WO2002088169A2 - Preparation of glucocorticosteroids, 16, 17 acetals or ketals of pregnane derivatives - Google Patents

Preparation of glucocorticosteroids, 16, 17 acetals or ketals of pregnane derivatives Download PDF

Info

Publication number
WO2002088169A2
WO2002088169A2 PCT/SE2002/000814 SE0200814W WO02088169A2 WO 2002088169 A2 WO2002088169 A2 WO 2002088169A2 SE 0200814 W SE0200814 W SE 0200814W WO 02088169 A2 WO02088169 A2 WO 02088169A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
reaction
hydrogen
alkyl group
Prior art date
Application number
PCT/SE2002/000814
Other languages
French (fr)
Other versions
WO2002088169A3 (en
Inventor
Jörgen Blixt
Bengt ÅSLUND
Original Assignee
Astrazeneca Ab
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU2002307602A priority Critical patent/AU2002307602A1/en
Publication of WO2002088169A2 publication Critical patent/WO2002088169A2/en
Publication of WO2002088169A3 publication Critical patent/WO2002088169A3/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J71/00Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005Oxygen-containing hetero ring
    • C07J71/0026Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031Oxygen-containing hetero ring cyclic ketals at positions 16, 17

Definitions

  • the present invention relates to processes for the preparation of glucocorticosteriods, particularly 16,17 acetals or ketals of pregnane derivatives.
  • R1 is a C1-C12 straight chain or branched alkyl group
  • R2 is hydrogen, or a C1-C4 straight chain or branched alkyl group
  • X is OH, CI, F or -O(CO)R3 wherein R3 is a C1-C22 straight chain or branched, saturated or unsaturated alkyl group; R4 is hydrogen, fluorine or chlorine;
  • R5 is hydrogen, methyl, fluorine or chlorine.
  • Particular compounds of formula I which can be prepared by the processes according to the invention are those wherein any one or more of the following apply: the 1 ,2-position is saturated;
  • R1 is a n-propyl group.
  • R2 is different from R1 ; particularly R2 is a hydrogen atom.
  • X is OH or O(CO)R3.
  • R3 is a straight chain or branched, saturated or unsaturated C10 to C19 alkyl group.
  • the acyl may be derived from any one of the following: C 10 H 21 COOH (undecanoic acid); CnH 23 COOH (lauric acid ); C 12 H 2 5COOH (tridecanoic acid); C 13 H 27 COOH (myristic acid ); d 4 H 9 COOH (pentadecanoic acid ); C 5 H 31 COOH (palmitic acid ); C 16 H 33 COOH (heptadecanoic acid ); C 17 H 35 COOH (stearic acid ); C 17 H 33 COOH (oleic acid ); C 17 H 31 COOH (linolic acid ); C 17 H 29 COOH (linolenic acid); C 18 H 37 COOH (nonadecanpic acid ); C 19 H 3g COOH (icosanoic acid).
  • the preferred acyl groups are derived from lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linolic acid, linolenic acid; and particularly palmitic acid (i.e. R3 is (CH 2 ) 1 CH 3 ).
  • R4 and R5 are both fluorine, or R4 and R5 are both hydrogen.
  • glucocorticosteroids can be used for therapy of inflammatory, allergic or immunologic diseases in respiratory airways (such as asthma, rhinitis), in skin (such as eczema, psoriasis) or in bowel (such as ulcerative colitis, Morbus Crohn).
  • respiratory airways such as asthma, rhinitis
  • skin such as eczema, psoriasis
  • bowel such as ulcerative colitis, Morbus Crohn.
  • Compounds of formula I are anti-inflammatory, immunosupressive and anti-allergic glucocorticosteroids useful as therapeutic agents.
  • the processes of the invention are particularly applicable to the synthesis of 16 ⁇ ,17 ⁇ - butylidenedioxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ ,21-dihydroxypregn-4-ene-3,20-dione (known also as rofleponide, described in European patent number 0570454) and to the synthesis of 16 ⁇ , 17 ⁇ -butylidenedioxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-21 -palmitoyloxypregn-4-ene-3,20- dione (known also as rofleponide palmitate, described in European patent number 0572451).
  • Rofleponide is a compound of formula I wherein the 1 ,2-position is saturated, R1 is n-propyl group, R2 is hydrogen, X is OH, R4 is fluorine, and R5 is fluorine.
  • Rofleponide palmitate is a compound of formula I wherein the 1 ,2-position is saturated, R1 is n-propyl group, R2 is hydrogen, X is O(CO)R3, R3 is (CH 2 ) 14 CH 3 , R4 is fluorine, and R5 is fluorine.
  • the processes of the invention are also conveniently applicable to the synthesis of 16 ⁇ , 17 ⁇ -butylidenedioxypregna-1,4-diene-11 ⁇ ,21-diol-3,20-dione (known also as budesonide, described in US patent number 3,929,768 and GB patent number 1,429,922).
  • Budesonide is a compound of formula I wherein the 1,2-position is a double bond, R1 is n-propyl, R2 is hydrogen, X is OH, R4 is hydrogen, and R5 is hydrogen.
  • European patent number 0355859 (trasacetalisation of the corresponding 16,17-acetonides with an aldehyde in the presence of perchloric acid as catalyst).
  • European patent number 0262108 and US patent number 4925933 describe processes for the preparation of particular 16,17-acetals or ketals of pregnane derivatives through transacetalisation of the corresponding 16,17-acetonides or by reaction of the 16,17-diol, providing a method of controlling the epimeric distribution in the preparation process.
  • One of the preparation processes involves reaction of an acetonide or diol with an aldehyde (or its acetal) or a ketone (or its ketal).
  • the reaction is carried out in a hydrocarbon solvent wherein the solubility of the acetonide or diol is less than 1 mg/l, and is catalysed by a hydrohalogen acid or an organic sulphonic acid in the presence of small grains of an inert material (such as silicone dioxide).
  • a hydrocarbon solvent wherein the solubility of the acetonide or diol is less than 1 mg/l, and is catalysed by a hydrohalogen acid or an organic sulphonic acid in the presence of small grains of an inert material (such as silicone dioxide).
  • European patent number 0570454, US patent number 5674861 and US patent number 593409 describe processes for preparing compounds of formula I wherein the 1 ,2-position is saturated, R1 is n-propyl, R2 is H, X is OH, R4 is fluorine and R5 is H or fluorine (for example, 16 ⁇ ,17 ⁇ -butylidenedioxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ ,21-dihydroxypregn-4- ene-3,20-dione or rofleponide).
  • One of the preparation processes involves transacetalisation of an acetonide having the formula (II)
  • the reaction is carried out by adding the steroid to a solution of the aldehyde together with an acid catalyst (for example perchloric acid, p-toluenesulfonic acid, hydrochloric acid in an ether, preferably dioxane, or in acetonitrile).
  • an acid catalyst for example perchloric acid, p-toluenesulfonic acid, hydrochloric acid in an ether, preferably dioxane, or in acetonitrile.
  • the reaction can also be performed in a reaction medium which is a hydrocarbon, preferably isooctane, wherein the solubility of the acetonide is less than 1mg/l, or in a halogenated hydrocarbon, preferably methylene chloride or chloroform.
  • the reaction is catalysed by a hydrohalogen acid (namely hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid and the corresponding oxohalogen acids such as perchloric acid) or an organic sulphonic acid (such as p- toluenesulfonic acid).
  • a hydrohalogen acid namely hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid and the corresponding oxohalogen acids such as perchloric acid
