CA1220468A - Process for the production of 17-esters of clobetasol - Google Patents
Process for the production of 17-esters of clobetasolInfo
- Publication number
- CA1220468A CA1220468A CA000445603A CA445603A CA1220468A CA 1220468 A CA1220468 A CA 1220468A CA 000445603 A CA000445603 A CA 000445603A CA 445603 A CA445603 A CA 445603A CA 1220468 A CA1220468 A CA 1220468A
- Authority
- CA
- Canada
- Prior art keywords
- beta
- epoxy
- dione
- diene
- methylpregna
- 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
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
This invention relates to an improved process for the preparation of 17-esters of Clobetasol having the formula II
which consists in treatment of 9.beta.,11.beta.-epoxy-16.beta.-methyl-pregna-1,4-diene-17,21-diol-3,20-dione 17-esters with mesyl chloride to give the corresponding 21-chloro-deriv-ative, followed by opening of the epoxide grouping with hydrogen fluoride. The invention also relates to new 17-esters of 21-chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methyl-pregna-1,4-diene-3,20-dione, useful as intermediates for the preparation of therapeutically active 9.alpha.-halo-11.beta.-hydroxy derivatives.
This invention relates to an improved process for the preparation of 17-esters of Clobetasol having the formula II
which consists in treatment of 9.beta.,11.beta.-epoxy-16.beta.-methyl-pregna-1,4-diene-17,21-diol-3,20-dione 17-esters with mesyl chloride to give the corresponding 21-chloro-deriv-ative, followed by opening of the epoxide grouping with hydrogen fluoride. The invention also relates to new 17-esters of 21-chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methyl-pregna-1,4-diene-3,20-dione, useful as intermediates for the preparation of therapeutically active 9.alpha.-halo-11.beta.-hydroxy derivatives.
Description
PI~OCESS FOR 'I`~E PRODUCTION OF 17-ESTERS OF CLOBETASOL
The present invention relates to a process for pre-paring 17-esters of Clobetasol. A further object is provided by Clobetasol 17-esters obtained according to the process of the invention. It is known from ~.S. Pa-tent n. 3,721,687 that Clobetasol 17-esters can be pre-pared from 17-esters of betamethasone via the correspon-ding 21-alkylsulphonates. However the reaction is slow, requiring reaction times of 1-3 days and the product is obtained in low yield and in an impure state, which necessitates chromatography and repeated crystallization in order to obtain the pure form.
It is an object of the present invention to provide a simple ;:nd efficient process for the production of Clo betasol 17-esters, which does not involve long reaction times and which furnishes the product in an easily puri-fied form and which is suitable for large-scale indu-strial application.
These objects have been obtained by providing a pro-cess wherein readily-available esters of 9beta,11beta-; ~0 epoxy-17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,~0-dione having the formula I
~.
~2~
~"0 ~''`1' 0~
wherein R is an alkyl group or aryl group of up to 6 carbon atoms and R' is hydroxy, are treated with metha nesulphonyl chloride to give the corresponding 21-mesy late derivatives having the general formula I, wherein R is as defined above and Rl is mesyloxy followed by treatment with lithium chloride to give the correspon-ding 21-chloro derivatives having the general formula I, wherein R is as defined above and ~' is chloro, which on treatment with hydrogen fluoride afford the correspon ding 17-esters of Clobetasol having the formula III
rCl =O
HO \~ )C~ 3 : O
~ wherein l~ is as defined above.
.~ . .
The success of the reaction sequence of this invention is surprising since the nucleophilic substitution of a 21-mesyloxy group by chloro in a substrate containing a 9beta,11beta epoxy group, without disruption of the 9beta, llbeta-epoxy group, was not foreseeable to one skilled in the art. The opening of 9beta,11beta-steroidal epoxi-des to the corresponding chlorohydrins by reaction with lithium chloride in acetic acid is known from U.S. patent n. 3,652,604. Under the reaction conditions of the inven-tion, however, no detectable amounts of chlorohydrins areformed. Indeed the yields of the 21-chloro 9beta,11beta-epoxy compounds are close to quantitative, which is remar kable considering the low yields obtained using the 9alpha-fluoro-llbeta~hydroxy compounds of U.S. patent n.
3,721,687.
A further surprising feature of the nucleophilic sub-stitution on the 9beta,11beta-epoxides is the ease with which the reaction proceeds. In U.S. patent n. 3,721,687 a similar substitution is conducted on 9alpha-fluoro-llbeta-hydroxy compounds under conditions requiring 3 days at reflux and utili~ing a 2000% excess of lithium chloride.
