WO1999005088A1 - Tamoxifen and analogues thereof - Google Patents
Tamoxifen and analogues thereof Download PDFInfo
- Publication number
- WO1999005088A1 WO1999005088A1 PCT/GB1998/002171 GB9802171W WO9905088A1 WO 1999005088 A1 WO1999005088 A1 WO 1999005088A1 GB 9802171 W GB9802171 W GB 9802171W WO 9905088 A1 WO9905088 A1 WO 9905088A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solvent
- tamoxifen
- isomer
- derivative
- precursor
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
Definitions
- This invention relates to tamoxifen and analogues thereof and particularly, although not exclusively, relates to a method of preparing a desired isomer of tamoxifen or an analogue thereof.
- Tamoxifen is a triphenylethylene derivative of formula
- tamoxifen analogues One of the most important analogues of tamoxifen is 4- hydroxytamoxifen (one of the main metabolites in patients) , which has an affinity for binding to oestrogen receptors which is 100 times higher than for tamoxifen itself. Accordingly, processes for stereoselect ive synthesis and/or isolation of substantially pure Z isomer of tamoxifen, 4 -hydroxytamoxifen and other analogues are desirable .
- the invention is based on the surprising, and previously unappreciated, discovery that one geometric isomer of tamoxifen or an analogue thereof can be predominantly removed from a mixture of isomers in the presence of certain solvents.
- a method of removing predominantly a first geometric isomer of tamoxifen or an analogue thereof from a mixture comprising said first geometric isomer and a second geometric isomer including the step of allowing the first isomer to crystallise in a solvent.
- the method comprises contacting a mixture which comprises said first and second isomers with said solvent .
- the method may include separating the crystallised product from the remainder.
- Said solvent is preferably able to dissolve the isomers in said mixture and is such as to allow re- crystallisation as aforesaid.
- said solvent is preferably contacted with the isomers in the mixture when said solvent is at a first temperature wherein said first temperature is suitably less than the boiling point of the solvent. Recrystallisation is suitably carried out at a second temperature which is less than said first temperature. It is believed that the temperature of the recrystallisation step affects the relative amounts of first and second isomers in the recrystallised product.
- recrystallisation is suitably carried out at greater than -4°C, preferably greater than 0°C, more preferably greater than 10°C, especially greater than 20°C.
- recrystallisation may be carried out at at least ambient temperature.
- Said second temperature may be within 30°C, suitably 25°C, preferably 20°C, more preferably 15°C, especially 10°C of the optimum temperature.
- Said 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.
- Said first temperature may be less than 200°C, preferably less than 160°C, more preferably less than 140°C, especially less than 120°C.
- Said first temperature may be less than the boiling point of the solvent, suitably by at least 10°C, preferably at least 20°C, more preferably at least 30°C, especially at least 40°C.
- Said 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. Said boiling point may be less than 300°C, suitably less than 250°C, preferably less than
- Various solvents may be selected for use in the method.
- said solvent includes a first solvent part.
- the first solvent part is an organic solvent with polar organic solvents being preferred.
- Said first solvent part may be an unsubstituted hydrocarbon or may include one or more functional groups.
- groups may be selected from -OH, -N0 2 , -CN, -O- and optionally substituted, especially unsubstituted, alkyl groups .
- the first solvent part may include two or, more preferably, one or fewer functional groups. Especially preferred is the case wherein the first solvent part includes only one functional group.
- Said first solvent part is preferably a protic solvent .
- a preferred functional group of said first solvent part is an -OH group.
- Said first solvent part may be aliphatic, alicyclic, aromatic or heteroaromatic .
- Said first solvent part is preferably aliphatic.
- Said first solvent part may include one or more, suitably at least two, preferably at least three, more preferably at least four, especially at least five carbon atoms.
- Said first solvent part may include twelve or fewer, suitably ten or fewer, preferably nine or fewer, more preferably eight or fewer, especially seven or fewer, carbon atoms .
