JP2001510819A - Tamoxifen and its congeners - Google Patents

Abstract

  (57) [Summary] The process for the production of the first geometric isomer of tamoxifen or homologues involves crystallizing the first isomer in hexanol, crystallizing the product in methanol, deriving the product of methanol crystallization, Producing the first isomer in purity.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to tamoxifen and homologues thereof, and in particular, but not exclusively,
The present invention relates to a method for producing a desired isomer of tamoxifen or a homolog thereof.

[0002] Tamoxifen is a drug used clinically in the treatment of hormone-dependent breast cancer.
formula

Embedded image Is a triphenylethylene derivative. For this purpose, only the Z isomer has the required anti-estrogenic activity, the E isomer is estrogenic. The same criteria for antiestrogens apply to homologues of tamoxifen. One of the most important homologs of tamoxifen is 4-hydroxy tamoxifen (one of the patient's major metabolites), which has a 100-fold higher affinity for binding to the estrogen receptor than tamoxifen itself. Thus, a method of stereoselective synthesis and / or separation of substantially pure Z isomers of tamoxifen, 4-hydroxy tamoxifen and other homologs is desired.

[0003] Known methods for the preparation of substantially pure Z isomers of tamoxifen and 4-hydroxy tamoxifen include J. Chem. Soc., Perkin Trans I 1987, 1101 and J. Org. Chem. 1990, 55, Stereoselective synthesis as described in 6184 (requires expensive catalyst) or described in J. Chem. Res., 1985 (S) 116, (M) 1342, 1986 (S) 58, (M) 771 There is a chromatographic separation of a mixture of E / Z isomers such as

[0004] It is an object of the present invention to provide a process for preparing tamoxifen or a homologue thereof that is rich in the desired isomer and which is superior to known processes.

[0005] The present invention is based on the previously unappreciated surprising discovery that certain geometric isomers of tamoxifen or its homologues can be predominantly removed from an isomer mixture in the presence of a particular solvent.

According to a first aspect of the present invention, the first geometric isomer of tamoxifen and its homologues is predominantly removed from a mixture comprising said first and second geometric isomers and the first isomer is dissolved in a solvent. There is provided a method comprising the step of crystallizing therein.

[0007] Preferably, the method comprises contacting a mixture comprising the first and second isomers with the solvent.

[0008] The method may include separating the crystallized product from the residue.

The solvent is preferably capable of dissolving the isomer in the mixture, for example for crystallization as described above. In this method, when the solvent is at the first temperature, the solvent is preferably contacted with the isomers in the mixture. The first temperature is suitably below the boiling point of the solvent. Recrystallization is suitably performed at a second temperature below the first temperature. It is believed that the temperature of the recrystallization step affects the relative amounts of the first and second isomers in the recrystallized product. For example, if the recrystallization is performed in a freezer at −4 ° C., the ratio of the amounts of the second geometric isomer and the first geometric isomer in the crystallized product will be such that the recrystallization is at room temperature (
(Approximately 22 ° C.). Therefore, the recrystallization is suitably performed at -4 ° C or higher, preferably at 0 ° C or higher, more preferably at 10 ° C or higher,
The above is performed. Conveniently, the recrystallization is performed at least at room temperature.

It will be appreciated that there may be an optimum temperature for recrystallization that maximizes the ratio of the amounts of the first and second geometric isomers in the crystallized product. The second temperature is within 30 ° C of the optimal temperature, suitably within 25 ° C, preferably within 20 ° C, more preferably 1 ° C.
It is within 5 ° C, especially within 10 ° C.

The first temperature is 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. . The first temperature is at most 200 ° C, preferably at most 160 ° C, more preferably at most 140 ° C, especially at most 120 ° C.

The first temperature is lower than the boiling point of the solvent, suitably lower than 10 ° C., preferably lower lower than 20 ° C., more preferably lower lower than 30 ° C., especially lower lower than 30 ° C. Up to 40 ° C.

