WO2001066562A1

WO2001066562A1 - Steroid derivatives and process for producing the same

Info

Publication number: WO2001066562A1
Application number: PCT/JP2001/001694
Authority: WO
Inventors: Makoto Nakazawa; Shigeo Ohzono; Kazuya Takaki
Original assignee: Kuraray Co., Ltd.
Priority date: 2000-03-08
Filing date: 2001-03-05
Publication date: 2001-09-13

Abstract

Steroid derivatives from which various estran derivatives (estran-3-O-sulfamate derivatives serving as an inhibitor of estrogen sulfatase producing estrogen which is a causative factor of estrogen-dependent mammary cancer, mammalian steroid 5-α-reductase inhibitor, etc.) can be easily introduced and which are industrially advantageous from the viewpoint of handling. Namely, steroid derivatives represented by the following general formula (III-1) wherein R1 represents alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl.

Description

Specification

Steroid derivative and method for producing the same

Technical field to which the invention belongs

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)].

Background art

As intermediates for the synthesis of 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].

Disclosure of the invention

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. In addition, 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. In the case of production, in order to introduce a sulfamoyloxy group at the 3-position of the resulting steroid compound having a rubamoyl group at the 17-position, the trifluoromethylsulfonyl group at the 3-position is once eliminated to obtain a hydroxyl group. There is a problem that the process must be complicated because it must be converted to a base.

Accordingly, 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. Steroid derivatives having a 17-trifluoromethylsulfonyloxy group in which the hydroxyl group at the 3-position is protected by a specific protecting group, particularly 3- (methoxycarbonyl) oxy-1,1,5, (10), When 16-tetraphenyl-1-fluorotrifluorosulfonate is reacted with carbon monoxide and an amine in the presence of a palladium compound, 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.

That is, the present invention

① General formula (III-1)

(In the formula, 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),

② Equation (I I I — 1,)

OSO CF

(«I-

0

CH O

(Hereinafter abbreviated as steroid derivative (1-1 ′)),

③ General formula (I)

(R

(Wherein, R ¹ is as defined above.) (Hereinafter abbreviated as estrone derivative (I)) to a general formula (II) in the presence of a base.

CF ₃ S0 ₂ R '(II)

(Wherein, 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)

(Abbreviated as (I I)), a method for producing a steroid derivative (I I I 1),

④Formula (I-1)

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,

⑤General formula (I I I)

(In the formula, R ⁴ represents an alkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group.) Hereinafter, the steroid derivative (III) will be referred to as carbon monoxide and the general formula (IV) in the presence of a palladium compound.

HNR ^ R 6 (IV)

(Wherein, 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. Represents an alkynyl group, an aryl group which may have a substituent or an aralkyl group which may have a substituent (s) (hereinafter abbreviated as "amine (IV)"). General formula (V) characterized by

(Wherein, R ⁵ and R ⁶ are as defined above), and a method for producing a steroid derivative (hereinafter, abbreviated as steroid derivative (V)), and

⑥This 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.

In the above general formula, 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.

As the alkenyl group constituting the alkenyl group represented by R ³ and the alkenyloxycarbonyl group represented by R ¹ and R ^4, 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.

As the alkynyl group constituting the alkynyl group represented by R ³ and the alkynyloxycarbonyl group represented by R ¹ and R ^4, an alkynyl group having 2 to 4 carbon atoms is preferable. For example, 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.

