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WO2001066562A1 - Derives steroides et leur procede de fabrication - Google Patents

Derives steroides et leur procede de fabrication Download PDF

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Publication number
WO2001066562A1
WO2001066562A1 PCT/JP2001/001694 JP0101694W WO0166562A1 WO 2001066562 A1 WO2001066562 A1 WO 2001066562A1 JP 0101694 W JP0101694 W JP 0101694W WO 0166562 A1 WO0166562 A1 WO 0166562A1
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WIPO (PCT)
Prior art keywords
group
methyl
general formula
ethyl
pentenyl
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PCT/JP2001/001694
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English (en)
Japanese (ja)
Inventor
Makoto Nakazawa
Shigeo Ohzono
Kazuya Takaki
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Kuraray Co Ltd
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Kuraray Co Ltd
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Filing date
Publication date
Application filed by Kuraray Co Ltd filed Critical Kuraray Co Ltd
Publication of WO2001066562A1 publication Critical patent/WO2001066562A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring

Definitions

  • the present invention relates to a steroid derivative and a method for producing the same.
  • Steroid derivatives produced according to the present invention include, for example, estran-3-0-sulfamat derivative [Steroids, 63] which acts as an inhibitor of estrogen sulfatase which produces estrogen which is a causative substance of estrogen-dependent breast cancer. Vol., P. 425 (1998)], and various estrane derivatives which can be used as inhibitors of mammalian steroid 5-H-reductase [Japanese Patent Application Publication No. 3-50450498; Journal * Ob. Medicinal Chemistry, Vol. 33, p. 937 (1990)].
  • estran derivatives such as estran-3-0-sulfamato derivatives or mammalian steroids 5-hydreductase inhibitors
  • conventional 3 17-bis (trifluoromethyl) Sulfonyloxy) Estra-1, 3, 5 (10), 16-tetraene is used [see Steroids, 63, 425 (1998)].
  • a method for converting a 17-position trifluoromethylsulfonyloxy group with a carbon monoxide and an amine in the presence of a palladium compound to a 17-position trifluoromethylsulfonyloxy group to convert the 17-position to a fulvamoyl group has been described. [Journal of Medicinal Chemistry, Vol. 33, p. 937 (1990); Japanese Patent Publication No. 3-504498; Steroids, Vol. 63 , 425 (1998); see Patent No. 2742331].
  • 3,17-bis (trifluoromethylsulfonyloxy) estra-1,3,5 (10), 16-tetraene is an oily substance and its purification requires silica gel column chromatography.
  • Estran 3-0-Sulfamate derivative or mammalian steroid 5-Hydredose inhibitor This is not necessarily an advantageous synthetic intermediate.
  • the above reaction was applied to 3,17-bis (trifluoromethylsulfonyloxy) estrar 1,3,5 (10), 16-tetrane to give an estrane-3-0-sulfamato derivative.
  • an object of the present invention is to provide a steroid derivative which can be derived into various ester derivatives and is industrially advantageous from the viewpoint of handling, and a method for producing the same.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a steroid derivative having a 17-trifluoromethylsulfonyloxy group in which the 3-position hydroxyl group is protected by a specific protecting group, particularly 3- (Methoxycarbonyl) oxy 1,1,3,5 (10), 16-tetraen-17-ol trifluoromethanesulfonate is crystalline at room temperature and can be purified by recrystallization I found something.
  • a specific protecting group particularly 3- (methoxycarbonyl) oxy-1,1,5, (10)
  • the 17-position is converted to a rubamoyl group and the 3-position hydroxyl protecting group Is deprotected to induce a hydroxyl group at the 3-position required when using 3,17-bis (trifluoromethylsulfonyloxy) estra-1,3,5 (10), 16-tetraene. It has been found that the deprotection step can be omitted, and the present invention has been completed.
  • R 1 represents an alkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group.
  • Steroid derivatives abbreviated as III-1-1
  • estrone derivative (I) to a general formula (II) in the presence of a base.
  • R 2 is a halogen atom, triflate Ruo b methylsulfonyl O alkoxy group or a general formula - represents N (R 3) a group represented by S 0 2 CF 3, R 3 is an alkyl group, alkenyl group, Represents an alkynyl group, an aryl group or an aralkyl group.
  • a trifluoromethanesulfonic acid derivative hereinafter referred to as a trifluoromethanesulfonic acid derivative
  • a steroid derivative (II1-1) characterized by reacting an estrone derivative (hereinafter abbreviated as an estrone derivative (1-1)) with a trifluoromethanesulfonic acid derivative (II) in the presence of a base. ') Manufacturing method,
  • R 4 represents an alkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group.
  • the steroid derivative (III) will be referred to as carbon monoxide and the general formula (IV) in the presence of a palladium compound.
  • R 5 and R 6 are each independently a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a group which may have a substituent.
  • amine (IV) amine
  • steroid derivative (V) a method for producing a steroid derivative
  • This is a process for producing a steroid derivative (V), which comprises reacting a steroid derivative (III-1,) with carbon monoxide and an amine (IV) in the presence of a palladium compound.
  • the alkyl group represented by R 3 and the alkyl group constituting the alkyloxycarbonyl group represented by R 1 and R 4 are preferably an alkyl group having 1 to 4 carbon atoms, for example, a methyl group, Ethyl group, n-propyl group, isopropyl group, Examples thereof include n-butyl group, isobutyl group, s-butyl group, and t-butyl group.
  • an alkenyl group having 2 to 4 carbon atoms is preferable, for example, a vinyl group, a propenyl group ( 1-propenyl group, 2-propenyl group), isopropenyl group, n-butenyl group (1-butenyl group, 2-butenyl group, 3-butenyl group), 2-methyl-1-propenyl group Group, 2-methyl-2-propyl group, 1-methyl-1-propenyl group and the like.