- Said first solvent part may have a boiling point of at least 50°C, suitably at least 75°C, preferably at least 100°C, more preferably at least 125°C, especially at least 150°C.
- Said 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.
- Said first solvent part is preferably an alcohol having one -OH group.
- Said first solvent part is more preferably hexanol .
- Said solvent may include a mixture comprising said first solvent part and a second solvent part .
- Said second solvent part may include any feature of said first solvent part described herein.
- said solvent consists essentially of said first solvent part as described.
- the method preferably includes a first step comprising allowing the first isomer to crystallise in a solvent as aforesaid and a second step which comprises allowing the product of the first step to crystallise in a solvent .
- said second solvent may have any feature of the solvent used in the first step (hereinafter “said first solvent”) .
- said first solvent and said second solvent are different.
- said second solvent has a lower boiling point than said first solvent, suitably by 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.
- Said second solvent is preferably an alcohol, preferably a C alcohol, especially a C,. 2 alcohol, with methanol being most preferred.
- the mixture used in the first step of the method is substantially pure.
- a purifying step may simply comprise washing a mixture to be used in said first step with a solvent .
- the solvent used in the washing (hereinafter “said third solvent”) may have any feature of said second solvent as described.
- the temperature of the third solvent in said washing step is less than the temperature of said first solvent when it is used and/or the temperature of said second solvent when it is used.
- Said third solvent preferably is the same as said second solvent and is, therefore, preferably methanol.
- said first geometric isomer is crystallised at some stage of said method from a solvent which includes or, preferably consists essentially of methanol .
- a solvent comprises at least 80 wt%, preferably at least 90 wt%, more preferably at least 95 wt%, especially at least 99 wt% of the referenced solvent, for example methanol.
- Said first step and/or said second step may be carried out under less than ambient light conditions.
- said step(s) is/are carried out substantially in the dark.
- the method uses a receptacle which is substantially opaque. Excluding or reducing the light intensity in said first and/or second steps is found to increase the amount of the preferred isomer isolated.
- analogue includes: a derivative of tamoxifen wherein one or more atoms or groups of tamoxifen have been replaced by other atoms or groups; or wherein a ring or rings is/are formed between juxtaposed atoms or groups of tamoxifen; and a precursor of tamoxifen or a derivative thereof which precursor exists in at least two geometric isomeric forms and which can be converted to tamoxifen or a said derivative thereof, suitably by a substitution reaction.
- Analogues of tamoxifen may include optionally- subst ituted triphenylalkyl or alkyl ene compounds .
- Preferred optionally-substituted triphenyl compounds are of general formula
- A, B and P each independently represents an optionally-substituted phenyl group and Q represents a hydrogen atom or an optionally-substituted alkyl, alkenyl, alkynyl or phenyl group; and wherein a pair of adjacent substituents A, B, P and Q are optionally arranged together to form part of a ring structure .
- Optional substituents as described herein include any substituents generally used to affect the activity of drugs for oral administration or which represent leaving groups and/or protecting groups which aid the preparation of such drugs.
- preferred optional substituents include halogen atoms, haloalkyl and hydroxy groups and optionally-substituted alkylcarboxy, alkoxy, phenoxy, alkylamino and alkylcarbonyl groups.
- Preferred alkyl, alkenyl and alkynyl groups may have up to 12, preferably up to 6, more preferably up to 4 carbon atoms .
- Q represents an optionally-substituted, preferably unsubstituted, alkyl group.
- said alkyl group is a C ⁇ to C 4 , more preferably a C ⁇ to C 2 , alkyl group.
- Q preferably represents an ethyl group.
- groups A, B and P independently represent an unsubstituted or monosubstituted phenyl group. Where a group A, B or P is substituted, it is preferably substituted in the 3- or, more preferably, the 4- position.
- group B is unsubstituted.
