WO2005044759A2 - Acetalization process for preparation of steroid compounds - Google Patents
Acetalization process for preparation of steroid compounds Download PDFInfo
- Publication number
- WO2005044759A2 WO2005044759A2 PCT/IN2004/000239 IN2004000239W WO2005044759A2 WO 2005044759 A2 WO2005044759 A2 WO 2005044759A2 IN 2004000239 W IN2004000239 W IN 2004000239W WO 2005044759 A2 WO2005044759 A2 WO 2005044759A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- preparation
- substituted
- budesonide
- Prior art date
Links
- 0 C[C@]([C@@](*)C(C1[C@](C)(C[C@@]2O)[C@]3(C(C*)=O)O*O[C@@]3C1)[C@@]2(*)[C@@]1(C)CC2)C1=CC2=O Chemical compound C[C@]([C@@](*)C(C1[C@](C)(C[C@@]2O)[C@]3(C(C*)=O)O*O[C@@]3C1)[C@@]2(*)[C@@]1(C)CC2)C1=CC2=O 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- 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
Definitions
- the present invention relates to a process for the preparation of 16,17-acetals of pregnane derivatives represented by a compound of formula 1. More specifically the present invention relates to a process for preparation of compound of formula 1 by reaction of 16,17-dihydroxy compound of formula 2,
- Formula 1 Formula 2 with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid.
- the present invention particularly relates to a process for the preparation of 16,17-acetals of formulae 5, 6, 7 or 8, namely, budesonide, ciclesonide, rofleponide and triamcinolone acetonide, respectively.
- the compounds of formula 1 are pharmacologically active compounds or are useful as intermediates for preparation of other active compounds.
- United States Patent No. 3929768 discloses unsymmetrical 16,17-alkylenedioxy steroids including budesonide, which are prepared by reacting the 16,17-dihydroxy compounds with aldehydes in dry dioxane solvent in presence of perchloric acid. In this process large excess of toxic solvent like dioxane (150 vols) and methylene chloride (1000 vols) has been used and the crude product is purified by column chromatography to obtain isomeric mixtutres, R/S ratio not specified.
- Patent Nos. 4835145 disclose a process for preparation of 16,17-acetals of pregnane derivatives from the corresponding 16,17- acetonides by reaction with aldehydes in aqueous HF or HC1 acid.
- Example 1 of the ' 145 patent exemplifies preparation of budesonide from desonide by reaction with butyraldehyde in HF acid (10 vols) wherein 22R isomer is formed predominantly.
- Hydrofluoric acid is a highly corrosive chemical and requires special equipment, poses environmental problems.
- United States Patent No. 6169178 relates to a process for the preparation of budesonide and of 16,17 acetals of pregnane derivatives structurally correlated thereto, comprising treating 16,17-diols, or of 16,17-ketals or cyclic acetals with aldehydes, in the presence of aqueous hydrobromic acid or hydriodic acid, used as reaction catalysts and solvents.
- European patent application EP 0994119 Al discloses a stereoselective process for preparation of 22R epimer of budesonide by reaction of 9 ⁇ -iodo budesonide or 9 ⁇ -bromo budesonide with butyraldehyde in the presence of aq HBr or HI.
- United States Patent No. 5556964 discloses a process for preparation of budesonide by reacting 16 ⁇ -hydroxyprednisolone in acetonitrile in the presence of p-toluene sulfonic acid as a catalyst.
- United States Patent No. 5310896 discloses preparation of budesonide via novel formyloxylated desonide intermediate compounds by reacting with butanal in the presence of a strong acid catalyst, preferably perchloric acid or fluroboric acid in a halogenated solvent.
- a strong acid catalyst preferably perchloric acid or fluroboric acid in a halogenated solvent.
- the PCT application WO 92/11280 discloses a method for preparation of (22R) epimer of budesonide by condensation reaction between ll ⁇ ,16 ⁇ ,17 ⁇ ,21-tetrahydroxy-l,4- pregnadiene-3,20-dione-21 -acetate with butyraldehyde in 70-80% HF acid.
