboxylic acid to the 4,6-diene deri-vative can be carried out in known manner as defined herein, for example by treating the steroid with an excess of thiocarboxylic acid without a solvent a~ ele~ated temperature. However, the reaction of the 4,6-steroid diene in a polar solvent, in particular an alcohol, preferably a lower alkanol contain~
ing 1 to 7 carbon atoms, with app. 1.5 to 3.5 moles of thiocarboxylic acid, if desired with the addition o~ water, gives better yields. The best yields are obtained at temperatures between O and app. 120C, for example by carry-ing out the reaction at the boiling point of the cited alcohols, for example methanol, ethanol, propyl alcohol, isopropyl alcohol, the butanols or penta-nols, in the absence of water, The most preferred temperatur0 range is that between 50 and 100C. In this way very good yields o~ the desired 7~acyl-~hio derivative are obtained without any appreciable formation of the 7~-isomer, In particular, lower thioalkanoic acids containing 1 to 7 carbon atoms, such as thioacetic acid, thiopropionic acid or thiovaleric acid, are used as thiocarboxylic acids.
The acetals to be used as starting materials are derived from any aliphatic, alicyclic, araliphatic or mixed aliphatic-alicyclic alcoholJ
pr~marily ~rom lower alkanols containing 1 to 7 carbon atoms or lower nlkane-diols containing 1 to 7 carbon atoms. In particular the ethylene glycol ace-tal o 3~,17~- dihydroxy-17~pregn-5-en-21-carbaldehyde is used as starting material.
The process can be illustrated by the following example of the r^-~ ' ~' ~ , ' .
'' . ' ''" '' :.',, ' ' ' ' .
.
.
~;S8~9 manufacture of spiron~lactone or canrenOne C3-oxo-17~-pregna-4,6-diene-21, 17-carbolactone~, ~herein the theoretical yields, referred to the starting material I', are indicated. As is evident, the total yield of spironolacton0 IV', referred to the starting material I', is 47% of theory, and of canrenone V', 61% of thcory:
ICH3 !;~~
1~ pyridineperbromide 2~ chromium trioxyde-pyridine 74,7% 3) Li2CO3 ~ dimethyl of theory ` formamide hioa~ tic acid ~J
III ~n. me ~anol IT' q~ ~ :~ < ~ -~--6~ ~ ..
SCOC~13 ;:
chromic acid 1) H2SO~ .
64% of theory referred to ~ . .
; compound II' 2) chromlc ac d IV' ~ V' ;
canrenone SCOChl3 ~aldadiene) spironolactone 61% of theory referred to 1' 47% of theory referred to l' . .
" r -1l-.Y ~ .
; ' ' ~ ' ' `' ' . . . . , ,,.. ... . : . , :. . ., ~ . .
8~
To make a comparison ~ith earlier processes, for example those of the German Offenlegung~schriften cited hereinbefore, the manufacture of I' from dehydro-epi-androsterone by the method used in the~e patent speci~ica-tions of reacting dehydro-epi-androsterone with a chloropropionaldehyde-acetal, for example the ethylene acetal, in the presence of lithium, must be included. This reaction affords a yield of app. 60~ of the theoretical amount. By converting all yields into percentages by weight, referred to dehydro-epi-androsterone, then in the manufacture of spironolactone by the process of the present invention, for example in Examples 2 and 7, the yield is app. 41 percent by weight, and in the manufacture of canrenone, for example according to Examples 2 and ~, the yield is app. ~3 percent by weight. On the other hand, as stated hereinbefore, the yields of the processes C to E are app. 10 to 23 percent by weight of spironolactone, referred to dehydro-epi-androsterone.
The process of the present invention can be carried out with a still higher yield of the desired end products, provided compound I' is obtained from dehydro-epi-androsterone by addition of chloropropionaldehyde-ethylsne acetal/Li, by choosing the following novel and invent~ve modifica-tion which, as particular embodiment of the process of the present inven-tion, also forms an object thereof. It has been found that, when reactingthe dehydro-epi-androsterone with the chloropropionaldehyde-acetal in the presence of lithium, a substantial amount of dehydro-epi-androsterone can be recovered by reacting the reaction product with steam following the roaction in known manner. Both dehydro-epi-androsterone ~nd the reaction product, for example the 17~-(3'-ethylenedioxy-propyl)-androst-5-en-3~,17-diol, can be readily separated from each other from the component which is not volatile in steam, by means of conventional purification operations, such as chromatography, for example through aluminium oxideJ and/or ; - 12 -.~1 1 1 ~i .
" . ~ .. ~: , , .
~o~
crystallisation. On account of this improvement in obtaining the starting material of the present invention, as illustrated for example in Example 8, it is possible to increase the yield or example of spironolactone, among other things as a consequence of the recovery of starting material, `
i.e. of dehydro-epi-androsterone to 50%, and of canrenone to 52%, of the ~eight of reacted dehydro-epi-androsterone.
A particular advantage of the present process also resides in the fact that in the steps of the reaction of the starting material with the brominating agent, and of the oxidation thereof and the dehydrobromination, l~ the 4,6-dien-3-one intermediate is formed as a unitary compound which can be ;~ -readily obtained pure, for example by mere crystallisation, As against this, in the processes C to E discussed at the outset, which all proceed via the 4,6-dien-3-one step according to formula VIII, it is difficult to obtain pure preparations of this constitution, since the products are invariably mixtures of alkoxy compounds which are epimeric at the 21a-carbon atom.