  • an alkynyl group having 2 to 4 carbon atoms is preferable.
  • an ethynyl group, a provinyl group (1— A propynyl group, a 2-propynyl group), a 1-butynyl group, a 2-butynyl group, and a 3-butynyl group is preferable.
  • an aryl group having 6 to 10 carbon atoms is preferable.
  • examples include a phenyl group and a naphthyl group (1-naphthyl group, 2-naphthyl group).
  • the aralkyl group constituting the aralkyl group represented by R 3 and the aralkyloxycarbonyl group represented by R 1 and R 4 are preferably an aralkyl group having 7 to 11 carbon atoms, for example, benzyl group, naphthyl Methyl group (naphthyl-1-methyl group, naphthyl-2-methyl group) and the like.
  • the alkyl group represented by R 5 and R 6 is preferably an alkyl group having 1 to 8 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and an s-alkyl group.
  • the alkenyl group represented by R 5 and R 6 is preferably an alkenyl group having 2 to 7 carbon atoms, for example, a vinyl group, a propenyl group, an isopropyl group, a 1-butenyl group, a 2-butenyl group, -Butenyl group, 1-methyl-1-propenyl group, 2-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-methylidene — 1-propane, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl Group, 1-methylidenebutyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methylidenebutyl, 3-methyl-1-butenyl, 3- Methyl-2-butenyl group, 3-methyl
  • the alkynyl group represented by R 5 and R 6 is preferably an alkynyl group having 2 to 6 carbon atoms, for example, ethynyl group, propynyl group (1-propynyl group, 2-propynyl group), 1-butynyl group, 2- Petynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl Group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, 3-methyl-1-pentynyl group, 4-methyl-1-pentynyl group, 3,3-dimethyl_1-butynyl group, 4 -Methyl-2-pentynyl group, 2-methyl-3-pentynyl group, 1,1-dimethyl-3-but
  • the aryl group represented by R 5 and R 6 is preferably an aryl group having 6 to 10 carbon atoms, for example, phenyl, naphthyl (1-naphthyl, 2-naphthyl) and the like.
  • the alkyl group, alkenyl group, alkynyl group, aryl group or aralkyl group represented by R 5 and R 6 may have a substituent, and examples of such a substituent include a hydroxyl group, an alkyloxy group, an alkenyloxy group, Alkynyloxy group, aryl —Ruoxy group, aralkyloxy group and the like.
  • the number of substituents may be one or more respectively.
  • the alkyl group constituting the alkyloxy group, the alkenyl group constituting the alkoxyloxy group, the alkynyl group constituting the alkynyloxy group, the aryl group constituting the aryloxy group and the aralkyl group constituting the aralkyloxy group are as described above. Examples thereof include an alkyl group, an alkenyl group, an alkynyl group, an aryl group and an aralkyl group represented by R 5 and R 6 .
  • Examples of the halogen atom represented by R 2 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • estrone derivative (III-1) or a steroid derivative (III-1) or a steroid derivative (III-1) is reacted with an estrone derivative (I) or an estrone derivative (I-1) in the presence of a base. Step for obtaining 111—1,)
  • the estrone derivative (I) or the estrone derivative (1-1) and the base are dissolved or suspended in a solvent under an inert gas atmosphere, and the trifluoromethanesulfonic acid derivative (II) is directly added to this solution.
  • add a solution dissolved or suspended in a solvent or add an estrone derivative (I) or an estrone derivative to a solution in which a trifluoromethanesulfonic acid derivative (II) is dissolved or suspended in a solvent.
  • the amount of the trifluoromethanesulfonic acid derivative (II) to be used is preferably in the range of 1 to 10 molar equivalents per 1 mol of the estrone derivative (I) or the estrone derivative (1-1), and is preferably 1 to 5 mole equivalents. A molar equivalent range is more preferred.
  • Examples of the base include lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium dicyclohexylamide, sodium dicyclohexylamide, potassium dicyclohexylamide, lithium bis (trimethylsilyl) amide, Metal amides such as sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide; metal hydrides such as lithium hydride, sodium hydride, hydrogen hydride; lithium tert-butoxide, sodium tert-butoxide, Potassium tert-butoxy Metal alkoxides such as trimethylamine, N, N-dimethylethylamine, N, N-getylmethylamine, triethylamine, isopropyldimethylamine, diisopropylethylamine, triisopropylamine, triptylamine, Tripentylamine, tetraethylethylenediamine, 1-methylpyrrolidine,
  • the reaction is preferably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran, getyl ether, and dimethoxetane; and carbonization such as pentane, hexane, heptane, octane, petroleum ether, toluene, and xylene. Hydrogen; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrachloroethane, cyclobenzene, o-dichlorobenzene, and mixtures thereof.
  • a liquid base can be used as the solvent (the amount of the solvent is not particularly limited, but is 1 to 2 with respect to the estrone derivative (I) or the estrone derivative (I-1)). A range of 100 times the weight is preferred.
  • the reaction temperature is preferably in the range of 100 to 200 ° C, more preferably in the range of 40 to 200 ° C.
  • the reaction time is preferably in the range of 0.1 to 48 hours, more preferably in the range of 1 to 36 hours.
  • the steroid derivative (III-1) or steroid derivative (III-1 ') obtained in this way can be used in ordinary isolation and purification of organic compounds. It can be isolated and purified by the method. For example, pour the reaction mixture into saline or water, add ethyl acetate, getyl ether, pentane, hexane, heptane, octane, petroleum ether, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane.
