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:
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)
with an aldehyde of the formula (III)
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)
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)
wherein 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). C. Reaction of a compound of the formula (VII)
wherein Y is halogen (such as chlorine, bromine, iodine) or mesylate or p-toluene- sulphonate, with a compound of the formula (VIII)
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)
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)
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 Na
2CO
3 (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.
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).
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).