US20080242868A1 - Process for preparing epothilone derivatives by selective catalytic epoxidation - Google Patents
Process for preparing epothilone derivatives by selective catalytic epoxidation Download PDFInfo
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- US20080242868A1 US20080242868A1 US12/056,393 US5639308A US2008242868A1 US 20080242868 A1 US20080242868 A1 US 20080242868A1 US 5639308 A US5639308 A US 5639308A US 2008242868 A1 US2008242868 A1 US 2008242868A1
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- dialkene
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
Definitions
- the invention relates to the subject-matter characterized in the claims, that is to say a novel selective epoxidation process for preparing the epothilone derivative of the formula I.
- the process of the invention affords the target compound of the formula I in high chemical and diastereomeric purity, very good yields and permits preparation on a large scale.
- a whole series of synthetically modified epothilone derivatives have been prepared, including those having an aromatic or heteroaromatic group in position 1 instead of the methylthiazole-methylvinyl side chains.
- Epothilone derivatives with fused aromatic heterocycles in position 1 are disclosed in the patent literature, e.g. by Schering AG, WO 00/66589 and Novartis WO 2000/037473. Since these compounds are very potent antitumour agents, it is of great interest to have an economic and efficient synthesis of this structural class available.
- the reaction mixture contains besides the target compound I also the beta isomer (Ia), from which corresponding impurities likewise arise in an analogous manner. Removal of all these by-products is time-consuming and takes place by difficult, elaborate and costly chromatography.
- MTO epoxidation catalyst
- MTO methyltrioxorhenium
- the present invention achieves this object and describes a novel process for preparing this epothilone derivative of the formula I starting from the dialkene of the formula II which is likewise known from the literature
- Aqueous hydrogen peroxide solution especially in an aprotic solvent at ⁇ 60° C. to ⁇ 20° C. is particularly suitable as epoxidizing agent.
- the compound of the formula (I) is obtained from the dialkene of the formula II
- One aspect of the invention represents the process described above when the preferred conditions
- a further embodiment of the invention represents the process described above when all the particularly preferred conditions are combined together, the intention being if no particularly preferred range is indicated that the preferred range is combined:
- a particular embodiment of the invention is a process for preparing the compound of the formula (I)
- the process is carried out precisely under the conditions of Example 1.
- One embodiment of the invention is one of the processes as described above, in which the reaction temperature is ⁇ 60° C. to ⁇ 20° C.
- the reaction takes place at temperatures of from ⁇ 55 to ⁇ 35° C.
- a further embodiment is the process as described in claim 1 , in which the reaction times are between 20-120 h.
- reaction times are from 40 to 80 h.
- the amount of methyltrioxorhenium is 1-5 mol %, where the amount is based on the dialkene.
- a further embodiment is one of the processes as described above, where the concentrations of the compound of the formula II are from 1 g in 5 ml of solvent to 1 g in 50 ml of solvent.
- a further embodiment is one of the processes as described above, where the dialkene is present in concentrations of from 1 g in 5 ml of solvent to 1 g in 20 ml of solvent.
- dichloromethane other solvents such as 1,2 dichloroethane, chloroform and mixtures thereof with pentane, hexane, heptane, cyclohexane or other low-boiling alkanes in various ratios, and aromatic solvents (arylalkanes) such as, for example, toluene, trifluorotoluene. It is also possible to employ dichloromethane mixed with the abovementioned alkanes and arylalkanes.
- Low-boiling alkanes mean straight-chain and branched alkanes and cycloalkanes having boiling points of about 35° C. to 100° C.
- the solvent is selected from the group of dichloromethane, 1,2-dichloroethane, chloroform, and mixtures thereof with pentane, hexane, heptane, cyclohexane, toluene or trifluorotoluene, or toluene or trifluorotoluene on their own.
- the solvent is selected from the group of mixtures of dichloromethane with pentane, hexane, heptane, cyclohexane, toluene, or trifluorotoluene.
- the solvent is selected from the group of dichloromethane and mixtures of dichloromethane with pentane, hexane, heptane, cyclohexane, toluene, or trifluorotoluene.
- C 1 -C 4 -alkyl means straight-chain or branched, for example methyl, ethyl, propyl, isopropyl.
- the amount of substituted pyridine is 10-20 mol %, the amount being based on the dialkene.
- aqueous hydrogen peroxide solution is employed.