As the aryl group represented by R ³ and the aryloxy group represented by R ¹ and R ^4, 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. Butyl group, t_butyl group, n-pentyl group, 1-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, n- Xyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl group, 1,2- Dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1,1,2-monotrimethylpropyl group, 1,2, 2 _ trimethylpro Group, 1 _ Echiru - 1 —Methylpropyl, 1-ethyl— 2-methylpropyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl group, 1,1-dimethylpentyl group, 1,2-dimethylpentyl group, 1,3-dimethylpentyl group, 1,4-dimethylpentyl group, 2,2-dimethylpentyl group, 2,3 —Dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl, 4,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl Group, 1,1,2-trimethylbutyl group, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group, 1,2,3-trimethylbutyl group, 1,3,3-trimethyl Butyl group, 2, 2, 3-trimethyl Butyl group, _2: 3, 3-trimethyl butyl group, 1-Echiru _ 1 one-methylbutyl group, 1-Echiru - 2-methylbutyl group, 1-Echiru - 3-methylbutyl group, 2-Echiru - 2-methylcarbamoyl Rubuchiru group, 2-Ethyl-3-methylbutyl group, 1-n-propylbutyl group, 1- (1-methylethyl) butyl group, 1,1,2,2-tetramethylpropyl group, 1-ethyl-1,2-dimethylpropyl Group, 1-ethyl-2,2-dimethylpropyl, 1-ethyl-1,2-dimethylpropyl, 1- (1-methylethyl) _2-methylpropyl, n-octyl, 1-methylheptyl , 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1,1-dimethylhexyl, 1,2-dimethylhexyl , 1,3-dimethylhexyl 1,4-dimethylhexyl group, 1,5-dimethylhexyl group, 2,2-dimethylhexyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5- Dimethylhexyl group, 3,3-dimethylhexyl group, 3,4-dimethylhexyl group, 3,5-dimethylhexyl group, 4,4-dimethylhexyl group, 4,5-dimethylhexyl group, 5, 5-dimethylhexyl, 1,1,2-trimethylpentyl, 1,1,3-trimethylpentyl, 1,1,4-trimethylpentyl, 1,2,2-trimethylpentyl, 1, , 2,3-Trimethylpentyl group, 1,2,4-Trimethylpentyl group, 2,2,3-Trimethylpentyl group, 2,2,4-Trimethylpentyl group, 3,3,4-Trimethylpentyl group, 1 —Ethyl 1-methylpentyl group, 1— Ethyl-2-methylpentyl, 1-ethyl-3-methylpentyl, 1-ethyl-4-methylpentyl, 1-methyl-2-ethylpentyl, 1-methyl-3-ethylpentyl, 1- ( n-propyl) pentyl group, 2- (n-propyl) pentyl group, 1- (1-methylethyl) pentyl group, 2- (1-methylethyl) pentyl group, 3-ethyl-4-methylpentyl group, 1, 1,2,2-tetramethylbutyl group, 1,1,2,3-tetramethylbutyl group, 1,1,3,3-tetramethylbutyl group, 1,2,2,3-tetramethylbutyl group, 1,2,3,3-tetramethylbutyl group, 2,2,3,3-tetramethylbutyl group, 1-ethyl—1,2-dimethylbutyl group, 1-ethyl-1,3-dimethylbutyl group, 1-ethyl-2,3-dimethylbutyl group, 1-ethyl-3,3-dimethylbutyl Group, 1-methyl-1- (butyl) butyl, 2-methyl-1- (n-propyl) butyl, 3-methyl-1- (n-propyl) butyl, 1-methyl-1 _ (1 -methylethyl) butyl group, 2-methyl-1-(1 -methylethyl) butyl group, 3-methyl-1-(1 -methylethyl) butyl group, 1-(1, 1 dimethylethyl) butyl group, 2 —Ethyl— 3,3-dimethylbutyl group, 1,2-dimethyl_1- (1-methylethyl) propyl group, 2,2-dimethyl—1- (1-methylethyl) propyl group, 1-ethyl—1, And a 2,2-trimethylpropyl 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- 3-butenyl group, 1-ethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-hexenyl group, 2-hexene Nyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-11-pentenyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1- Methyl -4-pentenyl group, 1-methylidenepentyl group, 2-methyl-1-pentenyl group, 2-methyl-2-pentenyl group, 2-methyl-3-pentenyl group, 2-methyl-4-pentenyl group , 2-methylidenepentyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 3-methyl-3-pentenyl, 3-methyl-4-pentenyl, 3-methylidenepentyl , 4-Methyl-1-pentenyl, 4-Methyl-2-pentenyl, 