- Group P is preferably unsubstituted or substituted by a halogen atom or hydroxy, optionally-substituted alkoxy or phenoxy, groups. Where group P is substituted, it is preferably substituted in the 4 -position. More preferably, group P is unsubstituted or substituted by an optionally- substituted phenoxy group. In an especially preferred embodiment, P is unsubstituted. Thus, preferably P represents an unsubstituted phenyl group.
- group A is monosubstituted by a halogen atom or hydroxy, optionally-substituted alkoxy or phenoxy, groups.
- group A is monosubstituted by an optionally-substituted alkoxy group.
- a preferred optionally- substituted alkoxy group is of general formula
- n represents an integer preferably in the range 1 to 8, more preferably 1 to 4 , especially 1 to 2; and X represents a leaving group, for example a halogen, especially a chlorine, atom, or a group of general formula
- R 1 and R 2 independently represent a hydrogen atom or an optionally-substituted, preferably unsubstituted, alkyl group.
- n represents 2.
- group A is monosubstituted by an alkoxy group of general formula II, wherein n represents 2.
- said mixture used in the method comprises a first analogue of tamoxifen (preferably a precursor of tamoxifen or tamoxifen derivative as described above) and the method includes the further step of derivatising the first geometric isomer removed in order to prepare tamoxifen or a derivative, especially an antiestrogenic derivative, thereof.
- the first analogue of tamoxifen more preferably said first geometric isomer of said first analogue, has less antiestrogenic activity compared to tamoxifen or a said derivative which is prepared in said further derivatising step.
- said precursor is a compound of general formula I described above wherein B, P and Q are as described above.
- A represents a phenyl group substituted, preferably at least at the 4-position, by a first moiety which includes an active atom or group which is arranged to react with a second moiety which includes a group of general formula III as described above in order to produce an optionally substituted alkoxy group of general formula II as described above.
- said first moiety includes a leaving group which is suitably X as described above.
- said first moiety comprises a group of general formula II as described above. Said first moiety is preferably reacted with an amine of general formula R'R 2 NH wherein R 1 and R 2 are as described above .
- the ring structure may be formed between pairs of substituents A, B, P and Q which are cis to one another.
- substituents A, B, P and Q which are cis to one another.
- Z represents an oxygen or sulphur atom or a group -CH 2 CH 2 - .
- adjacent substituents A, B, P and Q do not form part of a ring structure.
- the mixture used may 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 precursor of tamoxifen or tamoxifen derivative for use in the method may be prepared from a compound of general formula
- A, B, P and Q are as described in any statement herein.
- A, B, P and Q in said compounds of formula I and XII represent the same atoms or groups.
- the compound of formula XII may be dehydrated to prepare the compound of formula I .
- Dehydration may involve refluxing the compound of formula XII in a solvent in the presence of a strong acid, for example concentrated hydrochloric acid.
- the alkene derivative of formula XI is contacted with said solvent prior to the reaction with dimethylamine .
- the compound XI prepared contains 100% (according to HPLC analysis) of the desired Z isomer (which has the stereochemical configuration of compound XI shown in Scheme I) .
- Compound XI can then be converted by a simple reaction to tamoxifen with the stereochemistry being maintained.
- the method described above may be used to prepare tamoxifen or an analogue which includes greater than 99 wt%, suitably greater than 99.5 wt%, preferably greater than 99.7 wt%, more preferably greater than 99.8 wt%, especially greater than 99.9 wt%, of said first geometric isomer.
- a typical process for preparing 4 -hydroxytamoxifen involves derivatising compound X prepared according to the reaction scheme provided below.
- the invention extends to pharmaceutically acceptable forms, for example salts of tamoxifen or analogues thereof .
- the invention extends to a method of preparing tamoxifen or a derivative, especially an antiestrogenic derivative, thereof, the method including the steps of allowing a first geometric isomer of a precursor of tamoxifen or said derivative to crystallise in a solvent and derivatising said precursor in order to produce said tamoxifen or said derivative.