- One embodiment of the invention therefore relates to a process as defined in claim 1 , where UHP is used as epoxidizing agent.
- a reducing agent known to the skilled person such as, for example, sodium thiosulphate, sodium sulphite, vitamin C etc.
- aqueous acidic solutions for extractive removal of the pyridine catalyst
- KHSO 4 , H 2 SO 4 , HCl, phosphoric acid, methanesulphonic acid, TFA, citric acid in water for example, KHSO 4 , H 2 SO 4 , HCl, phosphoric acid, methanesulphonic acid, TFA, citric acid in water.
- a final wash with saturated aqueous NaCl solution is possible where appropriate, followed by drying over magnesium sulphate or sodium sulphate and then removal of the solvent by distillation in vacuo.
- the residue is purified by chromatography and then the compound of the formula (I) is finally purified by crystallization and isolated. However, it can also be filtered through a short layer of silica gel (removal of the pyridine catalyst) and then be directly crystallized. The yields achieved are 80-90%.
- the invention thus relates further to a process as described in claim 1 , which, after workup, is directly followed by a crystallization.
- the rhenium content of a compound of the formula I prepared in this way is ⁇ 7 ppm (LOD*:7 ppm) (*level of detection; method: ICP-OES).
- the detectability of amounts less than 7 ppm depends on how large the amount of epothilone derivative there is available for the measurement. A larger amount of epothilone derivative means that a content of less than 7 ppm rhenium is more likely to be detectable.
- a further aspect of the invention is also a product of the process of the invention which still contains rhenium.
- One aspect of the invention is the product of the formula I containing more than 0.0004 ppm rhenium.
- the final product contains >0.0004 ppm to 7 ppm rhenium.
- the final product contains >0.0004 ppm to 1 ppm rhenium.
- One aspect of the invention is the product of the formula I containing rhenium in the range from 0.01 ppm to 30 ppm.
- a further aspect of the invention is the product of the formula I containing rhenium in the range from 0.1 ppm to 30 ppm.
- the reaction product contains from 1 ppm up to 30 ppm rhenium.
- the final product contains ⁇ 7 ppm to 30 ppm rhenium.
- the final product contains 0.01 ppm to 7 ppm rhenium.
- the final product contains 0.01 ppm to 1 ppm rhenium.
- the novel process allows the compound of the formula (I) to be prepared in high diastereselectivity and yield and purity.
- the process is simple to operate and permits scaling-up into the multi-kg range. It has the great advantage beside the methods described in the prior art that no valuable substance is lost through attack on the exo double bond. This process is therefore to be categorized as a very practicable and economically valuable method.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Epoxy Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12/056,393 US20080242868A1 (en) | 2007-03-30 | 2008-03-27 | Process for preparing epothilone derivatives by selective catalytic epoxidation |
| US13/308,046 US8314248B2 (en) | 2007-03-30 | 2011-11-30 | Process for preparing epothilone derivatives by selective catalytic epoxidation |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102007016046A DE102007016046A1 (de) | 2007-03-30 | 2007-03-30 | Verfahren zur Herstellung von Epothilonderivaten durch selektive katalytische Epoxidierung |
| DE102007016046.3 | 2007-03-30 | ||
| US90741507P | 2007-04-02 | 2007-04-02 | |
| US12/056,393 US20080242868A1 (en) | 2007-03-30 | 2008-03-27 | Process for preparing epothilone derivatives by selective catalytic epoxidation |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US13/308,046 Division US8314248B2 (en) | 2007-03-30 | 2011-11-30 | Process for preparing epothilone derivatives by selective catalytic epoxidation |
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| Publication Number | Publication Date |
|---|---|
| US20080242868A1 true US20080242868A1 (en) | 2008-10-02 |
