WO2005095437A1

WO2005095437A1 - Method for producing steroid derivative

Info

Publication number: WO2005095437A1
Application number: PCT/JP2005/006035
Authority: WO
Inventors: Iwao Chujo; Koji Suzuki
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 2004-03-30
Filing date: 2005-03-30
Publication date: 2005-10-13

Abstract

Disclosed is a method for producing a steroid derivative represented by the formula (IV) below which is characterized by reacting a compound represented by the formula (I) below, a compound represented by the formula (II) below and carbon monoxide in the presence of a palladium compound and a tertiary phosphine compound represented by the formula (III) below. Also disclosed is a method for producing a steroid derivative represented by the formula (V) below which is characterized by comprising a step wherein a steroid derivative represented by the formula (IV) is obtained by reacting a compound represented by the formula (I) below, a compound represented by the formula (II) below and carbon monoxide in the presence of a palladium compound and a tertiary phosphine compound represented by the formula (III) below. (I), (II), (III), (IV), (V)

Description

Method for producing steroid derivatives

Technical field

The present invention relates to a method for producing a steroid derivative useful as a synthetic intermediate of an estrone sulfatase inhibitor or a steroid 5a-reductase inhibitor.

Background art

[0002] A steroid compound having a perfluoroalkylsulfo-loxy group at the 17-position is reacted with carbon monoxide and an amine in the presence of a radium compound and a tertiary phosphine compound to give the perfluoroalkylsulfonyl- There have been some known methods for converting a rouxyl group into a carbamoyl group (see Patent Documents 1 to 4 and Non-Patent Documents 1 to 3). In the methods described in these references, when a primary amine is used as an amine, the aminocarbonitrile reaction proceeds in good yield, and the 17-perfluoroalkylalkylsulfo-loxy group can be efficiently converted to a hepvamoyl group. Can be. However, when secondary amines, especially bulky secondary amines, are used, the yields are moderate. Specifically, a reaction example using diacetoxybis (triphenylphosphine) palladium as a palladium compound and diisopropylamine as an amine is described, but the yields are not good at 59% and 67%, respectively (non-patent literature). 1 and Non-Patent Document 2). In addition, a reaction example using palladium acetate as a radium compound, triphenylphosphine as a tertiary phosphine compound, and diisopropylamine as an amine has been reported, but the yield is not as good as 59% (Patent Reference 4). A reaction example using palladium acetate as a palladium compound, 1,3-bis (diphenylphosphino) propane as a tertiary phosphine compound, and di-n-propylamine, diisopropylamine, or N-ethylisopropylamine as an amine has been reported. No description of the yield is! / 収率 (see Patent Document 2). The present inventors have tried to repeat this reaction using diisopropylamine, and the yield was 57%, which was not good. This is thought to be due to the fact that when a secondary amine is used, the reaction hardly progresses due to its steric hindrance, and the methods described in the above references are not excellent methods in terms of yield! First of all, it is not suitable for industrial mass production. [0003] Patent Document 1: WO 89/11282 pamphlet

Patent Document 2: WO 00/43408 pamphlet

Patent Document 3: JP 2001-322995 A

Patent Document 4: Japanese Patent Publication No. 03-504498

Non-Patent Document 1: Journal of Medicinal Chemistry, Vol. 33, p. 937 (1990)

Non-Patent Document 2: Journal of Medicinal Chemistry, Vol. 33, p. 943 (1990)

Non-Patent Document 3: Steroids, Vol. 63, 42δ (1998)

Disclosure of the invention

Problems to be solved by the invention

[0004] It is an object of the present invention to provide a method for producing a steroid derivative useful as an intermediate for synthesizing an estrone sulfatase inhibitor or a steroid 5-a-reductase inhibitor.

Means for solving the problem

[0005] The present invention relates to the following (1) to (9).

