15-oxosteroid compound and process for producing the same

Abstract

Provided is a process for producing a compound, which has an oxo group specifically introduced on the 15-position of a steroid skeleton and which is useful as an intermediate, with a high yield without complicated steps. A compound represented by the formula (2) is allowed to react with an oxidant (e.g., a hypervalent iodine compound) and a co-oxidant (e.g., a peroxide) to produce a 15-oxosteroid compound represented by the formula (1), which is useful as an intermediate: ##STR00001##
wherein R.sub.1 to R.sub.3 are the same or different and each represent a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, or a haloalkoxy group, R.sub.4 represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acyl group, or an alkoxycarbonyl group, R.sub.5 represents a hydrogen atom, an alkyl group, or an acyl group, R.sub.6 represents a hydrogen atom, an alkyl group, an acyl group, or a sulfonyl group, X represents an oxygen atom (O) or a methylene group (CH.sub.2).

Claims

1. A 15-oxosteroid compound represented by the following formula (1): ##STR00011## wherein R.sub.1, R.sub.2, and R.sub.3 are the same or different and each represent a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, or a haloalkoxy group, R.sub.4 represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acyl group, or an alkoxycarbonyl group, R.sub.5 represents a hydrogen atom, an alkyl group, or an acyl group, R.sub.6 represents a hydrogen atom, an alkyl group, an acyl group, or a sulfonyl group, and X represents an oxygen atom (O) or a methylene group (CH.sub.2).

2. The 15-oxosteroid compound according to claim 1, which is represented by the following formula (1a): ##STR00012## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and X have the same meanings as defined in claim 1.

3. The 15-oxosteroid compound according to claim 1, wherein R.sub.1 is a halogen atom, R.sub.2 and R.sub.3 are the same or different and are an alkyl group or a haloalkyl group, R.sub.4 and R.sub.5 are the same or a different acyl group, R.sub.6 is a hydrogen atom, an acyl group, or a sulfonyl group, and X is an oxygen atom.

4. A process for producing a 15-oxosteroid compound recited in claim 1, the process comprising oxidizing a compound represented by the following formula (2): ##STR00013## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and X have the same meanings as defined in claim 1 with an oxidant and a co-oxidant.

5. The process according to claim 4, wherein a coexisting substance is added in the oxidation with the oxidant and the co-oxidant.

6. The process according to claim 4, wherein the oxidant contains a hypervalent iodine compound, and the co-oxidant contains a peroxide and/or a peroxy acid.

7. The process according to claim 4, wherein the compound is allowed to react with a hypervalent iodine compound and a peroxide in the presence of a strong acid in a solvent, then an alkali metal carbonate is added to the reaction system and the reaction is continued.

Description

DESCRIPTION OF EMBODIMENTS

(1) [15-Oxosteroid Compound]

(2) A compound represented by the above formula (1) is a novel compound and is useful for producing a compound having a high pharmacological activity (for example, an antiandrogenic activity).

(3) In the above formula (1), a halogen atom represented by each of R.sub.1 to R.sub.4 may include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The halogen atom may practically be a fluorine atom, a chlorine atom, or a bromine atom, particularly a fluorine atom or a chlorine atom.

(4) As examples of an alkyl group represented by each of R.sub.1 to R.sub.6, there may be mentioned a straight-chain or branched-chain C.sub.1-12alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, hexyl group, or octyl group. The alkyl group is usually a straight-chain or branched-chain C.sub.1-6alkyl group, preferably a straight-chain or branched-chain C.sub.1-4alkyl group, and more preferably a straight-chain or branched-chain C.sub.1-3alkyl group.

(5) An alkoxy group represented by each of R.sub.1 to R.sub.4 may include an alkoxy group corresponding to the alkyl group, for example, a straight-chain or branched-chain C.sub.1-12alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, or t-butoxy group. The alkoxy group is usually a straight-chain or branched-chain C.sub.1-6alkoxy group, preferably a straight-chain or branched-chain C.sub.1-4alkoxy group, and more preferably a straight-chain or branched-chain C.sub.1-3alkoxy group.