A consequence thereof is, among other things, that the puriication in the final step, for example of the spironolactone, is very tedi~us and compli-cated. In contradistinction thereto, products of such quality are obtained in the final steps of the present process that normally a simple purifica-tion, for example crystallisation, suffices to obtain entirely pure products.
T~e advantage o the present proce~s compared wlth that of process B of United States patents 3,738,983 and 3,270,008, besides ~he ad-vantages alreacly mentioned regarding the yields, also resides in the fact that it involves only a eew and technically simple oporations.
If desired, the compounds of the formula I, wherein Rl and R2 represent a further carbon-carbon bond between position 6 and 7, can be converted in kno~n manner into the salts, in particular the metal salts, of the corresponding 17~-hydroxy-21-carbox~lic acids, for example b~ treatment with metal hydroxides, such as potassium or sodium hydroxide, in a~ueous ~.... - . . . . .................. . . , . .:: . , : .... .
. . . . . .
- ~0~ 9 or alcoholic solution.
If desired, the compounds of the formula I obtained by the process o the present invention, wherein Rl and R2 represent a further carbon-carbon bond in 6,7-position, can be converted in known manner with a thiocarboxylic acid, in particular with a lower thioalkanoic acid, for example one of those referred to hereinbefore, into the compounds of the formula 1, in which Rl represent~ an acylthio group and R2 represents hydrogen.
The invention also comprises those embodiments of the process in which a compound obtained in any intermediate stage is used as starting material and the missing process steps are carried out, or the process is interrupted in any stage, or in which the starting materials are obtained in situ. The invention also has for its object the special embodiment described hereinabove in which the starting material is prepared by reacting dehydro-epi-androsterone with a chloropropionaldehyde-acetal in the presence of lithium~ and, following the reaction, the unreacted dehydro-epi-androsterone is recovered after treating the reaction mixture beforehand uith steam.
The invention also has for its object the embodiment of the present process in which compounds of the formula I, wherein R1 and R2 represent a further 6,7-carbon-carbon bond, are obtained first and then converted in known manner into the compounds of the formula I, wherein R
represents an acylthio group and R2 represents hydrogen.
The Eollowing ~xamples serve to illustrate the invention without restricting it to what is described thercin.
Example 1 2~ g of dehydro-epi-androsterone are dissolved in 500 ml of abs.
tetrahydr~uran, Then 5.2 g of lithium wire~ cut into small pieces, are added, ~fter cooling ~ith an ice bath to 0C, 38 g of ~-chloropropionalde-hyde ethylene acetal in 50 ml of abs, tetrahydrofuran are added dropwise ~,^?`.¦
. .
,.,' . ~
with stirring in an atmosphere of nitrogen in the course of 15 minutes.
During thi~ addition, the mixture is so intensively cooled ~ice/sodium chloride mixture) that the reaction temperature does not exceed 10C.
Stirring is subsequently continued for a further 2 1/2 hours at 0 C and `
overnight at room temperature ~under nitrogen). Excess pieces of lithium are then separated off and the reaction solution is poured into ice water.
Extraction is then performed with ethyl acetate and the extract is washed with saturated aqueous soaium chloride solution until neutral. The crude product obtained after drying the organic phase over Na2SO4 and evaporating it is filtered through 300 g of neutral A1203 of activity IIl unreacted reagent and nonsteroid impurities being eluted with 3 litres of petroleum ether/toluene ~1:1) mixture. With CH2C12 as eluant, 19.9 g of 17~-~3'-ethylenedioxy-propyl)-androst-5-en-3~,17~-diol are obtained in m.p. 181-182C after one recrystallisation from acetone/petroleum ether. Yield:
16.4 g ~60.6% of theory). IR. 3600, 3~50 cm 1~CH2C12). - NMR.: 0.87, s, CH3tl8); 1,02, s~, CH3(19); 3.50, m, CH~3); 3.92, m, -OC~l2C~120-; ~.91,t, J = ~, C~1(3'); 5.34, m, CH~6) ~CDC13).
Example 2 To 6 g of 17~-~3'-ethylenedioxy-propyl)-androst-5-en-3~,17~-diol in 60 ml of pyridine are added at 0C 5.~ g of solid pyridine hydrobromide perbromide. The mixture is then stirred for 3 hours at 0C under anhydrous conditions. One hour ater the start of this reaction, ~1.5 g of Cr03 in 6 ml o~ H20 are added dropwise, with stirring, to ~5 ml of ice-cold pyridine, the rate of addition be:Lng so chosen that the temperature in ~he flask does not exceed 10C. The pyridine chromate solution obtained is then stirred until completion of the parallel bromination reaction at 0C. The pyridine chromate solution is then poured into the bromination solution and the reaction mixture is stirred initially for a further 3 hours at ~C and then .~ .
. , .
l~S~
additionally overnight at room temperature. The batch is then diluted with a substantial amount of C~IC13 and washed 4 times in succession with saturated aqueous NaCl solution ten times with water. The organic phase is subsequent-ly dried over NA2S04 and evaporated to dryness ln vacuo.
The crude oxidation product is dissolved repeatedly in toluene to remove residual pyridine as an azeotrope and evaporated to dryness in vacuo.
