GB2327673A

GB2327673A - Tamoxifen and analogues thereof

Info

Publication number: GB2327673A
Application number: GB9815904A
Authority: GB
Inventors: John Double; Derek Maitland; Ioana Popa
Original assignee: Generic Biologicals Ltd; University of Bradford
Current assignee: Generic Biologicals Ltd; University of Bradford
Priority date: 1997-07-23
Filing date: 1998-07-21
Publication date: 1999-02-03
Anticipated expiration: 2018-07-21
Also published as: GB2327673B; NO20000329D0; GB9815904D0; HUP0002807A3; CA2297246A1; JP2001510819A; EP0998447A1; HUP0002807A1; NO316376B1; GB9715479D0; AU8452998A; NO20000329L; WO1999005088A1

Abstract

A method of preparing a first geometric isomer of tamoxifen or an analogue comprises allowing the first isomer to crystallise in hexanol and the product thereof to crystallise in methanol and then derivatising the product of the methanol crystallisation to prepare said first isomer in very high purity.

Description

TAMOXIPEN AND ANALOGUES THEREOF This invention relates to tamoxifen and analogues thereof and particularly, although not exclusively, relates to a method of preparing a desired isomer oi tamoxifen or an analogue thereof.

Tamoxifen is a triphenylethylene derivative oi formula

which is a drug in clinical use for the treatment oi hormone dependent breast cancer. For this purpose, only the Z isomer has the required antiestrogenic activity, the E isomer being oestrogenic. The same criteria oi antioestrogenecity applies to tamoxifen analogues. One oi the most important analogues of tamoxifen is 4hydroxytamoxifen (one of the main metabolites it patients), which has an affinity for binding to oestrogen receptors which is 100 times higher than for tamoxifez itself. Accordingly, processes for stereoselectiv synthesis and/or isolation of substantially pure Z isomer of tamoxifen, 4-hydroxytamoxifen and other analogues ar desirable.

Known processes for the preparation of substantiall 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 recrystallisation 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 -40C, 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 220C). Thus, recrystallisation is suitably carried out at greater than -40C, preferably greater than OOC, more preferably greater than 100C, especially greater than 200C.

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 250C, preferably 200C, more preferably 150C, especially 100C of the optimum temperature.

Said first temperature may be at least 500C, suitably at least 600C, preferably at least 700C, more preferably at least 80 C, especially at least 90 C. Said first temperature may be less than 2000C, preferably less than 1600C, 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 100C, preferably at least 200C, more preferably at least 300C, especially at least 400C.

Said 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 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, -NO2, -CN, -0- 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 500C, suitably at least 750C, preferably at least 1000C, more preferably at least 1250C, especially at least 1500C. Said boiling point may be less than 3000C, suitably less than 250 C, preferably less than 2250C, more preferably less than 2000C, especially less than 1750C.

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 300C, preferably at least 500C, more preferably at least 700C, especially at least 850C.

The boiling point of the second solvent may be less than 950C, is suitably less than 800C, is preferably less than 700C and is, more preferably, less than about 65"C.

Said second solvent is preferably an alcohol, preferably a Clg alcohol, especially a C12 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 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 at some stage of said method from a solvent which includes or, preferably consists essentially of methanol.

By "consists essentially", we mean that a solvent comprises at least 80 wt%, preferably at least 90 wt%, more preferably at least 95 wt%, especially at least 99 wt% of the referenced solvent, for example 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.

In the context of this specification, the term "analogue" includes: a derivative of tamoxifen wherein one or more atoms or groups of tamoxifen have been replaced by other atoms or groups; or wherein a ring or rings is/are formed between juxtaposed atoms or groups of tamoxifen; and a precursor of tamoxifen or a derivative thereof which precursor exists in at least two geometric isomeric forms and which can be converted to tamoxifen or a said derivative thereof, suitably by a substitution reaction.

Various analogues of tamoxifen which fall within the scope of the present invention are described in Endocrine Reviews, 11(4), 1990, 578-603.

Analogues of tamoxifen may include optionallysubstituted triphenylalkyl or alkylene compounds.

Preferred optionally-substituted triphenyl compounds are of general formula

wherein A, B and P each independently represents an optionally-substituted phenyl group and Q represents a hydrogen atom or an optionally-substituted alkyl, alkenyl, alkynyl or phenyl group; and wherein a pair of adjacent substituents A, B, P and Q are optionally arranged together to form part of a ring structure.

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 frm.

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, alkenyl, alkynyl and phenyl groups, preferred optional substituents include halogen atoms, haloalkyl and hydroxy groups and optionally-substituted alkylcarboxy, alkoxy, phenoxy, alkylamino and alkylcarbonyl groups.