(6) As examples of a halogen atom in a haloalkyl group and a haloalkoxy group represented by each of R.sub.1 to R.sub.3, there may be mentioned the halogen atom exemplified in the above. The halogen atom is usually a fluorine atom, a chlorine atom, or a bromine atom, particularly a fluorine atom or a chlorine atom. Examples of the haloalkyl group may include a straight-chain or branched-chain haloC.sub.1-12alkyl group such as chloromethyl group, trichloromethyl group, fluoromethyl group, trifluoromethyl group, 2,2,2-trichloroethyl group, perchloroethyl group, 2,2,2-trifluoroethyl group, perfluoroethyl group, or perfluoroisopropyl group. The haloalkyl group is usually a straight-chain or branched-chain haloC.sub.1-6alkyl group such as trichloromethyl group or trifluoromethyl group, preferably a haloC.sub.1-4alkyl group, and more preferably a haloC.sub.1-3alkyl group.

(7) As examples of the haloalkoxy group represented by each of R.sub.1 to R.sub.3, there may be mentioned a haloalkoxy group corresponding to the haloalkyl group, for example, a straight-chain or branched-chain haloC.sub.1-12alkoxy group such as trichloromethoxy group, trifluoromethoxy group, perchloroethoxy group, perfluoroethoxy group, or perfluoropropoxy group. The haloalkoxy group is usually a straight-chain or branched-chain haloC.sub.1-6alkoxy group such as trichloromethoxy group or trifluoromethoxy group, preferably a haloC.sub.1-4alkoxy group, and more preferably a haloC.sub.1-3alkoxy group.

(8) An acyl group represented by each of R.sub.4, R.sub.5, and R.sub.6 may include, for example, formyl group; a straight-chain or branched-chain C.sub.1-12alkyl-carbonyl group such as acetyl group, propionyl group, butyryl group, isobutyryl group, t-butyryl group, pentanoyl group (valeryl group), or hexanoyl group; a C.sub.3-10cycloalkyl-carbonyl group such as cyclohexylcarbonyl group; a C.sub.6-12aryl-carbonyl group which may have a substituent (such as a C.sub.1-4alkyl group, a halogen atom, or a nitro group), e.g., benzoyl group, toluoyl group, or naphthoyl group; and a heterocyclic acyl group having at least one hetero atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom (such as furoyl group, nicotinoyl group, or isonicotinoyl group). The acyl group is usually an alkylcarbonyl group, for example, a straight-chain or branched-chain C.sub.1-6alkyl-carbonyl group, preferably a C.sub.2-4alkyl-carbonyl group, and more preferably a C.sub.2-3alkyl-carbonyl group.

(9) An alkoxycarbonyl group represented by R.sub.4 may include, for example, a straight-chain or branched-chain C.sub.1-12alkoxy-carbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, or hexyloxycarbonyl group. The alkoxycarbonyl group is usually a straight-chain or branched-chain C.sub.1-6alkoxy-carbonyl group, preferably a C.sub.1-4alkoxy-carbonyl group, and more preferably a C.sub.1-3alkoxy-carbonyl group.

(10) As examples of a sulfonyl group represented by R.sub.6, there may be mentioned a C.sub.1-6alkanesulfonyl group such as methanesulfonyl group, ethanesulfonyl group, or t-butanesulfonyl group, and a C.sub.6-12arenesulfonyl group which may have a substituent (such as a C.sub.1-4alkyl group, a halogen atom, or a nitro group), e.g., benzenesulfonyl group or toluenesulfonyl group.

(11) X may be either an oxygen atom (O) or a methylene group (CH.sub.2).

(12) In the 15-oxosteroid compound represented by the above formula (1), R.sub.1 may practically be a halogen atom (e.g., a fluorine atom or a chlorine atom) and R.sub.2 and R.sub.3 may practically be the same or different and each represent an alkyl group (e.g., a straight-chain or branched-chain C.sub.1-4alkyl group) or a haloalkyl group (e.g., a straight-chain or branched-chain C.sub.1-4alkoxy group). Moreover, in practical cases, R.sub.4 and R.sub.5 may be the same or a different acyl group, for example, an alkylcarbonyl group (e.g., a straight-chain or branched-chain C.sub.1-4alkyl-carbonyl group), R.sub.6 may be a hydrogen atom or an acyl group (e.g., an alkylcarbonyl group such as a straight-chain or branched-chain C.sub.1-4alkyl-carbonyl group), and X may be an oxygen atom (O).

(13) The 15-oxosteroid compound represented by the formula (1) may be a racemate or may be an optical isomer. A preferred 15-oxosteroid compound includes an optically active substance (an optical isomer) represented by the following formula (1a):

(14) ##STR00006##

(15) wherein R.sub.1 to R.sub.6 and X have the same meanings as defined above.