- United Kingdom Patent No. GB 1469575 discloses a method for preparation of 16,17- acetals or ketals of 9 ⁇ -halosteroids of the pregnane series by reacting 16,17-dihydroxy- 9,11-epoxy pregnane derivatives with aldehyde or ketone in aqueous hydrogenhalide such as 40-70% HF or 20-37% HC1 acid.
- United States Patent No. 5750734 teaches preparation of 16,17-acetals of pregnane derivatives such as compound of formula I by transacetalization of the corresponding 16, 17-acetonides represented by compound of formula 9, by using sulphuric acid or
- the present invention provides an acetalization process for the preparation of 16,17- acetals of pregnane derivatives of formula 1 by reaction of 16,17-dihydroxy compound of formula 2 with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid.
- the process of the present invention involves use of phosphoric acid, which is environmentally safer and involves simple work-up and avoids the use of toxic chlorinated solvents/clioxane etc.
- the process of the present invention provides a 16,17-acetal of a pregnane derivative such as budesonide, a compound of formula 5 in the epimeric ratio of R/S almost 1 : 1 directly which conforms to pharmacopoeial specifications of British Pharmacopoeia.
- the present invention provides a process for the preparation of 16,17-acetals of pregi derivatives of compound of formula I
- Rt is H, C 1 -C12 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted;
- R 2 is C 1 -C1 2 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted; X is OH, CI, F or -OCOR group wherein R represents H or C ⁇ -C 12 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted;
- R 3 is H, F or CI; .
- R ⁇ is H, F or methyl;
- R 5 is H 3 CI or methyl; comprising reacting the compound of formula 2, wherein the substituents are as defined R4 Formula 2 above, with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid, wherein Re is Ct-C ⁇ alkyl and other substituents are as defined above.
- the present invention provides a process for the preparation of 16 ⁇ ,17 ⁇ - butylidenedioxy-l l ⁇ ,21-dihydroxypregna-l,4-diene-3,20-dione, a compound of formula 5
- Formula 5 comprising reacting 16 ⁇ -hydroxyprednisolone, a compound of formula 10, Formula 10 with butyraldehyde in phosphoric acid.
- the present invention provides acetalization process for preparation of 16,17-acetals of pregnane derivatives from corresponding 16,17-dihydroxy compounds in phosphoric acid.
- the acetalization reaction may conveniently be effected at a temperature within the range of about -10°C to about 50°C, and preferably at about 0°C to about 5°C.
- the acetalization reaction may conveniently be effected with the ratio of compound of formula 2:phosphoric acid being between the range of 1 :2 to 1:15, preferably between the range of 1 :3 to 1:5 wt/v.
- the process of the present invention may be conveniently effected using commercial (about 85% w/w) phosphoric acid.
- the compounds of formula 2 are known compounds and are commercially available or may be prepared according to known methods.
- the present invention particularly relates to a process for the preparation of 16,17-acetals of formulae 5, 6, 7 or 8, namely, budesonide, ciclesonide, rofleponide and triamcinolone acetonide, respectively, by reacting the appropriately substituted compound of formula 2 with an appropriately substituted compound of formulae 3 or 4 in phosphoric acid.
- the compound of formula 5 or the compound of formula 8 can be prepared;
- the compound of formula 6 can be prepared;
- by reacting the appropriately substituted compound of formula 6 can be prepared; by reacting the appropriately substituted compound of formula 2 with acetone, the compound of formula 7 can be prepared.
- the present invention provides a process for the preparation of 16 ⁇ ,17 -butylidenedioxy-ll ⁇ ,21-dihydroxypregna-l,4-diene-3,20-dione, a compound of formula 5
- the product can be isolated by dilution with aqueous solvent such as aqueous methanol and filtration/centrifugation.
- aqueous solvent such as aqueous methanol and filtration/centrifugation.
