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EP0929535A1 - Procede et nouveaux intermediaires - Google Patents

Procede et nouveaux intermediaires

Info

Publication number
EP0929535A1
EP0929535A1 EP97941446A EP97941446A EP0929535A1 EP 0929535 A1 EP0929535 A1 EP 0929535A1 EP 97941446 A EP97941446 A EP 97941446A EP 97941446 A EP97941446 A EP 97941446A EP 0929535 A1 EP0929535 A1 EP 0929535A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
substituted
formula
cycloalkyl
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Withdrawn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
EP97941446A
Other languages
German (de)
English (en)
Other versions
EP0929535A4 (fr
Inventor
Darrell R. Hutchison
Samantha K. Janisse
Michael J. Martinelli
Eric D. Moher
Kevin A. Sullivan
David L. Varie
David W. Hoard
John E. Toth
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.)
University of Hawaii at Manoa
Wayne State University
Eli Lilly and Co
University of Hawaii at Hilo
Original Assignee
University of Hawaii at Manoa
Wayne State University
Eli Lilly and Co
University of Hawaii at Hilo
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 University of Hawaii at Manoa, Wayne State University, Eli Lilly and Co, University of Hawaii at Hilo filed Critical University of Hawaii at Manoa
Publication of EP0929535A1 publication Critical patent/EP0929535A1/fr
Publication of EP0929535A4 publication Critical patent/EP0929535A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • 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
    • C07C235/32—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 containing six-membered aromatic rings
    • C07C235/34—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 containing six-membered aromatic rings 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
    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings

Definitions

  • This invention relates to the fields of pharmaceutical and organic chemistry and provides novel intermediates and processes useful for the preparation of cryptophycin compounds .
  • Antimetabolites have been used for a number of years as chemotherapeutic agents in the treatment of cancer.
  • a new class of antimetabolites, cryptophycin compounds are useful for disrupting the microtubule system and, thus, can be useful for the treatment of cancer.
  • the novel processes and intermediates of this invention are important elements in providing an efficient route for preparing other cryptophycin intermediates.
  • a special advantage provided is that the intermediates thus prepared have only minimal residual impurities. Ultimately, these intermediates can be linked to provide a total synthesis of cryptophycin compounds.
  • a number of problems must be resolved in order to accomplish a large scale total synthesis of a complex molecule such as the cryptophycin molecule. It is difficult to obtain intervening intermediates of sufficient purity, to be able to handle the materials easily and to obtain reliable yields when processes are carried out on the scale needed to obtain the quantities of compounds needed for pharmaceutical purposes.
  • novel intermediates and processes of this invention accomplish some of these goals.
  • one of the processes permits removal of a protecting group to provide an intermediate that can now be isolated as a convenient white solid.
  • the new coupling process results in unexpectedly greater yields and avoids what previously was an extra step of preparing a pentafluorophenyldiphenyl- phosphinic chloride coupling reagent.
  • a rhodium-catalyzed process prepares a novel fragment, called Fragment C, that is useful for an alternative synthesis of cryptophycin compounds.
  • Another process that is applicable to acid-and base sensitive products minimizes recrystallization and chromatography steps.
  • the processes and intermediates of this invention are important advances in the synthesis of useful cryptophycin compounds. These advances include, but are not limited to, increased efficiency, decreased cost, and improved purity.
  • this invention provides a novel intermediate of Formula XII
  • R 6 is Cj-Ce alkyl, substituted (Cj-C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, substituted C 3 -C ⁇ cycloalkyl, a heteroaromatic or substituted heteroaromatic group, or a group of formula Ilia, Ill'or III":
  • R 6a , R* 5 , and R 6c independently are H, halo or OR 18 ;
  • R 15 , R 16 , and R 17 independently are hydrogen, halo, (d-
  • R 18 and R 19 independently are hydrogen or C ⁇ -C 6 alkyl
  • R 23 is hydrogen or (C ⁇ -C 3 ) alkyl
  • Z is -(CH 2 ) n - or (C3-C5) cycloalkyl; n is 0, 1, or 2; and Z' is an aromatic or substituted aromatic group.
  • this invention provides a process for preparing an intermediate of Formula XII as defined supra, comprising contacting a compound of the formula XII'
  • this invention provides a new coupling process for preparing compounds of Formula XIII (known as Fragment A-B of the cryptophycins) :
  • Ar is an aromatic or heteroaromatic group, or a substituted aromatic or heteroaromatic group;
  • R 60 is an alcohol protecting group;
  • R 3 is C ⁇ -C 6 alkyl;
  • R* and R 5 are H; or
  • R* and R 5 together form a second bond;
  • R 6 is as defined supra; comprising contacting a compound of Formula XII as defined supra, with 1) a compound of Formula XV
  • R A is d-C 6 alkyl, C ⁇ -C 6 aralkyl, or Ar; and 3) a base.
  • this invention provides an improved process for preparing a compound of Formula XIII, as defined supra, comprising reacting a compound of Formula XII, as defined supra, with a compound of formula XV as defined supra, in the presence of 1) the coupling reagent diphenyl chlorophosphate [ (PhO) 2 P(0) Cl] ;and 2) an amine.
  • Carboxyl activation via phosphorous based reagents is an often used method for the synthesis of amides and related compounds.
  • FDPP pentafluorophenyl diphenylphosphinic chloride
  • R 1 is halo, SR, OR, amino, mono or di- (Ci-C ⁇ -alkyl) amino, tri (C ⁇ -C 6 -alkyl) ammonium, C ⁇ -C 6 -alkylthio, di (C]-C 6 - alkyl) sulfoniu , C ⁇ -C 6 -alkylsulfonyl, or C ⁇ -C 6 - alkylphosphonyl; and
  • R 2 is OH or SH; or R 1 and R 2 taken together form a second bond between C-18 and
  • R is H, C ⁇ -C 6 alkyl, C]-C 6 alkanoyl or Ar;
  • R 7 is H, C ⁇ -C 6 alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, benzyl, or benzyl substituted with up to three substituents independently selected from C ⁇ -C 6 -alkyl, halo, C ⁇ -C 6 -alkoxy, amino or NR 51 R 52 ; and
  • R 8 is H or C ⁇ -C 6 alkyl
  • R 7 and R ⁇ together form a C 3 -C ⁇ cycloalkyl ring;
  • R 51 and R ⁇ 2 independently are C : -C 3 alkyl;
  • R 9 is H, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 -alkynyl or (C,-C 6 alkyl) C3-C5 cycloalkyl;
  • R 10 is H or C ⁇ -Ce alkyl
  • X is 0, NH or ⁇ C1-C3 alkyl )N-; and Y is C, 0, NH, S, SO, S0 2 or (C1-C3 alkyl)N-; comprising contacting 1) a compound of Formula XVI
  • This invention also provides a process for preparing a compound of Formula XVII
  • R' a is C ⁇ -C 6 alkyl, with a rhodium catalyst and hydrogen gas; and optionally hydrolyzing the product to obtain the compound wherein R' is hydrogen.
  • this invention provides a process for preparing a compound of Formula XIX
  • R 7 , R 8 , R 9 and R 10 independently are H or d-C 6 alkyl; R p is tert-butoxycarbonyl (BOC) or benzyloxycarbonyl; comprising contacting a compound of Formula XX
  • this invention provides an improvement in the process for preparing a compound of formula XX by coupling a Fragment D compound of the formula:
  • R 7 and R 8 are as defined supra, but provided R 7 and R 8 cannot be H, in an inert organic solvent; the improvement comprising using the coupling reagent l,l ' - carbonyldiimidazole (CDI) .
  • CDI coupling reagent l,l ' - carbonyldiimidazole
  • catalytic quantity refers to less than a stoichiometric amount, but an amount sufficient to achieve the desired results.
  • the term is intended to have the meaning commonly understood in the art.
  • alkyl refers to an alkyl group with the designated number of carbon atoms. It may be saturated or unsaturated, and branched or straight chain. "Lower alkyl” means a C 1 -C5 alkyl group. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, propenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec- butyl, methyl-substituted butyl groups, pentyl, tert-pentyl, sec-pentyl, methyl-substituted pentyl groups and the like.
  • Substituted alkyl refers to a C ⁇ -C 6 alkyl group that may include up to three (3) substituents containing one or more heteroatoms. Examples of such substituents are OH, NH 2 , C0NH 2 , C0 2 H, P0 3 H 2 and S0 2 R 21 wherein R 21 is hydrogen, d- C 3 alkyl or aryl .
  • the term “cycloalkyl” refers to a saturated C 3 -C 8 cycloalkyl group.
  • a “substituted cycloalkyl group” refers to a cycloalkyl group having up to three C1-C3 alkyl, halo, or OR 21 substituents. The substituents may be attached at any available carbon atom. Cyclohexyl is an especially preferred cycloalkyl group.
