Synthesis of 2-hydroxyestradiol derivatives

Details Synthesis of 2-hydroxyestradiol derivatives Synthesis of 2-hydroxyestradiol derivatives

2001-08-07

2002-09-10

Qazi, Sabiha (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

C552S558000, C552S505000

Reexamination Certificate

active

06448419

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to an improved method for synthesizing 2-hydroxy-3,17&bgr;-estradiol derivatives and new intermediate compounds useful in synthesizing such estradiol derivatives.
BACKGROUND OF THE INVENTION
Originally discovered as an in vivo metabolite of 3,17&bgr;-estradiol, 2-methoxyestradiol has recently been shown to strongly inhibit vascularization of solid tumors making it a potential anticancer agent. Other 2-alkoxy-estradiol derivatives also possess potent anti-angiogenesis properties. A critical intermediate in the synthetic production of these 2-alkoxy-estradiol derivatives is 3,17&bgr;-protected 2-hydroxy-estradiol. The family of biologically active 2-alkoxy analogs are most commonly produced from alkylation of the corresponding 3,17&bgr;-protected 2-hydroxy analog.
A number of synthetic procedures exist for the production of 2-hydroxyestradiol and its subsequent conversion to the 2-alkoxy analogs. The most popular approach has been to prepare the 2-formyl-estradiol analog, treat it with an organic peracid under Baeyer-Villiger conditions and hydrolyze the resulting formate ester to the 2-hydroxy derivative. Although affording reasonable yields, these multi-step schemes are technically involved and require chromatographic purification at one or more steps. Other more direct approaches such as direct oxygenation of 2-lithiated estradiol analogs suffer from low yields and laborious purifications. Direct introduction of the 2-methoxy moiety via organometallic activation of the estradiol aromatic A-ring has been achieved. However, the difficult preparation and cost of the organometallic reagent make this synthesis unsuitable for large-scale use.
Given the anti-cancer potential of 2-alkoxy-estradiol derivatives, a need exists for a practical, scalable, high yielding and direct synthetic procedure for manufacture of such compounds.
SUMMARY OF THE INVENTION
The present invention is directed to an improved method for synthesizing 2-hydroxy-3,17&bgr;-estradiol derivatives and to intermediate compounds that are useful to produce such estradiol compounds. In particular, the present invention is directed to the preparation of 2-boronyl or 2-silyl modified estradiol analogs.
In accordance with the present invention, 3,17&bgr;-estradiol is reacted with a suitable organolithium reagent and either a suitable boron reagent or a suitable silicon reagent to form a compound represented by one of the corresponding structural formulae, respectively:
(If a boron reagent) (If a silicon reagent)
where R
1
and R
2
can be the same or different and each represents an alkaline stable hydroxy protecting group. Preferably, R
1
and R
2
are each methoxymethyl. R
3
, R
4
and R
5
are selected from the group consisting of halogens, alkyl, aryl, hydroxy, substituted or unsubstituted alkoxy, and substituted or unsubstituted aryl.
The organolithium reagent is preferably sec-butyllithium. The silicon and boron reagents are represented by the following corresponding formulae:
(silicon reagent) and (boron reagent)
R
3
, R
4
, R
5
, and R
6
are selected from the group consisting of halogens, alkyl, aryl, hydroxy, substituted or unsubstituted alkoxy, and substituted or unsubstituted aryl. Preferably, the silicon reagent is either dichlorodimethylsilane or diethoxydimethylsilane. Trimethyl borate is the preferred boron reagent.
The boronyl or silyl modified estradiol is subsequently oxidized to form the compound represented by the following structural formula:
where R
1
and R
2
are as described above. Sodium perborate is the preferred oxidizing agent for the boronyl derivative. Hydrogen peroxide is the preferred oxidizing agent for the silyl derivative.