- the present invention provides a process for preparation of 16 ,17 ⁇ -butylidenedioxy-l l ⁇ ,21-dihydroxypregna-l 3 4-di ' ene-3,20-dione, a compound of formula 5 comprising reaction of 16 ⁇ -hydroxyprednisolone, a compound of formula 10, with butyraldehyde in phosphoric acid at temperature of about 0°C to about 5°C.
- the mole ratio of the compound of formula 10:butyraldehyde may be between the range of 1 : 1.25 to 1 : 5, preferably 1:1.5 to 1:3.
- the compound of formula 5 is formed in the epimeric ratio R:S between the range of 60:40 to 50:50, preferably between the range of 53:47 to 58:42.
- the compound of formula 5 is formed in the R:S epimeric ratio of about 55:45, which conforms to British Pharmacopoieal specifications.
- the crude budesonide was dissolved in ethyl acetate-methanol mixture (4:1, 110ml) by heating at 60-65°C. Charcoal (lg) was added and stirred at 45-55° C for 1 hr. The charcoal was filtered, and 76ml of solvent mixture was distilled out from the filtrate under atmospheric pressure. The resulting slurry was cooled to 5 to 10° C and stirred at this temperature for 1 hour. The crystallized product was filtered, washed with ethyl acetate (10ml) and dried in an air oven at 55-60° C to obtain pure budesonide (Yield 9.5g, 83.3% overall, purity 99.75%, R/S ratio 54.6:45.4). The product meets specifications as per BP, as well as purity requirements as per ICH guidelines.
- the crude budesonide was dissolved in ethyl acetate-methanol mixture (4:1, 500ml) by heating at 60-65°C Intel Recovered 357ml of solvent mixture from the solution under atmospheric pressure. The resulting slurry was cooled to 0 to 5° C and stirred at this temperature for 1 hour. The crystallized product was filtered, washed with ethyl acetate (100ml) and dried in an air oven at 55-60° C to obtain pure budesonide (purity 99.83%, R/S ratio 57.4:42.6). The product meets specifications as per BP, as well as purity requirements as per ICH guidelines.
- the crude budesonide (20g) obtained as above was dissolved in ethyl acetate -methanol (4:1, 240ml) by heating at reflux. The hot solution was filtered, concentrated (to about 60ml) at atmospheric temperature, and cooled to 5-10° C. The crystallized product was filtered, washed with ethyl acetate (20ml) and dried in air oven at 55-60° C. Recovery 15.9g (overall purified yield 78.4%), purity 99.62%, ratio of R/S epimers, 57.06: 42.94).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The present invention provides acetalization process for preparation of 16,17-acetals of pregnane derivatives from corresponding 16,17-dihydroxy compounds in phosphoric acid.
Description
ACETALIZATION PROCESS FOR PREPARATION OF STEROID COMPOUNDS
The present invention relates to a process for the preparation of 16,17-acetals of pregnane derivatives represented by a compound of formula 1. More specifically the present invention relates to a process for preparation of compound of formula 1 by reaction of 16,17-dihydroxy compound of formula 2,
Formula 1 Formula 2 with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid.
The present invention particularly relates to a process for the preparation of 16,17-acetals of formulae 5, 6, 7 or 8, namely, budesonide, ciclesonide, rofleponide and triamcinolone acetonide, respectively.
The compounds of formula 1 are pharmacologically active compounds or are useful as intermediates for preparation of other active compounds.
BACKGROUND OF THE INVENTION
United States Patent No. 3929768 discloses unsymmetrical 16,17-alkylenedioxy steroids including budesonide, which are prepared by reacting the 16,17-dihydroxy compounds with aldehydes in dry dioxane solvent in presence of perchloric acid. In this process large excess of toxic solvent like dioxane (150 vols) and methylene chloride (1000 vols) has been used and the crude product is purified by column chromatography to obtain isomeric mixtutres, R/S ratio not specified.