  • an organic sulphonic acid such as p- toluenesulfonic acid.
  • the reaction is performed in the presence of small grains of an inert material, such as glass, ceramic, sifted silicone dioxide (sand) or inert metal particles, such as granulated stainless steel or tantalum in the reaction medium (when the reaction is performed in a hydrocarbon solvent).
  • the small grains of an inert material and effective stirring are used to divide the steroid-catalyst complex into a thin layer around the grains, enlarging the reactive surface and allowing the reaction with the aldehyde to proceed rapidly.
  • the inert grain material preferably silicone dioxide, SiO 2
  • the amount used in the reaction ranges from 1 :5 to 1 :50, preferably 1 :20.
  • European patent number 0572451 , US patent number 5614514 and US patent number 5888995 describe processes for preparing compounds of formula I wherein X is 0(CO)R3, R3 is a C10-C19 straight chain or branched, saturated or unsaturated alkyl group, R4 is fluorine and R5 is fluorine (for example, 16 ⁇ ,17 ⁇ -butylidenedioxy-6 ⁇ ,9 ⁇ - difluoro-11 ⁇ -hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione or rofleponide palmitate).
  • the compounds are prepared by any of the following alternative methods: A ⁇ Reaction of a compound of the formula (IV)
  • the esterification of the 21-hydroxy compound is effected by reacting the parent 21-hydroxy steroid with the appropriate carboxylic acid, advantageously in the presence of trifluoroacetic anhydride and preferably in the presence of an acid catalyst such as p- toluenesulphonic acid.
  • the reaction is advantageously performed in an organic solvent such as benzene or mefhylene chloride; the reaction being conveniently performed at a temperature of 20-100°C.
  • B ⁇ Reaction of a compound of the formula (IV) with a compound of the formula (VI)
  • z is a halogen atom (such as chlorine, bromine, iodine or fluorine) or the group
  • the parent 21-hydroxy compound may be treated with the appropriate carboxylic acid halide or anhydride, preferably in a solvent such as a halogenated hydrocarbon (such as methylene chloride) or an ether (such as dioxane) in the presence of a base such as triethylamine or pyridine, preferably at low temperature (-5°C to +30°C).
  • a solvent such as a halogenated hydrocarbon (such as methylene chloride) or an ether (such as dioxane)
  • a base such as triethylamine or pyridine
  • Y is halogen (such as chlorine, bromine, iodine) or mesylate or p-toluene- sulphonate, with a compound of the formula (VIII)
  • a + is a cation.
  • a salt of the appropriate carboxylic acid with an alkali metal such as lithium, sodium or potassium, or a triethylammonium or tributylammonium salt is reacted with the appropriate alkylating agent of the formula (VII).
  • the reaction is performed preferably in a polar solvent such as acetone, methylethyl ketone, dimethyl formamide or dimethylsulfoxide at a temperature in the range 25-100°C.
  • a final reaction step in order to resolve an epimeric mixture into its components may be necessary in case a pure epimer is desired.
  • the compound of formula I as defined above is prepared by a process (A) wherein a compound of the formula (X)
  • the molar ratio of the compound of formula (X) to aldehyde R1COR2 is preferably 1:5.
  • the reaction is preferably performed at a temperature around +20°C.
  • the organic solvent is preferably toluene.
  • the amount of catalyst ranges from 1 :1 to 1 :15 in molar ratios, and is preferably 1 :4. Using perchloric acid as catalyst gives excellent conversion.
  • the inert insoluble material (preferably silicone dioxide, SiO 2 ) should consist of free- . flowing grains having a particle size ranging from 0.1-1.0 mm, preferably 0.1-0.3 mm.
  • the amount used in the reaction ranges from 1:5 to 1 :50, preferably 1 :10, by weight.
  • the product is isolated by addition of aqueous sodium carbonate (Na 2 C0 3 ) and ethylacetate, removal of the grains, filtration, separation of the water layer and partial removal of organic solvent until the solvent/ethylacetate ratio is between 20-40% whereby the product crystallises upon cooling.
  • aqueous sodium carbonate Na 2 C0 3
  • ethylacetate aqueous sodium carbonate
  • removal of the grains filtration, separation of the water layer and partial removal of organic solvent until the solvent/ethylacetate ratio is between 20-40% whereby the product crystallises upon cooling.
  • Particular compounds of formula I which can be prepared by process (A) are those wherein X is OH, CI or F; most particularly those compounds wherein X is OH.
  • the most preferred compound which can be prepared by process (A) is 16 ⁇ ,17 ⁇ -butylidenedioxy- 6 ⁇ ,9 ⁇ -difiuoro-11 ⁇ ,21-dihydroxypregn-4-ene-3,20-dione (rofleponide).
  • the most active epimer of the compound of formula I the 22R-epimer, is almost exclusively obtained.
  • process (A) has several advantages due to improvement of the reaction- and work-up conditions.
  • the compound of formula I as defined above wherein X is O(CO)R3 is prepared by a process (B) wherein a compound of the formula (XI)
  • z is a halogen atom
  • the acid halide is charged in a hydrocarbon solvent
  • the reaction is performed in the temperature range 0°C to 50°C, at a dilution of 1 :3 to 1 :20, with vigorous stirring, in the presence of dimethylaminopyridine (DMAP) in molar ratio ranging from 1 :5 to 1:1000.
  • DMAP dimethylaminopyridine
  • a second hydrocarbon solvent is added and the first organic solvent is partially removed by distillation to be below a relevant first solvent/second solvent ratio before crystallisation.
  • the relevant ratio is 25-30% weight/weight.
  • z is a halogen atom such as chlorine, bromine, iodine or fluorine, and the group R3 is as defined above for a compound of formula (I).
  • the hydrocarbon solvent may be, for example, toluene, isooctane, heptane, etc; preferably it is toluene.
  • isooctane or a similar solvent
  • isooctane is added followed by distillation and further addition of isooctane in order to reach a relevant isooctane/toluene ratio before crystallisation.
  • the reaction is preferably performed at room temperature.
  • the reaction is preferably performed within a dilution range of 1 :3 to 1 :20, most preferably at a dilution of 1 :5.
  • DMAP is preferably present in molar ratio range 1 :20 to 1 :100, more preferably 1:30 to 1:100; DMAP is most preferably present in molar ratio 1:50.
  • the starting material is preferably a compound produced by process (A).
  • the reaction is preferably stopped by the addition of acetic acid in water.
  • the aqueous phase that is rapidly formed constitutes the only extraction procedure necessary to remove all organic and inorganic salt residues. After . extraction the water layer is removed and isooctane is added for crystallisation of the product.
  • the most preferred compound which can be prepared by process (B) is 16 ⁇ ,17 ⁇ - butylidenedioxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione (rofleponide palmitate).
  • process (B) the purity of the product obtained is significantly improved compared to previously known processes.
  • the controlled reaction conditions avoid or significantly reduce the formation of impurities so that the quality of the final product is improved.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)

