MXPA00000764A - Tamoxifen and analogues thereof - Google Patents

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

TAMOXIFEN AND ANALOGS OF THEMSELVES DESCRIPTION OF THE INVENTION This invention relates to tamoxifen and analogs thereof and particularly, although not exclusively, relates to a method for preparing a desired isomer of tamoxifen or an analog thereof. Tamoxifen is a triphenylethylene derivative of the 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 anti-estrogenic activity, the E-isomer is estrogenic. The same antiestrogenicity criterion applies to tamoxifen analogues. One of the most important analogs of tamoxifen is 4-hydroxy tamoxifen (one of the main metabolites in patients), which has an affinity for the link to estrogen receptors that is 100 times higher than for tamoxifen itself. By Accordingly, processes for the synthesis of stereoselectivity and / or isolation of the substantially pure Z isomer of tamoxifen, 4-hydroxy tamoxifen and other analogues are desirable. Known processes for the preparation of the isomer Substantially pure Z of tamoxifen and 4-hydroxy tamoxifen include stereoselective syntheses (involving expensive catalysis) 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 less appreciated, finding that a 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 predominantly removing a first geometric isomer of tamoxifen or an analogue thereof from a mixture comprising the first geometric isomer and a second geometric isomer, the method includes the step of allowing the first isomer crystallized in a solvent. Preferably, the method comprises contacting a mixture comprising the first and second isomers with the solvent. The method may include separating the crystallized product from the remainder. The solvent is preferably capable of dissolving the isomers in the mixture and is such as to allow recrystallization as mentioned above. In the method, the solvent is preferably contacted with the isomers in the mixture when the solvent is at a first temperature where the first temperature is less suitable than the boiling point of the solvent. The recrystallization is suitably carried out at a second temperature which is less than 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, it has been observed that, if the recrystallization 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 crystallized product is greater than the corresponding ratio observed when the recrystallization is carried out at room temperature (approximately 22 ° C).

Thus, recrystallization is suitably carried out at greater than -4 ° C, preferably higher than 0 ° C, more preferably higher than 10 ° C, especially higher than 20 ° C. Advantageously, the recrystallization can be carried out at a lower room temperature. It will be appreciated that this may be an optimum recrystallization temperature in which the ratio of the amount of the first geometric isomer to the second geometric isomer in the crystallized product is maximized. The 10 second temperature can be within 30 ° c, suitably ° C, preferably 20 ° C, more preferably 15 ° C, especially 10 ° C of the optimum temperature. The 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. The first temperature may be less than 200 ° C, preferably less than 160 ° C, more preferably less than 140 ° C, especially less than 120 ° C. The first temperature may be less than the boiling point 20 of the solvent, suitably by at least 10 ° C, preferably at least 20 ° C, more preferably at least ° C, especially at least 40 ° C. The 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. The point of gm JÉ.

Boiling may be less than 300 ° C, suitably less than 250 ° C, preferably less than 200 ° C, more preferably less than 175 ° C. Various solvents can be selected for use in the method. Preferably, the solvent includes a first part of the solvent. Preferably, the first part of the solvent is an organic solvent with polar organic solvents being preferred. The first part of the solvent may be an unsubstituted hydrocarbon or may include one or more functional groups. Such groups can be selected from -OH, -N02, -CN, -O- and alkyl groups, optionally substituted, especially unsubstituted. The first solvent part may include two or, more preferably, one or less functional groups. Especially preferred is the case where the first part of the solvent includes only one functional group. The first part of the solvent is preferably a protic solvent. A preferred functional group of the first part of the solvent is an -OH group. The first part of the solvent can be aliphatic, alicyclic, aromatic or heteroaromatic. The first