4-Methyl-3-pentenyl, 4-Methyl-4-pentenyl, 1-Ethyl-1-butenyl, 1-Ethyl 2-butenyl group, 1-ethyl-3— Butenyl group, 2-ethyl-1-butenyl group, 2-ethyl-2-butenyl group, 2-ethenyl-3-butenyl group, 1- (1-methylethyl) 1-1-propenyl group, 1-1 (1- Methylethyl) 1- 2-butenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1-heptenyl, 2-heptenyl Group, 3-heptenyl group, 4-heptenyl group, 5-heptenyl group, 6-heptenyl group, 1-methyl-1-hexenyl group, 1-methyl-2-hexenyl group, 1-methyl-3-hexenyl 1-methyl-4-hexenyl group, 1-methyl-5-hexenyl group, 1-methylidenehexyl group, 2-methyl-1-hexenyl group, 2-methyl-2-hexenyl group To 2-methyl-3-hexenyl, 2-methyl-4-hexenyl, 2-methyl_5- Cenyl, 2-methylidenehexyl, 3-methyl-1-hexenyl, 3-methyl-2-hexenyl, 3-methyl-3-hexenyl, 3-methyl-4-hexenyl, 3-methyl-5-hexenyl group, 3-methylidenehexyl group, 4-methyl-1-hexenyl group, 4-methyl-2-hexenyl group, 4-methyl-3-hexenyl group, 4-methyl-4 —Hexenyl group, 4-methyl-5-hexenyl group, 4-methylidenehexyl group, 5-methyl-1-hexenyl group, 5-methyl-2-hexenyl group, 5-methyl-3-hexenyl group, 5-methyl-4-hexenyl group, 5-methyl-5-hexenyl group, 1-ethyl-1-pentenyl group, 1-ethyl-2-pentenyl group, 1-ethyl-3-pentenyl group, 1-ethyl Tyl—4-pentenyl group, 2-ethyl—1-pentenyl group, 2 Echiru 2-Bae Pentenyl, 2 _ethyl— 3 —pentenyl, 2 —ethyl— 4 pentenyl, 3 —ethyl 1 pentenyl, 3 —ethyl— 2 —pentenyl, 3-ethyl—3—pentenyl, 3 —ethyl 4-pentenyl, '1,1-dimethyl-2-pentenyl, 1,1-dimethyl-3-pentenyl, 11-dimethyl-14-pentenyl, 22-dimethyl-13-pentenyl, 2 2 —dimethyl-4-pentenyl group, 33-dimethyl-1 —pentenyl group, 33-dimethyl-14-pentenyl group, 44 —dimethyl-1-pentenyl group, 44 —dimethyl-12-pentenyl group, 12-dimethyl-1-pentenyl group, 12-dimethyl-2-pentenyl group, 12-dimethyl-13-pentenyl group, 12-dimethyl-14-pentenyl group, 1-methylidene-12-methylpentyl group, 2—me 1,1-dimethylpentyl, 1,3-dimethyl-1-pentenyl, 1,3-dimethyl-2-pentenyl, 1,3-dimethyl-3-pentenyl, 1,3-dimethyl-4-pentenyl , 1 -methylidene-1 3 -methylpentyl group, 3-methylidene-1 1 -methylpentyl group, 1,4 -dimethyl-1 _pentenyl group, 1,4 -dimethyl-2 pentenyl group, 1,4 -dimethyl-3 —Pentenyl group, 1,4-dimethyl—4-pentenyl group, 1-methylidene—4-methylpentyl group, 1,1,2-trimethyl—2-butenyl group, 1,1,2—trimethyl_3-butenyl Group, 1,1-dimethyl-2, -methylidenebutyl, 1,1,3, trimethyl-2-butenyl, 1,1,3, tri'methyl-13-butenyl, 1,2,2, trimethyl-3- Butenyl group, 2, 2-dimethyl — 1-methylidene butyl group, 1, 2, 3 —trimethyl-1-butenyl group, 1, 2, 3 —trimethyl-2-butenyl group, 1, 2, 3 —trimethyl-3-butenyl group, 2,, 3 —Dimethyl— 1 —methylidenbutyl, 1,3-dimethyl-1- 2 —methylideptyl, 2,2,3 —trimethyl-3-butenyl, 2,3,3 —trimethyl-1-butenyl, 3,3— Dimethyl-2-methylidenebutyl group, 1-ethyl-1-1-methyl-2-butenyl group, 1-ethyl-1-methyl-3-butenyl group, 1-methyl-1-propyl-12-propenyl group, 1-ethylethyl 2-methyl-1-butenyl group, 1-ethyl-2-methyl-2-butenyl group, 1-ethyl-2- (methyl) -3-butenyl group, 1- (1-methylpropyl) —2-propenyl Group, 1-ethylidene-2-methylbutyl group, 1-ethyl 3-Methyl-1-butenyl group, 1_ethyl-3_methyl, 2-butenyl group, 1-ethyl-3-3-methyl-3-butenyl group, 1- (2-methylpropyl) -2-propyl group, 1 -Ethylidene _ 3-methylbutyl group, 1-methyl-2-ethyl-1 butenyl group, 1-methyl-2-ethyl-2-butenyl group, 1-methyl-2-ethyl group 3-butenyl group, 2-methyl-2 —Ethyl— 3-butenyl group, 1- (1-methylethyl) — 1-butenyl group, 1 _ (1-methylethyl) —2-butenyl group, 1- (1-methylethyl) —3-butenyl group, 2-methyl-1 —Propyl— 1-probenyl group, 2-methyl-1-propyl-12-propenyl group, 2- (1-methylethyl) — 1-butenyl group, 2— (1-methylethyl) —2— Butenyl, 2- (1-methylethyl) -3-butenyl, 2-ethyl Examples thereof include a 3-methyl-2-butenyl group and a 2-ethyl-3-methyl-3-butenyl group.