Abstract

Processes for the preparation of compounds of formula (I) involving transacetalisation of the relevant acetonide, or esterification of a compound of formula (I) wherein X is OH. Compounds of formula (I) may be anti-inflammatory, immunosupressive and anti-allergic glucocorticosteroids useful as therapeutic agents.

Description

CHEMICAL PROCESS
The present invention relates to processes for the preparation of glucocorticosteriods, particularly 16,17 acetals or ketals of pregnane derivatives.
The compounds which can be prepared by the processes according to the invention have the following general formula I:
Figure imgf000002_0001
wherein the 1 ,2-position is saturated or is a double bond;
R1 is a C1-C12 straight chain or branched alkyl group;
R2 is hydrogen, or a C1-C4 straight chain or branched alkyl group;
X is OH, CI, F or -O(CO)R3 wherein R3 is a C1-C22 straight chain or branched, saturated or unsaturated alkyl group; R4 is hydrogen, fluorine or chlorine;
R5 is hydrogen, methyl, fluorine or chlorine.
Particular compounds of formula I which can be prepared by the processes according to the invention are those wherein any one or more of the following apply: the 1 ,2-position is saturated;
R1 is a n-propyl group. R2 is different from R1 ; particularly R2 is a hydrogen atom. X is OH or O(CO)R3.
When X is O(CO)R3, R3 is a straight chain or branched, saturated or unsaturated C10 to C19 alkyl group. The acyl may be derived from any one of the following: C10H21COOH (undecanoic acid); CnH23COOH (lauric acid ); C12H25COOH (tridecanoic acid); C13H27COOH (myristic acid ); d4H 9COOH (pentadecanoic acid ); C 5H31COOH (palmitic acid ); C16H33COOH (heptadecanoic acid ); C17H35COOH (stearic acid ); C17H33COOH (oleic acid ); C17H31COOH (linolic acid ); C17H29COOH (linolenic acid); C18H37COOH (nonadecanpic acid ); C19H3gCOOH (icosanoic acid). The preferred acyl groups are derived from lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linolic acid, linolenic acid; and particularly palmitic acid (i.e. R3 is (CH2)1 CH3).
R4 and R5 are both fluorine, or R4 and R5 are both hydrogen.
It is known that glucocorticosteroids can be used for therapy of inflammatory, allergic or immunologic diseases in respiratory airways (such as asthma, rhinitis), in skin (such as eczema, psoriasis) or in bowel (such as ulcerative colitis, Morbus Crohn). Compounds of formula I are anti-inflammatory, immunosupressive and anti-allergic glucocorticosteroids useful as therapeutic agents.
The processes of the invention are particularly applicable to the synthesis of 16α,17α- butylidenedioxy-6α,9α-difluoro-11 β,21-dihydroxypregn-4-ene-3,20-dione (known also as rofleponide, described in European patent number 0570454) and to the synthesis of 16α, 17α-butylidenedioxy-6α,9α-difluoro-11 β-hydroxy-21 -palmitoyloxypregn-4-ene-3,20- dione (known also as rofleponide palmitate, described in European patent number 0572451). Rofleponide is a compound of formula I wherein the 1 ,2-position is saturated, R1 is n-propyl group, R2 is hydrogen, X is OH, R4 is fluorine, and R5 is fluorine.
Rofleponide palmitate is a compound of formula I wherein the 1 ,2-position is saturated, R1 is n-propyl group, R2 is hydrogen, X is O(CO)R3, R3 is (CH2)14CH3, R4 is fluorine, and R5 is fluorine. The processes of the invention are also conveniently applicable to the synthesis of 16α, 17α-butylidenedioxypregna-1,4-diene-11β,21-diol-3,20-dione (known also as budesonide, described in US patent number 3,929,768 and GB patent number 1,429,922). Budesonide is a compound of formula I wherein the 1,2-position is a double bond, R1 is n-propyl, R2 is hydrogen, X is OH, R4 is hydrogen, and R5 is hydrogen.
Processes for the preparation of particular 16,17 acetals of pregnane derivatives are described in European patent number 0164636, US patent number 4695625 and US patent number 4835145 (transketalisation of the corresponding 16,17-acetonides) and
European patent number 0355859 (trasacetalisation of the corresponding 16,17-acetonides with an aldehyde in the presence of perchloric acid as catalyst).
European patent number 0262108 and US patent number 4925933 describe processes for the preparation of particular 16,17-acetals or ketals of pregnane derivatives through transacetalisation of the corresponding 16,17-acetonides or by reaction of the 16,17-diol, providing a method of controlling the epimeric distribution in the preparation process. One of the preparation processes involves reaction of an acetonide or diol with an aldehyde (or its acetal) or a ketone (or its ketal). The reaction is carried out in a hydrocarbon solvent wherein the solubility of the acetonide or diol is less than 1 mg/l, and is catalysed by a hydrohalogen acid or an organic sulphonic acid in the presence of small grains of an inert material (such as silicone dioxide).
European patent number 0570454, US patent number 5674861 and US patent number 593409 describe processes for preparing compounds of formula I wherein the 1 ,2-position is saturated, R1 is n-propyl, R2 is H, X is OH, R4 is fluorine and R5 is H or fluorine (for example, 16α,17α-butylidenedioxy-6α,9α-difluoro-11 β,21-dihydroxypregn-4- ene-3,20-dione or rofleponide). One of the preparation processes involves transacetalisation of an acetonide having the formula (II)
Figure imgf000005_0001
with an aldehyde of the formula (III)
Figure imgf000005_0002