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

Preferably, Q represents an optionally-substituted, preferably unsubstituted, alkyl group. Preferably, said alkyl group is a Cl to C4, more preferably a Cl to C2, alkyl group. Q preferably represents an ethyl group.

Preferably, groups A, B and P independently represent an unsubstituted or monosubstituted phenyl group. Where a group A, B or P is substituted, it is preferably substituted in the 3- or, more preferably, the 4position.

Preferably, group B is unsubstituted.

Group P is preferably unsubstituted or substituted by a halogen atom or hydroxy, optionally-substituted alkoxy or phenoxy, groups. Where group P is substituted, it is preferably substituted in the 4-position. More preferably, group P is unsubstituted or substituted by an optionallysubstituted phenoxy group. In an especially preferred embodiment, P is unsubstituted. Thus, preferably P represents an unsubstituted phenyl group.

Preferably, group A is monosubstituted by a halogen atom or hydroxy, optionally-substituted alkoxy or phenoxy, groups. Preferably, group A is monosubstituted by an optionally-substituted alkoxy group. A preferred optionally-substituted alkoxy group is of general formula --O-(CH2)n (11) wherein n represents an integer preferably in the range 1 to 8, more preferably 1 to 4, especially 1 to 2; and X represents a leaving group, for example a halogen, especially a chlorine, atom, or. a group of general formula

wherein Rl and R2 independently represent a hydrogen atom or an optionally-substituted, preferably unsubstituted, alkyl group.

Preferably, n represents 2. In a preferred embodiment, group A is monosubstituted by an alkoxy group of general formula II, wherein n represents 2.

Preferably, said mixture used in the method comprises a first analogue of tamoxifen (preferably a precursor of tamoxifen or tamoxifen derivative as described above) and the method includes the further step of derivatising the first geometric isomer removed in order to prepare tamoxifen or a derivative, especially an antiestrogenic derivative, thereof. Preferably, the first analogue of tamoxifen, more preferably said first geometric isomer of said first analogue, has less antiestrogenic activity compared to tamoxifen or a said derivative which is prepared in said further derivatising step.

Preferably, said precursor is a compound of general formula I described above wherein B, P and Q are as described above. Preferably, A represents a phenyl group substituted, preferably at least at the 4-position, by a first moiety which includes an active atom or group which is arranged to react with a second moiety which includes a group of general formula III as described above in order to produce an optionally substituted alkoxy group of general formula II as described above. Preferably, said first moiety includes a leaving group which is suitably X as described above. Preferably, said first moiety comprises a group of general formula II as described above. Said first moiety is preferably reacted with an amine of general formula R1R2NH wherein Rl and R2 are as described above.

Where a pair of adjacent substituents A, B, P and Q are arranged together to form part of a ring structure, the ring structure may be formed between pairs of substituents A, B, P and Q which are cis to one another.

Examples of compounds of general formula I which have ring structures as described include:

wherein Z represents an oxygen or sulphur atom or a group - CH2CH2-.

Preferably, adjacent substituents A, B, P and Q de not form part of a ring structure.

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

A precursor of tamoxifen or tamoxifen derivative fo2 use in the method may be prepared from a compound ol general formula

wherein A, B, P and Q are as described in any statement herein. Preferably, A, B, P and Q in said compounds oi formula I and XII represent the same atoms or groups.

Advantageously, the compound of formula XII may bf 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, foz example concentrated hydrochloric acid.

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

Referring to Scheme I, preferably, the alkene derivative of formula XI 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 XI prepared contains 100% (according to HPLC analysis) of the desired Z isomer (which has the stereochemical configuration of compound XI shown in Scheme I). Compound XI 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 99.5 wt%, preferably greater than 99.7 wt%, more preferably greater than 99.8 wt%, especially greater than 99.9 wt%, of said first geometric isomer.

A typical process for preparing 4-hydroxytamoxifen involves derivatising compound X prepared according to the reaction scheme provided below.

The invention extends to pharmaceutically acceptable forms, for example salts of tamoxifen or analogues thereof.

The invention extends to a method of preparing tamoxifen or a derivative, especially an antiestrogenic derivative, thereof, the method including the steps of allowing a first geometric isomer of a precursor of tamoxifen or said derivative to crystallise in a solvent and derivatising said precursor in order to produce said tamoxifen or said derivative.

The invention extends to the use of a solvent for removing predominantly a first geometric isomer of tamoxifen or an analogue thereof from a mixture of isomers.

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 using a solvent as described herein.

The invention extends to the product of any process described herein.