  • “Lower alkoxy” means a alkyl group bonded to an oxygen atom.
  • allyl means a 2-propenyl group.
  • allyl scavenger is commonly understood in the art. Preferred allyl scavengers are pyrrolidine, piperidine, morpholine, and 1, 3-dicarbonyl compounds. An especially preferred allyl scavenger is morpholine.
  • halo refers to Cl, Br, F, or I .
  • aromatic group and “heteroaromatic group” refer to common aromatic rings having 4n + 2 pi electrons in a monocyclic or bicyclic conjugated system.
  • aryl refers to an aromatic group
  • aralkyl refers to an aryl (C ⁇ -C c -alkyl) group. Examples of aromatic groups are phenyl, benzyl and naphthyl.
  • Heteroaromatic groups will contain one or more oxygen, nitrogen and/or sulfur atoms in the ring. Examples of heteroaromatic groups include furyl, pyrrolyl, thienyl, pyridyl and the like.
  • aromatic or heteroaromatic groups When the aromatic or heteroaromatic groups are substituted, they may have from one to three independently selected C1-C7 alkyl, C ⁇ -C&-alkoxy or halo substituents.
  • the substituents may be attached at any available carbon atom.
  • Especially preferred heterocyclic groups are
  • amino protecting group refers to a standard amino protecting group that is either acid labile or can be removed under mildly basic to neutral conditions. Such groups are well known in the art. [See, for example, J.F. . McOmie, "Protective Groups in Organic Chemistry", Plenum Press, (London and New York, 1973); Greene, T.W.
  • Peferred amino protecting groups are acid labile.
  • An especially preferred amino protecting group for compounds of Formula XVII is tert-butoxycarbonyl ("BOC") .
  • BOC tert-butoxycarbonyl
  • the R 6 substituent in a Formula I compound contains an amino substituent, it must be protected using an amino protecting group.
  • alcohol protecting group is one that is introduced during a portion of the synthetic process to protect an alcohol group that might otherwise react in the course of chemical manipulations. The group is then removed at a later stage of the synthesis. Reactions for the formation and removal of such protecting groups are described in a number of standard works, including the two references listed supra.
  • a particularly useful alcohol protecting group is tert-butyldimethylsilyl (TBS) .
  • TBS tert-butyldimethylsilyl
  • the processes of this invention are preferably carried out in the presence of a solvent. Selection of an appropriate solvent is commonly understood in the art.
  • An inert organic solvent such as N, N-dimethylformamide (DMF) , ethyl acetate, dichloromethane, toluene or acetonitrile, or a mixture thereof, is recommended.
  • Epoxide ring means a three-membered ring whose backbone consists of two carbon and one oxygen atoms.
  • Aziridine ring means a three-membered ring whose backbone consists of two carbon and one nitrogen atoms.
  • Episulfide ring refers to a three-membered ring whose backbone consists of two carbon and one sulfur atoms.
  • halogenation examples include the addition of hydrogen halides, free radical halogenation, etc. Such methods are known in the art.
  • strong acid refers to an acid that has a pKa of 2 or less.
  • a hydrohalic acid is most suitable.
  • a preferred hydrohalic acid is hydrochloric acid.
  • Other mineral acids, such as phosphoric and sulfuric, and organic acids, such as tosic and acetic, may also be used.
  • base has its accepted meaning.
  • a base is a compound that yields hydroxyl ions in water or the negative ion of a solvent; or a base is any molecule or ion that can combine with protons or hydrogen ions, i.e. a proton acceptor.
  • the term includes, but is not limited to, N,N-diisopropylethylamine, carbonates, and other tertiary amines.
  • TBS refers to a tert-butyldimethylsilyl group.
  • Equations 2 and 3 are applicable to corresponding intermediates having various Ar, R 60 , and R 6 groups.
  • N-diisopropylethylamine are the illustrated solvent-base used in equations 2 and 3, and in that of equation 4 infra, any nonparticipating solvent or solvent combination-base will be appropriate for the processes.
  • Typical solvents include ethers, halogenated hydrocarbons, and esters.
  • Typical bases include tertiary amines and carbonates. An especially preferred base for these processes is diisopropylethylamine .
  • An especially preferred solvent for the process of eq. 4 is DMF. This process is especially useful because it provides improved yields. In addition, it makes it possible to use Ph 2 P(0)Cl, which is commercially available, to complete the macrolactamization.
  • Compound 8a is a known compound. It has been prepared by the reaction of ethyl cyanoacetate with methyl iodide in the presence of sodium ethoxide, a, and sodium hydride.
  • c [a) Hessler, J.C. J. Am. Chem. Soc. 1913, 35, 990. b)
  • hydrolysis conditions for preparing Compound 10 from Compound 9a can be readily determined.
  • Especially preferred hydrolysis agents are LiOH and NaOH.
  • Equation 7 The new allyl ester deprotection process is illustrated by Equation 7:
  • R , R , R 9 and R 10 have the meanings defined supra.
  • the Pd(PPh 3 ), catalyst should be present in an amount less than about four (4) mole percent.
  • the amount of Pd(PPh 3 ) 4 catalyst is less than two mole percent (2 %) . It is especially preferred that the amount of Pd(PPh 3 ), catalyst is about two tenths mole percent (0.2%) or less. In addition, using less catalyst provides a significant cost advantage.
  • Equation 7 process is when R 9 is isobutyl, and R 10 is hydrogen.
  • An especially preferred allyl scavenger is morpholine.
  • Preferred solvents for the process of Equation 7 are tetrahydrofuran, acetone, alcohols, acetonitrile, and ethyl acetate.
  • An especially preferred solvent is tetrahydrofuran .
  • the use of the allyl ester as a protecting group for carboxylic acids is well known and has been the subject of reviews. Kocienski, P. J. Protecting Groups; Georg Thieme Verlag: Stuttgart, 1994; pp 139-154; Greene, T. W.; Wuts, P. G. M.
  • Procedures A and B illustrate the isolation advantage of the new process over the prior art process:
  • PROCEDURE A (Barrowl) :
  • PROCEDURE B (new process) :
  • Table 1 illustrates the yield advantage provided by the new process.
  • Equation 7 can be run at a temperature of from about zero (0) to about seventy (70) degrees C.
  • a preferred temperature is about 25°C.
  • the necessary reaction time is related to the starting materials and operating temperature.
  • the optimum reaction time for a given process is, as always, a compromise which is determined by considering the competing goals of throughput, which is favored by short reaction times, and maximum yield, which is favored by long reaction times.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Intermédiaires et procédés utiles pour la préparation de composés cryptophycine.
EP97941446A 1996-09-06 1997-09-05 Procede et nouveaux intermediaires Withdrawn EP0929535A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US2552196P 1996-09-06 1996-09-06
US25521P 1996-09-06
PCT/US1997/015703 WO1998009955A1 (fr) 1996-09-06 1997-09-05 Procede et nouveaux intermediaires