The solvent is at least 30 ° C., suitably at least 40 ° C., preferably at least 50 ° C.
C., more preferably at least 60.degree. The boiling point is 300 ° C or lower, suitably 250 ° C or lower, preferably 200 ° C or lower, more preferably 175 ° C or lower.

Various solvents can be selected for use in the present method. Preferably, the solvent includes a first solvent portion. Preferably, the first solvent portion is an organic solvent, preferably a polar organic solvent.

[0015] The first solvent moiety is an unsubstituted hydrocarbon or comprises one or more functional groups. This group is _{-OH, -NO 2, -CN, -O-} , it is selected from particularly non-substituted alkyl group and contact alkyl group optionally substituted.

The first solvent moiety contains two, or more preferably, one or several functional groups. Particularly preferred is the case where the first solvent portion contains only one functional group.

[0017] The first solvent portion is preferably a protic solvent.

A preferred functional group of the first solvent moiety is an -OH group.

[0019] The first solvent portion is aliphatic, cycloaliphatic, aromatic or heteroaromatic. The first solvent portion is preferably aliphatic.

The first solvent portion contains one or more, suitably at least 2, preferably at least 3, more preferably at least 4, especially at least 5 carbon atoms.
The first solvent portion contains 12 or less, suitably 10 or less, preferably 9 or less, more preferably 8 or less, especially 7 or less carbon atoms.

The first solvent portion is 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. Has a boiling point. The boiling point is below 300 ° C, suitably below 250 ° C, preferably 2 ° C.
The temperature is 25 ° C. or lower, more preferably 200 ° C. or lower, particularly 175 ° C. or lower.

The first solvent part is preferably an alcohol having one —OH group. The first solvent portion is more preferably hexanol.

The solvent includes a mixture comprising the first and second solvent portions. The second solvent portion includes any of the features of the first solvent portion described herein. Preferably, however, the solvent consists essentially of the first solvent portion as described.

The method preferably comprises a first step comprising crystallizing the first isomer in a solvent as described above and a second step comprising crystallizing the product of the first step in a solvent. including.

The solvent used in the second step (hereinafter referred to as “second solvent”) has any characteristics of the solvent used in the first step (hereinafter referred to as “first solvent”). Preferably, the first solvent and the second solvent are different. Preferably the boiling point of the second solvent is lower than the boiling point of the first solvent, suitably lower than 30 ° C, preferably lower than 50 ° C,
More preferably, it is at least as low as 70 ° C., especially as low as 85 ° C.

The boiling point of the second solvent is 95 ° C. or lower, suitably 80 ° C. or lower, preferably 70 ° C. or lower,
More preferably, it is about 65 ° C. or less.

The second solvent is preferably an alcohol, preferably a C _1-4 alcohol, especially a C _1-2 alcohol, with methanol being most preferred.

[0028] Preferably, the mixture used in the first step of the method is substantially pure. Therefore, there may be a purification step before the first step. This simply involves washing the mixture used in the first step with a solvent. The solvent used for washing (hereinafter "third solvent") has any of the characteristics of the second solvent as described. Preferably, the temperature of the third solvent in the washing step is lower than when the first solvent is used and / or lower than when the second solvent is used. The third solvent is preferably the same as the second solvent, and is therefore preferably methanol.

Preferably, the first geometric isomer is crystallized from a solvent at some stage of the method. The solvent comprises, or preferably consists essentially of, methanol.

“Essentially composed” means that the solvent comprises at least 80 wt%, preferably at least 90 wt%, more preferably at least 95 wt%, especially at least 99 wt%, of the mentioned solvent, for example methanol. means.

The first step and / or the second step are performed under a condition darker than ambient lighting. Preferably, the step is performed substantially in the dark. Preferably, the method uses a substantially opaque container. Eliminating or reducing the light intensity in the first and / or second step increases the amount of the preferred isolated isomer.

In the context of this specification, the term “homolog” includes derivatives of tamoxifen in which one or more atoms or groups of tamoxifen are replaced by other atoms or groups;
Or a derivative of tamoxifen wherein multiple rings are formed between juxtaposed atoms or groups of tamoxifen; and precursors of tamoxifen or a derivative thereof. The precursor exists in at least two geometric isomeric forms and can be converted to tamoxifen or a derivative thereof, suitably by a substitution reaction.