  • Steroid derivative (II1-1) or steroid derivative (111-1,) is crystalline at room temperature, and hydrocarbons such as pentane, hexane, heptane, benzene, toluene and xylene; methanol, The purity can be further increased by performing a recrystallization operation using an alcohol such as ethanol, n-propanol or isopropanol; or a solvent such as water alone or as a mixture.
  • the reaction is carried out by dissolving the steroid derivative (III) or the steroid derivative (III-1 ′) in a solvent in the presence of carbon monoxide in the presence of a palladium compound, an amine (IV) and, if necessary, a tertiary compound.
  • a solution of a phosphine compound dissolved in a solvent or add a solution of a palladium compound, an amine (IV) and, if necessary, a tertiary phosphine compound to a solution of a steroid compound (III) or a steroid compound. It is preferable to add a solution obtained by dissolving the compound (III-11 ′) in a solvent.
  • the amount of the amine (IV) used is preferably in the range of 1 to 50 molar equivalents, more preferably 1 to 30 molar equivalents, per mol of the steroid derivative (III) or the steroid derivative (II1-1,). The range is more preferred.
  • Examples of the palladium compound include tetrakis (triphenylphosphine) palladium, ethylenebis (trimethylphosphine) palladium, ethylenebis (triphenylphosphine) palladium, styrenebis (trimethylphosphine) palladium, and styrenebis (trifly).
  • Enylphosphine) palladium, tris (Ethylene) palladium, Tris (styrene) palladium, Bis (dibenzylideneacetone) Palladium 'Zero-valent palladium compounds such as palladium chloride; palladium chloride, palladium bromide, palladium iodide, palladium acetate, dichlorobis (acetonitrile) palladium , Dichlorobis (penzonitrile) palladium, dichlorobis (trimethylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, lithium hexachloride paradate, sodium hexachloroparadate, potassium hexachloride paradate, tetra (acetonitrile) palladium bis (tetrafluoropropoxy O robo rate), bis (palladium (77 3 - ⁇ Lil) Kurori de), bis (palladium bis (7 3 -?
  • Palladium compounds There is no particular limitation on the amount of the palladium compound to be used. However, the amount of the palladium atom is 0.001 to 1 to 1 per mol of the steroid derivative (III) or the steroid derivative (111-1). The range of the molar equivalent is preferred, and the range of 0.001 to 0.3 molar equivalent is more preferred.
  • a tertiary phosphine compound coexist with the palladium compound for stabilization.
  • tertiary phosphine compounds include, for example, triarylphosphines such as triphenylphosphine and tristriphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; tributylphosphine, triisobutylphosphine and tritert-butylphosphine.
  • Trialkyl phosphine diphenylphosphinoethane, diphenylphosphinopropane, diphenylphosphinobutane, 2,2,1-bis (diphenylphosphino) _1,1, —diphosphine such as binaphthyl (BINAP)
  • triarylphosphine such as triphenylphosphine is preferable.
  • the amount of the tertiary phosphine compound used is preferably within a range of 10 mol or less per gram atom of palladium as a phosphorus atom contained in the tertiary phosphine compound. More preferably, it is 1-4 moles per gram atom.
  • the reaction is preferably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it does not adversely affect the reaction.
  • ethers such as tetrahydrofuran, getyl ether, and dimethoxetane
  • amides such as N, N-dimethylformamide
  • dimethyl sulfoxide esters such as ethyl acetate, dimethyl carbonate, ethylene carbonate, and ethyl carbonate
  • the amount of the solvent used is not particularly limited, but is preferably in the range of 1 to 200 times the weight of the steroid derivative (III) or the steroid derivative (111-1, 1).
  • the amount of carbon monoxide used in the present invention is not particularly limited, and the reaction can be carried out under normal pressure or under pressure, but the partial pressure of carbon monoxide is preferably in the range of 1 kPa to 10 MPa. and 10 kP a ⁇ 1 MP a is more preferably in the range of c, nitrogen in the reaction system, a gas inert to the reaction does not support insert also co-exist, such as argon.
  • the reaction temperature is preferably in the range of —100 to 200 ° C., more preferably in the range of 40 to 100 ° C.
  • the reaction time is preferably in the range of 0.5 to 48 hours, more preferably in the range of 1 to 36 hours.
  • the steroid derivative (V) thus obtained can be isolated and purified by a method generally used for isolation and purification of organic compounds.
  • the reaction mixture is poured into saline or water, extracted with an organic solvent such as ethyl acetate, ethyl ether, hexane, heptane, octane, petroleum ether, toluene, xylene, dichloromethane, and the like, if necessary.
  • the extract is washed with saturated aqueous sodium bicarbonate, diluted hydrochloric acid, water, saline, etc.
  • estrone derivative (I) and the estrone derivative (1-1) can be produced in the same manner as in the reference examples described below.
  • reaction liquid dimethyl carbonate 1 Dilute with 5 Oml, wash with 1.15% aqueous hydrochloric acid (52 ml, prepared from concentrated hydrochloric acid (2 ml) and water (5 Oml)), dry the organic layer over anhydrous magnesium sulfate, and concentrate to give white crystals.
  • reaction liquid dimethyl carbonate 1 Dilute with 5 Oml, wash with 1.15% aqueous hydrochloric acid (52 ml, prepared from concentrated hydrochloric acid (2 ml) and water (5 Oml)
  • aqueous hydrochloric acid 52 ml, prepared from concentrated hydrochloric acid (2 ml) and water (5 Oml)
  • Estran-3-O-sulfamato derivatives which act as inhibitors of estrogen-sulfatase, which produces estrogen, the causative agent of estrogen-dependent breast cancer, and suppress steroid 5-5-reductase in mammals
  • the present invention provides a steroid derivative which can be derived into various ester derivatives such as an agent and is industrially advantageous from the viewpoint of handling, and a method for producing the same.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