United states Patent Nos. 4835145 (the ' 145 patent) and 4695625 disclose a process for preparation of 16,17-acetals of pregnane derivatives from the corresponding 16,17- acetonides by reaction with aldehydes in aqueous HF or HC1 acid. Example 1 of the ' 145 patent exemplifies preparation of budesonide from desonide by reaction with butyraldehyde in HF acid (10 vols) wherein 22R isomer is formed predominantly. Hydrofluoric acid is a highly corrosive chemical and requires special equipment, poses environmental problems. In example 3 R/S ratio of about 1/1 is obtained but the reaction is performed at -78°C and at such low temperature substantial amount of starting compound will remain unreacted lowering the yield of the reaction.
United States Patent no. 4925933 (the '933 patent) discloses a transcaetalization process for preparation of 16,17-acetals of pregnane derivatives by reacting corresponding 16,17- acetonides or 16,17-diols with an aldehyde or ketone in a hydrocarbon or a halogenated hydrocarbon solvent together with a hydrohalogen acid or an organic sulphonic acid as catalyst. Use of perchloric acid is exemplified for preparation of budesonide from desonide. Variable epimeric ratios are reported depending on the solvent and reaction conditions and fairly large volumes of chlorinated solvents have been utilized.
United States Patent No. 6169178 relates to a process for the preparation of budesonide and of 16,17 acetals of pregnane derivatives structurally correlated thereto, comprising treating 16,17-diols, or of 16,17-ketals or cyclic acetals with aldehydes, in the presence of aqueous hydrobromic acid or hydriodic acid, used as reaction catalysts and solvents.
However, HI acid is corrosive, light sensitive and expensive and these acids pose environmental problems,
European patent application EP 0994119 Al discloses a stereoselective process for preparation of 22R epimer of budesonide by reaction of 9α-iodo budesonide or 9α-bromo budesonide with butyraldehyde in the presence of aq HBr or HI.
United States Patent No. 5556964 discloses a process for preparation of budesonide by reacting 16α-hydroxyprednisolone in acetonitrile in the presence of p-toluene sulfonic acid as a catalyst.
United States Patent No. 5310896 discloses preparation of budesonide via novel formyloxylated desonide intermediate compounds by reacting with butanal in the presence of a strong acid catalyst, preferably perchloric acid or fluroboric acid in a halogenated solvent.
The PCT application WO 92/11280 discloses a method for preparation of (22R) epimer of budesonide by condensation reaction between llβ,16α,17α,21-tetrahydroxy-l,4- pregnadiene-3,20-dione-21 -acetate with butyraldehyde in 70-80% HF acid.
United Kingdom Patent No. GB 1469575 discloses a method for preparation of 16,17- acetals or ketals of 9α-halosteroids of the pregnane series by reacting 16,17-dihydroxy- 9,11-epoxy pregnane derivatives with aldehyde or ketone in aqueous hydrogenhalide such as 40-70% HF or 20-37% HC1 acid.
These prior art processes use HF, HI, HBr or perchloric acid in the preparation of 16,17- acetals of pregnane derivatives.
United States Patent No. 5750734 teaches preparation of 16,17-acetals of pregnane derivatives such as compound of formula I by transacetalization of the corresponding 16, 17-acetonides represented by compound of formula 9, by using sulphuric acid or
*2 Formula 9 phosphoric acid, wherein Xι and X2 are hydrogen or halogen, R is hydrogen or acyl, Rg is hydroxyl, acyloxy or oxp and R9 is alkyl. This process proceeds to provide R isomer as a major component, however, pharmacopoeial specifications of British Pharmacopoeia the epimeric ratio for budesonide isomers R:S is between the range of 40:60 to 51:49.
The present invention provides an acetalization process for the preparation of 16,17- acetals of pregnane derivatives of formula 1 by reaction of 16,17-dihydroxy compound of formula 2 with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid. The process of the present invention involves use of phosphoric acid, which is environmentally safer and involves simple work-up and avoids the use of toxic chlorinated solvents/clioxane etc.
The process of the present invention provides a 16,17-acetal of a pregnane derivative such as budesonide, a compound of formula 5 in the epimeric ratio of R/S almost 1 : 1 directly which conforms to pharmacopoeial specifications of British Pharmacopoeia.
