Tamoxifen and analogues thereof

Details Tamoxifen and analogues thereof Tamoxifen and analogues thereof

1998-07-20

2001-01-09

Killos, Paul J. (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S319000

Reexamination Certificate

active

06172263

ABSTRACT:

This invention relates to tamoxifen and analogues thereof and particularly, although not exclusively, relates to a method of preparing a desired isomer of tamoxifen or an analogue thereof.
Tamoxifen is a triphenylethylene derivative of formula
which is a drug in clinical use for the treatment of hormone dependent breast cancer. For this purpose, only the Z isomer has the required antiestrogenic activity, the E isomer being oestrogenic. The same criteria of antioestrogenecity applies to tamoxifen analogues. One of the most important analogues of tamoxifen is 4-hydroxytamoxifen (one of the main metabolites in patients), which has an affinity for binding to oestrogen receptors which is 100 times higher than for tamoxifen itself. Accordingly, processes for stereoselective synthesis and/or isolation of substantially pure Z isomer of tamoxifen, 4-hydroxytamoxifen and other analogues are desirable.
Known processes for the preparation of substantially pure Z isomer of tamoxifen and 4-hydroxytamoxifen include stereoselective syntheses (involving expensive catalysts) as described in J. Chem. Soc., Perkin Trans I 1987, 1101 and J. Org. Chem. 1990, 55, 6184 or chromatographic separation of an E/Z mixture of isomers as described in J. Chem. Res., 1985 (S) 116, (M) 1342, 1986 (S) 58, (M) 771.
It is an object of the present invention to provide a method of preparing tamoxifen or an analogue thereof which is rich in the desired isomer and which may be advantageous over known methods.
The invention is based on the surprising, and previously unappreciated, discovery that one geometric isomer of tamoxifen or an analogue thereof can be predominantly removed from a mixture of isomers in the presence of certain solvents.
According to a first aspect of the invention, there is provided a method of removing predominantly a first geometric isomer of tamoxifen or an analogue thereof from a mixture comprising said first geometric isomer and a second geometric isomer, the method including the step of allowing the first isomer to crystallise in a solvent.
Preferably, the method comprises contacting a mixture which comprises said first and second isomers with said solvent.
The method may include separating the crystallised product from the remainder.
Said solvent is preferably able to dissolve the isomers in said mixture and is such as to allow re-crystallisation as aforesaid. In the method, said solvent is preferably contacted with the isomers in the mixture when said solvent is at a first temperature wherein said first temperature is suitably less than the boiling point of the solvent. Recrystallisation is suitably carried out at a second temperature which is less than said first temperature. It is believed that the temperature of the recrystallisation step affects the relative amounts of first and second isomers in the recrystallised product. For example, it has been observed that, if recrystallisation is carried out in a freezer at −4° C., then the ratio of the amount of the second geometric isomer to the first geometric isomer in the crystallised product is greater than the corresponding ratio observed when recrystallisation is carried out at ambient temperature (about 22° C.). Thus, recrystallisation is suitably carried out at greater than −4° C., preferably greater than 0° C., more preferably greater than 10° C., especially greater than 20° C. Advantageously, recrystallisation may be carried out at at least ambient temperature.
It will be appreciated that there may be an optimum temperature of recrystallisation wherein the ratio of the amount of first geometric isomer to second geometric isomer in the crystallised product is maximised. Said second temperature may be within 30° C., suitably 25° C., preferably 20° C., more preferably 15° C., especially 10° C. of the optimum temperature.
Said first temperature may be at least 50° C., suitably at least 60° C., preferably at least 70° C., more preferably at least 80° C., especially at least 90° C. Said first temperature may be less than 200° C., preferably less than 160° C., more preferably less than 140° C., especially less than 120° C.
Said first temperature may be less than the boiling point of the solvent, suitably by at least 10° C., preferably at least 20° C., more preferably at least 30° C., especially at least 40° C.
Said solvent may have a boiling point of at least 30° C., suitably at least 40° C., preferably at least 50° C., more preferably at least 60° C. Said boiling point may be less than 300° C., suitably less than 250° C., preferably less than 200° C., more preferably less than 175° C.
Various solvents may be selected for use in the method. Preferably, said solvent includes a first solvent part. Preferably, the first solvent part is an organic solvent with polar organic solvents being preferred.
Said first solvent part may be an unsubstituted hydrocarbon or may include one or more functional groups. Such groups may be selected from —OH, —NO
2
, —CN, —O— and optionally substituted, especially unsubstituted, alkyl groups.
The first solvent part may include two or, more preferably, one or fewer functional groups. Especially preferred is the case wherein the first solvent part includes only one functional group.
Said first solvent part is preferably a protic solvent.
A preferred functional group of said first solvent part is an —OH group.
Said first solvent part may be aliphatic, alicyclic, aromatic or heteroaromatic. Said first solvent part is preferably aliphatic.
Said first solvent part may include one or more, suitably at least two, preferably at least three, more preferably at least four, especially at least five carbon atoms. Said first solvent part may include twelve or fewer, suitably ten or fewer, preferably nine or fewer, more preferably eight or fewer, especially seven or fewer, carbon atoms.
Said first solvent part may have a boiling point of at least 50° C., suitably at least 75° C., preferably at least 100° C., more preferably at least 125° C., especially at least 150° C. Said boiling point may be less than 300° C., suitably less than 25° C., preferably less than 225° C., more preferably less than 200° C., especially less than 175° C.
Said first solvent part is preferably an alcohol having one —OH group. Said first solvent part is more preferably hexanol.
Said solvent may include a mixture comprising said first solvent part and a second solvent part. Said second solvent part may include any feature of said first solvent part described herein. Preferably, however, said solvent consists essentially of said first solvent part as described.
The method preferably includes a first step comprising allowing the first isomer to crystallise in a solvent as aforesaid and a second step which comprises allowing the product of the first step to crystallise in a solvent.
The solvent used in the second step (hereinafter “said second solvent”) may have any feature of the solvent used in the first step (hereinafter “said first solvent”). Preferably, said first solvent and said second solvent are different. Preferably, said second solvent has a lower boiling point than said first solvent, suitably by at least 30° C., preferably at least 50° C., more preferably at least 70° C., especially at least 85° C.
The boiling point of the second solvent may be less than 95° C., is suitably less than 80° C., is preferably less than 70° C. and is, more preferably, less than about 65° C.
Said second solvent is preferably an alcohol, preferably a C
1-4
alcohol, especially a C
1-2
alcohol, with methanol being most preferred.
Preferably, the mixture used in the first step of the method is substantially pure. Thus, prior to said first step, there may be a purifying step. This may simply comprise washing a mixture to be used in said first step with a solvent. The solvent used in the washing (hereinafter “said third solvent”) may have any feature of said second solvent as described. Preferably, the temperature of the third solvent in said washing step is less than the temperature of said first solvent when it is used and/or the temperature of said secon

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