EP1226142A2 - Verfahren zur herstellung von epothiolon-b und derivaten davon, sowie von zwischenprodukten für dieses verfahren - Google Patents

Verfahren zur herstellung von epothiolon-b und derivaten davon, sowie von zwischenprodukten für dieses verfahren

Info

Publication number
EP1226142A2
EP1226142A2 EP00948907A EP00948907A EP1226142A2 EP 1226142 A2 EP1226142 A2 EP 1226142A2 EP 00948907 A EP00948907 A EP 00948907A EP 00948907 A EP00948907 A EP 00948907A EP 1226142 A2 EP1226142 A2 EP 1226142A2
Authority
EP
European Patent Office
Prior art keywords
compound
formula
aldehyde
mmol
epothilone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00948907A
Other languages
English (en)
French (fr)
Inventor
Johann Mulzer
Harry Martin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP1226142A2 publication Critical patent/EP1226142A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • 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
    • C07D417/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a process for the production of epothilone B and derivatives as well as intermediate products for this process.
  • diastereomer-pure fragments as starting products and intermediate products are required for a successful epothilone synthesis.
  • Diastereomer purity is often decisive for the action and reliability of a pharmaceutical agent and thus a requirement for its production.
  • Epothilone derivatives were already described by H ⁇ fle et al. in WO 97/19086. These derivatives were produced starting from natural epothilone A or B.
  • n object of this invention is to indicate a process for the production of epothilone B and epothilone B derivatives, in which the cis-epoxide is introduced at a considerably earlier time via dihydroxylation-monosulfonation of a suitable (E)- olefin, whereby the ⁇ -configuraticn of the cis-epoxide is to come
  • T ⁇ S stands for a tributylsilyl group.
  • another suitable pro ective group can also be another suitable rrctective group can also be used as a starting compound, in v.-hich the epoxy group of the epothilone is already contained, and this epoxy group remains unchanged in all subsequent steps up to the end product.
  • Diagram 3 shows possible derivatizations that allow for the process according to the invention if compound 11 that is to be used and/or next steps 13 or 14 are modified as indicated. This invention therefore extends not only to the process for the production of epothilone B, but also to a process for the production of correspondingly modified derivatives that are derived from modified compounds 11, 13 or 14.
  • the invention also relates to the compounds of formulas 5 to 21, which are all new, as well as the correspondingly modified derivatives, which are obtained in the procedures indicated above and in diagram 3.
  • IR (Film) v ma ⁇ 2956, 2930, 2887, 2857, 1737, 1472, 1462, 1454, 1370, 1300, 1255, 1155, 1098, 939, 836, 776, 737 cm "1 .
  • IR (Film) v MX 3513 (br) , 2932, 2874, 2855, 1738, 1463, 1372, 1255, 1157, 1088, 836, 777 cm "1 .
  • IR (Film) v ma ⁇ 2955, 2874, 2857, 1740, 1656, 1505, 1439, 1380, 1312, 1230, 1180, 1077, 835, 778 cm "1 .
  • aldehyde 15 (di ⁇ olved in 1.5 ml of THF) is added in drop ⁇ within 2-3 minute ⁇ . After 15 minute ⁇ at -78°C, it is quenched with 4 ml of ⁇ aturated NH 4 C1 ⁇ olution while being ⁇ tirred vigorou ⁇ ly (initially ⁇ lowly then quickly added) , 6 ml of ether i ⁇ added, and the cooling bath i ⁇ replaced by a water bath. After thawing, ⁇ ome water i ⁇ added, and the pha ⁇ e ⁇ are ⁇ eparated after ⁇ haking out.
  • reaction mixture is concentrated by evaporation to about 5 ml and filtered on a short ⁇ ilica gel column (rewa ⁇ hed with 30 ml of hexane/ethyl acetate) . Removal of the ⁇ olvent and ⁇ ubsequent column chromatography (hexane/ethyl acetate 4:1) yield 18 mg (34%) of macrolactone 22 as a colorless oil.
  • NMR data are identical to the data of K. C. Nicolaou and A. Mantoulidis (Tet. Lett. 39 (1998) 8633-8636). HPLC analysi ⁇ with a comparison sample of A. Mantoulidis shows identical material.
  • Methylene chloride is predried on a ba ⁇ ic aluminum oxide column of activity ⁇ tage I (Woel ) and made absolute on calcium hydride. After predrying on a ba ⁇ ic aluminum oxide column over an 8:1 sodiu /pota ⁇ ium alloy, diethyl ether i ⁇ refluxed until ⁇ table blue coloring of the benzophenone indicator i ⁇ achieved, and it is fre ⁇ hly distilled off before use.