(16) The 15-oxosteroid compound represented by the above formula (1) or (1a) may have a physiological activity or a pharmacological activity. Use of the 15-oxosteroid compound of the present invention as an intermediate provides a compound having a physiological activity or a pharmacological activity simply with a high yield. For example, in the formula (1) or (1a), the group OR.sub.6 on the 7-position of the steroid skeleton may be eliminated with a usual method to prepare a compound which is represented by the following formula (3) or (3a) and which is described in the Nonpatent Document 1 (such as Compound

(17) ##STR00007##

(18) wherein R.sub.1 to R.sub.5 and X have the same meanings as defined above.

(19) Concretely, for example, the compound represented by the above formula (1) in which the group OR.sub.6 is hydroxyl group may be, for example, subjected to a dehydration reaction in the presence of an eliminating agent (such as thionyl chloride, phosphorus oxychloride, or Martin sulfurane) to prepare the compound represented by the formula (3) or (3a).

(20) Moreover, in a case where the compound has an alkoxy group as the group OR.sub.6, the alkoxy group may be converted into hydroxyl group with an action of an acid (for example, sulfuric acid, hydriodic acid, and hydrobromic acid) and subjected to the same dehydration reaction as above, thus preparing the compound represented by the formula (3) or (3a).

(21) In a case where the compound has an acyloxy group (such as acetyloxy group) or a sulfonyloxy group as the group OR.sub.6, the group OR.sub.6 may be eliminated (or liberated) by subjecting the compound to an elimination reaction in the presence of a basic solvent or a base (e.g., an alkali metal hydroxide, an alkali metal carbonate, and an alkali metal acetate such as sodium acetate or potassium acetate).

(22) [Process for Producing 15-Oxosteroid Compound]

(23) The 15-oxosteroid compound represented by the above formula (1) may be prepared by oxidizing the compound represented by the following formula (2). Even in a case where the compound represented by the following formula (2a) is oxidized, the optically active substance represented by the formula (1a) may be prepared while maintaining the configuration (steric configuration).

(24) ##STR00008##

(25) In the formulae, R.sub.1 to R.sub.6 and X have the same meanings as defined above.

(26) The compound represented by the above formula (2) or (2a) is a known substance. For example, the compound in which RE is hydroxyl group and the compound in which R.sub.6 is acetyl group are described as Compound 11 and Compound 13 in Chart 2 of Chem. Pharm. Bull. 40(4), 935-941 (1992). Thus, the compound represented by the formula (2) or (2a) may be prepared in accordance with the method described in this document, or if possible, may be commercially available one.

(27) The oxidation reaction may be carried out using an oxidant and a co-oxidant.

(28) Examples of the oxidant may include a hypervalent iodine compound (an organic periodide or a catalyst), e.g., iodosobenzene diacetate (or iodobenzene diacetate), [bis(trifluoroacetoxy) iodo]benzene, (di-tert-butylcarbonyloxyiodo)benzene, (hydroxytosyloxyiodo)benzene (Koser reagent), (difluoroiodo)toluene, 2-iodoxybenzoic acid, 2-iodoxybenzenesulfonic acid, iodosylbenzene, and iodoxybenzene. Moreover, the oxidant may be an active species or the above-mentioned catalyst generated from an organoiodine compound in the reaction system. These oxidants may be used alone or in combination. A preferred oxidant includes iodobenzene diacetate, [bis(trifluoroacetoxy)iodo]benzene, or other oxidants.

(29) The amount of the oxidant may be, for example, about 0.1 to 50 mol, preferably about 0.5 to 25 mol (e.g., about 1 to 20 mol), and more preferably about 2 to 10 mol (e.g., about 3 to 8 mol), relative to 1 mol of the compound represented by the formula (2).

(30) The co-oxidant may include a peroxide, for example, hydrogen peroxide, tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide, tert-amyl hydroperoxide, di-tert-amyl peroxide, cumene hydroperoxide, dicumyl peroxide, tert-butyl cumyl peroxide, tert-butyl peroxypyvalate, benzoyl peroxide, lauroyl peroxide, and ethylbenzene hydroperoxide; a peroxy acid, for example, peracetic acid, trichloroperacetic acid, trifluoroperacetic acid, perbenzoic acid, and p-nitroperbenzoic acid; and Oxone, for example, a potassium salt of persulfuric acid (potassium peroxymonosulfate). These co-oxidants may also be used alone or in combination. As the co-oxidant, practically used may be the peroxide or the peroxy acid, for example, the peroxide such as tert-butyl hydroperoxide (TBHP).