- the invention extends to the use of a solvent for removing predominantly a first geometric isomer of tamoxifen or an analogue thereof from a mixture of isomers .
- the invention extends to a method of preparing an antiestrogenic isomer of tamoxifen or an analogue thereof in purity of at least 99%, suitably at least 99.5%, preferably at least 99.7%, more preferably at least 99.8%, especially at least 99.9%, most preferably at least 99.95%, the method using a solvent as described herein.
- the invention extends to the product of any process described herein.
- Figure 1 is a ⁇ NMR spectrum for a mixture of isomers of a tamoxifen precursor, prepared in Example 1 ;
- Figures 2 to 4 provide further detail for the spectrum of Figure 1 ;
- Figure 5 is a ⁇ NMR spectrum for the product obtained in Example 1 after washing with methanol .
- Figure 6 is an ⁇ NMR spectrum of the material referred to in figure 5, after recrystallisation from hexanol in the dark;
- Figure 7 is a ⁇ NMR spectrum of the material referred to in figure 5, after recrystallisation from methanol in the dark;
- Figure 8 is an HPLC analysis on the product of figure 7.
- 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 ⁇ 0.80 to 1.05 shows two overlapping triplets corresponding to the CH 3 groups in the
- the critical point is the ratio of the heights of the peaks at 0.92 (for the Z) and 0.94 (for the E) , which is approximately 2:1.
- Figure 5 shows the ⁇ NMR spectrum of the pure solid obtained after the methanol washing of the crude reaction product.
- Figure 6 shows the ⁇ NMR spectrum of the solid obtained following the recrystallisation from hexanol of the product shown in Figure 5
- Figures 7 and 8 respectively show the ! H NMR and the HPLC analyses of the pure Z isomer obtained following the second recrystallisation, this time from methanol.
- the HPLC analysis we carried out under the following conditions: Hypersil ODS 5 mm, 250 x 4.0 mm column and 50% MeOH : 30%; MeCN : 20%; H 2 0 mobile phase at 1ml/min.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002297246A CA2297246A1 (en) | 1997-07-23 | 1998-07-21 | Tamoxifen and analogues thereof |
AU84529/98A AU8452998A (en) | 1997-07-23 | 1998-07-21 | Tamoxifen and analogues thereof |
HU0002807A HUP0002807A3 (en) | 1997-07-23 | 1998-07-21 | Process for removing geometric isomers of tamoxifen and analogues thereof from a mixture |
JP2000504090A JP2001510819A (en) | 1997-07-23 | 1998-07-21 | Tamoxifen and its congeners |
EP98935177A EP0998447A1 (en) | 1997-07-23 | 1998-07-21 | Tamoxifen and analogues thereof |
NO20000329A NO316376B1 (en) | 1997-07-23 | 2000-01-21 | Method of separating tamoxifen isomers |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9715479.3A GB9715479D0 (en) | 1997-07-23 | 1997-07-23 | Tamoxifen and analogues thereof |
GB9715479.3 | 1997-07-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999005088A1 true WO1999005088A1 (en) | 1999-02-04 |
Family
ID=10816289
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1998/002171 WO1999005088A1 (en) | 1997-07-23 | 1998-07-21 | Tamoxifen and analogues thereof |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0998447A1 (en) |
JP (1) | JP2001510819A (en) |
AU (1) | AU8452998A (en) |
CA (1) | CA2297246A1 (en) |
GB (2) | GB9715479D0 (en) |
HU (1) | HUP0002807A3 (en) |
NO (1) | NO316376B1 (en) |
WO (1) | WO1999005088A1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1064629A (en) * | 1962-09-13 | 1967-04-05 | Ici Ltd | Alkene derivatives |
EP0168175A1 (en) * | 1984-06-12 | 1986-01-15 | National Research Development Corporation | Preparation of tamoxifen |
EP0313799A2 (en) * | 1987-10-29 | 1989-05-03 | Klinge Pharma GmbH | Process for the preparation of trans-1,1,2-triphenyl-but-1-ene derivatives |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3462398D1 (en) * | 1983-05-24 | 1987-04-02 | Bristol Myers Co | Process for the conversion of the e isomer of 1,2-diphenyl-1-(4-(2-dimethylaminoethoxy)-phenyl)-1-butene to tamoxifen hcl |
ES2044860T3 (en) * | 1987-04-21 | 1994-01-16 | Heumann Pharma Gmbh & Co | STABLE ADDUCTS WITH Z-1- SOLVENTS (P-BETA-DI-METHYL-AMINO-ETOXI-FENIL) -1- (P-HIDROXI-FENIL) -2-FENIL-BUT-1-ENO. |
KR0169186B1 (en) * | 1993-10-25 | 1999-03-20 | 고바야시 유끼오 | Process for producing acid addition salt of z-isomer of triphenylethylene compound |
EP0738256B1 (en) * | 1994-01-03 | 1998-04-22 | Klinge Pharma GmbH | Method for the production of e-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3'-hydroxyphenyl)-2-phenyl-1-butene |
GB9601167D0 (en) * | 1996-01-20 | 1996-03-20 | Univ Bradford | Tamoxifen and analogues thereof |
-
1997
- 1997-07-23 GB GBGB9715479.3A patent/GB9715479D0/en active Pending
-
1998
- 1998-07-21 AU AU84529/98A patent/AU8452998A/en not_active Abandoned
- 1998-07-21 JP JP2000504090A patent/JP2001510819A/en not_active Withdrawn
- 1998-07-21 EP EP98935177A patent/EP0998447A1/en not_active Withdrawn
- 1998-07-21 CA CA002297246A patent/CA2297246A1/en not_active Abandoned
- 1998-07-21 GB GB9815904A patent/GB2327673B/en not_active Expired - Fee Related
- 1998-07-21 HU HU0002807A patent/HUP0002807A3/en unknown
- 1998-07-21 WO PCT/GB1998/002171 patent/WO1999005088A1/en not_active Application Discontinuation
-
2000
- 2000-01-21 NO NO20000329A patent/NO316376B1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1064629A (en) * | 1962-09-13 | 1967-04-05 | Ici Ltd | Alkene derivatives |
EP0168175A1 (en) * | 1984-06-12 | 1986-01-15 | National Research Development Corporation | Preparation of tamoxifen |
EP0313799A2 (en) * | 1987-10-29 | 1989-05-03 | Klinge Pharma GmbH | Process for the preparation of trans-1,1,2-triphenyl-but-1-ene derivatives |
Non-Patent Citations (2)
Title |
---|
M. JARMAN ET AL.: "The use of Octafluorotoluene and Pentafluoropyridine in the Synthesis of Pure Z- and E- Isomer of Derivatives of Tamoxifen.", J. CHEM. RES., SYNOP. (1985), (4), 116-117, XP002087120 * |
SRIKANTH, NATARAJAN ET AL: "Synthesis of heterocyclic analogs of tamoxifen as potential antiestrogens", J. CHEM. RES., SYNOP. (1997), (8), 274-275, XP002087119 * |
Also Published As
Publication number | Publication date |
---|---|
NO20000329D0 (en) | 2000-01-21 |
HUP0002807A1 (en) | 2001-11-28 |
CA2297246A1 (en) | 1999-02-04 |
NO316376B1 (en) | 2004-01-19 |
GB9715479D0 (en) | 1997-10-01 |
NO20000329L (en) | 2000-03-23 |
AU8452998A (en) | 1999-02-16 |
GB2327673A (en) | 1999-02-03 |
GB9815904D0 (en) | 1998-09-16 |
HUP0002807A3 (en) | 2002-01-28 |
GB2327673B (en) | 2002-03-27 |
EP0998447A1 (en) | 2000-05-10 |
JP2001510819A (en) | 2001-08-07 |
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