Title of Invention	"THE PREPARATION PROCESS FOR 16β-METHYL 17α-HYDROXY PREGNA 4,9(11)-DIENE 3,20-DIONE"
Abstract	The present invention relates to the preparation process for 16ß-methyl 17α-hydroxy pregna 4,9(1 l)-diene 3,20-dione of formula I:

Full Text

A subject of the present invention is a preparation process for 16ß-methyl 17α-hydroxy pregna 4,9(1 l)-diene 3,20-dione. Therefore a subject of the invention is a preparation process for the compound of formula(I): (Formula Removed) characterized in that a compound of formula (II) (Formula Removed) in which rings A and B represent a remainder: (Formula Removed) in which K represents an oxo radical or a protector group of the oxo radical of formula: ( C H 9 ) n or ( C H n is equal to 2 or 3 and R± represents an ether or ester remainder, is treated with a dehydration agent, in order to obtain a compound of formula (III): (Figure Remove)in which A and B have the meaning already indicated, which, when K represents an oxo radical, is subjected to the action of a suitable blocking agent of the oxo radical, in order to obtain the corresponding compound of formula (III), in which K has values different from the oxo radical, as defined previously, which compound of formula (III) is subjected to the action of an organometallic methylation agent, in order to obtain after hydrolysis of the intermediate imine, a methyl ketone of formula (IV): (Figure Remove)which is treated in a basic medium with an epoxidation agent in order to obtain a compound of formula (V): (Figure Remove) the 20-keto function of which is protected, in order to obtain a compound of formula (VI): (Figure Remove)in which K' represents a protector group of the ketone function identical to or different from K, of formula: (Figure Remove)n being defined as previously, which is treated with an organometallic methylation agent, in order to obtain the lep-methyl derivative of formula (VII): (Figure Remove)of which the ketone functions in positions 3 and 20 are unblocked, in order to obtain the expected product of formula (I). When R^ represents an ether remainder, it can be any remainder known to a man skilled in the art for blocking position 3 in this form and in particular it can be an alkyl radical containing 1 to 6 carbon atoms, an alkoxyalkoxyalkyl radical containing 3 to 8 carbon atoms, an aryl radical containing 6 to 10 carbon atoms or an aralkyl radical containing 7 to 12 carbon atoms. When Rx represents an alkyl radical, it is for example a methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl radical. When R! represents an alkoxyalkoxyalkyl radical, it isfor example a methoxyethoxymethyl radical. When R! represents an aralkyl radical, it is for example a benzyl or phenethyl radical. When R± represents an aryl radical, it is for example a phenyl radical or a phenyl radical substituted, in particular, by one or more alkyl radicals. When R-L represents an ether remainder, it can also be a silylated group, for example a trialkylsilyl group such as trimethylsilyl, tert-butyl dimethylsilyl or also for example a triarylsilyl group such as triphenylsilyl or a diarylalkyl-silyl group such as diphenyl tert-butylsilyl. When R-L represents an ester remainder, it can be any remainder known to a man skilled in the art for blocking position 3 in this form and in particular it can be a -COR.^ remainder, R^ being an alkyl, aryl or aralkyl radical as defined above. The protection of the ketone function in position 3 is carried out by methods known to a man skilled in the art. Thus there can be used in particular a mixed diol, dithiol or thiol of formula HO-(CH2)n-OH, HS-(CH2)n-SH or HO-(CH2)n~SH, in an acid medium, for example in the presence of concentrated hydrochloric or hydrobromic acid, in catalytic quantity, p-toluene sulphonic acid, or also in the presence of a Lewis acid such as zinc chloride, titanium tetrachloride or boron trifluoride preferably in the form of the etherate. There can also be used methylethyl dioxolane in the presence of an acid, for example one of those named above. There can also be used an alkyl, alkoxyalkoxyalkyl, aralkyl or aryl halide, in the presence