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-butynyl group, 1,2-dimethyl-3-butynyl group, 2,2-dimethyl-3-butynyl group , 2-ethyl-3-butynyl group, etc. You.

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. Is preferably an aralkyl group having 7 to 11 carbon atoms, and examples thereof include a benzyl group and a naphthylmethyl group (a naphthyl-1-methyl group and a naphthyl-2-methyl group).

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.

Hereinafter, each step will be described.

(1) An 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,)

In the reaction, 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. Alternatively, 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.

It is preferable to add (1-1) and a solution obtained by dissolving or suspending a base 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, 1-butylpyrrolidine, 1-methylbiperidine, 1,2,2,6,6-pentamethylpiperidine, 4-methylmorpholine, 1-methylbilol, 1-1 Phenylrubol, 1-methylindole, pyridine, 2-picoline, 2-ethylpyridine, 2,2'-dipyridyl, 3-picoline, 4-picoline, 2,3-lutidine, 2,4-lutidine, 3,4— Lutidine, 2,5-lutidine, 3,5-lutidine, 2,4,6-collidine, 2,6-diter Examples thereof include amine compounds such as t-butyl-4-methylpyridine, N, N-dimethylaniline, N, N-getylaniline, and 1,8-diazabicyclo [5.4.0] indene. The amount of the base to be used is preferably 1 molar equivalent or more, more preferably 1 to 10 molar equivalents, per 1 mol of the estrone derivative (I) or the estrone derivative (1-1).

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. In addition, among the above-mentioned bases, 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. Benzene, O-dichlorobenzene, and other organic solvents, and if necessary, the extract is washed with saturated aqueous sodium bicarbonate, dilute hydrochloric acid, water, saline, etc. to obtain acidic, basic, and aqueous solutions. Remove the volatile substances, dry with anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., and concentrate. 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.

(2) a step of reacting a steroid derivative (III) or a steroid derivative (III-1 ′) with carbon monoxide and an amine (IV) in the presence of a palladium compound to obtain a steroid derivative (V)

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. Add 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 -? Ariru)) divalent etc. 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.

It is preferable that a tertiary phosphine compound coexist with the palladium compound for stabilization. Such 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) In particular, triarylphosphine such as triphenylphosphine is preferable. When a tertiary phosphine compound is used, 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. For example, ethers such as tetrahydrofuran, getyl ether, and dimethoxetane; pentane, hexane, heptane, octane, and stone Hydrocarbons such as oil ether, toluene and xylene; amides such as N, N-dimethylformamide; dimethyl sulfoxide; esters such as ethyl acetate, dimethyl carbonate, ethylene carbonate, and ethyl carbonate; Is mentioned. 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. For example, 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. to remove acidic, basic, and water-soluble substances, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., and concentrated. The obtained crude product is purified by distillation, chromatography, recrystallization, etc., if necessary.

The estrone derivative (I) and the estrone derivative (1-1) can be produced in the same manner as in the reference examples described below.

Example

Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.