part of the solvent is preferably aliphatic. The first part of the solvent may include one or more, suitably at least two, preferably at least three, more preferably at least four, especially at least five carbon atoms. The first part of the solvent may include twelve or less, suitably ten or less, preferably nine or less, more preferably eight or less, especially seven or less, carbon atoms. The first part of the solvent 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. The boiling point may be less than 300 ° C, suitably less than 250 ° C, preferably less than 225 ° C, more preferably less than 200 ° C, especially less than 175 ° C. The first part of the solvent is preferably an alcohol having an -OH group. The first part of the solvent is more preferably hexanol. The solvent may include a mixture comprising the first part of the solvent and a second part of the solvent. The second part of the solvent may include any characteristic of the first part of the solvent described herein. Preferably, however, the solvent consists essentially of the first part of the solvent as described. The method preferably includes a first step comprising allowing the first isomer to crystallize in A solvent as mentioned above and a second step comprising allowing the product of the first stage to crystallize in a solvent. The solvent used in the second stage (hereinafter "second solvent") can have any characteristics of the solvent used in the first stage (hereinafter "first solvent"). Preferably, the first solvent and the second solvent are different. Preferably, the second solvent has a lower boiling point than the first solvent, suitably 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. The second solvent is preferably an alcohol, preferably a C 4 alcohol, especially a C 2 -2 alcohol, with methanol being more preferred. Preferably, the mixture used in the first step of the method is substantially pure. Thus, before the first stage, this can be a purification stage. This may simply comprise washing a mixture to be used in the first stage with a solvent. The solvent used in the wash (hereinafter "third solvent") can have any characteristic of the second solvent as described. Preferably, the temperature of the third solvent in the washing step is less than the temperature of the first solvent when it is used and / or the temperature of the second solvent when it 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 at some stage of the method of a solvent which includes or, preferably consists essentially of methanol. By "consists essentially" we understand that a solvent comprises at least 80% by weight, preferably at least 90% by weight, more preferably at least 95% by weight, especially at least 99% by weight of the indicated solvent, for example methanol. The first stage and / or second stage can be carried out under less than ambient light conditions. Preferably, step (s) is / are carried out substantially in the dark. Preferably, the method utilizes a receptacle which is substantially opaque. Excluding or reducing the intensity of light in the first and / or second stages is found to increase the amount of the preferred isolated isomer.

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 and which can be converted to tamoxifen or a derivative thereof isomeric forms, suitably by a substitution reaction. Various tamoxifen analogs that fall within the scope of the present invention are described in Endocrine Reviews, 11 (4), 1990, 578-603. Tamoxifen analogs may optionally include triphenylalkyl or substituted alkylene compounds. Preferred optionally substituted triphenyl compounds are of the general formula wherein A, B and P each independently represent 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 the general formula I can exist in different geometric isomeric forms and the formula is not intended, unless otherwise stated in the present, to be limited to any in such a way. Optionally the substituents as described herein they include any substituents generally used to affect the activity of drugs for oral administration, or represent Rooting groups and / or protecting groups that help the preparation of such drugs. In relation to alkyl, alkenyl, alkynyl and phenyl, the Preferred optional substituents include halogen atoms, haloalkyl and hydroxy groups, and alkylcarboxy, alkoxy, phenoxy, alkylamino and optionally substituted alkylcarbonyl. Preferred alkyl, alkenyl and alkynyl groups can have up to 12, preferably up to 6, more preferably up to 4 carbon atoms. Preferably, Q represents an optionally substituted alkyl group, preferably unsubstituted.