Under the conditions o~ the present invention the rea_ tiorl proceedc; to corllpletiorl in 1-3 hr a~ tempeL~tures rang ~;2 Q~
ing from 60 to 90 using only a slight excess of lithium chloride.
A distinct advantage of the present invention is that the intermediates are obtained in a sufficiently pure form by simple aqueous precipitation (or total extraction) so as to render intermediate purification unnecessary. Fur thermore the final products are obtained in such a pure state that they may be brought to pharmacopoeia standards by simple crystallization. Using the process of U.S. pa-tent n. 3,721,687 the intermediate require purification and the final product must be chromatographed and crystalli zed repeatedly. Thus the process of the present inven-tion is more suitable for large scale industrial use.
The first stage of the present invention consists of formation of a 21-mesylate derivative from the correspon-ding 21-hydroxy compound using methanesulphonyl chloride in pyridine, a known reaction. The yields in this step are almost quantitative.
The second stage of the invention consists in substitu-tion~of the 21-mesyloxy group by chloro. This process is conducted in a suitable dipolar aprotic solvent such as acetone, dimethylformamide, hexamethylphosphoric triamide, or mixtures thereof. We prefer to use dimethylformamide since the subst:r~tes have goocl solubility in this solvent, thus pernli~tin~ t:hc~ reac-ic)n to be cond~lct~ed at high con-, 5centrations (16-20% w/v), an importan~ factor in indu-strial production.
In contrast the process of U.S. patent n. 3,721,687 is conducted at a concentration of less than 1.5~ w/v.
The preferred source of chloride ions is anhydrous lithium chloride although any compound capable of furni-shing chloride ions may be used. An advantage of the process of the invention is that only a slight excess of lithium chloride is employed. The reaction may be con ducted at temperatures between 30 and 120, preferably.
The yields obtained in this step are surprisingly high (92-96~ of theory).
The final stage of the invention consists of conver-sion of the 9beta,11beta-epoxy group into the correspon-ding fluorohydrin using hydrogen fluoride, a known reaction. The fluorination may be conducted using con-ventional methods e.g. aqueous hydrofluoric acid or mix-tures of anhydrous hydrogen fluoride with tetrahydrofuran, dimethylformamide, urea, or pyridine. We find 70~ aque-ous hydrofluoric acid to be convenient and to give highYields.
The starting materials for the present invention, na-mely 9beta,11beta-epoxy-17,21-dihydroxy-16beta-methylpre gr)a-1,4-diene-3,20-dione 17-esters are either known or mtly be easily prepared from the comlnercially available ~Q~
betamethasone intermediate 9beta,11beta-epoxy-17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione using the procedure of U.S. patent n. 3,755,302.
Without furt~ler elaboration, it is believed that one skilled in the art can, using the preceding descrip-tion, utilize the present invention to its fullest ex-tent.
The following preferred, specific embodimen~s are, therefore to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the following examples all temperatures are in cle-grees Celsius.
Preparatio_ 1 To a suspension of 1 kg 9~,11B-epoxy-17,21-dihydroxy-; 16B-methylpregna-1,4-diene-3,20-dione in 7 lt dry tetra-hydrofuran and 1 lt triethylorthopropionate is added a solution of 10 g para-toluenesulphonic acid in 1 lt dry tetrahydrofuran. The mixture rapidly becomes a solu-tion and after 1 hr is neutralized with 100 g sodium ace-tate and poured into 50 lt water. I'he precipitated 17,21-ortho ester is collecte~ washed with water and suspended in 10 lt methanol. A solution of 20 ml acetic acid and 3 2 g sodium acetate in 4 lt water is added and t:ne mixtu re ilea!:ed under retlux for 3 hr, concentra~ed Lo cl volume of 4 lt and diluted with 10 lt water. The precipitated 9~ epoxy-17,21-dihydroxy-16~-methylpregna-1,4-diene-3,20-dione 17-propionate is collected, washed well with water and dried under vacuum. Yield: 1.1 kg.
A sample crystallized from diethyl ether had the follo wing characteristics:
m.p.: 150 with decomposition / ~_/ + 47.5 (C = 1, chloroform) ~ KBr -1 I.R. 3470, 1730, 1665, 1630, 1610 cm max F'urther 17-esters of 9~ -epoxy-17,21-dihydroxy-16~-methylpregna-1,4-diene-3,20-dione were prepared according to the above general method. For example, substitut.ing triethylorthobenzoate for triethylorthopropionate there was obtained the corresponding 17-benzoate having the following characteristics.
KBr I.R. ~ 3500, 1725, 1715, 1670, 1630, 1610, 1590, 1280, max 720 cm , m.p. 144-146C.