(1) Formula (I)

[0006] [Formula 1]

[Wherein, 2 represents a single bond or a double bond,

R ¹ is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted Substituted aryl, COR ^1A (wherein R ^1A is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl Alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl, or COOR ^1B (wherein R ^1B is ^1A )

R ² represents lower perfluoroalkyl. However, both nini located at bl and cl cannot be a double bond at the same time, and the compound represented by the formula (II)

[0008] [Formula 2]

HNR ³ R ⁴

(II)

(Wherein R ³ and R ⁴ are the same or different and are substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower Represents an alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl, or a substituted or unsubstituted alicyclic heterocyclic group wherein R ³ and R ⁴ are taken together with an adjacent nitrogen atom To form a palladium compound and a compound represented by the formula (III)

[0010] [Formula 3]

R ⁶

R ⁵ — P,

R ⁷

(III)

[0011] (wherein, R ⁵ represents a substituted or unsubstituted lower alkyl, and R ⁶ and R ⁷ are the same or different and represent a substituted or unsubstituted aryl). Reacting in the presence of a substance, characterized by the formula (IV) [0012] [Formula 4]

[0013] (where,

R ³ and R ⁴ are as defined above. However, both of the two located at b2 and c2 are not simultaneously a double bond).

(2) The process for producing a steroid derivative according to the above (1), wherein R ³ and R ⁴ are the same or different and are substituted or unsubstituted lower alkyl.

(3) R ¹ is COR ^la (where R ^la represents a substituted or unsubstituted lower alkyl) or COOR ^lb (where R ^lb is as defined above for R ^la ), and R ³ and R ^{4. The} method for producing a steroid derivative according to the above (1), wherein ⁴ is the same or different and is substituted or unsubstituted lower alkyl.

(4)!? ¹ is COCH or COOCH, R ² is trifluoromethyl, and R ³ and R ⁴ are

3 3

The method for producing a steroid derivative according to the above (1), which is propyl.

(5) The method for producing a steroid derivative according to (1) to (4) above, wherein R ⁵ is methyl and R ⁶ and R ⁷ are phenol.

(6) Palladium compound power The method for producing a steroid derivative according to any one of the above (1) to (5), which is a palladium compound.

(7) The method for producing a steroid derivative according to any one of the above (1) to (5), wherein the palladium compound is bis (dibenzylideneacetone) palladium or tris (dibenzylideneacetone) dipalladium.

Equation (8) (I) [0015] [Formula 5]

(Wherein ² , R ¹ and R ² have the same meanings as described above, provided that both of bl and cl are not simultaneously a double bond), Formula (II)

[0017] [Formula 6]

HNR ³ R ⁴

(II)

(Wherein R ³ and R ⁴ have the same meanings as defined above), respectively, and

, Palladium compound and formula (III)

[0019] [Formula 7]

(Hi)

(Wherein R ⁵ , R ⁶ and R ⁷ are as defined above) in the presence of a tertiary phosphine compound represented by the formula (IV)

[0021] [Formula 8]

(Where, two,

R ³ and R ⁴ are as defined above. However, located at b2 and c2 Wherein the two do not simultaneously form a double bond).

[Formula 9]

(Wherein R ³ and R ⁴ have the same meanings as described above), respectively.

(9) The method for producing a steroid derivative according to the above (8), wherein R ³ and R ⁴ are the same or different and are substituted or unsubstituted lower alkyl.

The invention's effect

The present invention provides a method for producing a steroid derivative useful as an intermediate for synthesizing an estrone sulfatase inhibitor or a steroid 5a-reductase inhibitor, and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the compounds represented by the formulas (I), (II), (III), (IV) and (V) are converted to the compounds (I), (II), (111) and (IV), respectively. ) And (V). The same applies to compounds of other formula numbers.

In the definition of each group of formulas (1), (11), (111), (IV) and (V),

As the lower alkyl, for example, a linear or branched alkyl having 1 to 10 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentinole, isopentyl, Neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, isootatyl, Noel, decyl and the like.

[0027] Examples of the cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, specifically, cyclopropynole, cyclobutynole, cyclopentynole, cyclohexynole, cycloheptinole, cyclooctyl, and the like.

As the lower alkenyl, for example, a linear, branched or cyclic C 2-8 alkyl Kale, specifically, bur, aryl, 1-probel, butyr, pentenyl, hexenyl, heptenyl, octenyl, cyclopentenyl, cyclohexeninole, 2,6-octactenyl, etc. .

As the lower alkynyl, for example, a straight-chain or branched alkynyl having 2 to 8 carbon atoms, specifically, ethur, 1-propyl, 2-propyl, butynyl, pentyl, pentyl, hexyl, heptyl And octyl.

Examples of aryl include monocyclic, bicyclic or tricyclic aryl having 6 to 14 carbon atoms, specifically, phenyl, naphthyl, indul, and anthral.