(31) The amount of the co-oxidant may be, for example, about 0.1 to 100 mol (e.g., about 1 to 50 mol), preferably about 1.5 to 30 mol, and more preferably about 5 to 25 mol (e.g., about 5 to 15 mol), relative to 1 mol of the compound represented by the formula (2).

(32) The oxidation reaction may be carried out in the coexistence of a coexisting substance (for example, an acid, a base, and a salt). The reaction in the presence of such a coexisting substance may improve the yield of an object compound.

(33) The acid may be any of an inorganic acid, an organic acid, and a Lewis acid. As examples of the inorganic acid, there may be mentioned a mineral acid such as hydrochloric acid, hydrogen chloride, hydrobromic acid, hydrogen bromide, sulfuric acid, sulfurous acid, fuming sulfuric acid, nitric acid, fuming nitric acid, nitrous acid, phosphoric acid, boric acid, hydrofluoboric acid, carbonic acid, or silicic acid.

(34) The organic acid may include an organic carboxylic acid compound and a sulfonic acid compound. As examples of the organic carboxylic acid compound, there may be mentioned an alkanecarboxylic acid which may have a halogen atom, such as formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, caproic acid, or lauric acid; a hydroxycarboxylic acid such as glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; a cycloalkanecarboxylic acid such as cyclohexanecarboxylic acid; a dicarboxylic acid or polycarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutamic acid, adipic acid, fumaric acid, maleic acid, or aconitic acid; and an arenecarboxylic acid or polycarboxylic acid such as benzoic acid, phthalic acid, mellitic acid, or cinnamic acid. Examples of the sulfonic acid compound may include an alkanesulfonic acid which may have a halogen atom, such as methanesulfonic acid or trifluoromethanesulfonic acid; an arenesulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid; and a cycloalkanesulfonic acid which may be a bridged cyclic compound, such as camphorsulfonic acid.

(35) The Lewis acid may include, for example, scandium trifluoromethanesulfonate and iron trifluoromethanesulfonate.

(36) These acids may be used alone or in combination. A preferred acid includes a strong acid, for example, an inorganic acid such as sulfuric acid, a haloalkanecarboxylic acid such as trifluoroacetic acid, and sulfonic acid. Practically used may be sulfuric acid.

(37) The amount of the acid (or acid catalyst) is not particularly limited to a specific one and may be, for example, about 0.0001 to 0.1 equivalents, preferably about 0.0005 to 0.05 equivalents, and more preferably 0.001 to 0.01 equivalents, relative to 1 mol of the compound represented by the formula (2).

(38) The base may include an inorganic base and an organic base. As examples of the inorganic base, there may be mentioned an alkali metal carbonate or hydrogen carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate; an alkali metal alkoxide such as t-butoxypotassium; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; an alkaline earth metal hydroxide such as calcium hydroxide or barium hydroxide; a polyvalent metal hydroxide such as aluminum hydroxide; and an alkylated alkali metal such as n-butyllithium. Examples of the organic base may include a tertiary amine such as pyridine or triethylamine. These bases or salts may also be used alone or in combination. As the base, the alkali metal carbonate, for example, potassium carbonate, may practically be used.

(39) The salt (including an inorganic halide) may include an inorganic salt, an organic acid salt, and a transition metal complex (or complex salt). As examples of the inorganic salt, there may be mentioned an inorganic acid salt, for example, a metal halide, e.g., an alkali metal halide such as sodium chloride, potassium chloride, or potassium bromide, and an alkaline earth metal halide such as calcium chloride; an alkali metal sulfate such as sodium sulfate or potassium sulfate, an alkaline earth metal sulfate such as magnesium sulfate, calcium sulfate, or barium sulfate, and a polyvalent metal sulfate such as aluminum sulfate, copper sulfate, iron sulfate, nickel sulfate, or cobalt sulfate; an alkali metal nitrate such as sodium nitrate or potassium nitrate, an alkaline earth metal nitrate such as magnesium nitrate or barium nitrate, and a polyvalent metal nitrate such as nickel nitrate. As examples of the organic acid salt, there may be mentioned a carboxylic acid salt (e.g., an acetate) such as magnesium acetate or manganese acetate. The transition metal complex (or complex salt) may include a cobalt complex. These salts may be a neutral salt.