SUMMARY OF THE PRESENT INVENTION
The present invention provides a process for the preparation of 16,17-acetals of pregi derivatives of compound of formula I
Rt is H, C1-C12 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted;
R2 is C1-C12 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted; X is OH, CI, F or -OCOR group wherein R represents H or Cι-C12 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted;
R3 is H, F or CI; .
R^is H, F or methyl; R5 is H3 CI or methyl; comprising reacting the compound of formula 2, wherein the substituents are as defined
R4 Formula 2 above, with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid, wherein Re is Ct-Cδ alkyl and other substituents are as defined above.
In one aspect the present invention provides a process for the preparation of 16α,17α- butylidenedioxy-l lβ,21-dihydroxypregna-l,4-diene-3,20-dione, a compound of formula 5
Formula 5 comprising reacting 16α-hydroxyprednisolone, a compound of formula 10,
Formula 10 with butyraldehyde in phosphoric acid.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides acetalization process for preparation of 16,17-acetals of pregnane derivatives from corresponding 16,17-dihydroxy compounds in phosphoric acid.
The acetalization reaction may conveniently be effected at a temperature within the range of about -10°C to about 50°C, and preferably at about 0°C to about 5°C.
The acetalization reaction may conveniently be effected with the ratio of compound of formula 2:phosphoric acid being between the range of 1 :2 to 1:15, preferably between the range of 1 :3 to 1:5 wt/v.
In one particular embodiment the process of the present invention may be conveniently effected using commercial (about 85% w/w) phosphoric acid.
The compounds of formula 2 are known compounds and are commercially available or may be prepared according to known methods.
The present invention particularly relates to a process for the preparation of 16,17-acetals of formulae 5, 6, 7 or 8, namely, budesonide, ciclesonide, rofleponide and triamcinolone acetonide, respectively, by reacting the appropriately substituted compound of formula 2 with an appropriately substituted compound of formulae 3 or 4 in phosphoric acid. For
example, by reacting the appropriately substituted compound of formula 2 with butyraldehyde, the compound of formula 5 or the compound of formula 8 can be prepared; by reacting the appropriately substituted compound of formula 2 with cyclohexanealdehyde, the compound of formula 6 can be prepared; by reacting the appropriately substituted compound of formula 2 with acetone, the compound of formula 7 can be prepared.
In a preferred embodiment, the present invention provides a process for the preparation of 16α,17 -butylidenedioxy-llβ,21-dihydroxypregna-l,4-diene-3,20-dione, a compound of formula 5
comprising reacting 16α-hydroxyprednisolone, a compound of formula 10,
with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid.
The product can be isolated by dilution with aqueous solvent such as aqueous methanol and filtration/centrifugation.
In a more preferred embodiment, the present invention provides a process for preparation of 16 ,17α-butylidenedioxy-l lβ,21-dihydroxypregna-l34-di'ene-3,20-dione, a compound of formula 5 comprising reaction of 16α-hydroxyprednisolone, a compound of formula 10, with butyraldehyde in phosphoric acid at temperature of about 0°C to about 5°C. The mole ratio of the compound of formula 10:butyraldehyde may be between the range of 1 : 1.25 to 1 : 5, preferably 1:1.5 to 1:3.
In a preferred embodiment when 16α-hydroxyprednisolone is reacted with butyraldehyde in presence of phosphoric acid according to the process of the invention the compound of formula 5 is formed in the epimeric ratio R:S between the range of 60:40 to 50:50, preferably between the range of 53:47 to 58:42.
In one preferred embodiment the compound of formula 5 is formed in the R:S epimeric ratio of about 55:45, which conforms to British Pharmacopoieal specifications.
We have also carried out comparative experimentation on preparation of budesonide from desonide using phosphoric acid at about 0-5°C. We have found that reaction time of about 21 hours is required compared to reaction time of about 4 hours when budesonide is prepared from 16α-hydroxyprednisolone according to the process of the invention.
The following non-limiting examples illustrate the invention.