The reaction is carried out by adding the steroid to a solution of the aldehyde together with an acid catalyst (for example perchloric acid, p-toluenesulfonic acid, hydrochloric acid in an ether, preferably dioxane, or in acetonitrile). The reaction can also be performed in a reaction medium which is a hydrocarbon, preferably isooctane, wherein the solubility of the acetonide is less than 1mg/l, or in a halogenated hydrocarbon, preferably methylene chloride or chloroform. The reaction is catalysed by a hydrohalogen acid (namely hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid and the corresponding oxohalogen acids such as perchloric acid) or an organic sulphonic acid (such as p- toluenesulfonic acid). The reaction is performed in the presence of small grains of an inert material, such as glass, ceramic, sifted silicone dioxide (sand) or inert metal particles, such as granulated stainless steel or tantalum in the reaction medium (when the reaction is performed in a hydrocarbon solvent). The small grains of an inert material and effective stirring are used to divide the steroid-catalyst complex into a thin layer around the grains, enlarging the reactive surface and allowing the reaction with the aldehyde to proceed rapidly. The inert grain material (preferably silicone dioxide, SiO2) consists of free-flowing small particles with size ranging from 0.1-1.0 mm, preferably 0.1-0.3 mm. The amount used in the reaction ranges from 1 :5 to 1 :50, preferably 1 :20. After reaction of the acetonide and ' aldehyde, a final reaction step in order to resolve an epimeric mixture into its components may be necessary in case a pure epimer is desired (column chromatography or chromatography on microparticulate bonded phase columns).
European patent number 0572451 , US patent number 5614514 and US patent number 5888995 describe processes for preparing compounds of formula I wherein X is 0(CO)R3, R3 is a C10-C19 straight chain or branched, saturated or unsaturated alkyl group, R4 is fluorine and R5 is fluorine (for example, 16α,17α-butylidenedioxy-6α,9α- difluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione or rofleponide palmitate). The compounds are prepared by any of the following alternative methods: A^ Reaction of a compound of the formula (IV)
Figure imgf000006_0001
with a compound of the formula (V)
O
V R3COH The esterification of the 21-hydroxy compound is effected by reacting the parent 21-hydroxy steroid with the appropriate carboxylic acid, advantageously in the presence of trifluoroacetic anhydride and preferably in the presence of an acid catalyst such as p- toluenesulphonic acid. The reaction is advantageously performed in an organic solvent such as benzene or mefhylene chloride; the reaction being conveniently performed at a temperature of 20-100°C. B^. Reaction of a compound of the formula (IV) with a compound of the formula (VI)
Figure imgf000007_0001
wherein z is a halogen atom (such as chlorine, bromine, iodine or fluorine) or the group
Figure imgf000007_0002
The parent 21-hydroxy compound may be treated with the appropriate carboxylic acid halide or anhydride, preferably in a solvent such as a halogenated hydrocarbon (such as methylene chloride) or an ether (such as dioxane) in the presence of a base such as triethylamine or pyridine, preferably at low temperature (-5°C to +30°C). C. Reaction of a compound of the formula (VII)
Figure imgf000007_0003
wherein Y is halogen (such as chlorine, bromine, iodine) or mesylate or p-toluene- sulphonate, with a compound of the formula (VIII)
Figure imgf000008_0001
wherein A+ is a cation. A salt of the appropriate carboxylic acid with an alkali metal (such as lithium, sodium or potassium,) or a triethylammonium or tributylammonium salt is reacted with the appropriate alkylating agent of the formula (VII). The reaction is performed preferably in a polar solvent such as acetone, methylethyl ketone, dimethyl formamide or dimethylsulfoxide at a temperature in the range 25-100°C.
In any of the methods A-C a final reaction step in order to resolve an epimeric mixture into its components may be necessary in case a pure epimer is desired.
The contents of the documents cited above are incorporated herein by reference.
We have now developed improved processes for the preparation of compounds of formula I as defined above, involving transacetalisation of the relevant acetonide to form a compound of formula I or esterification of a compound of formula I to form a further compound of formula I.
In a first aspect of the invention, the compound of formula I as defined above is prepared by a process (A) wherein a compound of the formula (X)
Figure imgf000008_0002
is reacted with an aldehyde having the formula R1COR2 in molar ratios ranging from 1:1 to 1 :10 in the temperature range 0°C to 40°C. The reaction is performed with vigorous stirring in an organic solvent and in the presence of perchloric acid as catalyst and small grains of an inert insoluble material having a particle size from 0.1 to 1.0 mm, until judged complete by HPLC. The product is isolated by extraction followed by a selective crystallisation.
The molar ratio of the compound of formula (X) to aldehyde R1COR2 is preferably 1:5. The reaction is preferably performed at a temperature around +20°C.
The organic solvent is preferably toluene.
The amount of catalyst (perchloric acid) ranges from 1 :1 to 1 :15 in molar ratios, and is preferably 1 :4. Using perchloric acid as catalyst gives excellent conversion.
The inert insoluble material (preferably silicone dioxide, SiO2) should consist of free- . flowing grains having a particle size ranging from 0.1-1.0 mm, preferably 0.1-0.3 mm. The amount used in the reaction ranges from 1:5 to 1 :50, preferably 1 :10, by weight.
The product is isolated by addition of aqueous sodium carbonate (Na2C03) and ethylacetate, removal of the grains, filtration, separation of the water layer and partial removal of organic solvent until the solvent/ethylacetate ratio is between 20-40% whereby the product crystallises upon cooling.