Substituting trimethylorthovalerate for triethylortho-propionate there was obtained the corresponding 17-vale-rate having the following characteristics:
m.p. 125-127 (from diethyl ether) ~ KBr -1 I.R. ~ 3510, 3~fiO, l740, lfi75, 16~0, lfil5 c~
Illa x To a solution of 1 kg of 9B,ll~-epoxy--17,21-dihydro-xy-16B-methylpregna--1,4-diene-3,20-dione 17-propionate, as obtained in Preparation 1, in 5 lt dry pyridine at 0 was added during 10 minO 500 ml methanesulphonyl chlori-de. After 30 min. at 0-5 the excess of reagent was des-troyed with 100 g ice and the reaction mixture poured into a well agitated mixture of 5.2 lt concentrated hydro chloric acid and 50 lt water at 0. The precipitate of 9B,llB-epoxy-17,21-dihydroxy-16B-methylpregna-1,4-diene-3,20-dione 17-propionate-21-mesylate was collected, wash ed thoroughly with water and dried under vacuum.
Yield : 11.8 kg.
A sample crystallized from diethyl ether had the following characteris~ics:
m.p. 139.5 /~ / + 60 (C = 1, chloroform) KBr I.R.~ 1750, 1730, 1670, 1635, 1615 cm max In a similar manner, but using the 17~acetat~ 17-but~
rate, 17-valerate, or 17-benzoate of 9B,llB-epoxy-17,21-dihydroxy-16B-methylpregna-1,4-diene-3,20-dione there was obtained the corresponding 21-mesylate derivatives.
Chemico--physical characteristics of 9fl,11B-epoxy-17,21-dihydroxy-lf)~3-methylprecJna-l,~-cliene-3,20-dione-l7-henzoa ~;~2~
g KBr te 21-mesylate: m.p. 194C. I.R.~ : 1740, 1710, 1665, I max 1630, 1605, 1585, 720 cm .
To a solution of 1.012 kg (2 moles) of 9n,11n-epoxy-17,21-dihydroxy-16n-methylpregna-1,4-diene-3,20-dione 17-propi_ nate 21-mesyla~e (Example 1) in 6.72 lt dry dimethylfor-mamide was added 106 g (2.S moles) of anhydrous lithium chloride and the mixture was heated under nitrogen for 1.5 hr at 85-90, cooled and poured slowly into 67 lt water at 2 with strong agitation. The precipitate of 21-chlo-ro-9~,11n-epoxy 17-hydroxy-16n-methylpregna-1,4-diene-3,20-dione 17-propionate was collected, washed well with water, and drled under vacuum.
Yield: 860 g (96% of theor.).
A sample crystallized from dichloromethane-diisopropyl ether had the following characteristics:
m.p. 110.
- -/ + 79.5 (C = 1, chloroform) KBr -1 I.R.~ 3450, 1740~ 1665, 1630, 1610, 1590 cm max In a similar manner, but using the 17-acetate, 17-butyrate, 17-valerate, or 17-benzoate of 9~,11n-epoxy-17,21-dihydroxy-16~-methylpregna-1,4 diene-3,20-dione 21-mesylate, obtained in ~xample 1, there was obtained the ~22q~
D corresponding 17-ester of 2l~chloro-9B~lls-epoxy-l7-hydro xy-16n-methylpregna-l,q-diene-3,20-dione.
Chemico-physical characteristics of 17-benzoate of 21-chloro-9~,llB-epoxy-17-hydroxy-16n-methylpregna-1,4-KBr diene-3,20~dione: m.p. 202~C. I.R. J 1740, 1710, -1 max 1665, 1630, 1605, 1585, 715 cm _ .
To 10 lt of 70~ aqueous hydrofluoric acid at -30 was added 1 kg of 21-chloro-9B,llB-epoxy-17-hydroxy-16~-methyl pregna-1,4-diene-3,20-dione 17-propionate (Example 2).
The mixture was brought to -20 and stirred at this tempe rature for 2.5 hr, and then poured slowly into 100 lt de-ionized water under agitation. The precipitate of Clobe-tasol 17-propionate was collected, washed thoroughly with water until neutral, and dried under vacuum.
Yield: 1020 g.
The crude product assaying at ca. 80% is readily puri-fied to >98% by crystallization from dichloromethane-dii sopropyl ether and/or ethanol/water. The purified product thus obtained is identical with an authentic sample.