The product is dissolved in 108 ml of abs. dimethyl formamide, treated with 10.8 g of LiBr and Li2C03 respectively, and heated, with stirring, in an atmosphere of nitrogen to 1~0C in the course of 15 minutes and kept at this temperature for a further 1 1/4 hours. The batch is afterwards allowed to cool, diluted ~ith ethyl acetate, and washed ten times with water and once with saturated sodium chloride solution. The organic phase is dried over Na2S0~, then concentrated in vacuo, and the residue is filtered through 100 g of neutral A1203 ~activity II). The apolar impurities are first eluted with 500 ml of toluene. The subsequent ethyl acetate eluates consist of 4.56 g of ll@-hydroxy-17~-t3~-ethylenedioxy-propyl)-androsta-4,6-dien-3-one, and melt at 132C after one recrystallisation from acetone/petroleum ether. Yield after recrystallisation: 4.44 g (74.7% of theory). IR.: 3570, 3450, 1655, 1620, 1585 cm (CH2C12). - UV.: 287 ~19700~ in C2H50H. - NMR.: 0.95, SJ
CH3(18); 1.10, s, CH3(19), ca. 3.95~ m, -OCH2CH~0-; 4,89, t, J = 4, CH(3');
5.65, s, CH~4~; 6.08, s (2H), CH(6) ~ CH~7) (CDC13). - ~D ~ ~ 6 ~ in CHC13~.
5 g o~ 17~-hydroxy-17~-~3'-ethylenediox~-prop~l~-androsta-~,6-dien_3 one are dIssolved at room temperature in 50 ml of methanol. Then 7.5 ml of water and 2.5 ml of thioacetic acid are added in succession and the mixture is stirred for 3 hours at room temperature. The batch is thereafter poured into ice-cold 2 normal a~ueous Na~lC03 solution and extrac-tion is performed with ethyl acetate. The extract is washed neutral with saturated aqueous NaCl so~ution, dried over sodium sulphate and concentrated q~ ~
,J ~ 1~ ~
.. ... . .. . . . .
-'~ ' . ' : , ' 65~34~
in vacuo, to yield 5.86 ~ of 7c~-acetrlthio-17~-hydroxy-17-C3'-ethylene-dioxy-propyl)-androst-4-en-3-one ~IR. 3450 ~wide) 1685, 1670, 1620 cm 1 (CH2C12); NMR. 0.92, s, CH3(18~; 1.22, s, CH3(19); 2.33, s, SCOCH3;
3.94, m, CH(7) ~ - OCH2CH20 -; 4.91, t, J = 4, CH(3'); bs, CH(4) (CDC13)], which ar0 further processed direct. The 5.86 g of crude product are dissolved in 200 ml of acetone and the solution is cooled to 0C. Then 10 ml of 8 normal Cr03 in 8 normal H2SO4 are added dropwise, with stirring, in such a way that the temperature does not exceed 10C. The mixture is then stirred for 45 minutes at room temperature. Then 5 ml of the above CrO3 solution are again added dropwise at room temperature and stirring is continued for a ~urther hour at this same temperature. Thereafter 10 ml of methanol are added, and the batch is stirred for 10 minutes and subse-quently diluted with ethyl acetate. The ethyl acetate phase is washed 3 times with saturated aqueous solutions of sodium acetate and sodium chloride respectively, dried over Na2SO4 and evaporated to dryness in vacuo.
Yield: 5.5 g of a crystalline product from which 2.75 g of spironolactone (7-acetylthio-3-oxo 17a-preg-4-en-21,17-carbolactone t51% of theory, referred to the aduct of Example 3), with a double melting point of 135 and 202C) are obtained by crystallisation from methanol at - 10C. [IR.
1770, 1670-1700 wide, 1620 cm 1 (CH2C12). UV. 240 ~19400) iD C2H50H. - MMR.
0,97~ s, CH3(18), 1.20, s, CH3(19); 2.31, s, SCOCH3; 2.84, 8-, I6 6= 15,I67= 4 I4 62, CH~6~):3.97, m, CH(7): 5,68) d.I - 2. CH(4~ (CDC13).
~xample 4 1 g o~ 17~-hydroxy-17a-~3'-ethyl0n0dioxy-propyl)-androsta-4,6-dien-3-one is re~luxed with 1 ml of normal aqueous ~12SO4 in 90 ml of acetone, with stirring, for 45 minutes. The mixture is then cooled to 0C, and with ~tirring, 7 ml of 8 normal Cr03 in 8 normal a~ueous H2SO4 are added dropwise ;- " : , , ~ , ,. . : .
s~g in the course of 15 minutes. The batch is kept for a further 10 minutes at 0C, then lO m] of methanol are added. The batch is diluted with ethyl acetate and washed ~ times with saturated aqueous solutions of sodium acetate and sodium chloride respectively. The organic phase is dried over Na2S04 and evaporated to dryness. The crude product is filtered in CH2C12 over Al203 (activity II), in the course of which 840 mg of 3-oxo-17~-pregna-
Yield: 5.5 g of a crystalline product from which 2.75 g of spironolactone (7-acetylthio-3-oxo 17a-preg-4-en-21,17-carbolactone t51% of theory, referred to the aduct of Example 3), with a double melting point of 135 and 202C) are obtained by crystallisation from methanol at - 10C. [IR.
1770, 1670-1700 wide, 1620 cm 1 (CH2C12). UV. 240 ~19400) iD C2H50H. - MMR.