OR; , & amp; amp; Preferably, the alkyl group is an alkyl group of Ci to C4, more preferably a Ci to C2. 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 at the 3-position or, more preferably, 4. Preferably, group B is unsubstituted. The Group P is preferably unsubstituted or substituted by a halogen or hydroxy atom, optionally substituted alkoxy or phenoxy groups. Where the group P is substituted, it is preferably substituted at the 4-position. More preferably, the group P is unsubstituted or substituted by an optionally substituted 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 or hydroxy atom, optionally substituted alkoxy or phenoxy groups. Preferably the group A is monosubstituted by an optionally substituted alkoxy group. An optionally substituted alkoxy group is of the formula -0- (CH2) n-X (II) wherein n represents an integer preferably in the range of 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 the general formula wherein R1 and R2 independently represent a hydrogen atom or an optionally substituted alkyl group, preferably unsubstituted. Preferably, n represents 2. In a preferred embodiment, the group A is monosubstituted by an alkoxy group of the general formula II, wherein n represents 2. Preferably, the mixture used in the method comprises a first tamoxifen analogue (preferably a tamoxifen precursor or tamoxifen derivative as described above) and the method includes the additional step of derivatizing the first geometric isomer removed for preparing tamoxifen or a derivative, especially an antiestrogenic derivative thereof. Preferably, the first tamoxifen analogue, more preferably the first geometric isomer of the first analog, has less anti-estrogenic activity compared to tamoxifen or a derivative which is prepared in the additional derivatization step. Preferably, the precursor is a compound of the general formula I, described above wherein B, P and Q are as described above. Preferably, A represents a substituted phenyl group, preferably at least at the 4-position, by a first portion that includes an active atom or group which is arranged to react with a second portion that includes a group of the general formula III as described above to produce an optionally substituted alkoxy group of the general formula II as described above. Preferably, the first portion includes a leaving group that is suitably x as described above. Preferably, the first portion comprises a group of the general formula II as described above. The first portion is preferably reactive with an amine of the general formula R1R2Nh wherein R1 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 can be formed between pairs of substituents A, B, P and Q which are cis for the other. Examples of compounds of the general formula I having H. 4T * fc ring structures as described include wherein Z represents an oxygen or sulfur atom or a group -CH2CH2 ~. Preferably, the adjacent substituents A, B, P and Q are not part of a ring structure. When the method involves contacting a mixture comprising first and second isomers, the mixture used can be prepared by known routes to tamoxifen and its derivatives for example as described in J. Chem. Research, 1985 (S) 116, (M ) 1342 and 1986 (S) 58, (M) 0771. A tamoxifen precursor or tamoxifen derivative for use in the method can be prepared from a compound of the general formula «& S &g ** - M? My ~? *? ** ~ i where A, B, P and Q are as described in any state herein. Preferably, A, B, P and Q in the compounds of formula I and XII represent the same atoms or groups. Advantageously, the compound of the formula XII can be dehydrated to prepare the compound of the formula I. The dehydration can involve refluxing the compound of the formula XII in a solvent in the presence of a strong acid, for example, concentrated hydrochloric acid. A typical reaction scheme for preparing tamoxifen is as shown in the following in Scheme I. ^^, ^. ^^^^ ÉIi ^ Referring to Scheme I, preferably, the alkene derivative of formula XI is contacted with the solvent prior to the reaction with dimethylamine. In one embodiment, it has been found that, after washing a mixture of geometric isomers of compound XI with methanol, followed by a first recrystallization step using hexanol and a second recrystallization step using methanol, compound XI prepared contains 100% (from according to HPLC analysis) of the desired Z-isomer (having the stereochemical configuration of compound XI shown in Scheme I). Compound XI can be converted by a simple reaction to tamoxifen with the stereochemistry being maintained. Thus, in general terms, the method described above can be used to prepare tamoxifen or an analog which includes more than 99% by weight, suitably more than 99.5% by weight, preferably more than 99.7% by weight, more preferably more than 99.8. % by weight, especially more than 99.9% by weight, of the first geometric isomer. A typical process for preparing 4-hydroxy tamoxifen involves the derivation of compound X prepared according to the reaction scheme provided in the following: (VED) (IX) (X) The invention extends to pharmaceutically acceptable forms, for example tamoxifen salts