  • the tetrahydrofuran (THF) is predried over KOH, filtered on a column that i ⁇ coated with basic aluminum oxide and then distilled on potassium with triphenylmethane as an indicator.
  • reaction ⁇ are monitored by thin-layer chromatography (TLC) on silica gel-60-aluminum foils with UV-indicator F 254 of the Merck Company.
  • TLC thin-layer chromatography
  • a ⁇ a mobile ⁇ olvent, in mo ⁇ t cases ⁇ olvent mixtures that con ⁇ i ⁇ t of hexane (Hex) and ethyl acetate (EE) are used.
  • Hex hexane
  • EE ethyl acetate
  • ani ⁇ aldehyde/glacial acetic acid/ ⁇ ulfuric acid (1:100:1) ha ⁇ been taken a ⁇ a ⁇ tandard dip reagent.
  • HPLC high-pre ⁇ sure liquid chromatographic ⁇ eparation ⁇
  • Dye Reagent I (F I) : In the case of mo ⁇ t compound ⁇ that can be reduced, 1 g of cerium (IV) ⁇ ulfate in 10 ml of concentrated ⁇ ulfuric acid and 90 ml of water yield an inten ⁇ ive blue color reaction during drying.
  • Dye reagent II A 10% ethanolic ⁇ olution of molbydatophosphoric acid represents another dip reagent for detecting unsaturated and reducible compounds.
  • the molybdate dye reagent ⁇ e ⁇ pecially pertaining to ⁇ everal functionalitie ⁇ , ⁇ how ⁇ a broader color ⁇ pectrum in the case of virtually identical reliability.
  • Dye reagent III 1 ml of ani ⁇ aldehyde in 100 ml of ethanol and 2 ml of concentrated ⁇ ulfuric acid repre ⁇ ents an extremely sensitive dye reagent that in addition al ⁇ o ⁇ how ⁇ probably the broade ⁇ t color ⁇ pectrum.
  • Dye reagent IV Like the ani ⁇ aldehyde reagent, 1 g of vanillin in 100 ml ethanol and 2 ml of concentrated ⁇ ulfuric acid i ⁇ a very ⁇ en ⁇ itive dye reagent with a broad color ⁇ pectrum.
  • Dye reagent V (F V) l g of 2 , 4-dinitrophenylhydrazine in 25 ml of ethanol, 8 ml of water and 5 ml of concentrated ⁇ ulfuric acid represent an excellent dip reagent that re ⁇ ponds selectively to aldehydes even without being heated and that responds somewhat more ⁇ lowly to ketone ⁇ .
  • Dye reagent VI (F VI) : A 0.5% aqueou ⁇ ⁇ olution of pota ⁇ sium permanganate indicate ⁇ groups that can be oxidized by decolorization, whereby unsaturated, non-aromatic structural units react spontaneously without heating.
  • the 1 H-NMR spectra are recorded a ⁇ an internal standard with a DRX 250 DRX 400 ⁇ pectrometer of the Bruker Company with the ⁇ ub ⁇ tance ⁇ a ⁇ a ⁇ olution in deuterated ⁇ olvent ⁇ and tetramethyl ⁇ ilane.
  • the evaluation of the spectra is carried out according to rules of the first order. If a signal multiplicity that occurs cannot be explained in this way, the indication of the observed line set i ⁇ done.
  • NOE- ⁇ pectro ⁇ copy Nuclear Overhau ⁇ er Effect
  • ⁇ ( ⁇ inglet) , d (doublet) , dd (double doublet) , ddd (6-line ⁇ y ⁇ tem with two identical coupling con ⁇ tant ⁇ or an 8-line ⁇ ystem in three different coupling constants) , t (triplet) , q (quartet) , quint (quintet) , ⁇ ext ( ⁇ extet) , sept (septet) , m (multiplet) , mc
  • the 13 C NMR ⁇ pectra are mea ⁇ ured a ⁇ an internal ⁇ tandard with an AC 250 of the Bruker Company with a CDC1 3 ⁇ ignal at 77.0 ppm, whereby the proton re ⁇ onances are wideband-coupled.
  • the infrared ⁇ pectra are recorded with device ⁇ of the Perkin-El er Company (model 257 or 580 B) and Nicolet Company (FTIR-interfero eter ⁇ y ⁇ tem 55XC) .
  • the oils are measured a ⁇ films between pota ⁇ ium bromide di ⁇ ks.
  • the bands are indicated according to decreasing wave number (cm "1 ).
  • de ⁇ ignation ⁇ are ⁇ elected: v ⁇ (very ⁇ trong) , ⁇ ( ⁇ trong) , m (medium) , w (weak) .
  • TBDPS tert-butyldiphenyl- ⁇ ilyl chloride
  • TBDPSCl tert-butyldiphenyl- ⁇ ilyl chloride
  • TBS tert-butyldimethyl- ⁇ ilyl chloride
  • TBSCI tert-butyldi ethyl- ⁇ ilyl chloride
  • TBSTriflate tert-butyldimethyl-silyl-triflate
  • TEA triethylamine, tert/t: tertiary
  • TFA trifluoroethanoic acid
  • TFAA trifluoroethanoic acid anhydride
  • TFMS trifluoromethane ⁇ ulfonic acid
  • THF tetrahydrofuran
  • TMS trimethyl ⁇ ilyl-, u: g-mol '1 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP00948907A 1999-07-22 2000-07-24 Verfahren zur herstellung von epothiolon-b und derivaten davon, sowie von zwischenprodukten für dieses verfahren Withdrawn EP1226142A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14500599P 1999-07-22 1999-07-22
US145005P 1999-07-22
PCT/US2000/020064 WO2001007439A2 (en) 1999-07-22 2000-07-24 Process for the production of epothiolone b and derivatives as well as intermediate products for this process