Particular compounds of formula I which can be prepared by process (A) are those wherein X is OH, CI or F; most particularly those compounds wherein X is OH. The most preferred compound which can be prepared by process (A) is 16α,17α-butylidenedioxy- 6α,9α-difiuoro-11 β,21-dihydroxypregn-4-ene-3,20-dione (rofleponide). Under the reaction conditions of process (A) the most active epimer of the compound of formula I, the 22R-epimer, is almost exclusively obtained. Compared to known processes for preparing compounds of formula I (as described above), process (A) has several advantages due to improvement of the reaction- and work-up conditions. These advantages include higher chemical conversion leading to higher yield and purity, a shorter reaction time, use of less inert insoluble material leading to less waste disposal, consumption of less solvent during reaction and work-up, a shorter work-up time (for example, due to use of sodium carbonate during isolation), increased robustness in the sense of conversion and epimeric distribution. In addition, the volume efficiency and productivity are substantially improved, and the aqueous waste volume is considerably reduced.
In a second aspect of the invention, the compound of formula I as defined above wherein X is O(CO)R3 is prepared by a process (B) wherein a compound of the formula (XI)
Figure imgf000010_0001
is reacted with an acid halide of the formula (XII)
O xπ R3-
wherein z is a halogen atom; the acid halide is charged in a hydrocarbon solvent; the reaction is performed in the temperature range 0°C to 50°C, at a dilution of 1 :3 to 1 :20, with vigorous stirring, in the presence of dimethylaminopyridine (DMAP) in molar ratio ranging from 1 :5 to 1:1000. A second hydrocarbon solvent is added and the first organic solvent is partially removed by distillation to be below a relevant first solvent/second solvent ratio before crystallisation. The relevant ratio is 25-30% weight/weight.
In a compound of formula (XI), the 1 ,2-position is saturated or is a double bond, and the groups R1 , R2, R4, R5 are as defined above for a compound of formula (l).
In a compound of formula (XII), z is a halogen atom such as chlorine, bromine, iodine or fluorine, and the group R3 is as defined above for a compound of formula (I).
The hydrocarbon solvent may be, for example, toluene, isooctane, heptane, etc; preferably it is toluene. Preferably isooctane (or a similar solvent) is added followed by distillation and further addition of isooctane in order to reach a relevant isooctane/toluene ratio before crystallisation.
The reaction is preferably performed at room temperature. The reaction is preferably performed within a dilution range of 1 :3 to 1 :20, most preferably at a dilution of 1 :5.
DMAP is preferably present in molar ratio range 1 :20 to 1 :100, more preferably 1:30 to 1:100; DMAP is most preferably present in molar ratio 1:50.
In process (B), the starting material, the compound of formula (XI), is preferably a compound produced by process (A). The reaction is preferably stopped by the addition of acetic acid in water. The aqueous phase that is rapidly formed constitutes the only extraction procedure necessary to remove all organic and inorganic salt residues. After . extraction the water layer is removed and isooctane is added for crystallisation of the product. The most preferred compound which can be prepared by process (B) is 16α,17α- butylidenedioxy-6α,9α-difluoro-11 β-hydroxy-21-palmitoyloxypregn-4-ene-3,20-dione (rofleponide palmitate).
Using process (B), the purity of the product obtained is significantly improved compared to previously known processes. The controlled reaction conditions avoid or significantly reduce the formation of impurities so that the quality of the final product is improved.
The invention will now be illustrated but not limited by the following Examples. Each exemplified process represents a particular and independent aspect of the invention.
EXAMPLE 1 (Process A)
16α,17α-butylidenedioxy-6α,9α-difluoro-11β,21-dihydroxypregn-4-ene-3,20-dione Fluocinolone acetonide (30g), 15 g butanal, 300 g of fine sand (SiO2) and 225 g of toluene are mixed at 500 rpm at +20° C. 36 g of 70% HCIO4 is then rapidly added. The reaction mixture is stirred at +20° C for another 2 hours and the reaction is followed on HPLC. The epimeric distribution eventually stops at about 22R/22S = 98/2.
The product is isolated by addition of aqueous Na2CO3 (14.0g dissolved in 90g water). After 10 minutes ethylacetate (75g) is added and the temperature increased to +60° C and the sand is then removed by filtration. The water layer is separated off. The organic solvent is partially removed until the solvent/ ethylacetate ratio is between 20-40%. Crystallisation is induced by lowering the temperature to -10° C (0.5° C/minute). The crystals are collected, washed with toluene (9 g) and dried under reduced pressure at elevated temperature to give 27.23g of the title compound. Purity is 95.8% (HPLC analysis) and the epimeric distribution is 22R/22S = 99.1/0.9.
Figure imgf000013_0001
Figure imgf000013_0002
EXAMPLE 2 (Process A)
16α,17α-butylidenedioxy-6α,9α-difluoro-11β,21-dihydroxypregn-4-ene-3,20-dione
Fluocinolone acetonide (30g), 15 g butanal, 300 g of fiηe sand (SiO2) and 225 g of toluene are mixed at 500 rpm at +20° C. 36 g of 70% HCIO4 is then rapidly added. The reaction mixture is stirred at +20° C for another 2 hours and the reaction is followed on HPLC. The epimeric distribution eventually stops at about 22R/22S = 98/2.
The product is isolated by addition of aqueous Na2CO3 (14.0g dissolved in 90g water). After 10 minutes ethylacetate (75g) is added and the temperature increased to +60° C and the sand is then removed by filtration. The water layer is separated off. The organic solvent is partially removed until the solvent/ ethylacetate ratio is between 20-40%. Crystallisation is induced by lowering the temperature to -10° C (0.5° C/minute). The crystals are collected, washed with toluene (9 g) and dried under reduced pressure at elevated temperature to give 27.26g of the title compound. Purity is 98.3% (HPLC analysis) and the epimeric distribution is 22R/22S = 99.3/0.7. EXAMPLE 3 (Process A)