Any feature of any aspect or embodiment described herein may be combined with any feature of any other aspect or embodiment 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 1H NMR spectrum of the material referred to in figure 5, after recrystallisation from hexanol in the dark; Figure 7 is a 1H NMR spectrum of the material referred to in figure 5, 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-l- butanone (3.75g, 12.4mmol) in ether (15ml) was added over 1 hour. The resulting mixture was ref fluxed for 16 hours, then poured into dilute hydrochloric acid (50ml) 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 (Na2SO4) 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). '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 5). The pure solid from above was dissolved in hot hexanol (1000C) and left to crystallise at ambient temperature. A 22:1 mixture of Z:E isomers (2.11 g, 47% (see Figure 6)) 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. 107-1090C, m/z 362/364 (chlorine atom present). 8H 0.92 (3H, t, J = 7.33 Hz, CH3), 2.46 (2H, q, J = 7.33 Hz, CH2CH3), 3.72 (2H, t, J = 5.86 Hz, OCH2CH2Cl), 4.09 (2H, t, J = 5.86 Hz, OCH2CH2Cl), 6.55 (2H, d, J = 8.79 Hz, aromatic protons ortho to OCH2CH2Cl), 6.79 (2H, d, J = 8.79 Hz, aromatic protons meta to OCH2CH2Cl), 7.10-7.38 (10H, m, the two remaining C5'S) (see Figure 5). The 2-chloroethoxy tamoxifen was reacted with dimethylamine in ethanol, under reflux, to produce the desired Z isomer of tamoxifen.

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

The expansion of the region 6 0.80 to 1.05 shows two overlapping triplets corresponding to the CH3 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 E), 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 1H 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 5 mm, 250 x 4.0 mm column and 50% MeOH : 30%; MeCN : 20%; H2O mobile phase at lml/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 Zand E- isomers. The following solvents were found to be effective: methanol, ethanol, propanol, iso-propanol, butanol, pentanol, cyclohexanol, acetonitrile, benzene, toluene, nitromethane, petroleum ether and dioxan.

The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, abstract and drawings), may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise each feature disclosed is one example only of a generic series of equivalent or similar features.

The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings) , or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

Claims

CLAIMS 1. 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.
2. A method according to Claim 1, wherein said solvent is contacted with said mixture at a first temperature which is less than the boiling point of the solvent and recrystallisation is then carried out at a second temperature which is greater than -40C.
3. A method according to Claim 2, wherein said second temperature is greater than 200C.
4. A method according to any preceding claim, wherein said solvent includes a first solvent part which is a polar organic solvent.
5. A method according to Claim 4, wherein said first solvent part is an alcohol having only one -OH group.
6. A method according to Claim 4 or Claim 5, wherein said first solvent part is hexanol.
7. A method according to any preceding claim, comprising allowing the first isomer to crystallise in said solvent (hereinafter "said first solvent") in a first step and subsequently allowing the crystallised product of the first step to crystallise in a solvent (hereinafter "said second solvent") in a second step.
8. A method according to Claim 7, wherein said second solvent has a lower boiling point than said first solvent.
9. A method according to Claim 8, wherein said second solvent comprises methanol.
10. A method according to any preceding claim, wherein said first geometric isomer is crystallised at some stage in said method from a solvent which includes methanol.
11. A method according to any preceding claim, wherein said first geometric isomer of tamoxifen or an analogue represents a precursor of tamoxifen or a derivative thereof which precursor can be converted to tamoxifen or a said derivative thereof.
12. A method according to Claim 11, wherein said precursor is prepared from a compound of general formula

wherein A, B and P independently represent an optionallysubstituted phenyl group and Q represents a hydrogen atom or an optionally-substituted alkyl, alkenyl, alkynyl or phenyl group.
13. A method according to Claim 11 or Claim 12, wherein said precursor is derivatised using a compound which includes a group of general formula

to convert said precursor to tamoxifen or said derivative, wherein Rl and R2 independently represent a hydrogen atom or an optionally-substituted alkyl group.
14. A method of preparing tamoxifen or a derivative, especially an antiestrogenic deriyative, thereof, the method including the steps of allowing a first geometric isomer of a precursor of tamoxifen or said derivative to crystallise in a solvent and derivatising said isomer in order to produce said tamoxifen or said derivative.
15. The use of a solvent for removing predominantly a first geometric isomer of tamoxifen or an analogue thereof from a mixture of isomers.
16. A method of preparing an antiestrogenic isomer of tamoxifen or an analogue thereof in purity of at least 99, the method using a solvent or solvents as described in any preceding claim.
17. A method substantially as hereinbefore described with reference to the Examples.
18. A use substantially as hereinbefore described with reference to the Examples.