Example 1
Preparation of 16α,17α-butylidenedioxy-llβ,21-dihydroxypregna-l,4-diene-3,20- dione, a compound of formula 5 (budesonide) from 16α-hydroxyprednisolone
A mixture of 16α-hydroxyprednisolone (lOg, 0.026mol) and n-butyraldehyde (5.9ml, 0.066 mol) in 85% phosphoric acid (40ml) was stirred at 0 to 5°C for 4.5 hrs. Methanol (50ml) and water (100ml) were successively added to the reaction mixture at 0 to 5°C and the resultant slurry was stirred for 1 hourr, filtered and washed with water (20 ml) and suck dried to obtain crude budesonide (yield 11.5 g, 99.12% on anhydrous basis, water content 1.4%, purity 96.02% and ratio of R/S epimers, 52.6:47.4)
Purification-
The crude budesonide was dissolved in ethyl acetate-methanol mixture (4:1, 110ml) by heating at 60-65°C. Charcoal (lg) was added and stirred at 45-55° C for 1 hr. The charcoal was filtered, and 76ml of solvent mixture was distilled out from the filtrate under atmospheric pressure. The resulting slurry was cooled to 5 to 10° C and stirred at this temperature for 1 hour. The crystallized product was filtered, washed with ethyl acetate (10ml) and dried in an air oven at 55-60° C to obtain pure budesonide (Yield 9.5g, 83.3% overall, purity 99.75%, R/S ratio 54.6:45.4). The product meets specifications as per BP, as well as purity requirements as per ICH guidelines.
Example 2
Preparation of 16α,17α-butylidenedioxy-llβ,21-dihydroxypregna-l,4-diene-3,20- dione, a compound of formula 5 (budesonide) from 16α-hydroxyprednisolone
A mixture of 16α-hydroxyprednisolone (50g, 0.136mol) and n-butyraldehyde (30.3ml, 0.340mol) in 85% phosphoric acid (200ml) was stirred at 0 to 5°C for 4.0 hrs. Methanol
(250ml) and water (500ml) were successively added to the reaction mixture at 0 to 5°C and the resultant slurry was stirred for 1 hour, filtered and washed with water (50 ml) and suck dried to obtain crude budesonide (purity: 98.04%, ratio of R/S epimers, 49.9:50.1)
Purification-
The crude budesonide was dissolved in ethyl acetate-methanol mixture (4:1, 500ml) by heating at 60-65°C„ Recovered 357ml of solvent mixture from the solution under atmospheric pressure. The resulting slurry was cooled to 0 to 5° C and stirred at this temperature for 1 hour. The crystallized product was filtered, washed with ethyl acetate (100ml) and dried in an air oven at 55-60° C to obtain pure budesonide (purity 99.83%, R/S ratio 57.4:42.6). The product meets specifications as per BP, as well as purity requirements as per ICH guidelines.
Comparative Example-Preparation of budesonide from desonide
To a stirred mixture of 85% phosphoric acid (200ml) and butyraldehyde (26.7ml, 0.30 moles) at 0-5°C was added desonide (50g, 0.12 moles). The mixture was further stirred 0- 5°C for 21.5 hours, and then methanol (200ml), and water (200ml) added sequentially. The resulting slurry was stirred for lhour at 5-10°C. The product was filtered, washed successively with methanol-water (1;1 mixture, 2 x 50ml) and suck dried. The weight of crude product was 50.98g (on dry basis, 98.6% yield) with R/S epimers in the ratio of about 54:46.
Purification-
The crude budesonide (20g) obtained as above was dissolved in ethyl acetate -methanol (4:1, 240ml) by heating at reflux. The hot solution was filtered, concentrated (to about 60ml) at atmospheric temperature, and cooled to 5-10° C. The crystallized product was filtered, washed with ethyl acetate (20ml) and dried in air oven at 55-60° C. Recovery 15.9g (overall purified yield 78.4%), purity 99.62%, ratio of R/S epimers, 57.06: 42.94).