16α,17α-butylidenedioxy-6α,9α-dffluoro-11β,21-dihydroxypregn-4-ene-3,20-dione Fluocinolone acetonide (30g), 15 g butanal, 300 g of fine sand (Si02) and 225 g of toluene are mixed at 1300 rpm at +20° C. 36 g of 70% HCIO4 is then rapidly added. The reaction mixture is stirred at +20° C for another 4.5 hours and the reaction is followed on HPLC. The epimeric distribution eventually stops at about 22R/22S = 98/2.
The product is isolated by addition of aqueous Na2CO3 (14.1g dissolved in 90g water). After 10 minutes ethylacetate (75g) is added and the temperature increased to +60° C and the sand is then removed by filtration. The water layer is separated off. The organic solvent is partially removed until the solvent/ ethylacetate ratio is between 20-40%. Crystallisation is induced by lowering the temperature to -10° C (0.3° C/minute). The crystals are collected, washed with toluene (9 g) and dried under reduced pressure at elevated temperature to give 20.07g of the title compound. Purity is 98.5% (HPLC analysis) and the epimeric distribution is 22R/22S = 99.4/0.6.
EXAMPLE 4 (Process A)
16α,17 -butylidenedioxy-6α,9α-difluoro-11β,21-dlhydroxypregn-4-ene-3,20-dione
To a nitrogen gas filled reactor toluene (67.5 Kg) and fine sand (SiO2) (90 kg) are added and stirred at 270 rpm at +22° C. Fluocinolone acetonide (9 Kg) is then charged followed by butanal (4.5 Kg) addition. The reactor is inertised again with nitrogen. HCIO4 70% (10.8 Kg) is then rapidly added. The reaction mixture is stirred at +22° C for 3 hours and the reaction is followed on HPLC. The epimeric distribution eventually stops at about 22R/22S = 98/2. The product is isolated by addition of aqueous Na2CO3 (4.23 Kg dissolved in 27.0 Kg water). After 20 minutes ethylacetate (22.5 Kg) is added and the temperature increased to +55° C and the sand is then removed by filtration. Ethylacetate (18 Kg) is added to the reactor and warmed to +55° C before washing the sand. The water layer is separated off. The organic solvent is partially removed (about 20 Kg condenses) until the solvent/ ethylacetate ratio is between 20-40% whereby the product crystallises upon cooling. The crystals are collected and dried under reduced pressure at elevated temperature to give 6.2Kg of the title compound. Purity is 95.8% (HPLC analysis) and the epimeric distribution is 22R/22S = 99.2/0.8.
EXAMPLE 5 (Process B) 16α,17α-butylidenedioxy-6α,9α-difluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene- 3,20-dione
To a well stirred slurry of 16α,17α-butylidenedioxy-6α,9α-difluoro-11 β,21-dihydroxypregn- 4-ene-3,20-dione (12g) of toluene (48g) are added triethylamine (3.6g) and dimethylaminopyridine, DMAP (0.06g) dissolved in toluene (6.3g) at +20°C. The temperature is decreased to +10°C and then excess paimitoylchloride (8.5g) dissolved in toluene (10.8g) is added during 30 minutes. After completion of the reaction, judged by HPLC, acetic acid (7.7g) in water (34.4g) is added at +20°C. After extraction, the water layer is removed and isooctane (60g) is added. The temperature is increased and solvent is removed by distillation under reduced pressure. More isooctane (60g) is added to a resulting toluene content of 20-35 %. Lowering the temperature to 0° C induces crystallisation (0.2-0.5°C/minute) and seeding was necessary. The crystals are collected and dried under reduced pressure at elevated temperature to give 12.96g of the title compound. Purity is 95.8% (HPLC analysis).
Figure imgf000016_0001
EXAMPLE 6 (Process B)
16α,17α-butylidenedioxy-6α,9α-difluoro-11 β-hydroxy-21-palmitoyloxypregn-4-ene- 3,20-dione
To a well stirred slurry of 16α,17α-butylidenedioxy-6α,9α-difluoro-11β,21-dihydroxypregn- 4-ene-3,20-dione (8g) in toluene (32g) are added triethylamine (2.6g) and dimethylaminopyridine, DMAP (0.04g) dissolved in toluene (8g) at +20°C. At +20°C excess paimitoylchloride (6.1g) dissolved in toluene (8g) is added during 35 minutes. After completion of the reaction, judged by HPLC, acetic acid (0.5g) in water (24g) is added at +20°C. After extraction, the water layer is removed and isooctane (40g) is added. The temperature is increased and solvent is removed by distillation under reduced pressure. More isooctane (40g) is added to a resulting toluene content of 20-35 %.
Lowering the temperature to 0° C induces crystallisation (0.2-0.5°C/minute) and seeding was necessary. The crystals are collected and dried under reduced pressure at elevated temperature to give 10.2g of the title compound. Purity is 95.8% (HPLC analysis). EXAMPLE 7 (Process B) 16α,17α-butylidenedioxy-6α,9α-difluoro-11β-hydroxy-21-palmitoyloxypregn-4-ene- 3,20-dione
To a well stirred slurry of 16α,17α-butylidenedioxy-6α,9α-difluoro-11β,21-dihydroxypregn- 4-ene-3,20-dione (4.97Kg) in toluene (20.0Kg) are added triethylamine (1.61 Kg) and dimethylaminopyridine, DMAP (13g) dissolved in toluene (5Kg) at +20°C. At +20°C excess paimitoylchloride (3.50Kg) dissolved in toluene (5Kg) is added during 30 minutes. Additional paimitoylchloride (0.29Kg) was added due to incomplete conversion judged by HPLC. After completion of the reaction, again judged by HPLC, acetic acid (0.32Kg) in water (17.9Kg) was added at +20°C. After extraction, the water layer is removed and isooctane (37.5Kg) is added. The temperature is increased and solvent is removed by distillation under reduced pressure. More isooctane (37Kg) is added to a resulting toluene content of 20-35 % (w/w). Lowering the temperature to 0° C induces crystallisation (0.2- 0.5°C/minute) and seeding was necessary. The crystals are collected and dried under reduced pressure at elevated temperature to give 6.9Kg of the title compound. Purity is 96.8% (HPLC analysis).

