EP1412322A2 - 3,5-dihydroxy-2,2-dimethyl-valeroamides proteges destines a la synthese d'epothilones et de derives de celles-ci, procedes de production de ces composes et utilisation de ceux-ci - Google Patents

3,5-dihydroxy-2,2-dimethyl-valeroamides proteges destines a la synthese d'epothilones et de derives de celles-ci, procedes de production de ces composes et utilisation de ceux-ci

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Publication number
EP1412322A2
EP1412322A2 EP02774500A EP02774500A EP1412322A2 EP 1412322 A2 EP1412322 A2 EP 1412322A2 EP 02774500 A EP02774500 A EP 02774500A EP 02774500 A EP02774500 A EP 02774500A EP 1412322 A2 EP1412322 A2 EP 1412322A2
Authority
EP
European Patent Office
Prior art keywords
general formula
benzyl
compounds
dimethyl
alkyl
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Withdrawn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
EP02774500A
Other languages
German (de)
English (en)
Inventor
Jürgen Westermann
Orlin Petrov
Johannes Platzek
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 EP1412322A2 publication Critical patent/EP1412322A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/18—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/002—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by oxidation/reduction reactions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction

Definitions

  • the invention relates to the subject matter characterized in the claims, that is new intermediates and processes for their preparation and use.
  • the process for the preparation of new intermediates is based on inexpensive starting materials, provides the intermediates in high enantiomeric purities, in high chemical purity, in good yields and allows large-scale production.
  • Epothilones are 16-membered macrolide rings isolated from cultures of the myxobacterium Sorangium cellosum and are representative of a class of promising antitumor agents that have been tested as effective against a variety of cancer lineages.
  • An overview of the syntheses is given by J. Mulzer et al. in J. Org. Chem. 2000, 65, 7456-7467.
  • Sg1 and Sg2 are protecting groups well known to those skilled in the art, e.g. the TBDMS group.
  • a possible production of the A building block is described, for example, in WO00 / 58254 (University of Wisconsin). Therein a synthesis of ⁇ -keto esters is disclosed, which can be converted in multi-stage sequences in the building block A. The chirality is introduced by an asymmetric hydrogenation of a Noyori ⁇ -ketoester:
  • the conversion of the ester group into a ketone can only be achieved by means of a multistage sequence.
  • the ester group (C-5 atom) is reduced to the alcohol, the oxidation to the aldehyde takes place, the Grignard addition of an alkyl radical with an alkylmagnesium or alkyllithium compound provides a secondary alcohol, which is subsequently oxidized.
  • a total of 6 steps are required.
  • the direct reaction of an ester is not selective because the intermediately produced product continues to react.
  • the following scheme shows the entire synthetic pathway:
  • J. Org. Chem. 2000, 65, 7456-7467 further describes an asymmetric synthesis of a ß-ketoester, wherein a variant is carried out in asymmetric form as aldol reaction.
  • the catalyst used in this method is D-Ts-valine, which can be prepared from the expensive amino acid D-valine. This method returns an ee value of 90%.
  • RE Taylor, Y. Chen, Org. Lett. (2001), 3 (14), 2221-2224 describes an asymmetric aldol reaction in which the yield is 71%.
  • the present invention has the object to be able to produce a universally usable starting intermediate of the general formula I and the optically pure antipodes of the general formulas Ia, Ib.
  • R1, R2 can be identical or different and independently of one another for an alcohol protecting group familiar to the person skilled in the art, for example benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl, trityl,
  • the compounds according to the invention are stable on storage and are for the most part crystalline solids and can be purified by crystallization. In this way, high chemical and optical yields (e.e.> 98%) can be achieved.
  • R 1 is a protective group as defined above, by cleavage of the protecting group R 1 according to the methods known to those skilled in the deprotection of alcohols produce (PJ Kocienski in "Protecting Groups", Georg Thieme Verlag Stuttgart , New York 1994 / Houben Weyl, 4 th Ed Vol Vl / 1b P. 737, Thieme Stuttgart 1984)
  • Y and R1 are as defined above and L is a silyl protecting group, e.g. TBDMS, TMS, TES, TIP, TBDPS is prepared in a manner known per se to those skilled in the art by the techniques of aldol condensation.