In a similar manner, but using the 17-acetate, 17-bu tyrate, 17-valerate, or 17-benzoate of 21-c:hIoro-9n,Il~-epo~cy-I7-hydroxy-16~-methyIpregna-1,4-diene-3,20-dione, obtained in Example 2, there was ob~ained the correspon-ding 17-ester of Clobetasol, whose chenlico-physical cha-racteristics are hereinafter reported:KBr Clobetasol 17-valerate: m.p.147C. I.R. ~ : 3330, max 1745, 1730, 1660, 1610, 1600;
KBr Clobetasol 17-ben~oate: m.p.l83C. I.R.J : 3390, max 1740, 1710, 1660, 1620, 1600, lS~0, 715.
The present invention relates to a process for pre-paring 17-esters of Clobetasol. A further object is provided by Clobetasol 17-esters obtained according to the process of the invention. It is known from ~.S. Pa-tent n. 3,721,687 that Clobetasol 17-esters can be pre-pared from 17-esters of betamethasone via the correspon-ding 21-alkylsulphonates. However the reaction is slow, requiring reaction times of 1-3 days and the product is obtained in low yield and in an impure state, which necessitates chromatography and repeated crystallization in order to obtain the pure form.
It is an object of the present invention to provide a simple ;:nd efficient process for the production of Clo betasol 17-esters, which does not involve long reaction times and which furnishes the product in an easily puri-fied form and which is suitable for large-scale indu-strial application.
These objects have been obtained by providing a pro-cess wherein readily-available esters of 9beta,11beta-; ~0 epoxy-17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,~0-dione having the formula I
~.
~2~
~"0 ~''`1' 0~
wherein R is an alkyl group or aryl group of up to 6 carbon atoms and R' is hydroxy, are treated with metha nesulphonyl chloride to give the corresponding 21-mesy late derivatives having the general formula I, wherein R is as defined above and Rl is mesyloxy followed by treatment with lithium chloride to give the correspon-ding 21-chloro derivatives having the general formula I, wherein R is as defined above and ~' is chloro, which on treatment with hydrogen fluoride afford the correspon ding 17-esters of Clobetasol having the formula III
rCl =O
HO \~ )C~ 3 : O
~ wherein l~ is as defined above.
.~ . .
The success of the reaction sequence of this invention is surprising since the nucleophilic substitution of a 21-mesyloxy group by chloro in a substrate containing a 9beta,11beta epoxy group, without disruption of the 9beta, llbeta-epoxy group, was not foreseeable to one skilled in the art. The opening of 9beta,11beta-steroidal epoxi-des to the corresponding chlorohydrins by reaction with lithium chloride in acetic acid is known from U.S. patent n. 3,652,604. Under the reaction conditions of the inven-tion, however, no detectable amounts of chlorohydrins areformed. Indeed the yields of the 21-chloro 9beta,11beta-epoxy compounds are close to quantitative, which is remar kable considering the low yields obtained using the 9alpha-fluoro-llbeta~hydroxy compounds of U.S. patent n.
3,721,687.
A further surprising feature of the nucleophilic sub-stitution on the 9beta,11beta-epoxides is the ease with which the reaction proceeds. In U.S. patent n. 3,721,687 a similar substitution is conducted on 9alpha-fluoro-llbeta-hydroxy compounds under conditions requiring 3 days at reflux and utili~ing a 2000% excess of lithium chloride.
Under the conditions o~ the present invention the rea_ tiorl proceedc; to corllpletiorl in 1-3 hr a~ tempeL~tures rang ~;2 Q~
ing from 60 to 90 using only a slight excess of lithium chloride.
A distinct advantage of the present invention is that the intermediates are obtained in a sufficiently pure form by simple aqueous precipitation (or total extraction) so as to render intermediate purification unnecessary. Fur thermore the final products are obtained in such a pure state that they may be brought to pharmacopoeia standards by simple crystallization. Using the process of U.S. pa-tent n. 3,721,687 the intermediate require purification and the final product must be chromatographed and crystalli zed repeatedly. Thus the process of the present inven-tion is more suitable for large scale industrial use.
The first stage of the present invention consists of formation of a 21-mesylate derivative from the correspon-ding 21-hydroxy compound using methanesulphonyl chloride in pyridine, a known reaction. The yields in this step are almost quantitative.
The second stage of the invention consists in substitu-tion~of the 21-mesyloxy group by chloro. This process is conducted in a suitable dipolar aprotic solvent such as acetone, dimethylformamide, hexamethylphosphoric triamide, or mixtures thereof. We prefer to use dimethylformamide since the subst:r~tes have goocl solubility in this solvent, thus pernli~tin~ t:hc~ reac-ic)n to be cond~lct~ed at high con-, 5centrations (16-20% w/v), an importan~ factor in indu-strial production.