Reference example 1

[Synthesis of 3- (methoxycarbonyl) oxy-1,3,5 (10) -triene-17-one] Under a nitrogen atmosphere, estrone [3-hydroxy-estra-1,3,5 (10) -triene 17-one] 5.001 (18.5 Ommo 1) and potassium carbonate 20.32 9 g (147.08 mmo 1) was suspended in 15 ml of dimethyl carbonate and cooled on ice. To this solution was added methyl chloroformate 8. 9 ml of (1 1 5. 1 8mmo 1) portionwise. After completion of the addition, the reaction mixture was stirred heated to 14 hours at room temperature _(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. As a result, 6.002 g of 3- (methoxycarbonyl) oxy-1,1,5- (10) -triene-17-one having the following physical properties was obtained (yield: 9.9%).

Melting point: 1 32 ~: L 34 ° C

Tfi- NMR spectrum _{(270MH z, CD C 1 3} , TMS, p pm) δ: 7. 2 88 (d, 1 H, d = 8. 90 H z), 6. 94 1 (dd, 1 H, d = 1, 9 8, 8.90 Hz), 6.902 (d, 1 H, d = l. 98 Hz), 3.892 (s, 3 H), 2.91 2 (dt , 2 H, J = 3.96, 3.96, 4.94 Hz), 1.9—2.6 (m, 7 H), 1.35-1.75 (m, 6 H ), 0.908 (s, 3 H)

UV (nm): Peak: 2 12.9 = l.69 x 104), 26.8.3 (£ = 1.49 x 103), 275.0 (ε = 1.37 x 1 03); Valley: 240. 5 = 2.17 x 10 2), 2 72.5 (e = 1.19 x 10 3)

Example 1

[Synthesis of 3- (methoxycarbonyl) oxy-1,3,5 (10), 16-tetraen-17-all trifluoromethane sulfonate]

Under a nitrogen atmosphere, the 3- (methoxycarbonyl) oxy-estra-1,3,5 (10) -trien-1 17-one obtained by the method of Reference Example 1 4.4969 g (13, 69 mmo 1) was dissolved in 40 ml of benzene with black mouth, 5.3 ml (38.03 mmo 1) of triethylamine was added, and the mixture was cooled with ice. To this solution, 5.6 ml (33.29 mmo 1) of trifluoroacetic anhydride was added little by little. After completion, the reaction solution was heated to room temperature and stirred for 26.5 hours. The reaction solution was poured into 30 ml of ice water, and an organic layer and an aqueous layer were separated. The organic layer was washed with a 2.5% aqueous hydrochloric acid solution (20 ml), and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained crude crystals were recrystallized from hexane to give 3- (methoxycarbonyl) oxyester 1,3,5 (10), 16-tetraene-17- having the following physical properties. 5.955 g of all trifluoromethanesulfonate was obtained (94% yield).

Melting point: 88 ° C

Ifi- NMR spectrum _{(270MH z, CD C 1 3} , TMS, p pm) δ:

7.259 (d, 1 H, d = 7.91 Hz), 6.936 (dd, 1 H, d = 1, 9 8, 7.91 Hz), 6.894 ( d, 1 H, d = l. 98 Hz), 5.61 (dd, 1 H, d = 1.98, 3.96 Hz), 2.35—2.45 (bdt : 1 H, J = 2.97, 1 2.86 Hz), 2.28-2.40 (ddd, 2 H, J = 2.97, 6.92, 14.84 Hz), 2.104 (dd, 1 H, J = 10.89, 14.84 Hz), 1.85-2.000 (m, 2 H), 1.798 (dd d , 1 H, J = 6.93, 10.88, 17.81 Hz), 1.4—1.72 (m, 4 H), 1.003 (s, 3 H)

¹³ C-NMR spectrum (6 7. 5MH z, CD C 1 3, TMS, p pm) δ: 1 59. 2 1, 1 54. 57, 149. 07, 1 38. 07, 1 37. 78, 1 26.1 1, 1 2 1.07, 1 1 9.48 (q, J = 32 0. l Hz), 1 1 8. 19, 1 14.5 1, 5 5.36, 5 3.56, 45.03, 44.35, 36, 32, 32.71, 29.19, 28.38, 26.51, 25.65, 15.33

UV (nm): Peak 2 0 7.5 = l. 98 x 104), 26.7.4 = l. 61 x 103) '274.9 (ε = 1.4 1 x 103) ; Valley: 240. 1 (ε = 3.76 x 10 2), 2 72.7 (£ = 1.27 x 10 3)