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

Homologs of tamoxifen can include optionally substituted triphenylalkyl or alkylene compounds. Preferred optionally substituted triphenyl compounds have the general formula

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

It will be appreciated that compounds of general formula I may exist in various geometric isomeric forms. This formula is not limited to any of these forms, unless the form is specifically mentioned herein.

The optional substituents as described herein may be any substituent commonly used to affect the activity of an orally administered drug, or a leaving group that facilitates the manufacture of such a drug. And / or a substituent representing a protecting group. For 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 are up to 12, preferably 6
And more preferably up to 4 carbon atoms.

Preferably, Q represents an optionally substituted, preferably unsubstituted, alkyl group. Preferably, the alkyl group is a C ₁ -C _4, more preferably an alkyl group of C ₁ -C _2. Q preferably represents an ethyl group.

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

Preferably, the group B is unsubstituted.

The P group is preferably unsubstituted or substituted with a halogen atom or hydroxy,
An optionally substituted alkoxy or phenoxy group. If the P group is substituted, it is preferably substituted at the 4-position. More preferably, the P group is substituted with an unsubstituted or optionally substituted phenoxy group. In a particularly preferred embodiment, P is unsubstituted. Thus, preferably, P represents an unsubstituted phenyl group.

Preferably, the group A is an alkoxy or phenoxy group monosubstituted with a halogen atom or hydroxy and optionally substituted. Preferably, group A is monosubstituted with an optionally substituted alkoxy group. Preferred optionally substituted alkoxy groups have the general formula

Embedded image Wherein n is an integer, preferably 1-8, more preferably an integer of 1-4, especially 1-2, and X is a leaving group such as a halogen, especially chlorine, an atom or a general formula

Embedded image Wherein R ¹ and R ² independently represent a hydrogen atom, an optionally substituted alkyl group or preferably an unsubstituted alkyl group.

Preferably, n represents 2. In a preferred embodiment, group A is mono-substituted by an alkoxy group of general formula II. In the formula, n represents 2.

Preferably, the mixture used in the method comprises a first homolog of tamoxifen (preferably a precursor of tamoxifen or a tamoxifen derivative as described above), wherein the method comprises tamoxifen or a derivative thereof, especially an anti-estrogen derivative Further deriving the first geometric isomer removed to produce Preferably, the first homolog of tamoxifen, more preferably the first geometric isomer of the first homolog, has reduced anti-estrogenic activity compared to the tamoxifen or derivative produced in the derivation step.

Preferably, the precursor is a compound of general formula I above, wherein B, P and Q are as described above. Preferably, A represents a phenyl group substituted by a first moiety, preferably in at least the 4-position. The first moiety comprises an active atom or group arranged to react with the second moiety, wherein the second moiety comprises a compound of the above general formula III to form an optionally substituted alkoxy group of the above general formula II Including the group of Preferably, said first portion comprises a leaving group suitably X. Preferably, the first part comprises a group of the above general formula II. Preferably, the first moiety is reacted with an amine of the general formula R ¹ R ² NH wherein R ¹ and R ² are as described above.

When a pair of adjacent substituents A, B, P and Q are arranged together to form a part of a ring structure, the ring structure is formed of substituents A, B, P and Q which are cis with respect to each other. It can be formed between pairs. Examples of compounds of general formula I having a ring structure as described include:

Embedded image

Embedded image

Embedded image [In the formula, Z represents an oxygen or sulfur atom or a —CH ₂ CH ₂ — group. ].

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

When the method comprises contacting a mixture comprising the first and second isomers, the mixture used can be, for example, J. Chem. Research, 1985 (S) 116, (M) 1342 and 1986 (S ) 58, (M) 0771 and can be prepared by known routes to tamoxifen and its derivatives.