Claims

CLAIMS:
What we claim is:
1. A process for preparing a compound of formula
Figure imgf000018_0001
wherein the 1,2-position is saturated or is a double bond;
R1 is a C1-C12 straight chain or branched alkyl group;
R2 is hydrogen, or a C1-C4 straight chain or branched alkyl group;
X is OH, CI, F or -O(CO)R3 wherein R3 is a C1-C22 straight chain or branched, saturated or unsaturated alkyl group;
R4 is hydrogen, fluorine or chlorine;
R5 is hydrogen, methyl, fluorine or chlorine; said process comprising reacting a compound of the formula (X)
Figure imgf000018_0002
with an aldehyde having the formula R1COR2 in molar ratios ranging from 1:1 to 1 :10 in the temperature range 0°C to 40°C, with vigorous stirring in an organic solvent and in the presence of perchloric acid as catalyst and of small grains of an inert insoluble material having a particle size from 0.1 to 1.0 mm.
2. A process as claimed in claim 1 wherein the product is isolated by extraction followed by crystallisation.
3. A process as claimed in claim 2 wherein the product is isolated by addition of sodium carbonate,
4. A process as claimed in any of the preceding claims wherein the molar ratio of perchloric acid ranges from 1 :1 to 1 :15.
5. A process as claimed in any of the preceding claims wherein the molar ratio of the compound of formula (X) to aldehyde R1COR2 is 1 :5.
6. A process as claimed in any of the preceding claims wherein the organic solvent is toluene.
7. A process as claimed in any of the preceding claims wherein the inert insoluble material ranges from 1 :5 to 1 :50 by weight.
8. A process as claimed in any of the preceding claims wherein the compound of formula (I) is 16α,17α-butylidenedioxy-6α,9α-difluoro-11 β,21-dihydroxypregn-4-ene-3,20- dione. A process for preparing a compound of formula
Figure imgf000020_0001
wherein the 1 ,2-position is saturated or is a double bond;
R1 is a C1-C12 straight chain or branched alkyl group;
R2 is hydrogen, or a C1-C4 straight chain or branched alkyl group;
X is O(CO)R3 wherein R3 is a C1-C22 straight chain or branched, saturated or unsaturated alkyl group;
R4 is hydrogen, fluorine or chlorine;
R5 is hydrogen, methyl, fluorine or chlorine; said process comprising reacting a compound of the formula (XI)
Figure imgf000020_0002
with an acid halide of the formula (XII)
Figure imgf000020_0003
wherein z is a halogen atom and the acid halide is charged in a hydrocarbon solvent; and the reaction is performed .in the temperature range 0°C to 50°C, at a dilution of 1:3 to 1:10, with vigorous stirring, in the presence of dimethylaminopyridine (DMAP) in molar ratio range from 1 :5 to 1:1000.
10. A process as claimed in claim 9 wherein the hydrocarbon solvent is toluene.
11. A process as claimed in either claim 9 or claim 10 wherein the reaction is performed at a dilution of 1 :5.
12. A process as claimed in any of claims 9 to 11 wherein DMAP is present in molar ratio 1 :30 to 1 :100.
13. A process as claimed in any of claims 9 to 12 wherein the compound of formula (I) is 16α, 17α-butylidenedioxy-6α,9α-difluoro-11 β-hydroxy-21 -palmitoyloxypregn-4-ene-3,20- dione.
PCT/SE2002/000814 2001-04-27 2002-04-24 Preparation of glucocorticosteroids, 16, 17 acetals or ketals of pregnane derivatives WO2002088169A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002307602A AU2002307602A1 (en) 2001-04-27 2002-04-24 Preparation of glucocorticosteroids, 16, 17 acetals or ketals of pregnane derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0110411A GB0110411D0 (en) 2001-04-27 2001-04-27 Chemical process
GB0110411.6 2001-04-27

