AU2001292132A1 - Process and intermediates for the production of 7-substituted antiestrogens - Google Patents
Process and intermediates for the production of 7-substituted antiestrogensInfo
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Description
PROCESS AND INTERMEDIATES FOR THE PRODUCTION OF 7-SUBSTITϋTED ANTIESTROGENS
The invention relates to a new processes useful in the preparation of pharmaceutical compounds such as fulvestrant, and to novel intermediates for use in the process.
US 4659516 describes a group of steroid derivatives, which have antioestrogenic activity.
Fulvestrant (Faslodex™, ZD9238, ICI 182,780) (Wakeling AE. J. Steroid Biochemistry 1990c; 37: 771-5, Wakeling AE, et al. J. Endocrinology 1987; 112: R7-10 and Wakeling AE et al. J. Steroid Biochemistry 1988; 3: 141-7) is a particular example of such a steroidal derivative and is the first in a new class of potent pure antioestrogens which is completely free of the partial agonist, oestrogen-like activity, associated with currently available antioestrogens like tamoxifen.
Fulvestrant has already demonstrated efficacy in a phase II trial in women whose breast cancer has progressed following tamoxifen therapy (Howell et al., The Lancet, 1995, 345. 29-30). Fulvestrant has a novel mechanism of action, described as an estrogen receptor downregulator, with clear evidence of anti-tumour activity in advanced breast cancer.
The chemical name for fulvestrant is 7-alpha-[9-(4,4,5,5,5- pentafluoropentylsulphinyl)nonyl]-estra-l,3,5(10)-triene-3,17β-diol, and this is represented as formula (I).
(I)
In US 4659516, column 4 et seq., a general process route is described for the preparation of compounds of a similar type to fulvestrant. A summary of the general process as it would apply to the preparation of fulvestrant is described in Scheme 1. A process route is also described in Bowler J. (co-inventor of US 4659516) Steroids (1989) 71-99 which is a similar route to that shown Scheme 1 hereinafter.
The applicants have found in particular, improved routes to these compounds. According to the present invention there is provided a process for preparing an intermediate compound of formula (II),
(ll)
where X is S, SO, SO2, O, NR6, N(O)R6, (PO)R6, NR7, COO-, NR7SO2, CONR6,
CSNR6, NR7CO, NR7C(NR8)NR6, NR7CS, NR7CONR6, SO2NR6 or CO, where R6 is hydrogen or Ci-βalkyl, R7 is hydrogen or
and R8 is cyano, hydrogen or nitro, n is an integer of from 3 to 14;
R is hydrogen or a hydroxy protecting group,
R1 is haloCi-ioalkyl, Ci.ioalkyl, C2_ιoalkenyl, C2-ι0cycloalkyl, carboxyCi-ioalkyl,
Ci-ioalkoxycarbonylCi-ioalkyl, aryl (such as phenyl), aryl(Cι_ιo)alkyl (such as phenyl(Cι_10)alkyl) or di(Cι-6alkyl)amino;
R2 is hydrogen, Ci-βalkyl or hydroxy,
R3 is hydrogen, Ci-βalkyl, C2.6alkenyl or C2-6alkynyl;
R4 is hydroxy, Ci-ioalkanoyloxy, carboxyCi-ioalkanoyloxy or aroyloxy (such as benzoyloxy);
R5 is Ci-βalkyl; which process comprises aromatisation of a compound of formula (III)
(in)
where R1, R2, R3, n, X and R5 are as defined in relation to formula (II) and R4 is a group R4 or a precursor group thereof, and thereafter if necessary or desired, carrying out one or more of the following steps: (i) removing any hydroxy protecting groups R; (ii) converting a precursor group R4 to a group R4, or where R4 is a group R , converting it to a different such group.
In particular, R4 is a group OR10 where R10 is a protecting group, for example a hydroxy protecting group such as acyloxy, in particular acetyloxy. In this case, removal of the protecting group using conventional methods such as those described in Protective Groups in Organic Synthesis, 2nd Edition, by Green et al. , published by John Wiley & Sons. In particular deprotection , for example by hydrolysis, preferably alkaline hydrolysis, with a base such as an alkali metal hydroxide, will yield a compound of formula (II) where R17 is hydroxy.
Aromatisation of the compound of formula (III) may be effected by various conventional methods, such as those described in Steroids (1989) 71-99 and Steroids (1994) 621-627. In a particularly preferred embodiment, the reaction is effected using a copper salt such as cupric bromide. Most preferably the reaction is effected in the presence of an acylating agent such as an acid anhydride, for example acetic anhydride. The copper salt, and preferably also acetic anhydride, is suitably added to a solution of a compound of formula (III) in an organic solvent such as acetonitrile, at moderate temperatures for example from about 0°-40°C and conveniently at about 20°C. Suitably, a salt, in particular an alkali metal halide such as lithium bromide, are added at the same time, in order to assist in the solubilisation of the copper salt and thus reduce the amount of solvent required. The use of an acetylating agent such as acetic anhydride in the aromatisation step has been found to protect the phenol in situ and prevent the formation of halogenated impurities, in particular 2-halo impurities such as the 2-bromo impurities of formula (A).