[0029] The alkylene portion of the aralkyl has the same meaning as the above-mentioned one from which one lower alkyl hydrogen atom is removed. The aralkyl part of the aralkyl includes, in addition to the groups mentioned in the definition of the aralkyl, for example, a bicyclic fused ring group condensed with a cycloalkyl, and specifically, indanyl, 1,2,3,4-tetrahydro Naphthyl, 6,7,8,9-tetrahydro-5H-benzocycloheptyl and the like.

[0030] The lower perfluoroalkyl includes, for example, a linear or branched perfluoroalkyl having 1 to 6 carbon atoms, specifically trifluoromethyl, pentafluoroethyl, heptafluoro. Propyl, heptafluoroisopropyl, nonafluorobutyl, nonafluoroisobutyl, pendecafluoropentyl, pendecafluoroisopentyl, tridecafluorohexyl and the like.

[0031] Examples of the alicyclic heterocyclic group formed together with an adjacent nitrogen atom include a 5- or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (such a monocyclic heterocyclic group). The cyclic heterocyclic group may contain another nitrogen atom, oxygen atom or sulfur atom), and a bicyclic or tricyclic condensed 3- to 8-membered ring containing at least one nitrogen atom A cyclic heterocyclic group (the condensed heterocyclic group may contain another nitrogen atom, an oxygen atom or a sulfur atom); and more specifically, pyrrolidinyl, piperidyl-containing piperazur, Examples thereof include thiomorpholino with morpholine, homopidragel with homopiberidi, tetrahydropyridinyl, tetrahydroquinolyl, and tetrahydroisoquinolinyl.

[0032] The substituents in the substituted lower alkyl, the substituted lower alkenyl and the substituted lower alkynyl may be the same or different and include, for example, halogens, amide-containing nitros and Mouth xy, oxo, mercapto, formyl containing carboxy, carbamoyl, cycloalkyl, lower alkylthio, lower alkyl sulfiel, lower alkyl sulfol, lower alkanolyl, lower alkoxycarbol, lower alkanol, substituted Lower alkanoyl [substituent (a) in the substituted lower alkanoyl may be the same or different and includes, for example, halogen having 1 to 3 substituents], lower alkoxy, substituted lower alkoxy [substituted lower alkoxy] The substituent has the same meaning as the substituent (a) in the above-mentioned substituted lower alkyl group.), A di-lower alkylamino-substituted di-lower alkylamino (the same substituents as those in the lower alkyl portion of the substituted di-lower alkylamino) are the same. Or different, e.g., halogen, hydroxy, carboxy having 1-3 Lower alkoxy, lower alkoxycarbol, etc.), aryl, substituted aryl (substituent (b) in the substituted aryl is the same or different and includes, for example, halogen, amino, nitro having 1 to 3 substituents) , Hydroxy, mercapto, cyano, carboxy, carbamoyl, cycloalkyl, lower alkoxycarbol, lower alkanoyloxy, di-lower alkylaminoaryloxy, aralkyloxy, lower alkyl, substituted lower alkyl [in the substituted lower alkyl] The substituent is the same as the substituent (a) in the above-mentioned substituted lower alkanoyl], lower alkoxy, substituted lower alkoxy [the substituent in the substituted lower alkanol is the same as the substituent (a) in the above-mentioned substituted lower alkanoyl] , Lower alkanoyl, substituted lower alkanoyl [substituted lower The substituent in lucanyl has the same meaning as the substituent (a) in the above-mentioned substituted lower alkenyl], aryl, substituted aryl (the substituent in the substituted aryl is the same as the substituent (a) in the above-mentioned substituted lower alkanol) ], Aryloxy, substituted aryloxy [substituents in the substituted aryloxy are the same as the substituents (b) in the substituted aryls], aralkyloxy, substituted aralkyloxy [the substituents in the substituted aralkyloxy are the same as those described above]. The substituent is the same as the substituent (b) in the substituted aryl, the aromatic heterocyclic group, the substituted aromatic heterocyclic group [the substituent in the substituted aromatic heterocyclic group is the same as the substituent (b) in the substituted aryl. Alicyclic heterocyclic group, substituted alicyclic heterocyclic group [Substituents in the substituted alicyclic heterocyclic group are the same as those in the above substituted aryl. That is synonymous with a substituent (b)], and the like.