The precursor of tamoxifen or tamoxifen derivative used in the present method has the general formula

Embedded image [Wherein A, B, P and Q are as described in the present specification. Preferably, formula I
And A, B, P and Q in the compounds of XII and XII represent the same atom or group].

Conveniently, the compound of formula XII is anhydrated to the compound of formula I. For dehydration, for example, the compound of formula XII in a solvent is refluxed in the presence of a strong acid such as concentrated hydrochloric acid.

A typical reaction scheme for producing tamoxifen is shown in Reaction Scheme I below.

Embedded image Reaction formula I

[0052] Referring to Scheme I, preferably, the alkene derivative of Formula XI is contacted with the solvent prior to reaction with dimethylamine. In one embodiment, the compound XI produced after washing the mixture of geometric isomers of compound XI with methanol and performing a first recrystallization step using hexanol and a second recrystallization step using methanol, 100% of the desired Z isomer (having the stereochemical structure of compound XI shown in Scheme I)
HPLC analysis). Compound XI can be converted to tamoxifen by a simple reaction while maintaining the stereochemical structure. Thus, in general, the method comprises at least 99 wt%, suitably at least 99.5 wt%, preferably at least 99.7 wt%, more preferably at least 99.8 wt%, especially at least 99.9 wt% of the first geometric isomer. 9
It can be used to make tamoxifen or homologs containing greater than wt%.

A typical method for producing 4-hydroxy tamoxifen requires deriving compound X, which is prepared according to the following scheme.

Embedded image

The present invention is further directed to a pharmaceutically acceptable form, such as a salt of tamoxifen or a homolog thereof.

The present invention further provides a method for producing tamoxifen or a derivative thereof, particularly an anti-estrogen derivative, wherein the first geometric isomer of tamoxifen or a precursor of the derivative is crystallized in a solvent, and the tamoxifen or the derivative thereof is crystallized. A process comprising deriving the precursor to produce a derivative.

The present invention further relates to the use of a solvent to predominantly remove the first geometric isomer of tamoxifen or a homologue thereof from the mixture of isomers.

The invention further relates to 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 A method for producing an anti-estrogenic isomer of tamoxifen or a homolog thereof having a purity of at least 99.95%, wherein the method uses a solvent as described herein.

The present invention relates to the product of any of the methods described herein.

[0059] Any feature of any aspect or embodiment described herein may be combined with any feature of any other aspect or embodiment described herein.

The present invention will now be described by reference to the accompanying drawings and examples. FIG. 1 is a ¹ H NMR spectrum of the isomer mixture of the tamoxifen precursor prepared in Example 1; FIG. 2-4 provides further details of the spectrum of FIG. 1; and FIG. ¹ is a ¹ H NMR spectrum of the product obtained in Example 1 after washing with methanol. FIG. 6 is the ¹ H NMR spectrum of the material of FIG. 5 after recrystallization from hexanol in the dark; FIG. 7 is the material of FIG. 5 after recrystallization from methanol in the dark. it is ¹ H N MR spectrum; and Figure 8 is an HPLC analysis of the product of Figure 7.