In contrast the process of U.S. patent n. 3,721,687 is conducted at a concentration of less than 1.5~ w/v.
The preferred source of chloride ions is anhydrous lithium chloride although any compound capable of furni-shing chloride ions may be used. An advantage of the process of the invention is that only a slight excess of lithium chloride is employed. The reaction may be con ducted at temperatures between 30 and 120, preferably.
The yields obtained in this step are surprisingly high (92-96~ of theory).
The final stage of the invention consists of conver-sion of the 9beta,11beta-epoxy group into the correspon-ding fluorohydrin using hydrogen fluoride, a known reaction. The fluorination may be conducted using con-ventional methods e.g. aqueous hydrofluoric acid or mix-tures of anhydrous hydrogen fluoride with tetrahydrofuran, dimethylformamide, urea, or pyridine. We find 70~ aque-ous hydrofluoric acid to be convenient and to give highYields.
The starting materials for the present invention, na-mely 9beta,11beta-epoxy-17,21-dihydroxy-16beta-methylpre gr)a-1,4-diene-3,20-dione 17-esters are either known or mtly be easily prepared from the comlnercially available ~Q~
betamethasone intermediate 9beta,11beta-epoxy-17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione using the procedure of U.S. patent n. 3,755,302.
Without furt~ler elaboration, it is believed that one skilled in the art can, using the preceding descrip-tion, utilize the present invention to its fullest ex-tent.
The following preferred, specific embodimen~s are, therefore to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the following examples all temperatures are in cle-grees Celsius.
Preparatio_ 1 To a suspension of 1 kg 9~,11B-epoxy-17,21-dihydroxy-; 16B-methylpregna-1,4-diene-3,20-dione in 7 lt dry tetra-hydrofuran and 1 lt triethylorthopropionate is added a solution of 10 g para-toluenesulphonic acid in 1 lt dry tetrahydrofuran. The mixture rapidly becomes a solu-tion and after 1 hr is neutralized with 100 g sodium ace-tate and poured into 50 lt water. I'he precipitated 17,21-ortho ester is collecte~ washed with water and suspended in 10 lt methanol. A solution of 20 ml acetic acid and 3 2 g sodium acetate in 4 lt water is added and t:ne mixtu re ilea!:ed under retlux for 3 hr, concentra~ed Lo cl volume of 4 lt and diluted with 10 lt water. The precipitated 9~ epoxy-17,21-dihydroxy-16~-methylpregna-1,4-diene-3,20-dione 17-propionate is collected, washed well with water and dried under vacuum. Yield: 1.1 kg.
A sample crystallized from diethyl ether had the follo wing characteristics:
m.p.: 150 with decomposition / ~_/ + 47.5 (C = 1, chloroform) ~ KBr -1 I.R. 3470, 1730, 1665, 1630, 1610 cm max F'urther 17-esters of 9~ -epoxy-17,21-dihydroxy-16~-methylpregna-1,4-diene-3,20-dione were prepared according to the above general method. For example, substitut.ing triethylorthobenzoate for triethylorthopropionate there was obtained the corresponding 17-benzoate having the following characteristics.
KBr I.R. ~ 3500, 1725, 1715, 1670, 1630, 1610, 1590, 1280, max 720 cm , m.p. 144-146C.
Substituting trimethylorthovalerate for triethylortho-propionate there was obtained the corresponding 17-vale-rate having the following characteristics:
m.p. 125-127 (from diethyl ether) ~ KBr -1 I.R. ~ 3510, 3~fiO, l740, lfi75, 16~0, lfil5 c~
Illa x To a solution of 1 kg of 9B,ll~-epoxy--17,21-dihydro-xy-16B-methylpregna--1,4-diene-3,20-dione 17-propionate, as obtained in Preparation 1, in 5 lt dry pyridine at 0 was added during 10 minO 500 ml methanesulphonyl chlori-de. After 30 min. at 0-5 the excess of reagent was des-troyed with 100 g ice and the reaction mixture poured into a well agitated mixture of 5.2 lt concentrated hydro chloric acid and 50 lt water at 0. The precipitate of 9B,llB-epoxy-17,21-dihydroxy-16B-methylpregna-1,4-diene-3,20-dione 17-propionate-21-mesylate was collected, wash ed thoroughly with water and dried under vacuum.
Yield : 11.8 kg.
A sample crystallized from diethyl ether had the following characteris~ics:
m.p. 139.5 /~ / + 60 (C = 1, chloroform) KBr I.R.~ 1750, 1730, 1670, 1635, 1615 cm max In a similar manner, but using the 17~acetat~ 17-but~
rate, 17-valerate, or 17-benzoate of 9B,llB-epoxy-17,21-dihydroxy-16B-methylpregna-1,4-diene-3,20-dione there was obtained the corresponding 21-mesylate derivatives.