of a base intermediately forming the enolate, for example a hydride, an alcoholate or an alkaline hydroxide. There can also be used a trialkyl, triaryl or diaryl-alkylsilyl halide in an alkaline medium as above. There can also be used a suitable acid chloride, operating in the presence of a base, which can be a nitrogenous base, for example triethylamine, pyridine, dimethylaminopyridine, or a mineral base, in particular a hydride, an alcoholate or an alkaline hydroxide. The dehydration agent is in particular phosphorus oxychloride, used preferably in the presence of a tertiary amine such as pyridine. There can also be used a Lewis acid such as ferric chloride, boron trifluoride and its complexes, for example the etherate, titanium tetrachloride, aluminium chloride or also tin chloride, a mineral acid such as sulphuric acid, a sulphonic acid such as paratoluene sulphonic acid or chlorosulphonic acid or a derivative such as methane sulphonyl chloride. The organometallic methylation agent producing themethylketone is for example a magnesium compound, a lithium compound, a cadmium compound or also a derivative of copper such as CH3Cu, (CH3)2CuMg or (CH3)2CuLi. A magnesium compound such as a methylmagnesium halide or methyllithium is more particularly preferred. The operation is carried out in a solvent which is preferably an ether such as ethyl ether, tetrahydrofuran or dioxane, but which can also be an aromatic solvent such as toluene or xylene. The operation can also be carried out in an ether-aromatic solvent mixture. The hydrolysis of the intermediately-formed imine is carried out using an aqueous acid, for example acetic acid, formic acid or a mineral acid such as hydrochloric acid. The epoxidation agent can be a peracid such as meta-chloroperbenzoic acid, perphthalic acid, pertungstic acid or also hydrogen peroxide used alone or in the presence of hexachloro- or hexafluoroacetone. The epoxidation agent can also be a hydroperoxide such as tertbutyl hydroperoxide, used in the presence of vanadium acetyl acetonate or other metals such as molybdenum, in catalytic quantity. Hydrogen peroxide is more particularly preferred. The operation is carried out in a slightly basic medium, either in the presence of a base, for example soda, or in a medium buffered, for example, with sodium acetate, disodium phosphate or sodium bicarbonate or by a trisodium phosphate - phosphoric acid mixture. The operation is carried out in an organic solvent such as methylene chloride, carbon tetrachloride, chloroform, methanol, tetrahydrofuran, dioxane, toluene, ethyl acetate or a mixture of these solvents, if appropriate in the presence of water. The protection of the 20-keto function is carried out in the form of the ketal, mixed ketal or dithioketal, by methods known to a man skilled in the art. Thus there can be used a mixed diol, dithiol or thiol of formula HO-(CH2)n-OH, HS-(CH2)n-SH or HO-(CH2)n-SH, in an acid medium, for example in the presence of concentrated hydrochloric or hydrobromic acid, in catalytic quantity, p-toluene sulphonic acid, or also in the presence of a Lewis acid such as zinc chloride, titanium tetrachloride or boron trifluoride preferably in the form of the etherate. The organometallic methylation agent which is reacted with the epoxide of formula (VI) is one of those which have been mentioned above, the preferred agents also being those which have been mentioned such as those above. The release of the ketone functions in positions 3 and 20 is carried out by means appropriate to the nature of the protector group. An acid agent in the presence of water or a water - alkanol mixture is used in the case of a ketal. It is for example a mineral or organic acid such as hydrochloric, hydrobromic, sulphuric, perchloric, nitric, paratoluene sulphonic, acetic, formic, oxalic acid or a mixture of acids, or also an acid resin, for example a sulphonic resin. In the case of a thioketal or a mixed ketal, the deprotection is carried out by the action of iodine in the presence of a base, for example an alkaline bicarbonate, or by the action of iodine in catalytic quantity, in the presence of an oxidizing