0,97~ s, CH3(18), 1.20, s, CH3(19); 2.31, s, SCOCH3; 2.84, 8-, I6 6= 15,I67= 4 I4 62, CH~6~):3.97, m, CH(7): 5,68) d.I - 2. CH(4~ (CDC13).
~xample 4 1 g o~ 17~-hydroxy-17a-~3'-ethyl0n0dioxy-propyl)-androsta-4,6-dien-3-one is re~luxed with 1 ml of normal aqueous ~12SO4 in 90 ml of acetone, with stirring, for 45 minutes. The mixture is then cooled to 0C, and with ~tirring, 7 ml of 8 normal Cr03 in 8 normal a~ueous H2SO4 are added dropwise ;- " : , , ~ , ,. . : .
s~g in the course of 15 minutes. The batch is kept for a further 10 minutes at 0C, then lO m] of methanol are added. The batch is diluted with ethyl acetate and washed ~ times with saturated aqueous solutions of sodium acetate and sodium chloride respectively. The organic phase is dried over Na2S04 and evaporated to dryness. The crude product is filtered in CH2C12 over Al203 (activity II), in the course of which 840 mg of 3-oxo-17~-pregna-
4,6-diene-21,17-carbolactone are eluted; m.p. 152-153C after crystallisa-tion from acetone/petroleum ether. Yield: 720 mg ~81.8% of theory).
IR.: 1770, 1658, 1620, 1585 cm 1 (CH2C12). - UV.: 283 (24000) in C2H50H. -NMR.: 1.00, s, CH3(18); 1.11, s, CH3(19); 5.67, s, CH(4); 6.08, s (2H), CH~6) ~ CH~7) ~CDC13).
Example 5 1 g of 3-oxo-17~-pregna-4,6-diene-21,17-carbolactone are dissolved at room temperature in 6 ml of methanol and to the solution are added in succession 1.5 ml of water and 0.5 ml of thioacetic acid. '~he mixture is stirred for 3 hours at room temperature and extracted with ethyl acetate.
The extract is washed in succession with 2 normal aqueous Na}lC03 solution and with saturated aqueous sodium chloride solution until the neutral point is reached. The organic phase is dried over Na2S04 and evaporated in vacuo, to yield 1,1 g of crude product from which 550 mg of spironolactone are obtained after crystallisation from methanol at -10C, ~ direct comparison reveals thls compound to be identical in every respect with tho preparation obta:lned in Example 3.
Example 6 3.4 g of 3-oxo-17~-pregna-4,6-diene-21,17-carbolactone are dis-solved in 10.2 ml Oe boiling methanol. Then 2 ml o thioacetic acid are added dropwise to the boiling solution in the course o 5 minutes and the mixture is boiled subsequently for a further 30 minutes, and then cooled to ~-~ 1 - 18 ~,,,.1 .
' 0C, whereupon the reaction product crystallises out, The batch is allowed to stand for 15 minutes at -10C and the crystals are collected by suction filtration, washed with lO ml of cold methanol and dried in vacuo at 40C.
Yield: 3.~1 g of pure spironolactone with a double melting point of 135 and 202C and which a direct comparison reveals to be identical in every respect with the material described in Example 3.
Example 7 1.80 g of 17~-hydroxy-17~-~3'-ethylenedioxy-propyl)-androsta-4,6-dien-3-one are dissolved in 5.1 ml of boiling methanol. Then 1 ml of thio-acetic acid are added dropwise to the boiling solution in the course of 5minutes and boiling is continued for a further 3~ minutes. The batch is ; thereafter cooled, diluted with ethyl acetate and the ethyl acetate extract is washed in succession ~ith aqueous solutions of N~lC03 and NaCl until the neutral point is reached. The organic phase is then dried over Na2S~ and evaporated to dryness in vacuo, to yield 2.09 g of crude product, ~hich is treated in 80 ml of acetone at 0C, with stirring, with ~ ml af a 8 normal CrO3 solution in 8 normal aqueous H2S0~. The mixture is subsequently stirred for 1 hour at room temperature, treated once more with 2 ml of the above CrO3 solution and stirred for 1 hour. Extraction is effected with ethyl acetate, the extract is washed 3 times wi~h saturated aqueous solu-tions of sodium acetate and NaCl respectively, dried over Na2S0~, and evaporated in vacuo to dryness. Yield: 1.87 g of crude spironolactone from which 1.25 g o~ pure compound are obtainecl after one crystall:isation from Ctl2C12-methanol. ~Physical data as in ~xamplc 3~.
Example 8 20 g of dehydro-epi-androsterone are dissolved in 500 ml of abs.