Chemico--physical characteristics of 9fl,11B-epoxy-17,21-dihydroxy-lf)~3-methylprecJna-l,~-cliene-3,20-dione-l7-henzoa ~;~2~
g KBr te 21-mesylate: m.p. 194C. I.R.~ : 1740, 1710, 1665, I max 1630, 1605, 1585, 720 cm .
To a solution of 1.012 kg (2 moles) of 9n,11n-epoxy-17,21-dihydroxy-16n-methylpregna-1,4-diene-3,20-dione 17-propi_ nate 21-mesyla~e (Example 1) in 6.72 lt dry dimethylfor-mamide was added 106 g (2.S moles) of anhydrous lithium chloride and the mixture was heated under nitrogen for 1.5 hr at 85-90, cooled and poured slowly into 67 lt water at 2 with strong agitation. The precipitate of 21-chlo-ro-9~,11n-epoxy 17-hydroxy-16n-methylpregna-1,4-diene-3,20-dione 17-propionate was collected, washed well with water, and drled under vacuum.
Yield: 860 g (96% of theor.).
A sample crystallized from dichloromethane-diisopropyl ether had the following characteristics:
m.p. 110.
- -/ + 79.5 (C = 1, chloroform) KBr -1 I.R.~ 3450, 1740~ 1665, 1630, 1610, 1590 cm max In a similar manner, but using the 17-acetate, 17-butyrate, 17-valerate, or 17-benzoate of 9~,11n-epoxy-17,21-dihydroxy-16~-methylpregna-1,4 diene-3,20-dione 21-mesylate, obtained in ~xample 1, there was obtained the ~22q~
D corresponding 17-ester of 2l~chloro-9B~lls-epoxy-l7-hydro xy-16n-methylpregna-l,q-diene-3,20-dione.
Chemico-physical characteristics of 17-benzoate of 21-chloro-9~,llB-epoxy-17-hydroxy-16n-methylpregna-1,4-KBr diene-3,20~dione: m.p. 202~C. I.R. J 1740, 1710, -1 max 1665, 1630, 1605, 1585, 715 cm _ .
To 10 lt of 70~ aqueous hydrofluoric acid at -30 was added 1 kg of 21-chloro-9B,llB-epoxy-17-hydroxy-16~-methyl pregna-1,4-diene-3,20-dione 17-propionate (Example 2).
The mixture was brought to -20 and stirred at this tempe rature for 2.5 hr, and then poured slowly into 100 lt de-ionized water under agitation. The precipitate of Clobe-tasol 17-propionate was collected, washed thoroughly with water until neutral, and dried under vacuum.
Yield: 1020 g.
The crude product assaying at ca. 80% is readily puri-fied to >98% by crystallization from dichloromethane-dii sopropyl ether and/or ethanol/water. The purified product thus obtained is identical with an authentic sample.
In a similar manner, but using the 17-acetate, 17-bu tyrate, 17-valerate, or 17-benzoate of 21-c:hIoro-9n,Il~-epo~cy-I7-hydroxy-16~-methyIpregna-1,4-diene-3,20-dione, obtained in Example 2, there was ob~ained the correspon-ding 17-ester of Clobetasol, whose chenlico-physical cha-racteristics are hereinafter reported:KBr Clobetasol 17-valerate: m.p.147C. I.R. ~ : 3330, max 1745, 1730, 1660, 1610, 1600;
KBr Clobetasol 17-ben~oate: m.p.l83C. I.R.J : 3390, max 1740, 1710, 1660, 1620, 1600, lS~0, 715.
Claims (23)
1. A process for the preparation of compounds of the formula II
wherein R is an alkyl group or aryl group of up to 6 carbon atoms, which comprises reacting a corresponding ester of 21-chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methyl-pregna-1,4-diene-3,20-dione with hydrofluoric acid.
wherein R is an alkyl group or aryl group of up to 6 carbon atoms, which comprises reacting a corresponding ester of 21-chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methyl-pregna-1,4-diene-3,20-dione with hydrofluoric acid.
2. Process as claimed in claim 1 wherein the hydrofluoric acid is used in aqueous form at concentrations ranging from 50 to 80% and at temperatures ranging from -40°C to 0°C.
3. Process as claimed in claim 2 wherein the aqueous hydrofluoric acid has a concentration of about 70% and the reaction is carried out at a temperature ranging from -30°
to -10°C.
to -10°C.