Publications (1)

Publication Number Publication Date
EP1226142A2 true EP1226142A2 (de) 2002-07-31

Family

ID=22511165

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00948907A Withdrawn EP1226142A2 (de) 1999-07-22 2000-07-24 Verfahren zur herstellung von epothiolon-b und derivaten davon, sowie von zwischenprodukten für dieses verfahren

Country Status (5)

Country Link
EP (1) EP1226142A2 (de)
JP (1) JP2003505459A (de)
AU (1) AU6233600A (de)
NO (1) NO20020308L (de)
WO (1) WO2001007439A2 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6204388B1 (en) 1996-12-03 2001-03-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
CA2273083C (en) 1996-12-03 2012-09-18 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
SI1483251T1 (sl) 2002-03-12 2010-03-31 Bristol Myers Squibb Co C cian epotilonski derivati
GB0221312D0 (en) 2002-09-13 2002-10-23 Novartis Ag Organic compounds
AU2008271631B2 (en) * 2007-07-04 2013-06-06 Sanofi Macrolactone derivatives
US20110300150A1 (en) 2010-05-18 2011-12-08 Scott Eliasof Compositions and methods for treatment of autoimmune and other disease

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4183099B2 (ja) * 1995-11-17 2008-11-19 ゲゼルシャフト・フュア・ビオテヒノロジッシェ・フォルシュング・ミット・ベシュレンクテル・ハフツング（ゲー・ベー・エフ） エポチロンｃおよびｄ、製造法ならびに組成物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0107439A3 *

Also Published As

Publication number Publication date
WO2001007439A3 (en) 2001-05-03
WO2001007439A2 (en) 2001-02-01
NO20020308L (no) 2002-03-21
NO20020308D0 (no) 2002-01-21
AU6233600A (en) 2001-02-13
JP2003505459A (ja) 2003-02-12

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