tetrahydrofuran. Then 5.2 g of clean lithium wire cut into small pieces are added. The mixture is cooled to 0C with an ice bath and 38 g of ~-chloropropionaldehyde ethylene acetal in 50 ml of abs. tetrahydrofuran are -~.! - 19 ;,5~
added drop~ise, ~ith ~tirring, in the course of 15 minutes in a nitrogen atmosphere. The reaction mixture is so intensively cooled that the tempera-ture does not rise above 10C. The mixture is then stirred for a further 2 1/2 hours at 0C and overnight at room temperature ~in both cases under nitrogen). Excess lithiu~ is then separated off and the mixture poured into ; ice water. Excess reagent and its degradation products are separated off by steam distillation The residue which is non-volatile in steam is finally ~ extracted with methylene chloride. The methylene chloride phase is washed neutral with saturated aqueous NaCl solutionl dried o~er Na2S0~ and evaporated to dryness in vaGuo. The crude product is filtered through 600 g of A1203 (activity II~ and in doing so 4 fractions are eluted with 1 litre of methylene chloride on each occasion. The column is then washed out with 6 fractions of meth~lene chloride/eth~l acetate mixture 4:1 (using 1 litre on each occasion). ~vaporation of the third frackion ~ield 3.2 g o~
unreacted crude dehydro-epi-androsterone from which 2 65 g o pure substance are recoverecl ~y crystallisation from acetone petroleum ekher. Fractions ~
to 10 yield 2~.1 g of 17~-(3-0th~1enedioxy-propyl)-androst-5-en-3~,17~-diol, which me}ts ak 181-182C~C ater crystallisation from methylene chloride/
petroleum. (Yield 17 g = 7~% of theory, taking into account the starting material recovered).
; ~ - 20 _ .. .....
,, i ' , ' , ' ' . ;i '~ '
IR.: 1770, 1658, 1620, 1585 cm 1 (CH2C12). - UV.: 283 (24000) in C2H50H. -NMR.: 1.00, s, CH3(18); 1.11, s, CH3(19); 5.67, s, CH(4); 6.08, s (2H), CH~6) ~ CH~7) ~CDC13).
Example 5 1 g of 3-oxo-17~-pregna-4,6-diene-21,17-carbolactone are dissolved at room temperature in 6 ml of methanol and to the solution are added in succession 1.5 ml of water and 0.5 ml of thioacetic acid. '~he mixture is stirred for 3 hours at room temperature and extracted with ethyl acetate.
The extract is washed in succession with 2 normal aqueous Na}lC03 solution and with saturated aqueous sodium chloride solution until the neutral point is reached. The organic phase is dried over Na2S04 and evaporated in vacuo, to yield 1,1 g of crude product from which 550 mg of spironolactone are obtained after crystallisation from methanol at -10C, ~ direct comparison reveals thls compound to be identical in every respect with tho preparation obta:lned in Example 3.
Example 6 3.4 g of 3-oxo-17~-pregna-4,6-diene-21,17-carbolactone are dis-solved in 10.2 ml Oe boiling methanol. Then 2 ml o thioacetic acid are added dropwise to the boiling solution in the course o 5 minutes and the mixture is boiled subsequently for a further 30 minutes, and then cooled to ~-~ 1 - 18 ~,,,.1 .
' 0C, whereupon the reaction product crystallises out, The batch is allowed to stand for 15 minutes at -10C and the crystals are collected by suction filtration, washed with lO ml of cold methanol and dried in vacuo at 40C.
Yield: 3.~1 g of pure spironolactone with a double melting point of 135 and 202C and which a direct comparison reveals to be identical in every respect with the material described in Example 3.
Example 7 1.80 g of 17~-hydroxy-17~-~3'-ethylenedioxy-propyl)-androsta-4,6-dien-3-one are dissolved in 5.1 ml of boiling methanol. Then 1 ml of thio-acetic acid are added dropwise to the boiling solution in the course of 5minutes and boiling is continued for a further 3~ minutes. The batch is ; thereafter cooled, diluted with ethyl acetate and the ethyl acetate extract is washed in succession ~ith aqueous solutions of N~lC03 and NaCl until the neutral point is reached. The organic phase is then dried over Na2S~ and evaporated to dryness in vacuo, to yield 2.09 g of crude product, ~hich is treated in 80 ml of acetone at 0C, with stirring, with ~ ml af a 8 normal CrO3 solution in 8 normal aqueous H2S0~. The mixture is subsequently stirred for 1 hour at room temperature, treated once more with 2 ml of the above CrO3 solution and stirred for 1 hour. Extraction is effected with ethyl acetate, the extract is washed 3 times wi~h saturated aqueous solu-tions of sodium acetate and NaCl respectively, dried over Na2S0~, and evaporated in vacuo to dryness. Yield: 1.87 g of crude spironolactone from which 1.25 g o~ pure compound are obtainecl after one crystall:isation from Ctl2C12-methanol. ~Physical data as in ~xamplc 3~.
Example 8 20 g of dehydro-epi-androsterone are dissolved in 500 ml of abs.
tetrahydrofuran. Then 5.2 g of clean lithium wire cut into small pieces are added. The mixture is cooled to 0C with an ice bath and 38 g of ~-chloropropionaldehyde ethylene acetal in 50 ml of abs. tetrahydrofuran are -~.! - 19 ;,5~
added drop~ise, ~ith ~tirring, in the course of 15 minutes in a nitrogen atmosphere. The reaction mixture is so intensively cooled that the tempera-ture does not rise above 10C. The mixture is then stirred for a further 2 1/2 hours at 0C and overnight at room temperature ~in both cases under nitrogen). Excess lithiu~ is then separated off and the mixture poured into ; ice water. Excess reagent and its degradation products are separated off by steam distillation The residue which is non-volatile in steam is finally ~ extracted with methylene chloride. The methylene chloride phase is washed neutral with saturated aqueous NaCl solutionl dried o~er Na2S0~ and evaporated to dryness in vaGuo. The crude product is filtered through 600 g of A1203 (activity II~ and in doing so 4 fractions are eluted with 1 litre of methylene chloride on each occasion. The column is then washed out with 6 fractions of meth~lene chloride/eth~l acetate mixture 4:1 (using 1 litre on each occasion). ~vaporation of the third frackion ~ield 3.2 g o~
unreacted crude dehydro-epi-androsterone from which 2 65 g o pure substance are recoverecl ~y crystallisation from acetone petroleum ekher. Fractions ~
to 10 yield 2~.1 g of 17~-(3-0th~1enedioxy-propyl)-androst-5-en-3~,17~-diol, which me}ts ak 181-182C~C ater crystallisation from methylene chloride/
petroleum. (Yield 17 g = 7~% of theory, taking into account the starting material recovered).