Claims
1. A process for the preparation of 16, 17-acetals of pregnane derivatives having formula 1
Ri is H, C1-C12 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted;
R2 is C1-C12 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted;
X is OH, CI, F or -OCOR group wherein R represents H or C1-C12 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted;
R3 is H, F or CI; R4 is H, F or methyl;
R5 is H, CI or methyl; comprising reacting the compound of formula 2, wherein the substituents are as defined
R4 Formula 2 above, with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid, wherein Re is Ci-C6 alkyl and other substituents are as defined above.
R. Rr\ /O g 2 ■*. ORg Formula 3 Formula 4
2. A process for the preparation of 16α,17α-butylidenedioxy-l lβ,21-dihydroxypregna- l,4-diene-3,20-dione, a compound of formula 5
3. The process as claimed in claim 2, wherein the reaction is carried out at temperature of about 0 to about 5°C.
4. The process as claimed in claim 3, characterized in that the compound of formula 5 is formed in the R:S epimeric ratio between the range of 60:40 to 50:50.
5. The process as claimed in claim 4, characterized in that the compound of formula 5 is formed in the R:S epimeric ratio between the range of 53:47 to 58:42.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN810/MUM/2003 | 2003-08-14 | ||
IN810MU2003 | 2003-08-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005044759A2 true WO2005044759A2 (en) | 2005-05-19 |
WO2005044759A3 WO2005044759A3 (en) | 2005-08-11 |
Family
ID=34566871
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2004/000239 WO2005044759A2 (en) | 2003-08-14 | 2004-08-10 | Acetalization process for preparation of steroid compounds |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2005044759A2 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009117120A1 (en) * | 2008-03-18 | 2009-09-24 | Sicor Inc. | Purification of air sensitive steroids |
CN101717428B (en) * | 2009-12-15 | 2012-11-21 | 浙江工业大学 | Method for synthesizing budesonide |
WO2013124395A1 (en) | 2012-02-23 | 2013-08-29 | Boehringer Ingelheim International Gmbh | Novel method for manufacturing of ciclesonide |
CN103275168A (en) * | 2013-05-27 | 2013-09-04 | 浙江仙琚制药股份有限公司 | Method for preparing budesonide |
AU2008331187B2 (en) * | 2007-11-30 | 2014-04-03 | Pfizer Limited | Novel glucocorticoid receptor agonists |
US10668167B2 (en) | 2016-06-02 | 2020-06-02 | Abbvie Inc. | Glucocorticoid receptor agonist and immunoconjugates thereof |
US10772970B2 (en) | 2017-12-01 | 2020-09-15 | Abbvie Inc. | Glucocorticoid receptor agonist and immunoconjugates thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL109983B1 (en) * | 1976-06-10 | 1980-06-30 | Inst Przemyslu Farmaceutic | Method of producing 6-alpha-fluoro-16 alpha,17 alpha-isopropylidenodioxy-21 hydroxy-4-pregnen-3,20-dione |
US5750734A (en) * | 1994-11-26 | 1998-05-12 | Rhone-Poulenc Rorer Limited | Process for the preparation of steroid derivatives |
-
2004
- 2004-08-10 WO PCT/IN2004/000239 patent/WO2005044759A2/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL109983B1 (en) * | 1976-06-10 | 1980-06-30 | Inst Przemyslu Farmaceutic | Method of producing 6-alpha-fluoro-16 alpha,17 alpha-isopropylidenodioxy-21 hydroxy-4-pregnen-3,20-dione |
US5750734A (en) * | 1994-11-26 | 1998-05-12 | Rhone-Poulenc Rorer Limited | Process for the preparation of steroid derivatives |
Non-Patent Citations (1)
Title |
---|