agent, in particular hydrogen peroxide, by the action of methyl iodide, glyoxylic acid, or also the salts of metals, such as mercury, cadmium, copper or silver. The operation can, in general, be carried out in a solvent such as a lower alkanol, for example methanol or ethanol, mixed with a halogenated solvent, for example methylene chloride, in the presence of water. In the case of a mixed ketal, deprotection is also carried out for example with a mercuric salt such as mercuric chloride in the presence of an acetic acid/potassium acetate buffer at about 100°C, with Raney nickel under the same conditions as above or with a hot hydrochloric acid - acetic acid mixture. In the case where R-j^ represents an ether or ester remainder, an acid treatment is also used, in particular under the conditions described above for the ketal. A particular subject of the invention is a process as defined previously, characterized in that at the start a compound of formula (II) is used in which rings A and B represent a remainder: (Figure Remove) n being defined as previously and in particular equal to 2. Also a particular subject of the invention is a process as defined previously characterized in that the 20-keto function is protected by the same ketal as in position 3 and in particular by an ethylenedioxy group. Also a subject of the invention is, as new industrial products, and notably as intermediate products useful for implementing the process of the invention, the product of formula (III), in which K has the definitions indicated previously, with the exception of an oxo radical, as well as the products of formulae (IV), (V), (VI) and (VII) as defined previously. The products of formula (II) used at the start of the process of the invention are known or can be prepared from the 3-keto product, described in the European Patent No. 263569, by processes known to a man skilled in the art. Among the possible references, there can be mentioned the French Patent 1,079,781, the East German Patent 281,394 or the Application WO 88/03534. The product of formula (I) is an important intermediate in the synthesis of betamethasone as is described for example in the European Patent 54810. The following example illustrates the invention without however limiting it. EXAMPLE; 16p-methyl I7o-hydroxy pregna 4,9(11)-diene 3,20-dione Stage A: cyclic 3-(1,2-ethanediyl) acetal of 17-cyano androst-5,9(ll),16(17)-trien-3-one 30 g of cyclic 3-(1,2-ethanediyl) acetal of 17a-hydroxy 17p-cyano androst-5,9(11) dien-3-one and 240 cm of anhydrous pyridine are mixed together under an inert gas atmosphere then 30 cm3 of phosphorus oxychloride is added. The reaction medium is maintained under agitation for 2 hours in an oil bath at 40°C then for 18 hours at 45°C. The mixture is poured into a mixture of 450 g of ice, 240 cm3 of hydrochloric acid at 22°Be and 100 cm3 of water. Agitation is carried out at ambient temperature followed by separation, and the crystals are washed with water then dried. The crude product is suspended in an isopropyl ether - isopropanol mixture (2-1) then the crystals are separated off and dried. 24.27 g of expected product is obtained. M.p. = 205-208°C. IR spectrum; (CHC13) Absorptions at 2217 cm"1 (CN), 1660, 1630 and 1593 cm"1 (C=C). NMR spectrum: (CDC13 + C5D5N - 300 MHz - ppm) 0.91 (s): 18-CH3; 1.23 (s): 19-CH3; 3.96: ketal; 5.44 (m)-5.45 (m) : H6 and Hl;L; 6.65: H16. Stage B: cyclic 3-(1,2-ethanediyl) acetal of pregna 5,9(11),16(17)-triene-3,20-dione 9 g of the product obtained in Stage A and 27 cm3 of toluene are mixed together under an inert gas atmosphere, O then 27 cm0 of a 3M solution of methylmagnesium chloride in tetrahydrofuran is introduced. The reaction medium is taken to 60/65°C for 3 hours 30 minutes then cooled down using an ice-methanol bath and 36 cm3 of tetrahydrofuran is added, then it is poured, under a nitrogen pressure, at 10°C maximum, into a mixture of 81 cm3 of ice, 27 cm3 of water and 135 cm3 of acetic acid cooled down with an ice-methanol bath. The temperature is allowed to rise to about 20°C, concentration is carried out under reduced pressure by gently heating with a water bath at 45°C then the reaction medium is poured into 20 volumes of a water and ice mixture. The temperature is allowed to rise, under agitation, then the crystals are separated off, washed with water and dried. 