  • TBDMS silyl protecting group
  • TMS TMS
  • TES TES
  • TIP TBDPS
  • R1 THP in JOC, 1984, 49, 2301-2309
  • R1 benzyl in J. Chem. Soc. Perk. Trans 1, 2000, 2429-2454.
  • R1 TBDMS in JOC, 2000, 65, 7456-7467
  • Optically active compounds of the general formula IIIa are accessible as follows 1. Separation of the racemic compound of the general formula III on chiral phase (Ref. G. Roussel, P. Pirs, Chirabase, Pure and Applied Chemistry, 1993, 65, 235-244), especially by SMB technique: (A. Seidel-Morgenstern et al., Chromat A 1998, 827/2, 175-191).
  • R3 is a C1-C6 alkyl group or an allyl-phenyl, or benzyl group, prepared according to methods known in the art esterification. and saponified by enzymatic or microbiological methods enantioselectively.
  • the resulting alcohol differs significantly in its Rf value from the ester used, so that both can be conveniently separated from each other, e.g. by
  • Nu is a leaving group such as CI, Br, imidazole, -OPh, -O-C6H4NO2, -O-C1-C4 alkyl, etc.
  • R 4 is a methyl, ethyl, benzyl group
  • R 4 is a methyl, ethyl, benzyl group
  • R4 is a C1-C6 alkyl, methyl, ethyl, tert-butyl, phenyl or benzyl group are prepared by introducing the protective group R2 by methods known in the art (see above).
  • Q stands for a hydrogen atom or a COOH group. If Q is a hydrogen atom, XIIIa is treated with an organic base, e.g. LDA deprotonated and then reacted with the activated acid derivative according to the methods known in the art. In the case of Q equal to COOH, condensation is carried out by the methods of the malonic acid half ester condensation, e.g. in J. Am. Chem. Soc. 1999, 121, 7050-7062, Synth. Commun. 1997, 27, 3227-3234.
  • racemic diol of general formula II can also starting from ß-keto esters of general formula XIII
  • A represents the residue of an optically active ketone, such as e.g. (-) menthone, (-) camphor, etc., and then splits off the ketal group according to the methods of protecting group chemistry known to those skilled in the art.
  • an optically active ketone such as e.g. (-) menthone, (-) camphor, etc.
  • the TBDMS group is preferred.
  • R 1 is a ketal-protecting group, particular preference is given to - (C (CH 3) 2) -.
  • the group Y may be preferred for the radicals:
  • N, N-dimethyl- (5-benzyloxy-2,2-dimethyl-3 (S) -hydroxy-pentanoic acid) amide 29.8 g (0.11 mol) of N-toluenesulfonyl-D-valine (Lit: J. Am. Chem. Soc., 1937, 59, 116-118) are dissolved at 0 ° C. in 100 ml of dichloromethane.
  • 100 ml of BH 3 -THF solution (1 molar) are added dropwise over 30 minutes and the mixture is stirred for a further 30 minutes. The solution is cooled to -78 ° C.
  • N, N-dimethyl- (3 (S) -3,5-di-tert-butyldimethylsilyloxy-2,2,2-dimethylpentanoic acid) amide To a solution of 3.96 g (20.95 mmol) of N, N-dimethyl- (3 (S) -3,5-dihydroxy-2,2-dimethyl-pentanoic acid) amide of the title compound of Example 1e, in 20 Dissolved ml of dimethylformamide, are added 7.13g (104.75 mmol) of imidazole and 7.9 g (52.37 mmol) of tert-butyldimethylsilyl chloride and stirred for 16 hours at room temperature.
  • the solution is poured into 200 ml of water and extracted 2 times with 50 ml of cyclohexane.
  • the organic phases are combined and evaporated to dryness in vacuo.
  • the residue is purified by flash chromatography on silica gel (hexane / MTB ether).
  • N-methyl-N-phenyl- (5-benzyloxy-2,2, -dimethyl-3 (S) -hydroxy-pentanoic acid) amide 500 mg of N-methyl-N-phenyl- (5-benzyloxy-2,2-dimethyl-3-oxo-pentanoic acid) amide of the title compound from Example 6b are reacted with a catalyst (prepared from 23.3 mg RuCl 2 (Ph) 2 and 62.6 mg S-BiNAP according to R. Selke, Angew Chem. 1998, 110, 1927-1930) (2 d at 40 ° C / 100 bar). Yield: Quantative Elemental Analysis:
  • N-methyl-N-phenyl- (3 (S) -3,5-dichlorodiphenylsilane -2,2, -dimethylpentanoic acid) amide To a solution of 5.26 g (20.95 mmol) of N-methyl-N-phenyl- (3 (S) -3,5-dihydroxy-2,2-dimethyl-pentanoic acid) amide of the title compound of Example 6d, dissolved in 20 ml of dimethylformamide are added 3.14 g (46.09 mmol) of imidazole and 5.83 g (23.05 mmol) of dichlorodiphenylsilane and stirred for 16 hours at room temperature.
  • Example 9a rac. N, N-dimethyl- (3-hydroxy-3-oxo-pentanoic acid) amide
  • Example 9b N, N-Dimethyl-3 (S) - (3,5-dihydroxy-2,2-dimethyl-pentanoic acid) amide 1.87 g (10 mmol) of rac. N, N-Dimethyl- (3-hydroxy-3-oxo-pentanoic acid) amide of the title compound of Example 1c are reacted with a catalyst (prepared from 75 mg RuCl 2 (Ph) 2 and 190 mg S-BiNAP according to R. Selke, Angew Chem. 1998, 110, 1927-1930) (2 d at 40 ° C / 100 bar). Yield: Quantative