Example 2

[Synthesis of 3-Hydroxy-Estrar 1, 35 (10), 16-Tetraen-1-1-heptylcarboxamide] Under a nitrogen atmosphere, 4.9 mg (22 / mol) of palladium acetate, 11.4 mg (43.5 mol) of triphenylphosphine and 5 ml of N, N-dimethylformamide were added to a 50 ml three-necked flask. Then, 6.5 g (56 mmo 1) of n-heptylamine was added to the solution, and the inside of the flask was replaced with a carbon monoxide atmosphere. To this solution was added 1.00 g of 3- (methoxycarbonyl) oxy-1,3,5 (10), 16-tetraene-1 17-ol trifluoromethanesulfonate obtained by the method of Example 1. 2. A solution prepared by dissolving 17 mmo 1) in 5.7 g of N, N-dimethylformamide was added dropwise at room temperature over 1 hour and 40 minutes. After completion of the addition, the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into 25 ml of a 2.5% aqueous hydrochloric acid solution and extracted with 100 ml of ethyl acetate. The extract is washed three times with 5 ml of a 2.5% aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate, and concentrated to give 3-hydroxy-estra-1, 3, 5 (10) having the following physical properties. : 1.83 g of 16-tetraene-17-N-heptylcarboxamide was obtained (97% yield).

Ifi- NMR spectrum _{(270MHz, CDC1 3, TMS,} p pm) δ: 7. 121 (d, 1H, J = 8. 90 H z), 6. 644 (dd, 1H, J = 2, 97, 8. 90 Hz), 6.586 (d, 1H, J = 8.90 Hz), 6.327 (dd, 1H, J = 3.39, 6.77 Hz), 5.653 (bt, 1H, J = 4.95 Hz), 5.095 (bs, 1H), 3.310 (dt, 2H, J2 5.93, 6.97 Hz), 2.8-2.9 (m , 2 H), 2.0—2.4 (m: 6H), 1.2—1.75 (m, 17 H), 1.018 (s, 3H), 0.882 (t, 3 H) , J = 6.93 Hz)

Industrial applicability

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.

Further, of the steroid derivative derivable to the above-mentioned estran derivative, An industrially advantageous production method is provided from the viewpoint of simplicity. This application is based on a patent application No. 2000-0-63826 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

General formula (-1)

(Wherein, R ¹ represents an alkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group).

2. Equation (I I 1-1,)

OSO CF ₃

(III-1)

0

CH.0

A steroid derivative represented by the formula:

3. General formula (I)

(Wherein, R ¹ represents an alkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group). In the presence of the general formula (II)

CF ₃ S0 ₂ R '(II)

(Wherein, 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, Which represents an alkynyl group, an aryl group or an aralkyl group), characterized by reacting a trifluoromethylsulfonic acid derivative represented by the general formula (III-11)

(Wherein, R ¹ is as defined above.) A method for producing a steroid derivative represented by the formula:

4. Equation (I-1)

In the presence of a base, an estrone derivative represented by the general formula (II)

CF ₃ S0 ₂ R '(II)

(Wherein, R ² represents a halogen atom, triflate Ruo b methylsulfonyl O alkoxy group or a general formula _N (R ³⁾ a group represented by S 0 ₂ CF _^3, R ₃ is an alkyl group, alkenyl group, alkynyl A trifluoromethylsulfonic acid derivative represented by the formula (III-

1 ')

Method _c for producing a steroid derivative represented by

5. General formula (I I I)

(In the formula, R ⁴ represents an alkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group.) In the presence of the compound, carbon monoxide and the general formula (IV) 6

HNR ³ R (IV)

(Wherein, R ⁵ and R ^{6 each} independently represent a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, A alkynyl group, an aryl group which may have a substituent or an aralkyl group which may have a substituent.)

Reacting an amine represented by the general formula (V)

(Wherein, R ⁵ and R ⁶ are as defined above.)

6. Equation (I I I _ 1 ')

In the presence of a palladium compound, carbon monoxide and general formula (IV)

HN R 6 (IV) (Wherein, R ⁵ and R ^{6 each} independently represent a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, A alkynyl group, an aryl group which may have a substituent or an aralkyl group which may have a substituent.

Reacting an amine represented by the general formula (V)

(Wherein, R ⁵ and R ⁶ are as defined above.)