9.03 g of crude product is obtained which is impasted in a mixture of 45 cm3 of methanol, 5 cm3 of water and 0.5 cm3 of triethylamine. After heating under reflux for one hour 30 minutes then cooling down to ambient temperature, the crystals are separated off, washed with methanol with 10% water and dried. 7.12 g of expected product is obtained. M.p. = 217-219°C. IR spectrum; (CHC13) Absorptions at 1664, 1590, 1361 cm"1: unsaturated , methyl ketone. NMR spectrum: (CDC13 + C5D5N - 300 MHz - ppm) 0.87 (s) : 18-CH3; 1.22 (s): 19-CH3; 2.26 (s): methyl-ketone; 3.94 (m): ketal; 5.44-5.45 (m): -CH= in positions 11 and 5; 6.71 (t): -CH= in position 16. Stage C; cyclic 3-(l,2-ethanediyl) acetal of 16a,17a-epoxy pregna 5,9(11)-diene-3,20-dione 7 g of the product obtained in Stage B, 70 cm3 of tetrahydrofuran and 35 cm3 of methanol are mixed together under an inert gas atmosphere. 7 cm3 of concentrated soda and 7 cm3 of hydrogen peroxide 200 volumes are introduced. The reaction medium is heated at 40/45°C for 17 hours then cooled down to ambient temperature and poured into a mixture of 70 cm3 of water and 70 g of ice. The mixture is maintained under agitation while allowing the temperature to rise then separation is carried out, followed by washing with water at the end of the oxidizing power and drying. 7.08 g of expected product is obtained, used as it is for the following stage. IR spectrum: (CHC13) Absorptions at 1704 (C=O), 901-855 cm"1 (epoxide). NMR spectrum; (CDC13 + C5D5N - 300 MHz - ppm) 1.00 (s): 18-CH3; 1.20 (s) : 19-CH3; 2.04 (s): methyl-ketone; 3.74 (s): -CH= in position 16; 3.94 (m): ketal; 5.40 (m) 5.51 (t): -CH= in positions 11 and 5. Stage D; cyclic 3,20 bis-(l,2-ethanediyl) acetal of 16a,17a- epoxy pregna 5,9(11)-diene-3,20-dione 4 g of the product obtained in Stage C, 40 cm3 of methylene chloride, 40 cm of ethylene glycol, 20 cm3 of ethyl orthoformate and 0.3 g of dihydrated paratoluene sulphonic acid are mixed together under an inert gas atmosphere. After 7 hours, concentration is carried out at a reduced pressure of 1 mbar at ambient temperature then the reaction medium is maintained under agitation for 30 minutes. Next it is poured into 300 cm of a 10% aqueous solution of sodium bicarbonate then degassed for 30 minutes. After separation, the crystals formed are washed with water then dried. The product is purified by chromatography on silica eluting with a toluene - ethyl acetate mixture (8-2) with 0.05% of triethylamine. The product obtained is taken up in cyclohexane, separated and dried under reduced pressure. 3.28 g of expected product is obtained. M.p. = 176-177°C. IR spectrum: (CHC13) Absence of C=0. Presence of ketal. NMR spectrum; (CDC13 + C5D5N - 300 MHz - ppm) 0.94 (s): 18-CH3; 1.20 (s): 19-CH3; 1.42 (s) : CH3~; 3.41 (s) : H in position 16; 3.85 to 4.05: ketal; 5.41 and 5.48: H in position 6 and H in position 11. Stage E; cyclic 3,20 bis-(1,2-ethanediyl) acetal of 16p-methyl 17a-hydroxy pregna 5,9(11)-diene-3,20-dione 24 cm3 a 3M solution of methyl magnesium bromide in ether is ice-cooled under an inert gas atmosphere. The solvent is evaporated off under reduced pressure and by warming with a bath at 60/65°C. Next 21 cm3 of tetrahydrofuran and 3 g of the product obtained in Stage D are introduced, then agitation is carried out for 16 hours while taking the temperature of the bath to 70°C. 4 cm3 of an ethereal solution of the above magnesium compound and 10 cm of tetrahydrofuran are added and agitation is carried out for 7 hours. A further 10 cm3 of tetrahydrofuran is added, the whole is maintained under reflux for 16 hours then cooled down to 40°C and poured into a mixture maintained at 0°C of 16 g of dihydrated sodium acid phosphate and 900 cm3 of water. The temperature is allowed to rise then separation is carried out and the product is washed with water and dried. The product is purified by impasting in 15 volumes of a methylene chloride - ethyl acetate