DATABASE CASREACT [Online] VIJAYKUMAR DANGE ET AL: 'An Efficient Route for the Preparation of a 21-Fluoro Progestin-16a-17a-Dioyolane, a High-Affinity Ligand for PET Imaging of the Progesterone Receptor.' Retrieved from STN Database accession no. (137:155098) & JOURNAL OF ORGANIC CHEMISTRY. vol. 67, no. 14, 2002, pages 4904 - 4910 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2008331187B2 (en) * | 2007-11-30 | 2014-04-03 | Pfizer Limited | Novel glucocorticoid receptor agonists |
US8822439B2 (en) | 2007-11-30 | 2014-09-02 | Pfizer Inc. | Glucocorticoid receptor agonists |
WO2009117120A1 (en) * | 2008-03-18 | 2009-09-24 | Sicor Inc. | Purification of air sensitive steroids |
CN101717428B (en) * | 2009-12-15 | 2012-11-21 | 浙江工业大学 | Method for synthesizing budesonide |
WO2013124395A1 (en) | 2012-02-23 | 2013-08-29 | Boehringer Ingelheim International Gmbh | Novel method for manufacturing of ciclesonide |
CN103275168A (en) * | 2013-05-27 | 2013-09-04 | 浙江仙琚制药股份有限公司 | Method for preparing budesonide |
US10668167B2 (en) | 2016-06-02 | 2020-06-02 | Abbvie Inc. | Glucocorticoid receptor agonist and immunoconjugates thereof |
US10772970B2 (en) | 2017-12-01 | 2020-09-15 | Abbvie Inc. | Glucocorticoid receptor agonist and immunoconjugates thereof |
Also Published As
Publication number | Publication date |
---|---|
WO2005044759A3 (en) | 2005-08-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1336513C (en) | Process for the preparation of 16, 17 acetals of pregnane derivatives and compounds obtained therefrom | |
HU212576B (en) | New process for producing budes onide | |
US20070117974A1 (en) | One-pot processes for preparing prednisolone derivatives | |
EP0262108B1 (en) | A method of controlling the empimeric distribution in the preparation of 16,17-acetals or ketals of pregnane derivatives | |
US20070135398A1 (en) | Process for the preparation of ciclesonide | |
HU216638B (en) | New method for producing 11-oxo-steroide derivatives | |
WO2005044759A2 (en) | Acetalization process for preparation of steroid compounds | |
US10875887B2 (en) | Process for preparation of obeticholic acid | |
KR20050028907A (en) | C-17 spirolactonization and 6,7 oxidation of steroids | |
EP2108653B2 (en) | Process for preparing budesonide | |
EP2675820A1 (en) | An improved process for preparation of levonorgestrel | |
NO153431B (en) | PROCEDURE FOR THE PREPARATION OF 6ALFA-HALOGEN-3-KETO-DELTA1,4-PREGNADIEN. | |
IL224325A (en) | Processes for preparation of 11-(oxo/ß-hydroxy)-16-methyl-21-hydroxy-pregna-1,4-diene-3,20-dione derivatives | |
NO177099B (en) | Analogous Process for Preparing New Therapeutically Active Steroid Derivatives | |
EP0994119B1 (en) | Stereoselective process for the preparation of the 22R epimer of budesonide | |
HU184189B (en) | Process for preparing pregnane derivatives substituted in position 17 | |
HU194906B (en) | New process for producing 21-hydroxy-20-oxo-delta-16-steroides | |
HU199872B (en) | Process for producing 16alpha,17alpha-alkilidenedioxy-11beta-hydroxypregno-1,4-diene-3,20-dione derivatives | |
HU196430B (en) | Process for producing 17-alpha-ethinyl-17-beta-hydroxy-18-methyl-4,15-estradien-3-one | |
KR820001643B1 (en) | Process for the preparation of 6-halo-pregrnanes | |
EP1422235A1 (en) | Stereoselective method of producing 6alpha-fluoropregnanes and intermediaries | |
AP157A (en) | Novel steroid derivatives. | |
CN117858886A (en) | Synthesis of Δ9,11 steroids | |
CA2568510C (en) | One-pot processes for preparing prednisolone derivatives | |
EP1207165A2 (en) | Isomerisation of 6beta-fluorosteroids into the corresponding 6alpha-fluoro derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
122 | Ep: pct application non-entry in european phase |