(40) The amount of the base or salt may be, for example, about 0.1 to 15 mol, preferably about 0.5 to 10 mol, and more preferably about 1 to 7 mol (e.g., about 2 to 6 mol), relative to 1 mol of the compound represented by the formula (2).

(41) The coexisting substance may positively coexist with the oxidant and the co-oxidant in the reaction, and the timing for the addition of the coexisting substance to the reaction system is not particularly limited to specific manner. The coexisting substance may be added to the reaction system in advance before the addition of the oxidant and the co-oxidant or may be added after the addition of the oxidant and the co-oxidant.

(42) The reaction may be carried out in a solvent. The solvent may include various solvents (particularly, a solvent inert or inactive to the reaction), for example, an ether-series solvent (e.g., a chain ether compound such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, or cyclopentyl methyl ether, and a cyclic ether compound such as tetrahydrofuran or dioxane), a hydrocarbon-series solvent [e.g., an aromatic hydrocarbon-series solvent (such as benzene, toluene, xylene, or chlorobenzene) and an aliphatic hydrocarbon-series solvent (such as pentane, hexane, heptane, or octane)], an amide-series solvent (such as N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone), an alcoholic solvent (e.g., an alkanol such as methanol, trichloromethanol, trifluoromethanol, ethanol, trifluoroethanol, trichloroethanol, n-propanol, 2-propanol, n-butanol, s-butanol, t-butanol, pentanol, or hexanol; a cycloalkanol such as cyclopropanol, cyclobutanol, cyclopentanol, or cyclohexanol; a diol such as ethylene glycol, 1,3-propanediol, 1,4-butanediol, or 1,5-pentanediol; and a polyhydric alcohol such as glycerin), an ester-series solvent (such as methyl acetate, ethyl acetate, or isopropyl acetate), a nitrile-series solvent (such as acetonitrile, propionitrile, or benzonitrile), a nitroalkane-series solvent (nitromethane, nitroethane), and a basic nitrogen-containing solvent (a tertiary amine, for example, a trialkylamine such as triethylamine, and a cyclic amine such as pyridine or quinoline). These solvents may be used alone or as a mixed solvent. A preferred solvent may be a mixed solvent containing at least two kinds of organic solvents, for example, a mixed solvent of 2,2,2-trifluoroethanol and chlorobenzene.

(43) The reaction may be carried out at a temperature of about 50 C. to 50 C. (for example, about 30 C. to 0 C.), and the atmosphere may be, for example, an oxygen-containing atmosphere (e.g., in air) or an inert atmosphere. Moreover, the reaction may usually be carried out while continuously or intermittently adding a strong oxidant to the reaction system.

(44) The reaction in the presence of the base or the salt may also be carried out at a temperature of about 50 C. to 50 C. (for example, about 30 C. to 0 C.) as described above.

(45) After the completion of the reaction, the reaction mixture may be separated and purified by a usual separation and purification means, for example, a method such as solvent extraction, neutralization, concentration, washing, crystallization, or recrystallization, to give an object compound with a high yield.

(46) Incidentally, the Nonpatent Document 2 discloses the oxidation reaction of a substrate such as acetyloxycyclopentane with the oxidant and the co-oxidant in the presence of the acid. However, in the Nonpatent Document 2, an object compound is only obtained with a low yield. In contrast, according to the present invention, oxidizing the compound having the specific substituent at the 7-position of the steroid skeleton can selectively or specifically introduce an oxo group on the 15-position of the steroid skeleton, while maintaining an optical activity for an optically active substance, and can produce an object compound with high conversion and selectivity.

EXAMPLES

(47) The following examples are intended to describe this invention in further detail and should by no means be interpreted as defining the scope of the invention.

Example 1

(48) ##STR00009##

(49) The above compound (2a-1) was subjected to an oxidation reaction to give the above compound (1a-1).

(50) Specifically, a mixture of 6-chloro-7-hydroxy-3,20-dioxo-2-oxapregn-4-en-17-yl acetate (the above compound (2a-1), 90.0 g), 2,2,2-trifluoroethanol (162 mL), and chlorobenzene (2.520 L) was cooled to 242 C., and iodobenzene diacetate (409.2 g) and sulfuric acid (0.3 mL) was added thereto. To the resultant mixture was added dropwise a tert-butyl hydroperoxide aqueous solution (301 mL) having a concentration of 70% at the same temperature, and the resulting mixture was stirred for 40 minutes while maintaining the above temperature. To the reaction mixture was added potassium carbonate (131.8 g) while maintaining the above temperature, and the resulting mixture was stirred for 44 hours at the same temperature.