or analogs thereof. The invention extends to a method of preparing tamoxifen or a derivative, especially an antiestrogenic derivative thereof, the method includes the steps of allowing a first geometric isomer of a tamoxifen precursor or derivative to crystallize in a solvent and derivatization of the precursor for produce tamoxifen or the derivative. The invention extends to the use of a solvent to predominantly remove a first geometric isomer of tamoxifen or an analogue thereof from a mixture of isomers. The invention extends to a method of preparing an anti-estrogenic isomer of tamoxifen or an analog thereof in a 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 %, more preferably at least 99.95%, the method uses a solvent as described herein. The invention extends to the product of any process described herein. Any feature of any aspect or mode described herein may be combined with any feature or any other aspect or mode described herein. BRIEF DESCRIPTION OF THE DRAWINGS The invention will now be described, by way of example, with reference to the accompanying figures in which: Figure 1 is a 1H NMR spectrum for a mixture of isomers of a tamoxifen precursor, prepared in Example 1; Figure 2 to 4 provides additional details for the spectrum of Figure 1; Figure 5 is a spectrum of 1H NMR for the product obtained in Example 1 after washing with methanol. Figure 6 is a spectrum of 1 H NMR of the material mentioned in Figure 5, after recrystallization of hexanol in the dark; Figure 7 is a spectrum of XH NMR of the material mentioned in Figure 5, after recrystallization of the l ^ gíwí »ftéa ^^ tt ^ í; ,,. ái-! S ^ í: _ £? i? Ji '» j mnn ** 4É ^ MÉ g¡ | methanol in the dark; and Figure 8 is an HPLC analysis on the product of Figure 7. Example 1 Preparation of the Tamoxifen Z isomer A solution of bromobenzene (3.92 g, 25 mmol) in ether (5 ml) containing a crystal of iodine was added drip to a suspension of magnesium turnings (0.63 g, 26 mmol) in ether (5 ml) at reflux. After the addition was complete, the reaction mixture was cooled to room temperature and a solution of l- [4- (2-chloroethoxy) phenyl) -2-phenyl-1-butanone (3.75 g, 12.4 mmol) in ether (15 ml) was added for 1 hour. The resulting mixture was refluxed for 16 hours, then was poured into dilute hydrochloric acid (50 ml) and extracted with ether (3x40 ml). The combined ether layers were concentrated, the residual oil was dissolved in ethanol (10 ml) and brought to reflux with concentrated hydrochloric acid (5 ml) for 4 hours. The organic phase was separated, dried (Na 2 SO 4), and evaporated to dryness to give a yellow oil, which remained at room temperature for 5 minutes, turned a pale yellow solid (4.99 g, 111% -nb this yield suggested the presence of impurities ). 1 H NMR (see Figures 1 to 4 and discussion below) shown this to be a 2: 1 mixture of Z and E isomers. The solid was - «-Ji). then covered with methanol and stirred at room temperature to form a fine suspension. 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 above pure solid was dissolved in hot hexanol (100 ° C) and allowed to crystallize at room temperature. A 22: 1 mixture of Z: E isomers (2.11 g, 47% (see Figure 6)) was produced, and this product was in turn recrystallized from methanol to dissolve the material in the minimum amount of boiling methanol. to give a pure Z-isomer (as confirmed by XH NMR and HPLC - see Figures 7 and 8) of 2-chloroethoxy tamoxifen (1.55 g, 34.6% yield). P.f. 107-109 ° C. m / z 362/364 (chlorine atom present). dH 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, 0CH2CH2C1), 4.09 (2H, t, J = 5.86 Hz, 0CH2CH2C1), 6.55 (2H, d, J = 8.79 Hz, ortho aromatic protons at 0CH2CH2C1), 6.79 (2H, d, J = 8.79 Hz, meta aromatic protons at 0CH2CH2C1), 7.10-7.38 (10H, m , the remaining two CeHs's) (see Figure 5). The 2-chloroethoxy tamoxifen was reacted with dimethylamine in ethanol, under reflux, to produce the desired Z-isomer of tamoxifen. H NMR Data Analysis 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 from 0.80 to 1.05 shows two crosslinked triplets corresponding to the CH3 groups in the Z and E derivatives respectively. The critical point is the ratio of peak heights to 0.92 (for Z) and 0.94 (for E), which is approximately 2: 1. The expansion of region 4.00 to 4.35 reveals similar information where the relationships are 10: 6.4 and 5.56: 3.43. Similarly, the expansion of region 3.6 to 3.9 shows the ratio of 2.46: 1. All these measurements suggest an approximate ratio of 2: 1. The discussion with reference to Figure 1 also applies to the spectrum of Figures 6 and 7 mentioned in the following. Figure 5 shows the 1H NMR spectrum of the pure solid obtained after methanol, washing the crude reaction product. Figure 6 shows the 1H NMR spectrum of the solid obtained following the recrystallization of hexane from the product shown in Figure 5, and Figures 7 and 8 respectively show the 1H NMR and the HPLC analysis of the pure Z-isomer obtained following the second recrystallization, this instead of methanol. The HPLC analysis was carried out under the following conditions: Hypersil ODS 5 mm, column 250 x 4.0 mm and 50% MeOH: 30%; MeCN: 20%; H2 mobile phase at 1 ml / min. As an alternative to the use of hexanol followed by methanol as described in Example 1, other solvents -Í5V, < - "? 