Cette invention concerne des dérivés stéroïdiens à partir desquels divers dérivés estran (dérivés d'estran-3-O-sulfamate agissant comme inhibiteur de l'oestrogène produisant une oestrogène sulfatase elle-même facteur responsable du cancer du sein dépendant d'oestrogènes, comme inhibiteur de la stéroïde-5-α-réductase mammaire, etc.) peuvent être facilement introduits et qui sont avantageux au plan de la manipulation industrielle. Il s'agit plus précisément de dérivés stéroïdiens représentés par la formule générale suivante (III-1) dans laquelle R1 représente un alkyloxycarbonyle, alkènyloxycarbonyle, alkynyloxycarbonyle, aryloxycarbonyle ou aralkyloxycarbonyle.
PCT/JP2001/001694 2000-03-08 2001-03-05 Derives steroides et leur procede de fabrication Ceased WO2001066562A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-63826 2000-03-08
JP2000063826 2000-03-08

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WO2001066562A1 true WO2001066562A1 (fr) 2001-09-13

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990000560A1 (fr) * 1988-07-05 1990-01-25 Kuraray Co., Ltd. Composes steroidiques
US4937237A (en) * 1988-12-23 1990-06-26 Smithkline Beckman Corporation Phosphinic acid substituted aromatic steroids as inhibitors of steroid 5-60 -reductase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990000560A1 (fr) * 1988-07-05 1990-01-25 Kuraray Co., Ltd. Composes steroidiques
US4937237A (en) * 1988-12-23 1990-06-26 Smithkline Beckman Corporation Phosphinic acid substituted aromatic steroids as inhibitors of steroid 5-60 -reductase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CACCHI SANDRO ET AL.: "Palladium-catalyzed carbonylation...carboxylic acid derivatives", TETRAHEDRON LETTERS, vol. 26, no. 8, 1985, pages 1109 - 1112, XP002939736 *

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