Here, lower alkyl, cycloalkyl and aryl are as defined above, The lower alkyl part of lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and di-lower alkylamino, and the aryl part of aryloxy and aralkyloxy have the same meanings as the above lower alkyl and aryl, respectively. The two lower alkyl moieties of di-lower alkylamino may be the same or different, and the alkylene moiety of aralkyloxy has the same meaning as the above-mentioned lower alkyl atom except for one hydrogen atom.

[0034] Halogen means each atom of fluorine, chlorine, bromine and iodine.

As the aromatic heterocyclic group, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a 3- to 8-membered ring is condensed Bicyclic or tricyclic condensed aromatic heterocyclic groups containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically pyridyl, pyridonyl , Pyrazyl, pyrimidinyl, pyridazyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, chel, furyl, thiazolyl, oxazolyl, indolyl Indazolyl, benzimidazolyl, isoxazolyl, benzotriazolyl, benzothiazolyl, benzo Kisazoriru, purinyl, Atarijiniru, carbazolyl, and the like.

As the alicyclic heterocyclic group, for example, a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, 3 to 8 And a condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is a condensed bicyclic or tricyclic fused ring. Includes pyrrolidinyl, pyrrolidonyl, piperidino, piperidyl, piperazinyl, morpholinyl morpholinyl

Thiomorphol-containing thiomorpholiel, homopiperidi-containing homopiperidyl, homopiperazinyl, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydrofural, tetrahydrovillal, dihydrobenzofural and the like.

[0036] The substituent in the substituted cycloalkyl, substituted aryl, substituted aralkyl and substituted alicyclic heterocyclic group formed together with the adjacent nitrogen atom includes the above-mentioned substituted lower alkyl group. Alkyl, substituted lower alkenyl and substituted lower alkyl in the definition of substituents, and lower alkyl, substituted lower alkyl [substituents in the substituted lower alkyl are substituents ω and Synonymous], lower alkenyl, substituted lower alkenyl [the substituent in the substituted lower alkenyl is the same as the substituent (a) in the substituted lower alkanol], aralkyl, substituted aralkyl [substitution in the substituted aralkyl] The group has the same meaning as the substituent (b) in the above substituted aryl].

Here, lower alkyl, lower alkenyl and aralkyl have the same meanings as above.

Next, the present invention will be described in detail.

Manufacturing method

Compound (IV) can be obtained by reacting compound (I), compound (II) and carbon monoxide in the presence of a palladium compound and compound (III) in an inert solvent.

[0038] The compound (II) is preferably used in an amount of 1 to 100 equivalents, more preferably 2 to 20 equivalents, based on the compound (I).

Examples of the palladium compound include tetrakis (triphenylphosphine) palladium, ethylenebis (trimethylphosphine) palladium, ethylenebis (triphenylphosphine) palladium, styrenebis (trimethinolephosphine) palladium, and styrenebis (triphenylinolephosphine). In) palladium, tris (ethylene) palladium, tris (styrene) palladium, bis (tri-tert-butylphosphine) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, 1,1, -bis (Diphenylphosphino) Fe-valent palladium compounds such as palladium senpalladium and palladium chloroform, palladium chloride, palladium bromide, palladium iodide, palladium acetate, palladium trifluoroacetate, palladium trifluoroacetate, (Ceto-tolyl) palladium, dichlorobis (benzo-tolyl) palladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (trimethylphosphine) palladium, diacetoxybis (triphenylphosphine) palladium, diacetoxybis (trimethylphosphine) palladium, lithium hexachloro Oral paradate, sodium hexaclo oral paradate, potassium hexaclo oral paradate, tetra (acetonitrile) palladium bis (tetrafluoroborate), bis [para Jiumu (7 ³ -? Ariru) chloride, bis [palladium bis (7 ³ -? Ariru) divalent force palladium compounds, and the like preferably zero-valent palladium compound force more preferably tertiary phosphine compound such as a A zero-valent palladium compound that does not have a ligand is used. The amount of the palladium compound to be used is not particularly limited, but is usually 0.00001 to 1 equivalent, preferably 0.001 to 0.3 equivalent, as palladium atom relative to compound (I).

Examples of the compound (III) include methyldiphenylphosphine, ethyldiphenylphosphine, propyldiphenylphosphine, butyldiphenylphosphine, hexyldiphenylphosphine, methyldinaphthylphosphine, and the like. The amount of compound (III) to be used is generally 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to a palladium atom as a phosphorus atom contained.