2fi_í¡9 ** • wb *" «- a were tested to evaluate 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, iso-propanol, butanol, pentanol, cyclohexanol, acetonitrile, benzene, toluene, nitromethane, petroleum ether and dioxane The attention of the reader is directed to all the papers and documents that are presented concurrently with or previous to this specification in connection with this application and that are open to public inspection with this specification, and the contents of such papers and documents are incorporated herein for reference. All the features described in this specification (including any claims annexes, extract and drawings), and / or all stages of any method or process already described, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. 20 Each characteristic described in this specification (including any appended claims, extract and drawings), may be replaced by alternative features that serve the same, equivalent or similar purpose, unless expressly stated otherwise. way. Thus, unless they are expressly established from another -inmi ^ ftf ^ i ^^^^ way each feature described is an example only of a generic series of equivalent or similar features. The invention is not restricted to the details of the above modality (s). The invention extends to any novelty, or any novel combination, of the features described in this specification (including any appended claims, extract and drawings), or to any novelty, or any novel combination, of the steps of any method or process already described. . t ^^^ Sfc ^ ..., ... ^^^^^

Claims (16)

1. V ** ' CLAIMS 1. A method for predominantly removing a first geometric isomer of tamoxifen or an analogue thereof from a mixture characterized in that it comprises the first geometric isomer and a second geometric isomer, the method includes the step of allowing the first isomer to be recrystallized from a solvent.
2. 2. The method according to claim 1, characterized in that the solvent is brought into contact with the mixture at a first temperature, which is lower than the boiling point of the solvent and the recrystallization is then carried out at a second temperature which is greater than -4 ° C.
3. 3. The method according to claim 2, characterized in that the second temperature is greater than 20 ° C. .
4. The method according to any preceding claim, characterized in that the solvent includes a first part of the solvent that is a polar organic solvent.
5. 5. The method according to claim 4, characterized in that the first part of the solvent is an alcohol having only one -OH group.
6. 6. The method according to claim 4 or claim 5, characterized in that the first part *, ~ of the solvent is hexanol.
7. The method according to any preceding claim, characterized in that it comprises letting the first isomer crystallize in the solvent (hereinafter "first solvent" in a first step and subsequently leaving the crystallized product of the first stage to crystallize in a solvent ( hereinafter "second solvent") in a second step
8. 8. The method according to claim 7, characterized in that the second solvent has a lower boiling point than the first solvent
9. 9. The method according to the claim 8, characterized in that the second solvent comprises methanol
10. 10. The method according to any preceding claim, characterized in that the first geometric isomer is crystallized at some stage in the method of a solvent that includes methanol
11. 11. The method according to any claim, characterized in that the first geometric isomer of tamoxifen or a The analogue represents a precursor of tamoxifen or a derivative thereof in which the precursor can be converted to tamoxifen or a derivative thereof.
12. 12. The method in accordance with the claim U ^^^^^^ j ^^ 11, characterized in that the precursor is prepared from a compound of the general formula wherein A, B and P independently represent an optionally substituted phenyl group and Q represents a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl or phenyl group.
13. The method according to claim 11 or claim 12, characterized in that the precursor is derivatized using a compound that includes a group of the general formula: to convert the precursor to tamoxifen or derivative, wherein Ri and R2 independently represent a hydrogen atom or an optionally substituted alkyl group.
14. 14. A method of preparing tamoxifen or a derivative, especially an antiestrogenic derivative thereof, the method includes the steps of allowing a first geometric isomer of a tamoxifen precursor or derivative to crystallize from a solvent and derive the isomer to produce tamoxifen or the derivative.
15. 15. The use of a solvent to predominantly remove a first geometric isomer of tamoxifen or an analogue thereof from a mixture of isomers.
16. 16. A method of preparing an anti-estrogenic isomer of tamoxifen or an analog thereof in a purity of at least 99%, the method using a solvent or solvents as described in any preceding claim. & * - * - £ * »^^, * ^ ri ¡i ^