(A) This is probably a result of the fact that acetyloxy groups are produced instead of hydroxy groups in the intermediate. For example, the following 2-Br impurity, was found to occur using the prior published route to fulvestrant.
This impurity was found to be very difficult to remove by crystallisation in the purification of fulvestrant. By using acetic anhydride in the process the formation of this product is largely eliminated. Furthermore, by using an acetylating agent in the reaction, the product of the aromatisation reaction is a compound of formula (II) where R is acetyl. This may conveniently be removed in optional step (i), which, where R12 is also an acyl group such as acetyl, may be combined with step (ii) in a single reaction.
In a further preferred embodiment, thiourea is added subsequent to the aromatisation reaction to precipitate copper waste from the reaction mixture prior to the deacetylation step.
Thus in a further embodiment, the invention provides a method of preparing a compound of formula (XIII).
(Xiii)
where X, n, R1, R2, R3 and Rs are as defined in relation to formula (II), by reacting a compound of formula (XIV)
(XIV) where X, n, R1, R2, R3 and R5 are as defined in relation to formula (II), and R20 is hydrogen or a protecting group, in particular an acetyl group, with a copper salt in the presence of an acetic anhydride, and then hydrolysing the thus formed acetyloxy groups. A particular compound of formula (II) which can be prepared by the method of the invention is an intermediate used in the preparation of fulvestrant of formula (I). Such a compound is a compound of formula (HA).
(HA) Compounds of formula (III) are novel intermediates and form a further aspect of the invention.
These compounds are suitably prepared by reacting a compound of formula (IN)
(IV) where R2, R3 and R5 are as defined in relation to formula (II), and R4 is as defined in relation to formula (III), with a compound of formula (N)
(CH2)n\χ
R1
(V) where n, X and R1 are as defined in relation to formula (II) and Z is a leaving group.
Suitable leaving groups Z are conventional groups such as halo, mesylate and tosylate, but in a particularly preferred embodiment, Z is a metal halide of formula Rn-M where M is a metal ion and R11 is a halogen atom.
Preferably M is selected from magnesium, zinc, aluminium and titanium. A preferred metal atom M is magnesium.
Preferably Rπ is selected from chlorine, bromine and iodine. A preferred halo R11 is bromine. Thus, in a preferred embodiment, the compound of formula (N) is an organometallic reagent and in particular is a Grignard reagent.
The coupling reaction between the organometallic reagent (N) and a compound of formula (IN) is promoted by the addition of a cuprous salt, such as a halide or cyanide (where preferably the salt is a chloride), optionally complexed with a ligand containing sulphur or phosphorus, all dissolved in a suitable solvent. In a particular embodiment, it has been found that only catalytic amounts of the cuprous salt, for example less than 0.01 mol equivalents, are necessary. A suitable solvent is an ether, preferably tetrahydrofuran.
Using this reaction, it has been found that there is a greater preponderance of a preferred isomeric form of the compound of formula (III). Specifically, the bond indicated by an asterisk in the following copy of formula (III) may be in two stereochemical orientations giving rise to an α and a β form of the product.
(III)
It has been found, in particular in the case of fulvestrant that the α form is preferred. The previously published route to this compound resulted in a mixture of α/β forms of about 1.9:1, whereas using an organometallic compound of formula (N) as described above, higher levels of the preferred α form, for example in a ratio of α /β of 2.5:1 are achievable.
Where the compound of formula (V) is an organometallic reagent, it is conveniently formed by the addition of element metal M to the alkyl halide of formula (VI),
(NI) wherein n, R1 and X are as defined in relation to formula (II) and R11 is as defined above in relation to formula (N), in a suitable solvent, such as tetrahydrofuran or ether.
Compounds of formula (N) where Z is, a leaving group and compounds of formula (NI) are either known compounds (see for example WO93/06124 Example 4c) or they can be prepared from known compounds by conventional methods.
The reaction between compounds of formula (IN) and (N), is a novel method and forms a further aspect of the invention.
In particular in the above compounds (II), (III), (IV), (V) and (VI), R1 is a haloalkyl group and in particular is a group of formula -(CH2)3CF2CF3.
Suitable examples of R2 are hydrogen or Cι-3alkyl, but preferably hydrogen.
Preferably, R3 is hydrogen.
A particular example of a suitable group R4 is hydroxy or alkanoyloxy such as acetoxy. In particular in these compounds R4 is hydroxy and R4 is acetoxy.
Suitably R5 is a Cι-3alkyl group, and in particular methyl.
In these compounds also, n is preferably 9.
Preferred groups X are S, SO or SO2. For the purposes of the present application however, a particularly preferred group X is S.
Compounds of formula (TI) are therapeutic steroid derivatives, or intermediates used in the preparation of such compounds. In particular, compounds of formula (II) where X is S may be oxidised, in particular using oxidising agents such as hydrogen peroxide or periodate, to convert the group X to a group SO, and thereafter subject to further purification as necessary. The products may be obtained in the form of free compounds, pharmaceutically-acceptable salts thereof, esters thereof or any possible solvates of either of these. The methods and intermediates of the invention form a new economical route for the preparation of certain steroid derivatives, including fiilvestrant. This route for the preparation of fulvestrant is conveniently summarised in Scheme 2 hereinafter.
The Scheme 1 route has the following disadvantages when compared to the Scheme 2 route: 1. There are seven steps from the expensive "dienone" intermediate.
2. There are no crystalline intermediates between the starting material and the final product. Therefore, isolation and purification between steps is difficult.
3. The yield is low - needing approximately a ratio by weight of 11 of dienone to produce 1 of fulvestrant. 4. The step of adding the side chain to the 7 position of the dienone steroid is favourable to the preferred α position compared to the unwanted β position at a ratio of 1.9:1.
The process of Scheme 2 offers several advantages when compared to the process of Scheme 1.
1. There are only four steps from the dienone intermediate. 2. Although in the case of fulvestrant, none of the intermediates can be crystallised, making isolation and purification difficult, the whole reaction can be carried out in solution until the final product is obtained which can be crystallised out of solution. 3. The yield is greatly improved - needing approximately a ratio by weight of 2 of dienone to produce 1 of fulvestrant. 4. The α / β ratio is improved to about 2.5 :1.
The unwanted β form of fulvestrant is removed after the oxidation step as the final step prior to purification by recrystallisation.
In a particular embodiment, the process of the invention is used to produce a compound of formula (II A) as defined above, by reacting a compound of formula (Vffl) as defined below, and removal of the protecting group R12. Suitably in this case, R is acetyl and is removed by alkaline hydrolysis. Therefore in a further aspect, the invention provides a process for the preparation of fulvestrant which comprises coupling a compound of formula (Nil)
(VII) wherein R12 is a protecting group, with a compound of formula (X),
L \^\^^/-\/\/ S ^^\/ CF2CF3
(X) wherein L is a suitable leaving group, and to the product formed performing the following three steps
(1) aromatisation of the A-ring
(2) removing protecting group R12
(3) oxidation of the sulphide to the sulphoxide to form fulvestrant.
In particular L is a leaving group Z as defined above in relation to formula (V). Preferred protecting groups R12 are acyl groups such as acetyl.
As described above, the aromatisation of the A-ring is suitably effected in the presence of an acetylating agent such as acetic anhydride. This protects the phenol ring in situ, and furthermore, produces yields an intermediate of formula (IX)
OR12
(IX)
wherein R is acetyl and R12 is as defined above. The group R may then be removed simultaneously with the group R12 in step (2) in particular where the latter is acetyl.
The oxidation step may also be performed by the skilled reader according to known techniques. Care should be taken in the choice of reagents and conditions used to avoid formation of the sulphone. Any agent known in the art for the oxidation of sulphide to sulphoxide may be used, for example, hydrogen peroxide, a peracid (such as periodate or 3-chloroperoxybenzoic or peroxyacetic acid), gaseous oxygen in the presence of platinum or halogens and sources of positive halogen such as sodium hypochlorite and cerium IN salts. The oxidation is generally carried out under as mild conditions as possible in order to reduce the risk of over oxidation. In a preferred process, 2.0 mole equivalents of hydrogen peroxide are used.
A further particular feature of the invention is a process for the preparation of a compound of formula (VIII),
(VIII) whereiinn RR1122 iiss aa pprrootteeccttiinngg ggrroouupp,, ccoommpprrising coupling a compound of formula,
(vπ)
(VII) wherein R12 is a protecting group, with a compound of formula X,
• CF2CF3
(X) wherein L is a suitable leaving group, as described above.
In particular, the compound of formula (X) is a compound of formula (XT)
R11 " M \^^^^^^^ S ^~ ^ CF2CF3
(XI)
wherein M is a metal atom and Rn is a halo atom. The reaction is suitably carried out as described above in relation to the reaction between compounds of formula (IV) and (V). Thus, preferably M is selected from magnesium, zinc, aluminium and titanium. A preferred metal atom M is magnesium. Preferably R11 is selected from chlorine, bromine and iodine. A preferred halo Rπ is bromine. Preferably the organometallic reagent is a Grignard reagent.
The coupling reaction between the organometallic reagent of formula (XI) and a compound of formula IX is promoted by the addition of a cuprous salt, such as a halide or cyanide (where preferably the salt is a chloride), optionally complexed with a ligand containing sulphur or phosphorus, all dissolved in a suitable solvent. It has been found that only catalytic amounts of the cuprous salt are necessary.
A suitable solvent is an ether, preferably tetrahydrofuran.
The organometallic reagent (XI) is conveniently formed by the addition of element metal M to the alkyl halide of formula (XII)
. CF2CF3
(XII)
wherein R11 is as defined above, in a suitable solvent, such as tetrahydrofuran or ether. The invention further provides a process for the preparation of fulvestrant, or a pharmaceutically acceptable salt or ester thereof, or a hydrate of any of these, which comprises
(a) coupling a compound of formula (IX) as defined above, with a compound of formula (XI) as defined above; by the addition of a cuprous salt; all being dissolved in a suitable solvent to form a product of formula (VIII)
(VIII)
(b) aromatisation of the A-ring;
(c) removing protecting group R12 and
(d) oxidising the sulphide group to sulphoxide to form fulvestrant.
Yet a further specific embodiment involves an aromatisation and deacetylation to produce fulvestrant intermediates. In particular, it comprises a method of preparing a compound of formula (XIII A)
(XIIIA) by reacting a compound of formula (XI VA)
(XIVA) where R ,2oυ is hydrogen or a protecting group, in particular an acetyl group, with a copper salt in the presence of an acetic anhydride, and then hydrolysing the thus formed acetyloxy groups.
The invention is illustrated by the following non-limiting examples, wherein notations such as EAS and PHS are as shown Scheme 2 hereinafter.
Example 1
Preparation of Grignard Initiator
The terms relative volume and relative weight refer to the weight of Bromide. Bromide (0.2 mol equivalents) is added to magnesium raspings (1.15 mol equivalents) and tetrahydrofuran (2.0 relative volumes), then iodine (0.001 relative weight) is added to initiate the reaction. The mixture is diluted with more tetrahydrofuran (2.75 relative volumes) and the temperature is raised to about 45°C. More Bromide (0.8 mol equivalent) is added in several portions. The mixture is cooled, excess magnesium is allowed to settle out and the solution of Grignard reagent initiator is decanted prior to use in the next stage.
Example 2
Preparation of Fulvestrant EAS
The term relative volume refers to the weight of Dienone. To a solution of Grignard reagent initiator (about 0.05 mol equivalent) maintained under a nitrogen atmosphere are added magnesium raspings (2.19 mol equivalents) and tetrahydrofuran (8.4 relative volumes) and the mixture is heated to about 45°C. Bromide (0.247 mol equivalent) is added to initiate the reaction, then the mixture is diluted with tetrahydrofuran (2.2 relative volumes) and more Bromide (1.54 mol equivalents) is added in several portions, maintaining the temperature at about 45°C. The mixture is cooled and excess magnesium is allowed to settle out. To initiate subsequent batches of Grignard reagent, 17% of the solution is retained and the remaining 83% of the solution is decanted for use in the next stage.
The solution of Grignard reagent (1.35 mol equivalents) in tetrahydrofuran is diluted with more tetrahydrofuran (2.1 relative volumes) and cooled to -34°C. Cuprous chloride (0.078 mol equivalent) is added, followed by a solution of Dienone (1.00 mol equivalent) in tetrahydrofuran (4.7 relative volumes). The reaction is quenched with a solution of acetic acid (4.47 mol equivalents) in tetrahydrofuran (1.3 relative volumes) and the mixture is warmed to 20°C, then diluted with water (7.0 relative volumes).
Tetrahydrofuran is removed by distillation and, after the addition of more water (3.0 relative volumes), the product is extracted into isohexane (5.0 relative volumes). The
organic phase is separated and washed with 25% w/v aqueous potassium chloride (4.9 relative volumes). The solution of Fulvestrant EAS in isohexane thereby obtained is suitable for use directly in the next stage. The yield of Fulvestrant EAS is in the range 90-95%.
Example 3
Preparation of Fnivestrant PHS
The term relative volume refers to the weight of Fulvestrant EAS.
Isohexane is distilled from the solution of Fulvestrant EAS (nominally 1.00 mol equivalent) and replaced by acetonitrile (3.0 relative volumes). A solution of cupric bromide (2.36 mol equivalents), lithium bromide (1.66 mol equivalents) and acetic anhydride (1.15 mol equivalents) in acetonitrile (3.0 relative volumes) is added over about three hours, mamtaining the temperature at about 20°C. A further portion of acetic anhydride (0.85 mol equivalent) is added and after four hours the solution is poured into a mixture of thiourea (3.78 mol equivalents), toluene (3.0 relative volumes) and water (5.0 relative volumes) cooled to below 10°C. The pH of the mixture is adjusted to about 3 by the addition of dipotassium hydrogen phosphate (2.20 mol equivalents) and the precipitated copper complex is removed by filtration. The filter cake is washed with toluene (4.0 relative volumes) and the toluene solution containing Fulvestrant Acetyl PAS is washed three times with 10% w/v sodium chloride solution (3.0 relative volumes) at about 60°C. The toluene is removed by distillation and replaced by methanol (3.0 relative volumes). 47% w/w Sodium hydroxide solution (2.80 mol equivalents) is added and the mixture is held at 30°C for five hours. At the end of the hydrolysis, the aqueous methanolic solution is extracted three times with isohexane (2.7 relative volumes) and neutralised with acetic acid (2.37 mol equivalents). Methanol is removed by distillation and the residue is partitioned between water (1.3 relative volumes) and ethyl acetate (4.0 relative volumes). The organic phase is concentrated by distillation to provide fulvestrant PHS as an approximately 50% w/w solution in ethyl acetate which is suitable for use directly in the next stage. The yield of Fulvestrant PHS is in the range 80-85%).
Example 4
Preparation of Fulvestrant
The term relative volume refers to the weight of Fulvestrant PHS.
The solution of Fulvestrant PHS (nominally 1.00 mol equivalent) in ethyl acetate is diluted with ethyl acetate (2.5 relative volumes). Acetic acid (6.00 mol equivalents) is added, followed by 17% w/v aqueous hydrogen peroxide (2.00 mol equivalents) and the mixture is stirred at 23°C for 8 hours. A further portion of ethyl acetate (2.0 relative volumes) is added and excess hydrogen peroxide is destroyed with a solution of sodium sulphite (1.50 mol equivalents) in water (3.5 relative volumes). The mixture is neutralised with dilute aqueous sodium hydroxide (6.30 mol equivalents) and the organic phase is separated off and washed with water (2.0 relative volumes). The ethyl acetate solution is dried and concentrated by distillation (to about 2.5 relative volumes), then cooled to 10°C with seeding to promote crystallisation. The solid is filtered off and washed with cold ethyl acetate (1.0 relative volume). Further crystallisations from ethyl acetate (about 2.5 relative volumes) are carried out to achieve the required purity. The overall yield of Fulvestrant from Dienone is about 30%.
Scheme 1
Fulvestrant Crude
Scheme 2
Dienone Bromide
PHS
Fulvestrant Crude
Fulvestrant Pure
Claims (33)
1. A process for preparing an intermediate compound of formula (II)
(H)
where X is S, SO, SO2, O, NR6, N(O)R6, (PO)R6, NR7, COO-, NR7SO2, CONR6,
CSNR6, NR7CO, NR7C(NR8)NR6, NR7CS, NR7CONR6, SO2NR6 or CO, where R6 is hydrogen or Ci-βalkyl, R7 is hydrogen or Ci-βalkyl and R8 is cyano, hydrogen or nitro, n is an integer of from 3 to 14; R is hydrogen or a hydroxy protecting group,
R1 is haloCi-ioalkyl, Ci-ioalkyl, C2_ιoalkenyl, C2.ιocycloalkyl, carboxyCi-ioalkyl,
Ci-ioalkoxycarbonylCi-ioalkyl, aryl (such as phenyl), aryl(Cι_ιo)alkyl (such as phenyl(Cι-ιo)alkyl) or di(Cι-6alkyl)amino;
R2 is hydrogen, Cι-6alk l or hydroxy, R3 is hydrogen, Cι.6alkyl, C2.6alkenyl or C2.6alkynyl;
R4 is hydroxy, Ci-ioalkanoyloxy, carboxyCi.ioalkanoyloxy or aroyloxy (such as benzoyloxy);
R5 is Cι-6alkyl; which process comprises aromatisation of a compound of formula (III)
(III) where R1, R2, R3, n, X and R5 are as defined in relation to formula (II) and R4 is a group R4 or a precursor group thereof, and thereafter if necessary or desired, carrying out one or more of the following steps: (i) removing any hydroxy protecting groups R; (ii) converting a precursor group R4 to a group R4, or where R is a group R , converting it to a different such group.
2. A process according to claim 1 wherein the R is an acyl group.
3. A process according to claim 2 wherein R is acetyl group.
4. A process according to any one of the preceding claimsl wherein R4 is a group OR10 where R10 is a hydroxy protecting group.
5. A process according to claim 2 where R10 is an acyl group, removable by alkaline hydrolysis.
6. A process according to claim 4 wherein both R and R10 are acetyl, and optional steps (i) and (ii) are conducted together in a single deacylation step
7. A process according to any one of the preceding claims wherein the aromatisation of the compound of formula (III) is effected in the presence of acetic anhydride so as to produce a compound of formula (II) where R is acetyl.
8. A process according to any one of the preceding claims wherein the aromatisation is effected using a copper salt.
9. A process according to claim 8 wherein the copper salt is cupric bromide.
10. A process according to claim 8 or claim 9 wherein the aromatisation reaction is effected in the presence of an alkali metal salt.
11. A process according to any one of claims 8 to 10 wherein thiourea is used to precipitate copper waste after the aromatisation.
12. A process according to any one of the preceding claims wherein the compound of formula (III) is prepared by reacting a compound of formula (IV)
R4'
(IV) where R , R , R >4' and R are as defined in claim 1, with a compound of formula (V)
(C 2)n\
W (V) where n, X and R1 are as defined in claim 1 and Z is a leaving group.
13. A process according to claim 12 wherein in the compound of formula (V), Z is a metal halide of formula Rπ-M where M is a metal ion and R11 is a halogen atom.
14. A process according to claim 13 wherein M is magnesium.
15. A process according to any one of claims 12 to 14 wherein the coupling reaction is conducted in the presence of a catalytic amount of a cuprous salt.
16. A process according to claim 15 wherein the cuprous salt is cuprous chloride.
17. A process according to any one of the preceding claims wherein in the compound of formula (II), X is S, and this is then oxidised to a group SO.
18. A process according to claim 17 wherein the oxidation is carried out using hydrogen peroxide or periodate.
19. A compound of formula (III) as defined in claim 1.
20. A compound according to claim 19 which is of formula (VIII)
wherein R12 is a protecting group.
21. A compound according to claim 20 wherein R12 is an acetyl group.
22. A process for preparing a compound according to any one of claims 18 to 21, which process comprises reacting a compound of formula (IV)
R4'
(IV) where R2, R3, R4 and R5 are as defined in claim 1, with a compound of formula (V)
(CH2)n\χ
R1
(N) where n, X and R1 are as defined in claim 1 and Z is a leaving group.
23. A process according to claim 22 wherein in the compound of formula (V), Z is a metal halide of formula Rn-M where M is a metal ion and R11 is a halogen atom.
24. A process according to claim 23 wherein M is magnesium.
25. A process according to any one of claims 22 to 24 wherein the coupling reaction is conducted in the presence of a catalytic amount of a cuprous salt.
26. A process according to claim 25 wherein the cuprous salt is cuprous chloride.
27. A process according to claim 1 for the preparation of a compound of formula (IIA)
("A) which process comprises aromatisation of a compound of formula (VIII) as defined in claim 20, and removal of the protecting group R12.
28. A process according to claim 1 for the preparation of fulvestrant which comprises coupling a compound of formula (Nil)
(Nil) wherein R12 is a protecting group, with a compound of formula (X),
L ,^/χ s^/^/s^ S ^/\^ CF2CF3
(X) wherein L is a suitable leaving group, and to the product formed performing the following three steps (1) aromatisation of the A-ring
(2) removing protecting group R12
(3) oxidation of the sulphide to the sulphoxide to form fulvestrant.
29. A process according to claim 22 for the preparation of a compound of formula (VIII),
(VIII) wherein R12 is a protecting group, comprising coupling a compound of formula VII,
(VII) wherein R12 is a protecting group, with a compound of formula X,
.CF2CF3
(X) wherein L is a suitable leaving group.
30. A process according to claim 29 wherein the compound of formula (X) is a compound of formula (XI)
R11 -M- . CF2CF3
(XI) wherein M is a metal atom and Rn is a halo atom.
31. A process for the preparation of fulvestrant of formula (I)
(I) or a pharmaceutically acceptable salt or ester thereof, or a hydrate of any of these, which comprises
(a) coupling a compound of formula IX as defined in claim 27 with a compound of formula (XT) as defined above; by the addition of a cuprous salt; all being dissolved in a suitable solvent to form a product of formula (VIII)
(VIII)
(b) aromatisation of the A-ring;
(c) removing protecting group R12; and
(d) oxidising the sulphide group to sulphoxide to form fulvestrant.
32. A method of preparing a compound of formula (XIII)
(XIII) where X, n, R1, R2, R3 and R5 are as defined in relation to formula (II), by reacting a compound of formula (XIV)
(XIV) where X, n, R , R , R and R are as defined in relation to formula (II), and R is hydrogen or a protecting group, in particular an acetyl group, with a copper salt in the presence of an acetic anhydride, and then hydrolysing the thus formed acetyloxy groups.
33. A method according to claim 32 for the preparation of a compound of formula (XIIIA)
(XIIIA) by reacting a compound of formula (XIV A)
(XIVA) where R20 is hydrogen or a protecting group, in particular an acetyl group, with a copper salt in the presence of an acetic anhydride, and then hydrolysing the thus formed acetyloxy groups.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2007201740A AU2007201740B2 (en) | 2000-10-14 | 2007-04-19 | Process and intermediates for the production of 7-subsituted antiestrogens |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0025221.3A GB0025221D0 (en) | 2000-10-14 | 2000-10-14 | New process |
| GB0025221.3 | 2000-10-14 | ||
| PCT/GB2001/004485 WO2002032922A1 (en) | 2000-10-14 | 2001-10-09 | Process and intermediates for the production of 7-substituted antiestrogens |
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| AU2007201740A Division AU2007201740B2 (en) | 2000-10-14 | 2007-04-19 | Process and intermediates for the production of 7-subsituted antiestrogens |
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| Publication Number | Publication Date |
|---|---|
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| AU2001292132B2 AU2001292132B2 (en) | 2007-01-25 |
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| AU9213201A Pending AU9213201A (en) | 2000-10-14 | 2001-10-09 | Process and intermediates for the production of 7-substituted antiestrogens |
| AU2007201740A Expired AU2007201740B2 (en) | 2000-10-14 | 2007-04-19 | Process and intermediates for the production of 7-subsituted antiestrogens |
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| Application Number | Title | Priority Date | Filing Date |
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| AU9213201A Pending AU9213201A (en) | 2000-10-14 | 2001-10-09 | Process and intermediates for the production of 7-substituted antiestrogens |
| AU2007201740A Expired AU2007201740B2 (en) | 2000-10-14 | 2007-04-19 | Process and intermediates for the production of 7-subsituted antiestrogens |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US7947667B2 (en) |
| EP (2) | EP1918295B1 (en) |
| JP (2) | JP4363846B2 (en) |
| KR (2) | KR100864266B1 (en) |
| CN (1) | CN1255425C (en) |
| AR (2) | AR034561A1 (en) |
| AT (1) | ATE403667T1 (en) |
| AU (3) | AU2001292132B2 (en) |
| BR (1) | BR0114649A (en) |
| CA (1) | CA2425572C (en) |
| CY (1) | CY1108398T1 (en) |
| DE (1) | DE60135240D1 (en) |
| DK (1) | DK1328538T3 (en) |
| EG (1) | EG23373A (en) |
| ES (2) | ES2309094T3 (en) |
| GB (1) | GB0025221D0 (en) |
| IL (2) | IL155172A0 (en) |
| MX (1) | MXPA03003302A (en) |
| MY (2) | MY149146A (en) |
| NO (1) | NO326020B1 (en) |
| NZ (1) | NZ525096A (en) |
| PT (1) | PT1328538E (en) |
| SA (1) | SA01220570B1 (en) |
| SI (1) | SI1328538T1 (en) |
| WO (1) | WO2002032922A1 (en) |
| ZA (1) | ZA200302526B (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0025221D0 (en) | 2000-10-14 | 2000-11-29 | Astrazeneca Ab | New process |
| GB0123961D0 (en) | 2001-10-05 | 2001-11-28 | Astrazeneca Ab | Process and intermediates |
| CA2574967A1 (en) * | 2004-07-27 | 2006-02-09 | Sicor, Inc. | A process for the preparation of 7.alpha.-alkylated 19-norsteroids |
| US20100174101A1 (en) * | 2007-09-24 | 2010-07-08 | Xi'an Liband Pharmaceutical Co., Ltd. | Process for the manufacture of 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)- triene-3,17-beta-diol |
| EP2070942A1 (en) | 2007-12-13 | 2009-06-17 | Bayer Schering Pharma Aktiengesellschaft | Method for aromatising 19-nor-androst-4-en-3-ones to estra-1,3,5(10)-trienes |
| CN101525364B (en) * | 2008-03-07 | 2012-12-12 | 杭州九源基因工程有限公司 | Crystal form of fulvestrant and preparation method thereof |
| US8063249B1 (en) | 2008-04-25 | 2011-11-22 | Olema Pharmaceuticals, Inc. | Substituted triphenyl butenes |
| CN102391341B (en) * | 2011-08-09 | 2013-05-22 | 福建省微生物研究所 | Method for preparing 6,7-dehydro-17beta-hydrocarbon acyloxy nandrolone |
| CN102600064A (en) * | 2012-03-31 | 2012-07-25 | 西安力邦制药有限公司 | Fulvestrant or fulvestrant derivative sustained release preparation and preparation method thereof |
| CA2884806A1 (en) | 2012-10-22 | 2014-05-01 | Intas Pharmaceuticals Limited | An improved process for the preparation of fulvestrant |
| CN103788164A (en) * | 2012-10-31 | 2014-05-14 | 正大天晴药业集团股份有限公司 | Preparation method of fulvestrant |
| CN103965280B (en) * | 2014-05-21 | 2016-04-20 | 天津孚音生物科技发展有限公司 | A kind of preparation method of fulvestrant intermediate |
| WO2015181116A1 (en) | 2014-05-26 | 2015-12-03 | Crystal Pharma, S.A.U. | Process and intermediades for the preparation of 7-alkylated steroids |
| CN104387435B (en) * | 2014-12-10 | 2017-05-10 | 天津孚音生物科技发展有限公司 | Compound and preparation method and application thereof |
| KR101640747B1 (en) | 2015-05-20 | 2016-07-19 | 이금운 | Insert type led lighting apparatus capable of expanding their size |
| CN107488205A (en) * | 2016-06-13 | 2017-12-19 | 重庆圣华曦药业股份有限公司 | A kind of preparation method of fulvestrant about material and its detection method in the formulation |
| CN110818764A (en) * | 2018-08-07 | 2020-02-21 | 重庆圣华曦药业股份有限公司 | Method for preparing fulvestrant intermediate by using charging monitoring system |
| CN111018936B (en) * | 2019-11-12 | 2021-10-29 | 广州曼翔医药有限公司 | Synthesis method of fulvestrant related substance E |
| CN116535454A (en) * | 2023-04-28 | 2023-08-04 | 香港中文大学（深圳） | Fulvestrant compound and preparation method and application thereof |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7305171A (en) * | 1973-04-13 | 1974-10-15 | ||
| GB8327256D0 (en) * | 1983-10-12 | 1983-11-16 | Ici Plc | Steroid derivatives |
| US5595985A (en) * | 1989-03-10 | 1997-01-21 | Endorecherche Inc. | Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia |
| DE4132182A1 (en) | 1991-09-24 | 1993-03-25 | Schering Ag | 11 (BETA) SUBSTITUTED 14, 17-ETHANOESTRATRIA, METHOD FOR PRODUCING THESE COMPOUNDS, AND THEIR USE FOR THE PRODUCTION OF MEDICINAL PRODUCTS |
| US5211831A (en) | 1991-11-27 | 1993-05-18 | Mcgean-Rohco, Inc. | Process for extending the life of a displacement plating bath |
| DE19622457A1 (en) * | 1996-05-24 | 1997-11-27 | Schering Ag | 7alpha- (5-methylaminopentyl) estratrienes, process for their preparation, pharmaceutical preparations which contain these 7alpha- (5-methylaminopentyl) estratrienes and their use for the manufacture of medicaments |
| US5952319A (en) * | 1997-11-26 | 1999-09-14 | Research Triangle Institute | Androgenic steroid compounds and a method of making and using the same |
| AU2001249661B2 (en) * | 2000-03-31 | 2005-02-17 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Methods of making the 4-n-butylcyclohexanoic and the undecanoic acid esters of (7 alpha, 11 beta)-dimethyl-17 beta-hydroxy-4-estren-3-one and their medical use |
| GB0025221D0 (en) | 2000-10-14 | 2000-11-29 | Astrazeneca Ab | New process |
| GB0123961D0 (en) | 2001-10-05 | 2001-11-28 | Astrazeneca Ab | Process and intermediates |
-
2000
- 2000-10-14 GB GBGB0025221.3A patent/GB0025221D0/en not_active Ceased
-
2001
- 2001-10-09 KR KR1020037005110A patent/KR100864266B1/en active IP Right Grant
- 2001-10-09 DE DE60135240T patent/DE60135240D1/en not_active Expired - Lifetime
- 2001-10-09 ES ES01972358T patent/ES2309094T3/en not_active Expired - Lifetime
- 2001-10-09 BR BR0114649-1A patent/BR0114649A/en not_active Application Discontinuation
- 2001-10-09 AT AT01972358T patent/ATE403667T1/en active
- 2001-10-09 ES ES08150796.4T patent/ES2581379T3/en not_active Expired - Lifetime
- 2001-10-09 WO PCT/GB2001/004485 patent/WO2002032922A1/en active Application Filing
- 2001-10-09 KR KR1020087013092A patent/KR20080056029A/en not_active Application Discontinuation
- 2001-10-09 AU AU2001292132A patent/AU2001292132B2/en not_active Expired
- 2001-10-09 SI SI200130863T patent/SI1328538T1/en unknown
- 2001-10-09 AU AU9213201A patent/AU9213201A/en active Pending
- 2001-10-09 EP EP08150796.4A patent/EP1918295B1/en not_active Expired - Lifetime
- 2001-10-09 JP JP2002536303A patent/JP4363846B2/en not_active Expired - Lifetime
- 2001-10-09 CA CA002425572A patent/CA2425572C/en not_active Expired - Lifetime
- 2001-10-09 NZ NZ525096A patent/NZ525096A/en not_active IP Right Cessation
- 2001-10-09 IL IL15517201A patent/IL155172A0/en unknown
- 2001-10-09 CN CNB018202705A patent/CN1255425C/en not_active Expired - Lifetime
- 2001-10-09 PT PT01972358T patent/PT1328538E/en unknown
- 2001-10-09 US US10/398,924 patent/US7947667B2/en not_active Expired - Fee Related
- 2001-10-09 MX MXPA03003302A patent/MXPA03003302A/en active IP Right Grant
- 2001-10-09 EP EP01972358A patent/EP1328538B1/en not_active Expired - Lifetime
- 2001-10-09 DK DK01972358T patent/DK1328538T3/en active
- 2001-10-10 EG EG20011065A patent/EG23373A/en active
- 2001-10-12 MY MYPI2010001633A patent/MY149146A/en unknown
- 2001-10-12 MY MYPI20014756A patent/MY145819A/en unknown
- 2001-10-12 AR ARP010104814A patent/AR034561A1/en active IP Right Grant
- 2001-12-04 SA SA01220570A patent/SA01220570B1/en unknown
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2003
- 2003-03-31 ZA ZA200302526A patent/ZA200302526B/en unknown
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2007
- 2007-04-19 AU AU2007201740A patent/AU2007201740B2/en not_active Expired
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2008
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2009
- 2009-05-08 JP JP2009113404A patent/JP5133937B2/en not_active Expired - Lifetime
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