[0061]Example 1 Preparation of Z isomer of tamoxifen An ether solution (5 ml) of bromobenzene (3.92 g, 25 mmol) containing iodine crystals was suspended in an ether suspension of magnesium turning (0.63 g, 26 mmol) (5 ml).
) Was added dropwise at reflux. After the addition was completed, the reaction mixture was cooled to room temperature and 1-
A solution of [4- (2-chloroethoxy) phenyl] -2-phenyl-1-butanone (3.75 g, 12.4 mmol) in ether (15 ml) was added over 1 hour. The resulting mixture was refluxed for 16 hours, then poured into dilute hydrochloric acid (50 ml) and treated with ether (3 ×
40 ml). The combined ether layer was concentrated, and the residual oil was ethanol (10 ml).
) And refluxed with concentrated hydrochloric acid (5 ml) for 4 hours. The organic phase was separated and dried (Na _Two SO_Four) And evaporated to dryness to give a yellow oil which was left at room temperature for 5 minutes to give a pale yellow
(4.99 g, 111% -nb) This yield indicates the presence of impurities.
Suggest)).¹1 H NMR (see FIGS. 1-4 and the analysis below) indicated that this was a mixture of Z and E isomers in a 2: 1 mixing ratio. Cover the solid with methanol
And stirred at room temperature until a purified suspension was formed. The suspension was filtered and mixed at a mixing ratio of 3
. Obtain a pure white solid (3.82 g, 85%) that is a mixture of 2: 1 Z: E isomers
(See FIG. 5). Dissolve the pure solid from above in warm methanol (100 ° C.)
Crystallized on standing. A mixture of Z: E isomers at a mixing ratio of 22: 1 (2.11 g,
47% (see FIG. 6)) and the product is then reduced with a minimum amount of boiling methanol.
The substance was recrystallized from methanol by dissolving to give 2-chloroethoxy
The pure Z isomer of moxifen (1.55 g, 34.6% yield) was obtained (¹(See FIGS. 7 and 8 as confirmed by H NMR and HPLC). M.p.107
-109 ° C, m / z 362/364 (presence of chlorine atom), δ_H 0.92 (3H
, t, J = 7.33Hz, CH_Three), 2.46 (2H, q, J = 7.33 Hz, CH_TwoCH_Three), 3.72 (2H, t, J = 5.86 Hz, OCH)_TwoCH_TwoCl), 4.09 (2 H, t, J = 5.86 Hz, OCH_TwoCH_TwoCl), 6.55 (2H, d, J = 8.79H
z, OCH_TwoCH_TwoAromatic proton ortho to Cl), 6.79 (2H, d, J =
8.79 Hz, OCH_TwoCH_TwoAromatic proton meta to Cl), 7.10-7.3
8 (10H, m, 2 residual C₆H_Five) (See FIG. 5). 2-chloroethoxy tamoxife
Is reacted with dimethylamine in ethanol under reflux to give the desired tamoxifen
The Z isomer of was prepared.

Analysis of ¹ H NMR Data FIGS. 1-4 show a mixture of E- and Z-forms of compound XI described in Scheme I.

The extension of the region δ from 0.80 to 1.05 shows two overlapping triplets, each corresponding to the CH ₃ group of the Z- and E-derivatives. The critical point is the ratio of the peak heights at 0.92 (for Z) and 0.94 (for E), approximately 2: 1.

The expansion of the area from 4.00 to 4.35 reveals similar information with ratios of 10: 6.4 and 5.56: 3.43. A similar expansion from region 3.6 to 3.9 indicates a ratio of 2.46: 1. All of these measurements suggest that the ratio is about 2: 1. The analysis with respect to FIG. 1 also applies to the spectra of FIGS. 6 and 7 below.

FIG. 5 shows a ¹ H NMR spectrum of a pure solid obtained after washing the crude reaction product with methanol. FIG. 6 shows the ¹ H NMR spectrum of the solid obtained after recrystallization from hexanol, the product shown in FIG. FIGS. 7 and 8 respectively depict ¹ H NMR and HPLC analysis of the pure Z isomer obtained after the second recrystallization from methanol. HPLC analysis was performed under the following conditions: Hypersil ODS 5 mm, 250 × 4.0 mm column and 50% MeOH: 30%; MeCN: 20%;
H ₂ O mobile phase 1 ml / min.

Instead of using hexanol and then methanol as described in Example 1,
Other solvents were tested to assess the ability to predominantly remove the Z isomer of 2-chloroethoxy tamoxifen from a mixture of Z- and E-isomers. The following solvents have been found to be effective: methanol, ethanol, propanol, isopropanol, butanol, pentanol, cyclohexanol, acetonitrile, benzene, toluene, nitromethane, petroleum ether and dioxane.

Attention should be paid to all materials and documents that were filed at the same time as, or earlier than, the specification relating to the present application and published with the present specification, and the contents of all such materials and documents shall be incorporated by reference. Is a part of the present specification.