[0040] Examples of the inert solvent include halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, Ν, Ν-dimethylformamide (DMF), Ν, Ν-dimethylacetamide, and 1-methyl-2-pi- Amides such as loridinone, 1,3-dimethyl-2-imidazolidinone, aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran, dioxane, getyl ether and cyclopentyl methyl ether, ethyl acetate, propyl acetate and isopropyl acetate Or a mixed solvent thereof. The amount of the solvent to be used is generally 1- to 200-fold weight, preferably 5- to 20-fold weight, relative to compound (I).

[0041] The amount of carbon monoxide used in the reaction is not particularly limited, and the reaction can be carried out under normal pressure or under pressure. Further, an inert gas such as nitrogen or argon may coexist in the reaction. The reaction can be carried out preferably at a partial pressure of carbon monoxide of 0.01 to 20 MPa, more preferably 0.1 to 1 MPa.

The reaction is usually carried out at a temperature between -20 ° C and the boiling point of the solvent used, preferably at a temperature of 0 to 60 ° C, and is completed in 5 minutes to 24 hours.

[0042] The starting compound (I) can be obtained by the method described in WO00 / 43408, JP-A-2001-322995 or a method analogous thereto, and the starting compounds (II) and (III) are commercially available products as they are. Or can be used after purification.

Conversion of compound (IV) to compound (V) can be performed, for example, by the following method. The conversion of -OR ¹ (wherein R ¹ is as defined above) to sulfamoyloxy is, for example, For example WO99 / 03876, WO00 / 43408, Journal of Medicinal Chemistry, Vol. 33, p. 937 (1990), Tetrahedron Letters, Vol. 33, 937 Page (1990) and the like. Reduction of the double bond located at a2, b2 and Z or c2 can be performed, for example, by using Recueil des Travaux Chimiques des? & 3-8 & 3. 91 (8), p. 1095 (1972) and the like.

The target compound in each of the above production methods is isolated and purified by a separation and purification method commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, and the like. be able to. In addition, the intermediate can be subjected to the next reaction without purification.

Some of the compounds (1), (II) and (III) may have various isomers such as geometric isomers, stereoisomers such as optical isomers, and tautomers. In the method for producing the steroid derivative of the above, all possible isomers, including these, and mixtures thereof in any ratio can be used. Further, some of the compounds (IV) and (V) may have various isomers such as stereoisomers such as geometric isomers and optical isomers, and tautomers. The preparation method can be applied to the preparation of all possible isomers including these and mixtures thereof in any ratio.

When the salts of compounds (IV) and (V) are obtained, when the compounds (IV) and (V) are obtained in the form of a salt, they may be purified as they are, or may be obtained in the free form. In this case, compounds (IV) and (V) may be dissolved or suspended in an appropriate solvent, and then isolated and purified by adding an acid or a base.

Compounds (IV) and (V) and salts thereof may be present in the form of a carohydrate with water or various solvents. These adducts are also included in the present invention.

Table 1 shows specific examples of the compound (IV) obtained by the present invention.

[Table 1] table 1

Hereinafter, the present invention will be more specifically described with reference to Examples and Comparative Examples. The scope of the present invention is not limited to these Examples.

Example 1

[0048] Synthesis of 17-diisopropyl rubamoyl-1,3,5 (10), 16-estraditetraen-3-yl acetate (Compound 1)

17- (Trifluoromethanesulfo-roxy) -1,3,5 (10), 16-estraditetraen-3-yl acetate (2.00 g) and tris (dibenzylideneacetone) dipalladium (64.0 mg) were placed in a flask. After weighing and substituting the inside of the flask with carbon monoxide, methyldiphenylphosphine (52 μL), DMF (20 mL) and diisopropylamine (12.6 mL) were added and stirred at room temperature for 5 hours. Toluene (100 mL) and 3 mol / L hydrochloric acid (60 mL) were added to the reaction mixture, and the layers were separated. The organic layer was washed with 5% brine (100 mL) and dried over anhydrous magnesium sulfate. Organic layer After concentration, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain Compound 1 (1.71 g, 90%) as colorless crystals.