Publications (2)

Publication Number Publication Date
WO2002088169A2 true WO2002088169A2 (en) 2002-11-07
WO2002088169A3 WO2002088169A3 (en) 2003-01-09

Family

ID=9913626

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2002/000814 WO2002088169A2 (en) 2001-04-27 2002-04-24 Preparation of glucocorticosteroids, 16, 17 acetals or ketals of pregnane derivatives

Country Status (3)

Country Link
AU (1) AU2002307602A1 (en)
GB (1) GB0110411D0 (en)
WO (1) WO2002088169A2 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009108118A1 (en) * 2008-02-27 2009-09-03 Astrazeneca Ab 16 alpha, 17 alpa-acetal glucocorticosteroidal derivatives and their use
WO2009112557A2 (en) * 2008-03-13 2009-09-17 Farmabios S.P.A. Process for the preparation of pregnane derivatives
US8163724B2 (en) 2007-10-04 2012-04-24 Astrazeneca Ab Glucocorticosteroids, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
US8338587B2 (en) 2009-04-03 2012-12-25 Astrazeneca Ab Compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1405519A (en) * 1973-07-18 1975-09-10 American Cyanamid Co Triamcinolone derivative
EP0355859A1 (en) * 1985-04-04 1990-02-28 Aktiebolaget Draco Process for the preparation of intermediates for 11-beta,16-alpha,17-alpha,21-tetrahydroxypregna-3,20-dione 16-alpha,17-alpha-acetals and 21-esters thereof
WO1992013872A1 (en) * 1991-02-04 1992-08-20 Aktiebolaget Astra Novel steroids

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07277987A (en) * 1994-04-05 1995-10-24 Green Cross Corp:The Steroid antiphlogistic external agent

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1405519A (en) * 1973-07-18 1975-09-10 American Cyanamid Co Triamcinolone derivative
EP0355859A1 (en) * 1985-04-04 1990-02-28 Aktiebolaget Draco Process for the preparation of intermediates for 11-beta,16-alpha,17-alpha,21-tetrahydroxypregna-3,20-dione 16-alpha,17-alpha-acetals and 21-esters thereof
WO1992013872A1 (en) * 1991-02-04 1992-08-20 Aktiebolaget Astra Novel steroids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [Online] DOC. NO. 124:66610 AKABOSHI FUMIHIKO ET AL.: 'Topical pharmaceutical compositions contating anntiinflammatory steroids', XP002954685 Retrieved from STN Database accession no. 1996:38628 & JP 7 277 987 A 24 October 1995 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8163724B2 (en) 2007-10-04 2012-04-24 Astrazeneca Ab Glucocorticosteroids, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
WO2009108118A1 (en) * 2008-02-27 2009-09-03 Astrazeneca Ab 16 alpha, 17 alpa-acetal glucocorticosteroidal derivatives and their use
WO2009112557A2 (en) * 2008-03-13 2009-09-17 Farmabios S.P.A. Process for the preparation of pregnane derivatives
WO2009112557A3 (en) * 2008-03-13 2010-01-21 Farmabios S.P.A. Process for the preparation of pregnane derivatives
US8338587B2 (en) 2009-04-03 2012-12-25 Astrazeneca Ab Compounds

Also Published As

Publication number Publication date
GB0110411D0 (en) 2001-06-20
WO2002088169A3 (en) 2003-01-09
AU2002307602A1 (en) 2002-11-11

Similar Documents

Publication Publication Date Title
WO2007054974A2 (en) A green chemistry process for the preparation of pregnadiene esters
JP4297994B2 (en) Novel 6-hydroxy and 6-oxo-androstane derivatives active on the cardiovascular system and pharmaceutical compositions containing them
US10112970B2 (en) Process for the preparation of 17-desoxy-corticosteroids
EP0262108A1 (en) A method of controlling the empimeric distribution in the preparation of 16,17-acetals or ketals of pregnane derivatives
AU725606B2 (en) Process for the preparation of 17-esters of 9alpha,21- dihalo-pregnane-11beta,17alpha-diol-20-ones
JP3746174B2 (en) Method for producing mometasone furoate
EP1242444B1 (en) Process for preparing 17alpha-acetoxy-11beta- 4-n,n-(dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione, intermediates useful in the process, and processes for preparing such intermediates
KR100809510B1 (en) Process for the production of 16,17-[cyclohexylmethylenbis0xy]-11,21-dihydroxy-pregna-1,4-dien-3,20-dion or its 21-isobutyrat by transketalisation
JPH05170788A (en) New steroid derivatives of pregna-1,4-diene-3,20-diones, their production, their use in production of substituted 16,17-methylenedioxy derivatives and new intermediates
WO2002088169A2 (en) Preparation of glucocorticosteroids, 16, 17 acetals or ketals of pregnane derivatives
JPS6244560B2 (en)
JPH075629B2 (en) Novel steroid compound and pharmaceutical composition containing the same
JPH0665283A (en) New process for producing 20-keto-21alpha-hydroxysteroid compound and intermediate
CS250695B2 (en) Method of pregnane derivatives production
US4565656A (en) Preparation of 17β-hydroxyacetyl-17α-ol-steroids
EP0994119B1 (en) Stereoselective process for the preparation of the 22R epimer of budesonide
CS232737B2 (en) Method of production of new delta (1,3,5)-3-chloropregnane derivatives
JPH0565294A (en) 20-isocyano-20-sulfonyl-delta 16-steroid and process for producing same
JP2004538294A (en) Stereoselective production method of 6α-fluoropregnane and intermediate
US6861521B2 (en) Stereoselective transacetalization of steroidal C-22 acetonide
KR820001643B1 (en) Process for the preparation of 6-halo-pregrnanes
JPH09118687A (en) Production of 17-alpha-hydroxy-20-oxopregnane, and its production intermediate

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 BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE 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 NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE 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 NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP