AU2003200764B2 - Tamoxifen and analogues thereof - Google Patents

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Invention Title: "TAMOXIFEN AND ANALOGUES THEREOF" The following statement is a full description of this invention, including the best method of performing it known to me/us: 4J-1- 1 TAMOXTFEN AND MAALOGUES

THEREOF

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

N

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 antiescrogenic activity, the E isomer being oestrogenic. The same criteria of antioestrogenecity applies to tamoxifen analogues. One of the most important analogues of tamoxifen .is 4hvdroxytamoxifen (one of the main metabolites in patients), which has an affinity for binding to oestrogen receptors which is 100 times higher than for tamoxrien i"self. Accordingly, processes for scereoselec:ive synthesis and/or isolation of substantially pure Z isomer c: tamoxifer., 4-hvdroxycamoxifen and other analogues are desirable.

Known processes for the preparation of subscancially pure Z isomer of camoxifen and 4-hvdroxyzamoxifen inclu-d 2 stereoselective syntheses (involving expensive catalysts) as described in J.

Chem. Soc., Perkin Trans 11987, 1101 and J. Org. Chem. 1990, 55, 6184 or cl-f rmatographic separation of an E/Z mixture of isomers as described in J.

Chem. Res., 1985 116, 1342, 1986 58, 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 a precursor of tamoxifen or a precursor of an analogue of tamoxifen from a mixture comprising said first geometric isomer and a second geometric isomer, wherein said precursor is of general formula:

A

P 0 wherein A represents a phenyl group substituted by a group -0-(CH2)n X, where n is an integer, X is a leaving group, P represents an unsubstituted phenyl group, B represents an unsubstituted or monosubstituted phenyl group and Q represents an optionally-substituted alkyl group, the method including a first step comprising allowing the first isomer to crystallise in a first solvent and a second step comprising allowing a product of the first step to crystallise in a second solvent wherein said second solvent comprises methanol.

The method may include separating the crystallised product from the remainder.

In the method, said first solvent is preferably contacted with the isomers in the mixture when said first 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 0 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 0 Thus, recrystallisation is suitably carried out at greater than -4OC, preferably greater than 0OC, more preferably greater than 10 0 C, especially greater than 20 0

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 300C, suitably 250C, preferably 20 0

C,

more preferably 15 0 C, especially 10 0 C of the optimum temperature.

Said first temperature may be at least 500C, suitably at least 6000, preferably at least 700C, more preferably at least 80 0 C, especially at least 900C. Said first temperature may be less than 2000C, preferably less than 1601C, more preferably less than 1400C, especially less than 1200C.

Said first temperature may be less than the boiling point of the solvent, suitably by at least 10 C, preferably at least 200C, more preferably at least 300C, especially at least 400C.

Said first solvent may have a boiling point of at least 300C, suitably at least 400C, preferably at least 500C, more preferably at least 600C. Said boiling point may be less than 3000C, suitably less than 2500C, preferably less than 2000C, more preferably less than 1750C.

Various solvents may be selected for use in the method. Preferably, said first 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, 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 5000, suitably at least 75 0 C, preferably at least 1000C, more preferably at least 1250C, especially at least 150 0 C. Said boiling point may be less than 3000C, suitably less than 2500C, preferably less than 225 0 C, more preferably less than 200 0 C, especially less than 175CC.

Said first solvent part is preferably an alcohol having one -OH group.

Said first solvent part is more preferably hexanol.

Said first 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.

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 300C, preferably at least 500C, more preferably at least 700C, especially at least 851C.

The boiling point of the second solvent may be less than 950C, is suitably less than 801C, is preferably less than 700C and is, more preferably, less than about 65 0

C.

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 second solvent when it is used. Said third solvent preferably is the same as said second solvent and is, therefore, preferably methanol: Preferably, said first geometric isomer is crystallised from a solvent which consists essentially of methanol.

By "consists essentially", we mean that a solvent comprises at least wt%, preferably at least 90 wt%, more preferably at least 95 wt%, especially at least 99 wt% of methanol.

Said first step and/or said second step may be carried out under less than ambient light conditions. Preferably, said step(s) is/are carried out substantially in the dark. Preferably, the method uses a receptacle which is substantially opaque. Excluding or reducing the light intensity in said first and/or second steps is found to increase the amount of the preferred isomer isolated.

It will be appreciated that the compound of general formula I may exist in different geometric isomeric forms and the formula is not intended, unless otherwise stated herein, to be limited to any such form.

Optional substituents as described herein include any substituents generally used to affect the activity of drugs for oral administration or which represent leaving groups and/or protecting groups which aid the preparation of such drugs. In relation to alkyl and phenyl groups, preferred optional substituents include halogen atoms, haloalkyl and hydroxy groups and optionally-substituted alkylcarboxy, alkoxy, phenoxy, alkylamino and alkylcarbonyl groups.

M

Preferred alkyl groups may have up to 12, preferably up to 6, more preferably up to 4 carbon atoms.

Preferably, Q represents an unsubstituted alkyl group. Preferably, said alkyl group is a C1 to C 4 more preferably a C 1 to C2, alkyl group. Q preferably represents an ethyl group.

Preferably, group B is unsubstituted.

Preferably, n represents an integer in the range 1 to 8, more preferably 1 to 4, especially 1 to 2; and X represents a halogen, especially a chlorine, atom.

Preferably, n represents 2.

Preferably, the method includes a further step of derivatising the first geometric isomer removed in the method in order to prepare tamoxifen or a derivative, especially an antiestrogenic derivative, thereof.

When the method involves contacting a mixture which comprises first and second isomers, the mixture used may be prepared by known routes to tamoxifen and its derivatives for example as described in J.Chem. Research, 1985 116, 1342 and 1986 58, 0771.

A precursor of tamoxifen or analogue of tamoxifen for use in the method may be prepared from a compound of general formula A B H--OH (XII) wherein A, B, P and Q are as described in any statement herein. Preferably, A, B, P and Q in said compound of formulae I and XIII represent the same atoms or groups.

Advantageously, the compound of formula XlI may be dehydrated to prepare the compound of formula I. Dehydration may involve refluxing the compound of formula XII in a solvent in the presence of a strong acid, for example concentrated hydrochloric acid.

Tamoxifen or an analogue of tamoxifen may be prepared by derivatising a said first geometric isomer prepared as described above, said first geometric isomer being derivatised using a compound which includes a group of general formula

R

1

N

wherein R, and R 2 independently represent a hydrogen atom or an optionally-substituted alkyl group.

A typical reaction scheme for preparing tamoxifen is as shown below in Scheme I.

Mt ocil c1 1 c OCI C1 2 C1 OCIICI 1C1OH 2

II

tPhMgllr- 4 Oil h -co 0 N1I(CIT) 1 Gel 1 1 C12N(Cl1 3 h Referring to Scheme I, preferably, the alkene derivative of formula Xl is contacted with said solvent prior to the reaction with dimethylamine. In one embodiment, it is found that, after washing a mixture of geometric isomers of said compound XI with methanol, followed by a first recrystallisation step using hexanol and a second recrystallisation step using methanol, the compound Xl prepared contains 100% (according to HPLC analysis) of the desired Z isomer (which has the stereochemical configuration of compound Xl shown in Scheme Compound Xl can then be converted by a simple reaction to tamoxifen with the stereochemistry being maintained. Thus, in general terms, the method described above may be used to prepare tamoxifen or an analogue which includes greater than 99 wt%, suitably greater than 99.5wt preferably greater than 99.7 wt%, more preferably greater than 99.8 wt%, especially greater than 99.9 wt%, of said first geometric isomer.

The invention extends to a method of preparing an antiestrogenic isomer of tamoxifen or an analogue thereof in purity of at least 99%, suitably at least 99.5%, preferably at least 99.7%, more preferably at least 99.8%, especially at least 99.9%, most preferably at least 99.95%, the method being as described according to the invention described herein.

The invention will now be described, by way of example, with reference to the accompanying figures wherein: Figure 1 is a 1H NMR spectrum for a mixture of isomers of a tamoxifen precursor, prepared in Example 1; Figures 2 to 4 provide further detail for the spectrum of Figure 1; Figure 5 is a 1H NMR spectrum for the product obtained in Example 1 after washing with methanol.

Figure 6 is an 'H NMR spectrum of the material referred to in figure after recrystallisation from hexanol in the dark; Figure 7 is a 1 H NMR spectrum of the material referred to in figure after recrystallisation from methanol in the dark; and Figure 8 is an HPLC analysis on the product of figure 7.

Example 1 Preparation of Z isomer of Tamoxifen A solution of bromobenzene (3.92g, 25mmol) in ether (5ml) containing a crystal of iodine was added dropwise to a suspension of magnesium turnings (0.63g, 26mmol) in ether (5ml) at reflux. After the addition was complete, the reaction mixture was cooled to room temperature and a solution of 1-[4-(2-chloroethoxy) phenyl]-2-phenyl-1-butanone (3.75g, 12.4mmol) in ether (15ml) was added over 1 hour. The resulting mixture was refluxed for 16 hours, then poured into dilute hydrochloric acid (50mi) and extracted with ether (3x40ml). The combined ether layers were concentrated, the residual oil was dissolved in ethanol (10ml) and refluxed with concentrated hydrochloric acid (5ml) for 4 hours. The organic phase was separated, dried (Na 2

SO

4 and evaporated to dryness to give a yellow oil, which upon standing at room temperature for 5 minutes became a pale yellow solid (4.99 g, 111% n.b. this yield suggests the presence of impurities). 1 H NMR (see Figures 1 to 4 and discussion below) showed this to be a 2:1 mixture of the Z and E isomers. The solid was then covered with methanol and stirred at room temperature until a fine suspension formed.