Publications (2)

Publication Number Publication Date
EP0929535A1 true EP0929535A1 (fr) 1999-07-21
EP0929535A4 EP0929535A4 (fr) 2001-05-23

Family

ID=21826566

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97941446A Withdrawn EP0929535A4 (fr) 1996-09-06 1997-09-05 Procede et nouveaux intermediaires

Country Status (5)

Country Link
EP (1) EP0929535A4 (fr)
JP (1) JP2001502298A (fr)
AU (1) AU4335297A (fr)
CA (1) CA2263764A1 (fr)
WO (1) WO1998009955A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034252A2 (fr) * 1998-12-07 2000-06-15 Eli Lilly And Company Procede de crotylboration permettant de produire des composes de cryptophycine
EP1229934B1 (fr) 1999-10-01 2014-03-05 Immunogen, Inc. Compositions et methodes de traitement du cancer utilisant des immunoconjugues et des agents chimiotherapeutiques
CA2475567A1 (fr) 2002-02-07 2003-08-14 Covalent Partners, Llc Compositions pour nanofilms et membrane
CN102448927A (zh) * 2009-04-01 2012-05-09 力奇制药公司 活性亚甲基基团的二甲基化的方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3567834A (en) * 1969-06-16 1971-03-02 Bristol Myers Co Method of producing sedation
US4739120A (en) * 1986-08-21 1988-04-19 The Dow Chemical Company Process for the hydrogenation of nitriles to primary amines
DE3904119A1 (de) * 1989-02-11 1990-08-16 Hoechst Ag Polymerfixiertes methotrexat, verfahren zur herstellung und verwendung
IT1239029B (it) * 1989-10-12 1993-09-20 Poli Ind Chimica Spa Processo per la preparazione dell'acido 3-(l-piroglutamil)-l- tiazolidin-4-carbossilico e suoi derivati.
EP0518295A3 (en) * 1991-06-14 1993-09-01 Millipore Corporation Allyl side chain protection in peptide synthesis
EP0735819B1 (fr) * 1993-12-21 2001-07-11 University Of Hawaii cryptophycines
BR9408458A (pt) * 1993-12-28 1997-08-05 Rhone Poulenc Chimie Catalisador de hidrogenação e processos de preparação do mesmo e de hidrogenação de nitrilas em aminas
GEP20002206B (en) * 1995-03-07 2000-08-25 Wane State Univ Cryptophycins, Method for its Production, Pharmaceutical Composition on Their basis and Use
ATE201018T1 (de) * 1996-02-27 2001-05-15 Lilly Co Eli Cryptophycinderivate und ihre verwendung als antimikrotubuli mittel

Also Published As

Publication number Publication date
WO1998009955A1 (fr) 1998-03-12
JP2001502298A (ja) 2001-02-20
AU4335297A (en) 1998-03-26
EP0929535A4 (fr) 2001-05-23
CA2263764A1 (fr) 1998-03-12

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