Melting point: 114 ° C (decomposition)

1H-NMR (CDC1, δ, ppm) 1.09 (s, 3H), 1.08-1.69 (m, 14H), 1.93-2.00 (m, 2H),

Three

2.10-2.17 (m, IH), 2.28 (s, 3H), 2.28-2.33 (m, 3H), 2.87-2.94 (m, 2H), 3.45 (brs, IH), 4.27 (brs, IH), 5.67 ( d, J = 1.5 Hz, IH), 6.81 (d, J = 2.4 Hz, IH), 6.86 (dd, J = 2.4, 8.5 Hz, IH), 7.27 (d, J = 8.5 Hz, IH)

MASS [ESI (+)] m / z 424 (M + H) ⁺ , 382, 323, 253.

HRMS [ESI (+)] calcd for CNO (M + H): 424.2852, found 424.2845.

27 38 3

Example 2

Synthesis of 17-diisopropyl-lubamoyl-1,3,5 (10), 9 (11), 16-estradipentaen-3-yl acetate (Compound 2)

17- (Trifluoromethanesulfo-roxy) -1,3,5 (10), 9 (11), 16-estradipentaene-3-yl acetate (4.39 g) and tris (dibenzylideneacetone) dipalladium (45.7 mg ) Into a flask, replace the inside of the flask with carbon monoxide, add methyldiphenylphosphine (41 μL), DMF (43 mL), diisopropylamine (27.5 mL), and add 3 hours at room temperature. Stirred. Toluene (250 mL) and 2 mol / L hydrochloric acid (100 mL) were added to the reaction solution and separated, and the organic layer was washed with 2 mol / L hydrochloric acid (50 mL) and 5% brine (100 mL). Then, it was dried over anhydrous magnesium sulfate. After concentrating the organic layer, the residue was purified by silica gel column chromatography (toluene: ethyl acetate = 10: 1) to obtain Compound 2 (3.48 g, 84%) as pale yellow crystals.

Melting point: 161 ° C (decomposition)

'H-NMR (CDC1, δ, ppm) 1.05 (s, 3H), 1.21 (brs, 12H), 1.41-1.53 (m.IH),

Three

1.69-1.79 (m, IH), 2.01-2.34 (m, 4H), 2.28 (s, 3H), 2.39-2.48 (m, 2H), 2.82-2.95 (m, 2H), 3.47 (brs, IH), 4.28 (brs, IH), 5.70 (dd, J = 1.5, 3.1 Hz, IH), 6.21-6.23 (m, IH), 6.82 (d, J = 2.5 Hz, IH), 6.85 (dd, J = 2.5, 8.6 Hz, IH), 7.60 (d, J = 8.6 Hz, IH)

MASS [ESI (+)] m / z 422 (M + H) ⁺ , 380, 361, 338, 251. HRMS [ESI (+)] calcd for CH NO (M + H): 422.2695, found: 422.2683

27 36 3

Example 3

Synthesis of Ν, Ν-diisopropyl-3- (methoxycarboxy) -1,3,5 (10), 16-estraditetraene-17-carboxamide (Compound 3)

Weigh 3- (methoxycarboxy) -1,3,5 (10), 16-estraditetraene-17-yltrifluoromethanesulfonate (2.00 g) and tris (dibenzylideneacetone) dipalladium (39.4 mg) into a flask. After the inside of the flask was replaced with carbon monoxide, methyldiphenylphosphine (32 μL), DMF (20 mL) and diisopropylamine (12.2 mL) were added, and the mixture was stirred at room temperature for 4.5 hours. Ethyl acetate (150 mL) and 1 mol / L hydrochloric acid (100 mL) were added to the reaction solution, and the mixture was separated. The organic layer was washed with 5% brine (100 mL) and dried over anhydrous magnesium sulfate. After concentrating the organic layer, the residue was purified by silica gel column chromatography (toluene: ethyl acetate = 5: 1) to obtain Compound 3 (1.71 g, 89%) as pale yellow crystals.

Melting point: 131 ° C (decomposition)

1H-NMR (CDC1, δ, ppm) 1.09 (s, 3H), 1.30 (brs, 12H), 1.41-1.71 (m.7H),

Three

1.91-2.01 (m, 2H), 2.07-2.18 (m, 1H), 2.27-2.40 (m, 3H), 2.86-2.94 (m, 2H), 3.42 (brs, 1H), 3.90 (s, 3H), 4.31 (brs, 1H), 5.67--5.68 (m, 1H), 6.88 (d, J = 2.6 Hz, 1H), 6.93 (dd, J = 2.6, 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz , 1H)

MASS [ESI (+)] m / z 440 (M + H) ⁺ , 398, 356, 235.