; ~ - 20 _ .. .....
,, i ' , ' , ' ' . ;i '~ '
Claims (25)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of compounds of the formula I
wherein R1 represents an .alpha.-acylthio group and R2 represents hydrogen, or R1 and R2 together represent a further 6,7 C-C bond, which process comprises reacting an acetal of 3.beta., 17-dihydroxy-17.alpha.-pregn-5-en-21-carbaldehyde in basic or neutral medium with a brominating agent to add bromine to the double bond, oxidising the 3-hydroxy-5,6-dibromo compound so formed with a hexavalent chro-mium compound under basic or neutral conditions to convert the 3-hydroxyl group to a 3-oxo group, dehydrobrominating the 3-one compound to obtain a 4, 6-dien-3-one compound, reacting the 4,6-dien-3-one compound with a compound of hexavalent chromium in acid solution and, if a compound in which R1 represents an acylthio group and R2 is hydrogen is required, reacting the 4,6-dien-3-one compound, either before or after reaction with the hexavalent chromium com-pound in acid solution, with a thiocarboxylic acid to introduce an acylthio group at the 7-position.
wherein R1 represents an .alpha.-acylthio group and R2 represents hydrogen, or R1 and R2 together represent a further 6,7 C-C bond, which process comprises reacting an acetal of 3.beta., 17-dihydroxy-17.alpha.-pregn-5-en-21-carbaldehyde in basic or neutral medium with a brominating agent to add bromine to the double bond, oxidising the 3-hydroxy-5,6-dibromo compound so formed with a hexavalent chro-mium compound under basic or neutral conditions to convert the 3-hydroxyl group to a 3-oxo group, dehydrobrominating the 3-one compound to obtain a 4, 6-dien-3-one compound, reacting the 4,6-dien-3-one compound with a compound of hexavalent chromium in acid solution and, if a compound in which R1 represents an acylthio group and R2 is hydrogen is required, reacting the 4,6-dien-3-one compound, either before or after reaction with the hexavalent chromium com-pound in acid solution, with a thiocarboxylic acid to introduce an acylthio group at the 7-position.
2, A process according to claim 1 wherein the 4,6-dien-3-one compound is treated with acid before being reacted with the hexavalent chromium com-pound in acid solution.
3. A process according to claim 1 wherein a compound of formula I is produced in which R1 and R2 represent a further 6,7 C-C bond and the compound of formula I is converted into a metal salt of the corresponding 17-hydroxy-21-carboxylic acid.
4. A process according to claim 3 wherein the compound of formula I is converted into a metal salt of the corresponding 17-hydroxy-21-carboxy-lic acid by reaction with sodium or potassium hydroxide in aqueous or alco-holic solution.
5. A process according to claim 1 for the manufacture of compounds of formula I wherein an acylthio group R1 is derived from a lower thioalka-noic acid containing 1 to 7 carbon atoms.
6. A process according to claim 1 for the manufacture of compounds of the formula I wherein an acylthio group R1 is the acetylthio group.
7. A process according to claim 1, 5 or 6, wherein an acetal which is derived from a lower aliphatic alkanol or alkanediol of 1 to 7 carbon atoms is used as starting material.
8. A process according to claim 1, 5 or 6, wherein the ethylene gly-col acetal of 3.beta. ,17.beta. -dihydroxy-17.alpha.-pregn-5-en-21-carbaldehyde is used as starting material.
9. A process according to claim 1, 5 or 6 wherein a brominating agent selected from the group consisting of a) bromine in a tertiary aromatic nitro-gen base and b) a perbromide of a tertiary aromatic ntirogen base or a hydro-halogen salt thereof, or an adduct of bromine and an ether, in a lower ali-phatic chlorinated hydrocarbon, an ether, a ketone, a di-lower alkyl-lower alkanoic acid amide, is used.
10. A process according to claim 1, 5 or 6 wherein there is used as brominating agent a perbromide of a tertiary aromatic nitrogen base or a hydro-halogen salt thereof or an adduct of bromine and an ether in a lower aliphatic chlorinated hydrocarbon, an ether, a ketone, a di-lower alkyl-lower alkanoic acid amide, in the presence of a buffer or in a tertiary aromatic nitrogen base.
11. A process according to claim 1, 5 or 6, wherein pyridine hydro-bromide perbromide in pyridine is used as brominating agent and the reaction is carried out at or below room temperature.
12. A process according to claim 1, 5 or 6, wherein the 5,6-dibromo adduct is oxidised with chromium trioxide or with chromic acid in a tertiary aromatic base at a temperature between about -10° and about +30°C.
13. A process according to claim 1, 5 or 6, wherein the 5,6-dibromo adduct is oxidised with chromium trioxide or with chromic acid in pyridine at a temperature between about -10° and about +30°C.