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| US12/056,393 Abandoned US20080242868A1 (en) | 2007-03-30 | 2008-03-27 | Process for preparing epothilone derivatives by selective catalytic epoxidation |
| US13/308,046 Expired - Fee Related US8314248B2 (en) | 2007-03-30 | 2011-11-30 | Process for preparing epothilone derivatives by selective catalytic epoxidation |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US13/308,046 Expired - Fee Related US8314248B2 (en) | 2007-03-30 | 2011-11-30 | Process for preparing epothilone derivatives by selective catalytic epoxidation |
Country Status (13)
| Country | Link |
|---|---|
| US (2) | US20080242868A1 (https=) |
| EP (1) | EP2142539A2 (https=) |
| JP (1) | JP2010523481A (https=) |
| KR (1) | KR20090125259A (https=) |
| CN (1) | CN101652362B (https=) |
| AR (1) | AR066692A1 (https=) |
| CA (1) | CA2681806A1 (https=) |
| CL (1) | CL2008000901A1 (https=) |
| DE (1) | DE102007016046A1 (https=) |
| PA (1) | PA8773901A1 (https=) |
| TW (1) | TW200902538A (https=) |
| UY (1) | UY30985A1 (https=) |
| WO (1) | WO2008119563A2 (https=) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114539143A (zh) * | 2022-01-28 | 2022-05-27 | 安徽瑞邦生物科技有限公司 | 一种4-氰基吡啶的纯化方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6387927B1 (en) * | 1998-12-22 | 2002-05-14 | Novatis Ag | Epothilone derivatives and their use as antitumor agents |
| US20040019088A1 (en) * | 2002-03-01 | 2004-01-29 | Schering Ag | Use of Epothilones in the treatment of brain diseases associated with proliferative processes |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR023792A1 (es) | 1999-04-30 | 2002-09-04 | Bayer Schering Pharma Ag | Derivados 6-alquenilo- y 6-alquinilo-epotilona, los procedimientos para prepararlos y su empleo en productos farmaceuticos |
| GB0405898D0 (en) * | 2004-03-16 | 2004-04-21 | Novartis Ag | Organic compounds |
-
2007
- 2007-03-30 DE DE102007016046A patent/DE102007016046A1/de not_active Withdrawn
-
2008
- 2008-03-27 US US12/056,393 patent/US20080242868A1/en not_active Abandoned
- 2008-03-27 CA CA002681806A patent/CA2681806A1/en not_active Abandoned
- 2008-03-27 KR KR1020097020329A patent/KR20090125259A/ko not_active Withdrawn
- 2008-03-27 UY UY30985A patent/UY30985A1/es not_active Application Discontinuation
- 2008-03-27 CN CN2008800103886A patent/CN101652362B/zh not_active Expired - Fee Related
- 2008-03-27 WO PCT/EP2008/002652 patent/WO2008119563A2/de not_active Ceased
- 2008-03-27 JP JP2010500148A patent/JP2010523481A/ja not_active Withdrawn
- 2008-03-27 EP EP08734992A patent/EP2142539A2/de not_active Withdrawn
- 2008-03-28 PA PA20088773901A patent/PA8773901A1/es unknown
- 2008-03-28 TW TW097111589A patent/TW200902538A/zh unknown
- 2008-03-28 AR ARP080101279A patent/AR066692A1/es not_active Application Discontinuation
- 2008-03-28 CL CL200800901A patent/CL2008000901A1/es unknown
-
2011
- 2011-11-30 US US13/308,046 patent/US8314248B2/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6387927B1 (en) * | 1998-12-22 | 2002-05-14 | Novatis Ag | Epothilone derivatives and their use as antitumor agents |
| US20040019088A1 (en) * | 2002-03-01 | 2004-01-29 | Schering Ag | Use of Epothilones in the treatment of brain diseases associated with proliferative processes |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114539143A (zh) * | 2022-01-28 | 2022-05-27 | 安徽瑞邦生物科技有限公司 | 一种4-氰基吡啶的纯化方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| TW200902538A (en) | 2009-01-16 |
| CA2681806A1 (en) | 2008-10-09 |
| US8314248B2 (en) | 2012-11-20 |
| EP2142539A2 (de) | 2010-01-13 |
| KR20090125259A (ko) | 2009-12-04 |
| UY30985A1 (es) | 2008-10-31 |
| PA8773901A1 (es) | 2008-11-19 |
| JP2010523481A (ja) | 2010-07-15 |
| AR066692A1 (es) | 2009-09-09 |
| CN101652362B (zh) | 2012-10-10 |
| DE102007016046A1 (de) | 2008-10-23 |
| CN101652362A (zh) | 2010-02-17 |
| WO2008119563A2 (de) | 2008-10-09 |
| WO2008119563A3 (de) | 2009-02-12 |
| CL2008000901A1 (es) | 2008-10-17 |
| US20120077984A1 (en) | 2012-03-29 |
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