mixture (9-1) with 0.05% of triethylamine, then by chromatography on silica, eluting with the same mixture and 2.42 g of expected product is obtained. M.p. = 180-18l°C. IR Spectrum; (CHC13) Absorptions at 3580 cm"1: OH; 1670-1644 cm"1: C=C. NMR spectrum: (CDC13 + C5D5N - 300 MHz - ppm) 0.87 (s): 18-CH3; 1.19 (d): CH3-CH-; 1.20 (s): 19-CH3; 1.39 (s): CH3-C-; 3.85 to 4.05: ketals; 5.45 and 5.48: H in position 6 and H in position 11. Stage F: lep-methyl 17a-hydroxy pregna 4,9(11)-diene 3,20-dione 2 g of the product obtained in Stage E, 15 cm3 of acetone and 5 cm3 of water are mixed together under an inert gas atmosphere. 4 drops of concentrated sulphuric acid are introduced and the mixture is heated for 4 hours 30 minutes in a bath at 60°C. Next 20 cm3 of water is added then the reaction medium is allowed to cool down, the crystals are separated off and washed with water then dried. 1.55 g of expected product is obtained. M.p. = 173°C. IR spectrum: (CHC13) Absorptions at 3610 cm"1: -OH; 1709-1353 cm"1: CO-CH3; 1663-1616 cm"1: 3 A 4 keto. NMR spectrum: (CDC13 - 300 MHz - ppm) 0.87 (s): 18-CH3; 1.19 (d, J = 7): CH3-CH-; 1.34 (s): 19-CH3; 2.27 (s): -CO-CH3; 3.01 (s): 1H mobile; 5.52 (m): H in position 11; 5.75 (m): H in position 4. WE CLAIM: 1. The preparation process for 16ß-methyl 17α-hydroxy pregna 4,9(1 l)-diene 3,20-dione of formula (I): (Formula Removed) characterized in that a compound of formula (II): (Formula Removed) in which rings A and B represent a remainder: (Formula Removed) in which K represents an oxo radical or a protector group of the oxo radial of formula: n is equal to 2 or 3 and Rl represents an ether or ester remainder, is treated with a dehydration agent, in order to obtain a compound of formula (III): (Formula Removed) in which A and B have the meaning already indicated, which, when K represents an oxo radical, is subjected to the action of a suitable blocking agent of the oxo radical, in order to obtain the corresponding compound of formula (III), in which K has values different from the oxo radical, as defined previously, which compound of formula (III) is subjected to the action of an organometallic methylation agent, in order to obtain after hydrolysis of the intermediate imine, a methyl ketone of formula (IV): (Formula Removed) which is treated in a basic medium with an epoxidation agent in order to obtain a compound of formula (V): (Formula Removed) the 20-keto function of which is protected, in order to obtain a compound of formula (VI): (Formula Removed) in which K' represents a protector group of the ketone function identical to or different from K, of formula: (Formula Removed) in being defined as previously, which is treated with an organometallic methylation agent, in order to obtain the 16 -methyl derivative of formula (VII): (Formula Removed) of which the ketone functions in positions 3 and 20 are unblocked, in order to obtain the expected product of formula (I). 2. Process as claimed in claim 1, characterized in that the dehydration agent is phosphorus oxychloride, used in the presence of a tertiary amine. 3. Process as claimed in claim 1, characterized in that the organometallic methylation agent is a methylmagnesium halide or methyllithium. 4. Process as claimed in claim 1, characterized in that the epoxidation agent is hydrogen peroxide, 5. Process as claimed in claim 1, characterized in that the organometallic methylation agent which is reacted with the epoxide of formula (VI) is one of those mentioned in claim 3. 6. Process as claimed in any one of claims 1 to 5, characterized in that a compound of formula (II) is used at the start in which rings A and B represent a remainder: (Formula Removed) n being defined as previously and in particular equal to 2. 7. Process as claimed in any one of claims 1 to 6, characterized in that the 20-keto function is protected by the same ketal as in position 3 and in particular by an ethylenedioxy group. 8. The preparation process for the compound of formula I as defined in claim 1 substantially as herein described with reference to the foregoing examples.

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