14. A process according to claim 1, wherein the dehydrobromination of the chromic acid oxidation product is carried out with an inorganic basic agent or with a nitrogen-containing aromatic base.
15. A process according to claim 14, wherein a lithium halide in the presence of a basic salt of an alkali metal or alkaline earth metal is used.
16. A process according to claim 15, wherein lithium bromide in the presence of lithium carbonate is used and the dehydrobromination is carried out in a dialkylamide or a lower aliphatic carboxylic acid at temperatures between 80° and 150°C.
17. A process according to claim 1, wherein the 4,6-dien-3-one derivative containing the 17-propionaldehyde acetal side-chain is treated with a compound of hexavalent chromium in a mineral acid solution.
18. A process according to claim 17, wherein the oxidation is carried out with chromium trioxide in sulphuric acid.
19. A process according to claim 18 wherein the oxidation is carried out in the presence of acetone.
20. A process according to claim 17, wherein the oxidation is carried out with chromium trioxide in a lower alkane carboxylic acid containing 1 to 7 carbon atoms.
21. A process according to claim 17, 18 or 20 wherein a preliminary treatment with sulphuric acid or a lower alkane carboxylic acid containing 1 to 7 carbon atoms is carried out before the treatment with a compound of hexa-valent chromium in acid solution.
22. A process according to claim 1, wherein treatment of any .DELTA.4'6-3-one-steroid-diene first mentioned with a thiocarboxylic acid is effected in a lower alkanol containing 1 to 7 carbon atoms using about 1.5 to 3.5 moles of thiocarboxylic acid and a temperature between 0° and 120°C.
23. A process according to claim 22, wherein the resulting compound is treated with chromium trioxide in sulphuric acid or in a lower alkane car-boxylic acid of 1 to 7 carbon atoms.
24. A process according to claim 1, 5 or 6, wherein the 4,6-dien-3-one compound first mentioned in claim 1 is oxidised with chromium oxide in sulphuric acid or a lower alkane carboxylic acid of 1 to 7 carbon atoms and is reacted with a thiocarboxylic acid in a lower alkanol containing 1 to 7 carbon atoms using about 1.5 to 3.5 moles of thiocarboxylic acid and a temperature between 0° and 120°C.
25. A process according to claim 1, 5 or 6 wherein the 3.beta.,17-dihydroxy-17.alpha. -pregn-5-en-21-carbaldehyde is prepared by reacting dehydro-epi-androsterone with a chloropropionaldehyde acetal in the presence of lithium, and the reaction mixture obtained after this reaction is treated with steam and unreacted dehydro-epi-androsterone is recovered from the residue of the steam distillation by crystallisation or chromatography.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH769675A CH612953A5 (en) | 1975-06-13 | 1975-06-13 | Process for the preparation of steroid carbolactones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1065849A true CA1065849A (en) | 1979-11-06 |
Family
ID=4329149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA254,684A Expired CA1065849A (en) | 1975-06-13 | 1976-06-11 | Process for the manufacture of steroid carboxylic acid lactones |
Country Status (12)
| Country | Link |
|---|---|
| JP (2) | JPS52256A (en) |
| AT (1) | AT356299B (en) |
| BE (1) | BE842870A (en) |
| CA (1) | CA1065849A (en) |
| CH (2) | CH612953A5 (en) |
| DE (1) | DE2625723A1 (en) |
| DK (1) | DK142992C (en) |
| FR (1) | FR2313934A1 (en) |
| GB (1) | GB1548259A (en) |
| MX (1) | MX3537E (en) |
| NL (1) | NL7606350A (en) |
| SE (1) | SE416951B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8334375B2 (en) | 2009-04-10 | 2012-12-18 | Evestra, Inc. | Methods for the preparation of drospirenone |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3330084A1 (en) * | 1983-08-17 | 1985-03-07 | Schering AG, 1000 Berlin und 4709 Bergkamen | 7 alpha -Alkoxycarbonyl-3-oxo-17 alpha -pregn-4-ene-21,17-carbolactones and their 21-carboxylic acid salts, process for the preparation thereof, and pharmaceutical products containing these |
| JPS6095799A (en) * | 1983-10-31 | 1985-05-29 | Nec Corp | Programmable read-only memory |
| CN101731164B (en) * | 2009-11-12 | 2012-06-27 | 中国水产科学研究院渔业机械仪器研究所 | Closed water-flowing type aquaculture net cage |
| CN108047299B (en) * | 2017-12-29 | 2021-11-09 | 广西万德药业有限公司 | Preparation method of important intermediate of canrenone |
| CN113528607B (en) * | 2021-08-08 | 2023-07-11 | 浙江神洲药业有限公司 | Method for preparing spirolactone by chemical-enzymatic method |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1250818B (en) * | 1963-10-01 | 1967-09-28 | G. D. Searle & Co., Chicago, 111. (V. St. A.) | Process for the production of 3-oxozl4.asteroids |