All features disclosed herein (including the appended claims, the abstract and the drawings), and / or all steps of the thus disclosed methods or steps,
Any combination is possible, except for at least a combination in which these features and / or steps conflict with each other.

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

The present invention does not limit the details of the above embodiments. The present invention is based on any novel or combination of features disclosed herein (the accompanying claims, abstract and drawings) or any novel or steps of any method or process thus disclosed. Regarding the combination.

[Brief description of the drawings]

1 is a ¹ H NMR spectrum of a mixture of isomers of a tamoxifen precursor prepared in Example 1. FIG.

FIG. 2 provides further details of the spectrum of FIG.

FIG. 3 provides further details of the spectrum of FIG.

FIG. 4 provides further details of the spectrum of FIG.

FIG. 5 is a ¹ H NMR spectrum of the product obtained in Example 1 after washing with methanol.

FIG. 6 is a ¹ H NMR spectrum of the material described in FIG. 5 after recrystallization from hexanol in the dark.

FIG. 7 is a ¹ H NMR spectrum of the material described in FIG. 5 after recrystallization from methanol in the dark.

FIG. 8 is an HPLC analysis of the product of FIG.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor John Double UK, Beady 7.1 Deepie, West Yorkshire, Blood Ford, University of Bradford (72) Inventor Derek Maitland United Kingdom, Beady 7.1 Deepie, West Yorkshire, Bradford, University of Bradford (72) Inventor Ioana Popa, United Kingdom, Beady 7.1 Deepy, West Yorkshire, Bradford, University of Bradford F-term ( Reference) 4H006 AA01 AA02 AB29 AD15 BB14 BC51

Claims (16)

[Claims] 1. A method for predominantly extracting a first geometric isomer of tamoxifen or a homologue thereof from a mixture containing the first geometric isomer and the second geometric isomer, wherein the first isomer is crystallized in a solvent. A method comprising the step of: 2. contacting the solvent with the mixture at a first temperature below its boiling point;
The method of claim 1, wherein the recrystallization is performed at a second temperature of 4 ° C or higher. 3. The method of claim 2, wherein said second temperature is 20 ° C. or higher. 4. The method of claim 1, wherein said solvent comprises a first solvent portion that is a polar organic solvent.
-3. 5. The method of claim 4, wherein said first solvent moiety is an alcohol having only one —OH group. 6. The method of claim 4, wherein said first solvent portion is hexanol. 7. The first step is to crystallize the first isomer in the solvent (hereinafter referred to as “first solvent”), and then in the second step the crystallization product of the first step is dissolved in a solvent ( Hereinafter referred to as "second solvent").
Method 6. 8. The method of claim 7, wherein said second solvent has a lower boiling point than said first solvent. 9. The method of claim 8, wherein said second solvent comprises methanol. 10. The method of claim 1, wherein said first geometric isomer is formed from a solvent comprising methanol in the same step;
10. The method of claim 1-9, wherein the crystallization is performed in the same manner. 11. The method of claim 1, wherein the first geometric isomer of tamoxifen or a homologue represents a precursor of tamoxifen or a derivative thereof, wherein the precursor can be converted to tamoxifen or a derivative thereof. Method. 12. The precursor has the general formula: Wherein A, B and P independently represent an optionally substituted phenyl group;
Represents a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl or phenyl group]. 13. The precursor of the general formula Wherein R ₁ and R ₂ independently represent a hydrogen atom or an optionally substituted alkyl group, wherein the precursor is converted to tamoxifen or a derivative thereof. Item 11. The method according to Item 11 or 12. 14. A method for producing tamoxifen or a derivative thereof, particularly an anti-estrogen derivative, comprising the step of crystallizing a first geometric isomer of a precursor of tamoxifen or a derivative thereof in a solvent, wherein the isomer is obtained. Inducing to produce said tamoxifen or a derivative thereof. 15. Use of a solvent to predominantly remove the first geometric isomer of tamoxifen or a homologue thereof from a mixture of isomers. 16. A method for producing an anti-estrogen isomer of tamoxifen or a homolog thereof in at least 99% purity, using one or more solvents according to claim 1-15.