The present invention is further directed to novel 2-boronyl or 2-silyl modified estradiols and methods of preparing these novel compounds, which are useful intermediates in forming 2-hydroxy-3,17&bgr;-estradiol derivatives.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, methods of synthesizing the foregoing novel compounds are provided. 2-alkoxy estradiols and a numbering system for identifying each carbon atom in the estradiol ring system are shown in the following structural formula:
where R
10
is an alkyl group or a substituted alkyl group.
As used in the description, and in the claims, “alkyl” represents a straight-chain or branched hydrocarbon radical of 1 to 10 carbons in all its isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, etc. The alkyl group can optionally contain one or more double or triple bonds. The term “aryl” signifies a phenyl-, or an alkyl-, nitro- or halo-substituted phenyl group. The term “alkoxy” signifies the group alkyl-O—. Suitable substituents on an alkyl group or phenyl group include one or more halogens (e.g., fluoro, chloro, bromo and iodo), nitro, nitrile, —NH
2
, —NH (alkyl), —NH (substituted alkyl), —N (alkyl)
2
, —N(substituted alkyl)
2
, carbonyl groups, —CONH
2
, —CONH(alkyl), —CONH(substituted alkyl), CON(alkyl)
2
, —CON(substituted alkyl)
2
, —CO
2
H, —COO(alkyl) and —COO (substituted alkyl). Halogenated alkyl groups can contain more than one kind of halogen. Examples of suitable alkyl or substituted alkyl groups include methyl, ethyl, n-propyl, iso-propyl, trifluoromethyl, trifluoroethyl, NO
2
—CH
2
—CH
2
—, (CH
3
)N—CH
2
—CH
2
—, —CH
2
CH
2
—CO—R′, wherein R
10
is —H, alkyl, substituted alkyl, —OH, —O (alkyl), —O(substituted alkyl), —NH
2
, —NH(alkyl), —NH (substituted alkyl), —N(substituted alkyl)
2
and —N(alkyl)
2
.
The following reaction scheme depicts the production of 2-methoxyestra-3,17&bgr;-diol (5) by preparing a 2-boronyl or 2-silyl modified estradiol analog in accordance with the present invention. This synthesis is described in greater detail below.
Synthesis of 2-Methoxyestra-3,17&bgr;-diol
In accordance with the foregoing reaction scheme, a first intermediate (2) is prepared from 3,17&bgr;-estradiol (1) by protecting the two hydroxyl groups to form a compound represented by Structural Formula (I):
where R
1
and R
2
may be the same or different and each is independently a hydroxyl protecting group. As used herein, hydroxyl refers to alcohols and phenolic groups. A suitable “protecting group” is substantially inert with respect to the reagents used in the subsequent reactions in the disclosed synthesis of 2-alkoxy estradiols and does not cause, for example, undesired side reactions. Hydroxyl protecting groups are well known in the art and are described in, for example, Chapters 2 and 3 of Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley & Sons (1999), the entire disclosure of which is herein incorporated by reference. The skilled artisan can select suitable groups for use in the disclosed synthesis as well as conditions for applying and removing the hydroxyl protecting groups.
Preferably, R
1
is a protecting group that promotes ortho-lithiation at the 2-position. Such a protecting group contains an atom bearing a lone pair of electrons &bgr; to the hydroxyl oxygen. Such an atom is a heteroatom and preferably an oxygen atom. The general description of these types of ortho-directing protecting groups are substituted methyl ethers such as methoxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, and tetrahydrofuranyl. Methoxymethyl is most preferred for its selective promotion of lithiation at the 2-position over the 4-position. Correspondingly, it is preferred that R
1
and R
2
are each methoxymethyl.
The first intermediate (2) is reacted with an organolithium reagent and a boron or a silicon reagent to form a second intermediate having Structural Formula (II) from the boron reagent or (III) from the silicon reagent:
where R
1
and R
2
are as described above with respect to Structural Formula (I) and R
3
, R
4
and R
5
are halogens, alkyl, aryl, hydroxy, substituted or unsubstituted alkoxy, or substituted or unsubstituted aryl.
Organolithium reagents are well known in the art. Examples of suitable organolithium reagents in

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