| US3682894A (en) * | 1970-02-24 | 1972-08-08 | Searle & Co | Process for preparing 3-oxo-delta4,6-steroids |
| DE2248834A1 (en) * | 1972-10-05 | 1974-04-11 | Hoechst Ag | METHOD FOR MANUFACTURING BETA (3-KETO-7 ALPHA-ACETYLTHIO-17BETA-HYDROXY4-ANDROSTEN-17 ALPHA-YL) -PROPIONIC ACID GAMMA -LACTONE |
| DE2251476A1 (en) * | 1972-10-20 | 1974-05-02 | Hoechst Ag | PROCESS FOR THE PRODUCTION OF BETA (3-KETO-7 ALPHA-THIOACYL-17 BETA-HYDROXY4-ANDROSTEN-17 ALPHA -YL) -PROPIONIC ACID GAMMA -LACTONES |
-
1975
- 1975-06-13 CH CH769675A patent/CH612953A5/en not_active IP Right Cessation
-
1976
- 1976-05-21 SE SE7605799A patent/SE416951B/en not_active IP Right Cessation
- 1976-06-09 DE DE19762625723 patent/DE2625723A1/en not_active Ceased
- 1976-06-11 DK DK264476A patent/DK142992C/en active
- 1976-06-11 FR FR7617760A patent/FR2313934A1/en active Granted
- 1976-06-11 GB GB2430576A patent/GB1548259A/en not_active Expired
- 1976-06-11 BE BE167857A patent/BE842870A/en not_active IP Right Cessation
- 1976-06-11 MX MX30176U patent/MX3537E/en unknown
- 1976-06-11 AT AT425476A patent/AT356299B/en not_active IP Right Cessation
- 1976-06-11 CA CA254,684A patent/CA1065849A/en not_active Expired
- 1976-06-11 NL NL7606350A patent/NL7606350A/en unknown
- 1976-06-12 JP JP6824976A patent/JPS52256A/en active Granted
-
1979
- 1979-04-05 CH CH318579A patent/CH617443A5/en not_active IP Right Cessation
-
1984
- 1984-08-10 JP JP16662584A patent/JPS6056998A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8334375B2 (en) | 2009-04-10 | 2012-12-18 | Evestra, Inc. | Methods for the preparation of drospirenone |
Also Published As
| Publication number | Publication date |
|---|---|
| BE842870A (en) | 1976-12-13 |
| NL7606350A (en) | 1976-12-15 |
| DK142992C (en) | 1981-10-05 |
| DE2625723A1 (en) | 1976-12-23 |
| MX3537E (en) | 1981-02-10 |
| FR2313934A1 (en) | 1977-01-07 |
| JPS6056998A (en) | 1985-04-02 |
| ATA425476A (en) | 1979-09-15 |
| DK142992B (en) | 1981-03-09 |
| CH612953A5 (en) | 1979-08-31 |
| SE416951B (en) | 1981-02-16 |
| JPS6357438B2 (en) | 1988-11-11 |
| DK264476A (en) | 1976-12-14 |
| JPS52256A (en) | 1977-01-05 |
| GB1548259A (en) | 1979-07-11 |
| CH617443A5 (en) | 1980-05-30 |
| AT356299B (en) | 1980-04-25 |
| FR2313934B1 (en) | 1978-10-20 |
| JPS6159320B2 (en) | 1986-12-16 |
| SE7605799L (en) | 1976-12-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SU1340593A3 (en) | Method of producing derivatives of delta 4-9-19-norsteroids | |
| CA1065849A (en) | Process for the manufacture of steroid carboxylic acid lactones | |
| DK165838B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF 17,17-BIS (SUBSTITUTED THIO) -3-KETOONROSTEN COMPOUNDS | |
| KR100274369B1 (en) | Process for the preparation of 11-ketosteroid derivatives | |
| JP5430603B2 (en) | Guggulsterone and method for producing guggulsterol | |
| JP2005523306A (en) | Manufacturing method of eplerenone | |
| JP2000514058A (en) | Process for the preparation of 17-esters of 9α, 21-dihalo-pregnane-11β, 17α-diol-20-one | |
| FI83522C (en) | Process for the preparation of therapeutically useful 10-alkynyl-e strand derivatives | |
| US4192802A (en) | Process for the manufacture of steroid carboxylic acid lactones | |
| US5504203A (en) | Process for preparing 17,20-epoxy steroids | |
| EP0027023B1 (en) | Furyl intermediates of cardenolides, their synthesis and production of cardenolides and their isomers therefrom | |
| JP3037507B2 (en) | Novel steroid derivatives of pregna-4,9 (11), 17 (20) -trien-3-one, their preparation, pregna-4,9 (11), 16-trien-3,20-dione type Use in the production of steroid compounds and novel intermediates | |
| HU203114B (en) | Process for producing 9(11)-dehydrosteroids | |
| HU212666B (en) | Novel process for producing hydrocortisone | |
| HU218484B (en) | New process for producing 10beta-h-steroids | |
| Miyano | Synthesis of aldosterone | |
| US4054563A (en) | Process for the manufacture of spiro compounds of the steroid series | |
| US7112670B2 (en) | Crystal form | |
| US4472310A (en) | 5β-Hydroxy-Δ6 -steroids and process for the preparation thereof | |
| Johns | 12. alpha., 13. beta.-Etiojervane analog of testosterone | |
| US3761498A (en) | New process of preparation of steroids | |
| Broess et al. | Synthetic approaches toward total synthesis of 12β-methyl-and 12-methylene-19-norpregnanes | |
| US20060111332A1 (en) | Process and intermediates to prepare17beta-hydroxy-7alpha-methyl-19-nor-17alpha-pregn -5(10)-en-20-yn-3-one | |
| US2818414A (en) | Production of steroid compounds | |
| DK143138B (en) | PROCEDURE FOR PREPARING 18,18-DIFLUOROSTEROIDS |