HRMS [ESI (+)] calcd for CNO (M + H): 440.2801, found: 440.2804.

27 38 4

Example 4

Synthesis of Compound 1 Using Methyldifluorophosphine and Palladium Acetate

17- (Trifluoromethanesulfo-loxy) -1,3,5 (10), 16-estraditetraen-3-yl acetate (100 mg) and palladium acetate (1.6 mg, 3 mol%) are weighed into a flask. After the inside of the flask was replaced with carbon monoxide, methyldiphenylphosphine (2.6 L, 6 mol%), DMF (1 mL) and diisopropylamine (0.63 mL) were added and stirred at room temperature for 5 hours. After the reaction, acetonitrile was removed and the yield of compound 1 was calculated by liquid high performance chromatography (HPLC) analysis. Table 2 shows the production rates. The HPLC measurement conditions are as follows. HPLC measurement conditions

Equipment: Hitachi, Ltd.

Column: YMC ODS-AM AM-312, 150 mm X 6.0 mm (YMC Corporation)

Mobile phase: Acetonitrile Z0.04 mol / L Aqueous potassium dihydrogen phosphate solution = 2Zl

Temperature: 40 ° C

Flow rate: 1.0 mL / min

Detection: UV (215 nm)

Example 5

Synthesis of Compound 1 using methyldiphenylphosphine and tris (dibenzylideneacetone) dipalladium

17- (Trifluoromethanesulfo-roxy) -1,3,5 (10), 16-estraditetraene-3-yl acetate (100 mg) and tris (dibenzylideneacetone) dipalladium (3.2 mg, 3 mol% ) Is weighed into a flask, and the inside of the flask is replaced with carbon monoxide. Then, methyldiphenylphosphine (2.6 L, 6 mol%), DMF (1 mL) and diisopropylamine (0.63 mL) are added to the flask. The mixture was stirred at room temperature for 5 hours. After the reaction, acetonitrile was added, and the production rate of Compound 1 was calculated by liquid high-speed chromatography (HPLC) analysis. Table 2 shows the production rates. The HPLC measurement conditions are the same as in Example 4.

COMPARATIVE EXAMPLES 1-3: Palladium acetate as a palladium compound and triphenylphosphine, tri (p-tolyl) phosphine or 1,3- (diphenylphosphino) propane as a tertiary phosphine compound 1 Synthesis of

17- (Trifluoromethanesulfo-roxy) -1,3,5 (10), 16-estraditetraen-3-yl acetate (100 mg) and palladium acetate (1.6 mg, 3 mol% as palladium atom) After weighing the mixture into a flask and replacing the inside of the flask with carbon monoxide, the tertiary phosphine conjugate (6 mol% as a phosphorus atom), DMF (1 mL) and diisopropylamine (0.63 mL) are added to the flask, and the mixture is cooled to room temperature. And stirred for 4 to 6 hours. After the reaction, acetonitrile was added, and the production rate of Compound 1 was calculated by liquid high-speed chromatography (HPLC) analysis. Table 2 shows the production rates. The HPLC measurement conditions are the same as in Example 4.

Comparative Example 4: Synthesis of compound 1 using tetrakis (triphenylphosphine) palladium 17- (trifluoromethanesulfo-loxy) -1,3,5 (10), 16-estraditetraen-3-yl acetate (100 mg) and tetrakis (triphenylphosphine) palladium (8.1 mg, palladium atom 3 mol%) was weighed into a flask, the inside of the flask was replaced with carbon monoxide, DMF (1 mL) and diisopropylamine (0.63 mL) were added, and the mixture was stirred at room temperature for 5 hours. After the reaction, acetonitrile was removed and the yield of compound 1 was calculated by liquid high performance chromatography (HPLC) analysis. Table 2 shows the production rates. The HPLC measurement conditions are the same as in Example 4.

Comparative Example 5: Synthesis of disulfide compound 1 using tris (dibenzylideneacetone) dipalladium as a palladium compound and triphenylphosphine as a tertiary phosphine disulfide

17- (Trifluoromethanesulfo-roxy) -1,3,5 (10), 16-estraditetraen-3-yl acetate (100 mg) and tris (dibenzylideneacetone) dipalladium (3.2 mg, as palladium atom 3 mol%) was weighed into a flask, and the inside of the flask was replaced with carbon monoxide. Then, triphenylphosphine (3.7 mg, 6 mol% as a phosphorus atom), DMF (1 mL) and diisopropylamine (0.63%) were added. mL) and stirred at room temperature for 5 hours. After the reaction, acetonitrile was caloried, and the production rate of compound 1 was calculated by liquid high performance chromatography (HPLC) analysis. Table 2 shows the generation rates. The HPLC measurement conditions are the same as in Example 4.