(51) The resulting reaction mixture was poured into a cooled solution containing sodium pyrosulfite (90.0 g) and sodium chloride (540.0 g) in water (1.53 L) and having a temperature of 2 C., the reaction vessel was washed with ethyl acetate (720 mL), and the combined mixture was stirred at a room temperature. The resulting mixture was separated into an upper layer (or phase) and a lower layer (or phase), and the lower layer was re-extracted with ethyl acetate (360 mL). These upper layers were combined, and the combined upper layers were washed with a solution containing sodium dihydrogen phosphate (180.0 g) and sodium chloride (270.0 g) in water (1.8 L) and having a pH of 7.5 adjusted with sodium hydroxide having a concentration of 30% by weight. Then, the resulting organic layer was washed with a solution containing sodium chloride (225.0 g) in water (720 ml), and the washed layer was concentrated at a temperature of not higher than 50 C. under a reduced pressure until the remaining amount was reduced to about 2.52 L. The concentrate was stirred vigorously, and heptane (5.4 L) was added thereto. The resulting mixture was stirred at 18 C. overnight. The precipitated crystal was collected by filtration and was washed with heptane (315 mL). The resulting crude crystal was dissolved in a mixture of acetone (378 mL) and water (38 mL), and water (1.44 L) was added thereto with vigorous stirring. The resulting suspension was concentrated at a temperature of not higher than 50 C. under a reduced pressure until the remaining amount was reduced to about 1.44 L. The suspension was stirred for 75 minutes at 10 C., and the crystal was collected by filtration and was washed with water (270 mL). The resulting crystal was dried at 50 C. for 10 hours to give 6-chloro-7-hydroxy-3,15,20-trioxo-2-oxapregn-4-en-17-yl acetate (the above compound (1a-1), 65.2 g (70.1% yield)). The compound was purified by column chromatography (elution solvent n-hexane:ethyl acetate=1:1 to 1:2) to obtain an analytical sample.

(52) NMR: .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.83 (3H, s), 1.48 (3H, s), 1.49-1.71 (4H, m), 2.12-2.22 (1H, m), 2.14 (3H, s), 2.19 (3H, s), 2.46-2.56 (2H, m), 2.78 (1H, d, J=11.2 Hz), 3.49 (1H, d, J=20.0 Hz), 4.09, 4.22 (2H, ABq, J=10.8 Hz), 4.47 (1H, d, J=2.9 Hz), 5.04 (1H, brs), 6.01 (1H, s)

(53) MASS: m/z 438 (M.sup.+)

Example 2

(54) ##STR00010##

(55) The above compound (1a-1) was subjected to a dehydration reaction to give the above compound (3a-1).

(56) Specifically, a mixture of 6-chloro-7-hydroxy-3,15,20-trioxo-2-oxapregn-4-en-17-yl acetate (the above compound (1a-1), 9.35 g) and dichloromethane (240 ml) was cooled with ice under an argon atmosphere, and to the mixture was added dropwise a solution of Martin sulfurane (bis[,-bis (trifluoromethyl)benzenemethanolato]diphenylsulfur) (20 g) indichloromethane (110 ml). The resulting mixture was stirred at a room temperature overnight.

(57) The reaction mixture was concentrated under a reduced pressure. The resulting concentrate was purified by column chromatography (elution solvent n-hexane:ethyl acetate=1:1 to 2:3) to give 17-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,15,20-trione (the above compound (3a-1), 5.8 g (64.7% yield)).

Comparative Example

(58) In accordance with Chart 2 and the conditions of each reaction step described in the Nonpatent Document 1, Compound 12 was prepared from Compound 8 as a starting material via Compound 9 and Compound 10. The yield was 7.8%. Furthermore, Compound 16 was prepared from Compound 12 via Compound 13, Compound 14, and Compound 15a. The yield was 7.7%.

INDUSTRIAL APPLICABILITY

(59) The 15-oxosteroid compound of the present invention represented by the formula (1) can produce the compound having the oxo group on the 15-position of the steroid skeleton by the elimination of the group OR.sub.6. Thus, the compound of the present invention is useful as an intermediate for producing the compound having a high pharmacological activity (for example, an antiandrogenic activity).