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  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
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Abstract

L'invention concerne de nouveaux 3,5-dihydroxy-2,2-diméthyl-valéroamides protégés destinés à la synthèse d'épothilones et de dérivés de celles-ci, ainsi que des procédés de production de ces composés et l'utilisation de ceux-ci pour produire des épothilones ou des dérivés de celles-ci.
EP02774500A 2001-08-03 2002-08-05 3,5-dihydroxy-2,2-dimethyl-valeroamides proteges destines a la synthese d'epothilones et de derives de celles-ci, procedes de production de ces composes et utilisation de ceux-ci Withdrawn EP1412322A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10138348A DE10138348A1 (de) 2001-08-03 2001-08-03 Geschützte 3,5-Dihydroxy-2,2-dimethyl-valeroamide für die Synthese von Epothilonen und Derivaten und Verfahren zur Herstellung und die Verwendung
DE10138348 2001-08-03
PCT/EP2002/008726 WO2003014063A2 (fr) 2001-08-03 2002-08-05 3,5-dihydroxy-2,2-dimethyl-valeroamides proteges destines a la synthese d'epothilones et de derives de celles-ci, procedes de production de ces composes et utilisation de ceux-ci

Publications (1)

Publication Number Publication Date
EP1412322A2 true EP1412322A2 (fr) 2004-04-28

Family

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EP02774500A Withdrawn EP1412322A2 (fr) 2001-08-03 2002-08-05 3,5-dihydroxy-2,2-dimethyl-valeroamides proteges destines a la synthese d'epothilones et de derives de celles-ci, procedes de production de ces composes et utilisation de ceux-ci

Country Status (16)

Country Link
EP (1) EP1412322A2 (fr)
JP (1) JP2004537589A (fr)
KR (1) KR20040029394A (fr)
CN (2) CN1807403A (fr)
AR (1) AR036207A1 (fr)
BR (1) BR0211649A (fr)
CA (1) CA2456255A1 (fr)
DE (1) DE10138348A1 (fr)
IL (1) IL160159A0 (fr)
MX (1) MXPA04000954A (fr)
NO (1) NO20040912L (fr)
PE (1) PE20030345A1 (fr)
PL (1) PL367430A1 (fr)
RU (1) RU2004106530A (fr)
WO (1) WO2003014063A2 (fr)
ZA (1) ZA200401727B (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6867305B2 (en) 1996-12-03 2005-03-15 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
JP4579351B2 (ja) 1996-12-03 2010-11-10 スローン−ケッタリング インスティトュート フォア キャンサー リサーチ エポチロンの合成とその中間体及びその類似物並びにその使用
WO2003029195A1 (fr) 2001-09-28 2003-04-10 Sumika Fine Chemicals Co., Ltd. Intermediaires pour l'elaboration d'un derive de l'epothilone, et leur procede de production
DE10326195A1 (de) * 2003-06-07 2004-12-23 Schering Ag Geschützte 5,7-Dihydroxy-4,4-dimethyl-3-oxoheptansäureester und 5,7-Dihydroxy-2-alkyl-4,4-dimethyl-3-oxoheptansäureester für die Synthese von Epothilonen- und Derivaten und Verfahren zur Herstellung dieser Ester
CN110857276B (zh) * 2018-08-22 2021-03-02 中国科学院化学研究所 一类手性β-羟基酰胺类化合物及其制备方法与应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4824980A (en) * 1988-09-02 1989-04-25 Dow Corning Corporation Process to produce O-silyl O,N-ketene acetals
US6211412B1 (en) * 1999-03-29 2001-04-03 The University Of Kansas Synthesis of epothilones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03014063A2 *

Also Published As

Publication number Publication date
JP2004537589A (ja) 2004-12-16
PE20030345A1 (es) 2003-04-10
KR20040029394A (ko) 2004-04-06
CA2456255A1 (fr) 2003-02-20
CN1807403A (zh) 2006-07-26
IL160159A0 (en) 2004-07-25
WO2003014063A3 (fr) 2003-05-01
PL367430A1 (en) 2005-02-21
MXPA04000954A (es) 2004-04-20
NO20040912L (no) 2004-03-02
ZA200401727B (en) 2005-04-12
WO2003014063A2 (fr) 2003-02-20
DE10138348A1 (de) 2003-02-27
RU2004106530A (ru) 2005-07-27
AR036207A1 (es) 2004-08-18
BR0211649A (pt) 2004-07-13
CN1538952A (zh) 2004-10-20

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