4. Process as claimed in claim 1 wherein the starting ester is 21-chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methyl-pregna-1,4-diene-3,20-dione 17-propionate.
5. Process as claimed in claim 1 wherein the ester of 21-chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione is produced by reacting 9.beta.,11.beta.-epoxy-17, 21-dihydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 17-esters with mesyl chloride to form corresponding 21-mesyl-ates and reacting the 21-mesylate with a chloride ion to form the corresponding 21-chloro derivative.
6. Process as claimed in claim 5 wherein the starting ester is selected from 17-propionate, 17-acetate, 17-butyr-rate, 17-valerate or 17-benzoate of 9.beta.,11.beta.-epoxy-17,21-dihydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione.
7. Process as claimed in claim 6 wherein the starting compound is 17-propionate of 9.beta.,11.beta.-epoxy-17,21-dihydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione.
8. Process for the preparation of 21-chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 17-esters characterized in that the corresponding 17 esters of 9.beta.,11.beta.-epoxy-17,21-dihydroxy-16.beta.-methylpregna-1,4-diene 3,20-dione 21-mesylate are subjected to selective nucleo-philic displacement of the 21-mesyl group by means of chloride ions.
9. Process as claimed in claim 8 wherein the selective nucleophilic displacement of the 21-mesiloxy group by means of chloride ions is carried out in an aprotic dipolar solvent.
10. Process as claimed in claim 9 wherein the selective nucelophilic displacement is carried out at temperatures ranging from 30 to 120°C, for a time varying from 1 to 3 hours and with concentrations ranging from 15 to 20% w/v.
11. Process as claimed in claim 10 wherein the chloride ions source is anhydrous lithium chloride and the solvent is dimethyl formamide.
12. Process as claimed in claim 8, 9 or 10 wherein 9.beta.,11.beta.-epoxy-17,21-dihydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 17-propionate 21-mesylate is transformed into 21-chloro-9.beta., 11.beta.-epoxy-17-hydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 17-propionate.
13. 21-Chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 17-esters whenever produced according to claim 8 or an obvious chemical equivalent.
14. Process as claimed in claim 8 wherein the 17-ester is a 17-propionate.
15. 21-Chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 17-propionate whenever produced according to claim 14 or an obvious chemical equivalent.
16. Process as claimed in claim 8 wherein the 17-ester is a 17-acetate.
17. 21-Chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 17-acetate whenever produced according to claim 16 or an obvious chemical equivalent.
18. Process as claimed in claim 8 wherein the 17-ester is a 17-butyrrate.
19. 21-Chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 17-butyrrate whenever produced according to claim 18 or an obvious chemical equivalent.
20. Process as claimed in claim 8 wherein the 17-ester is a 17-valerate.
21. 21-Chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 17-valerate whenever produced according to claim 20 or an obvious chemical equivalent.
22. Process as claimed in claim 8 wherein the 17-ester is a 17-benzoate.
23. 21-Chloro-9.beta.,11.beta.-epoxy-17-hydroxy-16.beta.-methylpregna-1,4-diene-3,20-dione 17-benzoate whenever produced according to claim 22 or an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT20334/83A IT1194178B (en) | 1983-03-29 | 1983-03-29 | PROCESS FOR THE PREPARATION OF 17-ESTERS OF CLOBETASOLO AND COMPOUNDS OBTAINED |
| IT20334A/83 | 1983-03-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1220468A true CA1220468A (en) | 1987-04-14 |
Family
ID=11165811
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000445603A Expired CA1220468A (en) | 1983-03-29 | 1984-01-19 | Process for the production of 17-esters of clobetasol |
Country Status (10)
| Country | Link |
|---|---|
| JP (2) | JPS59205399A (en) |
| CA (1) | CA1220468A (en) |
| CH (1) | CH661930A5 (en) |
| DK (1) | DK42884A (en) |
| FI (1) | FI840344A (en) |
| IT (1) | IT1194178B (en) |
| NL (1) | NL8400910A (en) |
| NO (1) | NO840065L (en) |