The suspension was filtered to give a pure white solid (3.82 g, 85%) which was a 3.2:1 mixture of Z:E isomers (see Figure The pure solid from above was dissolved in hot hexanol (100 0 C) and left to crystallise at ambient temperature. A 22:1 mixture of Z:E isomers (2.11 g, 47% (see Figure was produced, and this product was in turn recrystallised from methanol by dissolving the material in the minimum amount of boiling methanol to give pure (as confirmed by 1H NMR and HPLC see Figures 7 and 8) Z isomer of 2-chloroethoxy tamoxifen (1.55 g, 34.6% yield). M.p. 107-109 0 C, m/z 362/364 (chlorine atom present). aH 0.92 (3H, t, J 7.33 Hz, CH 3 2.46 (2H, q, J 7.33 Hz, CH 2

CH

3 3.72 (2H, t, J 5.86 Hz, OCH 2

CH

2 CI), 4.09 (2H, t, J 5.86 Hz, OCH2CH 2 CI), 6.55 (2H, d, J 8.79 Hz, aromatic protons ortho to

OCH

2

CH

2 CI), 6.79 (2H, d, J 8.79 Hz, aromatic protons meta to

OCH

2

CH

2 CI), 7.10-7.38 (10H, m, the two remaining CeH5's) (see Figure The 2-chloroethoxy tamoxifen was reacted with dimethylamine in ethanol, under reflux, to produce the desired Z isomer or tamoxifen.

Analysis of 1 H NMR data Figures 1 to 4 represent a mixture of the E- and Z- forms of compound XI described above in Scheme I.

The expansion of the region a 0.80 to 1.05 shows two overlapping triplets corresponding to the CH 3 groups in the Z- and E- derivatives respectively. The critical point is the ratio of the heights of the peaks at 0.92 (for the Z) and 0.94 (for the which is approximately 2:1.

The expansion of the 4.00 to 4.35 region reveals similar information where ratios are 10:6.4 and 5.56:3.43. Similarly expansion of the region 3.6 to 3.9 shows the ratio to be 2.46:1. All of these measurements suggest an approximate 2:1 ratio. The discussion with reference to figure 1 also applies to the spectra of figures 6 and 7 referred to below.

Figure 5 shows the 'H NMR spectrum of the pure solid obtained after the methanol washing of the crude reaction product. Figure 6 shows the 1H NMR spectrum of the solid obtained following the recrystallisation from hexanol of the product shown in Figure 5, and Figures 7 and 8 respectively show the 1H NMR and the HPLC analyses of the pure Z isomer obtained following the second recrystallisation, this time from methanol. The HPLC analysis we carried out under the following conditions: Hypersil ODS (Trade Mark) 5 mm, 250 x 4.0 mm column and 50% MeOH 30%; MeCN

H

2 0 mobile phase at Iml/min.

As an alternative to the use of hexanol followed by methanol as described in Example 1, other solvents were tested to assess their ability to predominantly remove the Z isomer of 2-chloroethoxy tamoxifen from a mixture of Z- and E- isomers. The following solvents were found to be effective: methanol, ethanol, propanol, isopropanol, butanol, pentanol, cyclohexanol, acetonitrile, benzene, toluene, nitromethane, petroleum ether and dioxan.

Claims (12)

1. A method of removing predominantly a first geometric isomer of a precursor of tamoxifen or a precursor of an analogue of tamoxifen from a mixture comprising said first geometric isomer and a second geometric isomer, wherein said precursor is of general formula: A A P 0 wherein A represents a phenyl group substituted by a group -O-(CH2)n X, where n is an integer, X is a leaving group, P represents an unsubstituted phenyl group, B represents an unsubstituted or mono- substituted phenyl group and Q represents an optionally-substituted alkyl group, the method including a first step comprising allowing the first isomer to crystailise in a first solvent and a second step comprising allowing a product of the first step to crystallise in a second solvent wherein said second solvent comprises methanol.

2. A method according to any preceding claim, wherein said first solvent includes a first solvent part which is a polar organic solvent.

3. A method according to claim 2, wherein said first solvent part is an alcohol having only one -OH group.

4. A method according to claim 2 or claim 3, wherein said first solvent part is aliphatic.

A method according to any of claims 2 to 4, wherein said first solvent part has at least two carbon atoms and twelve or fewer carbon atoms.

6. A method according to any of claims 2 to 5, wherein said first solvent part has a boiling point of at least 1000C.

7. A method according to any of claims 4 to 6, wherein said first solvent part is hexanol.

8. A method according to any preceding claim, wherein said precursor is of formula and is prepared from a compound of formula LI

9. A method of preparing tamoxifen or an analogue of tamoxifen, the method comprising derivatising a first geometric isomer of a precursor prepared in a method according to any preceding claim, said first geometric isomer being derivatised using a compound which includes a group of general formula -N^ R2 wherein R 1 and R 2 independently represent a hydrogen atom or an optionally-substituted alkyl group.

A method according to claim 9, wherein R, and R 2 represent methyl groups.

11. A method of preparing an antiestrogenic isomer of tamoxifen or an analogue thereof in purity of at least 99%, the method being as described in claim 9 or claim

12. A method substantially as hereinbefore described with reference to the Examples. ,i