[Table 2]

Table 2

From the results in Table 2, it can be seen that when methyldiphenylphosphine is used as the tertiary phosphine compound, Compound 1 can be obtained at a higher yield in comparison with the case where other tertiary phosphine conjugates are used.ゎゎ

Industrial applicability The present invention provides a method for producing a steroid derivative useful as an intermediate for synthesizing an estrone sulfatase inhibitor or a steroid 5a-reductase inhibitor.

Claims

[Wherein, 2 represents a single bond or a double bond,

R ¹ is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted Substituted aryl, COR ^1A (wherein, R ^1A is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl- Represents a substituted or unsubstituted aralkyl or substituted or unsubstituted aryl, or COOR ^1B (wherein R ^1B is as defined above for R ^1A ),

[Formula 11]

HNR ³ R ⁴

(II)

(In the formula, R ³ and R ⁴ are the same or different and are substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkyl. Represents a substituted or unsubstituted aralkyl or substituted or unsubstituted aryl, or R ³ and R ⁴ together with an adjacent nitrogen atom form a substituted or unsubstituted alicyclic heterocyclic group ) And the carbon monoxide are converted to a palladium compound and a compound of formula (III)

[Formula 12] R ⁶

R ⁵ _P (

R ⁷

(ill)

Wherein R ⁵ represents a substituted or unsubstituted lower alkyl, and R ⁶ and R ⁷ are the same or different and represent a substituted or unsubstituted aryl. Formula (IV) characterized by reacting in the presence

[Formula 13]

(Wherein, R 2, R ¹ , R ³ and R ⁴ have the same meanings as described above, provided that the two located at b2 and c2 do not simultaneously form a double bond) Manufacturing method.

[2] The process for producing a steroid derivative according to claim 1, wherein R ³ and R ⁴ are the same or different and are substituted or unsubstituted lower alkyl.

[3] R ¹ is COR ^la (where R ^la represents a substituted or unsubstituted lower alkyl) or COOR ^lb (where R ^lb is as defined above for R ^la ), and R ³ and R ^{2. The} method for producing a steroid derivative according to claim 1, wherein ⁴ is the same or different and is substituted or unsubstituted lower alkyl.

[4] R ¹ is COCH or COOCH, R ² is trifluoromethyl, and R ³ and R ⁴ are isoprene

3 3

2. The method for producing a steroid derivative according to claim 1, which is a mouth pill.

[5] The method for producing a steroid derivative according to any one of claims 1 to 4, wherein R ⁵ is methyl and R ⁶ and R ⁷ are phenol.

[6] The method for producing a steroid derivative according to any one of claims 1 to 5, wherein the palladium compound is an SO-valent palladium compound.

[7] The palladium compound is bis (dibenzylideneacetone) palladium or tris (dibenzylideneacetone). 6. The method for producing a steroid derivative according to claim 1, wherein the steroid derivative is diacetone.

Formula (I)

[Formula 14]

(Wherein ² , R ¹ and R ² have the same meanings as described above, provided that both of bl and cl are not simultaneously a double bond), a compound represented by the formula (II )

[Formula 15]

HNR ³ R ⁴

(II)

(Wherein R ³ and R ⁴ are as defined above) and carbon monoxide, a palladium compound and a compound of the formula (III)

[Formula 16]

(ill)

(Wherein R ⁵ , R ⁶ and R ⁷ are as defined above) in the presence of a tertiary phosphine ligated compound represented by the formula (IV)

[Formula 17]

(Wherein, 2, R ¹ , R ³ and R ⁴ have the same meanings as described above, however, both of = located at b2 and c2 are not simultaneously a double bond) Equation (V) characterized by including the step of obtaining

[Formula 18]

(Wherein, R ³ and R ⁴ have the same meanings as described above), respectively.

[9] The method for producing a steroid derivative according to claim 8, wherein R ³ and R ⁴ are the same or different and are substituted or unsubstituted lower alkyl.