| SE (1) | SE8400145L (en) |
| YU (1) | YU54684A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727458A (en) * | 2018-05-10 | 2018-11-02 | 浙江仙居仙乐药业有限公司 | A kind of synthetic method of 17- propionic esters |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111944002A (en) * | 2020-07-29 | 2020-11-17 | 河南利华制药有限公司 | Beclomethasone dipropionate intermediate and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1253831A (en) * | 1968-01-19 | 1971-11-17 | Glaxo Lab Ltd | 9alpha,21-DIHALOPREGNANE COMPOUNDS |
| JPS51125372A (en) * | 1975-03-31 | 1976-11-01 | Taisho Pharmaceut Co Ltd | Aprocess for preparing pregnane steroid-17-ester-21-halides |
-
1983
- 1983-03-29 IT IT20334/83A patent/IT1194178B/en active
-
1984
- 1984-01-09 NO NO840065A patent/NO840065L/en unknown
- 1984-01-10 CH CH113/84A patent/CH661930A5/en not_active IP Right Cessation
- 1984-01-12 SE SE8400145A patent/SE8400145L/en not_active Application Discontinuation
- 1984-01-19 CA CA000445603A patent/CA1220468A/en not_active Expired
- 1984-01-27 FI FI840344A patent/FI840344A/en not_active Application Discontinuation
- 1984-01-31 DK DK42884A patent/DK42884A/en not_active Application Discontinuation
- 1984-01-31 JP JP59015957A patent/JPS59205399A/en active Granted
- 1984-01-31 JP JP59015956A patent/JPS59205397A/en active Pending
- 1984-03-22 NL NL8400910A patent/NL8400910A/en not_active Application Discontinuation
- 1984-03-28 YU YU00546/84A patent/YU54684A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727458A (en) * | 2018-05-10 | 2018-11-02 | 浙江仙居仙乐药业有限公司 | A kind of synthetic method of 17- propionic esters |
Also Published As
| Publication number | Publication date |
|---|---|
| FI840344A (en) | 1984-09-30 |
| JPS59205397A (en) | 1984-11-20 |
| JPS6228160B2 (en) | 1987-06-18 |
| DK42884D0 (en) | 1984-01-31 |
| YU54684A (en) | 1986-10-31 |
| CH661930A5 (en) | 1987-08-31 |
| NL8400910A (en) | 1984-10-16 |
| NO840065L (en) | 1984-10-01 |
| IT8320334A0 (en) | 1983-03-29 |
| SE8400145L (en) | 1984-09-30 |
| SE8400145D0 (en) | 1984-01-12 |
| IT1194178B (en) | 1988-09-14 |
| DK42884A (en) | 1984-09-30 |
| JPS59205399A (en) | 1984-11-20 |
| FI840344A0 (en) | 1984-01-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR890000761B1 (en) | Aromatic heterocyclic esters of steroide and preparing procer there of | |
| US4041055A (en) | Process for the preparation of 17α-hydroxyprogesterones and corticoids from androstenes | |
| US4036831A (en) | Trimethyl siloxane steroid intermediates | |
| CA2191324C (en) | Process for preparing .delta.9,11 and 21-chloro corticosteroids | |
| EP1395603B1 (en) | Preparation of flumethasone and its 17-carboxyl androsten analogue | |
| CA1220468A (en) | Process for the production of 17-esters of clobetasol | |
| CA1155108A (en) | 17.alpha.-ACYLOXY-5.beta. AND 5.alpha. CORTICOIDS | |
| CA1065848A (en) | 16-METHYL-9.alpha.-HALO STEROID ESTERS, ETHERS AND PREPARATION THEREOF | |
| US4929395A (en) | 16α-methylation process | |
| JPS591720B2 (en) | Method for producing 6-halo-pregnane compound | |
| JP2004534795A5 (en) | ||
| AU2002310616A1 (en) | Preparation of flumethasone and its 17-carboxyl androsten analogue | |
| US4990612A (en) | 16α-methylation process | |
| EP0097328A2 (en) | Process for preparation of steroids | |
| JP2005530679A (en) | Method for preparing 6α-fluorocorticosteroid | |
| US4704455A (en) | 16α-methylatedΔ17(20)-corticoids | |
| KR840001809B1 (en) | Process of selective solvolysis | |
| KR960011781B1 (en) | 16Ñß-G(A)-METHYLATION PROCESS | |
| EP0170500B1 (en) | Novel 9 alpha-fluoro- or chloro-corticosteroid esters and a process for their preparation | |
| US4207235A (en) | Selective epoxidation of steroidal bromohydrins | |
| US3980680A (en) | Process for the preparation of 21-desoxy-17-acyloxy-4-pregnenes and of 21-iodo-21-desoxy-17-acyl oxy-4-pregnene intermediates useful therein | |
| JP2000128897A (en) | Stereoselective method for preparing 22r epimer of budesonide | |
| JPS5855156B2 (en) | Pregnane 6 Beta Fluoro 3- Keto Delta 1 4- Steroid | |
| JPS5834480B2 (en) | Method for producing 16 beta-methyl-17 alpha-acyloxy-1,4-diene-21-halosteroid compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |