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  • 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
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/12—Radicals substituted by oxygen atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • 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
• • 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

• the invention relates to compounds useful in the synthesis of analogs of halichondrin B.
• Eribulin mesylate a nontaxane microtubule dynamics inhibitor
• eribulin and other halichondrin B analogs are described in International Publication No. WO 2005/118565 and U.S. Patent No. 6,214,865. New intermediates for the synthesis of
• halichondrin B analogs in particular eribulin, are desirable.
• the invention features compounds useful for the synthesis of analogs of halichondrin B, such as eribulin, including pharmaceutically acceptable salts thereof, e.g., eribulin mesylate.
• the invention provides a compound having the formula
• Exemplary compounds have the formula (la):
• Q is -(CH 2 ) 3 0Y], for example wherein Yj, together with the oxygen to which it is bound, is an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group.
• Yi is pivaloyl, acetyl, benzoyl, p-bromobenzoyl, p-methoxybenzoyl, 1-naphthoyl, 2-naphthoyl, o-phthaloyl, benzyl, p-methoxybenzyl, triphenylmethyl, tri(C 1 -C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6
• heteroaryl (Cl-C6 alkyl)silyl, or (C6-C10 aryl or C1-C6 heteroaryl)di(Cl-C6 alkyl)silyl.
• X is halogen
• Z is halogen or (Cl- C6)alkylsulfonate (such as triflate, iodide, or bromide).
• the compounds are of the formula (lb):
• Yj is H, pivaloyl, benzoyl, p- bromobenzoyl, 1-naphthoyl, 2-naphthoyl, p-methoxybenzoyl, or o-phthaloyl or a salt thereof.
• X is bromo, chloro, fluoro, or oxo; or
• Z is halogen, Cl- C12 alkoxy, C2-C12 alkylsulfonate, C2-C12 alkenylsulfonate, carbocyclic C6- C20 arylsulfonate, C4-C19 heteroarylsulfonate, monocyclic C1-C6
• heteroarylsulfonate (C6-C15)aryl(Cl-C6)alkylsulfonate, (C4- C 19)heteroaryl(C 1 -C6)alkylsulfonate, (C 1 -C6)heteroaryl(C 1 -C6)alkylsulfonate, or diazonium; or combinations thereof.
• X is halogen or oxo
• R is H or - OY 2 ;
• n is 1 or 2;
• Y 1; Y 2 , Y 3 , and Y 4 are each independently H or a hydroxyl protecting group;
• T is oxo or -OY 5 ; and
• Y 5 is H or a hydroxyl protecting group, or Y 5 , together with the oxygen atom to which it is bound, is a leaving group.
• Q is -(CH 2 ) 3 OYj.
• Y together with the oxygen atom to which it is bound can be an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group;
• Y 3 and Y 4 can each, independently and together with the oxygen atom to which it is bound, be an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group, or
• Y 3 and Y 4 together with the oxygen atoms to which they are bound can be a cyclic carbonate, cyclic boronate, acetal, ketal, or cyclic silylene hydroxyl protecting group or 1, 1,3,3-tetraisopropylsiloxanediyl;
• T can be -OY 5 ; and/or Y 5 , together with the oxygen atom to which it is bound, can be an ester, carbonate, carbamate, sulfonate, or ether
• Yj is, for example, pivaloyl, acetyl, benzoyl, p-bromobenzoyl, p- methoxybenzoyl, 1-naphthoyl, 2-naphthoyl, o-phthaloyl, benzyl, p- methoxybenzyl, triphenylmethyl, tri(C 1 -C6 alkyl)silyl, tri(C6-C 10 aryl or C 1 - C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6 heteroaryl)(Cl-C6 alkyl)silyl, or (C6-C10 aryl or C1-C6 heteroaryl)di(Cl -C6 alkyl)silyl; Y 3 and Y 4 are, for example, each independently tri(Cl-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 al
• X is halogen.
• the invention features a compound having the formula (III):
• R is H or -OY 2 ;
• n is 1 or 2;
• Y,, Y 2 , Y 3 , and Y 4 are each independently H or a hydroxyl protecting group;
• U is halogen or -OY 6 ;
• Y 5 is H or a hydroxyl protecting group or Y 5 , together with the oxygen atom to which it is bound, is a leaving group; and
• Y 6 is H or a hydroxyl protecting group or Y , together with the oxygen atom to which it is bound, is a leaving group, provided that when Q is -(CH 2 ) 3 OY ! , U is -OY 6 , wherein -OY 6 is a leaving group, and Yj
• Q is -(CH 2 ) 3 OY 1 .
• Y together with the oxygen atom to which it is bound is, for example, an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group; each of Y 3 and Y 4 is, for example, independently and together with the oxygen atom to which it is bound, an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group, or Y 3 and Y 4 together with the oxygen atoms to which they are bound are, for example, a cyclic carbonate, cyclic boronate, acetal, ketal, or cyclic silylene hydroxyl protecting group or 1,1,3,3-tetraisopropylsiloxanediyl; and/or Y 5 , together with the oxygen atom to which it is bound, is, for example, an ester, carbonate, carbamate, sulfonate, or
• Yj is pivaloyl, acetyl, benzoyl, p-bromobenzoyl, p- methoxybenzoyl, 1-naphthoyl, 2-naphthoyl, o-phthaloyl, benzyl, p- methoxybenzyl, triphenylmethyl, tri(Cl-C6 alkyl)silyl, tri(C6-C10 aryl or Cl- C6 heteroaryl)silyl, di(C6-C10 aryl or C1 -C6 heteroaryl)(C 1 -C6 alkyl)silyl, or (C6-C10 aryl or C1-C6 heteroaryl)di(Cl-C6 alkyl)silyl; Y 3 and Y 4 are each independently tri(Cl-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl,
• Y 5 is H or a hydroxyl protecting group
• Y 6 is H
• -OY 6 is a leaving group, such as (Cl-C6)alkylsulfonate, (C6-C10 aryl or Cl- C6 heteroaryl)sulfonate, (C6-C15)aryl(Cl-C6)alkylsulfonate, or (Cl- C6)heteroaryl(Cl-C6)alkylsulfonate.
• Specific leaving groups include mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, or benzylsulfonate.
• the invention further features use of the compounds of the invention, e.g., Compounds E-AM, in the manufacture of ER-804028 and analogs of halichondrin B, such as eribulin, or a pharmaceutically acceptable salt thereof, e.g., eribulin mesylate.
• the invention features a method of synthesizing ER- 804028 by
• step (ii) reacting the product of step (i) under Vasella fragmentation conditions to produce a compound of formula (III):
• step (iii) reacting the product of step (ii) under conditions for intramolecular Williamson etherification to produce ER-804028:
• the invention features a method of synthesized
• step (ii) reacting the product of step (i) under Vasella fragmentation conditions to produce a compound of formula (III):
• step (iii) reacting the product of step (ii) under conditions for intramolecular Williamson etherification to produce ER-804028:
• the method may include salifying eribulin to produce the pharmaceutically acceptable salt thereof, e.g., eribulin mesylate. Additional intermediates and reaction conditions are described herein.
• the present invention includes the various stereoisomers of the compounds and mixtures thereof, unless otherwise specified. Individual stereoisomers of the compounds of the present invention are prepared synthetically from
• a diastereomer of a compound of the invention is present in a mixture at a ratio of 10:1, 20:1, 30:1, 50:1, or greater as compared to other diastereomers.
• Compounds useful in the invention may be isotopically labeled compounds.
• Useful isotopes include hydrogen, carbon, nitrogen, and oxygen (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, and 17 0).
• Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically- labeled reagent in place of a non-isotopically-labeled reagent.
• a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety.
• other atoms such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms.
• an unsubstituted C2 alkyl group has the formula -CH 2 CH 3 .
• a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups.
• a reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.
• acetal is meant >CHR (or -CHR-), wherein R is H, alkyl, alkenyl, aryl, or arylalkyl.
• acyl is meant -C(O)R, wherein R is H, alkyl, alkenyl, aryl, or arylalkyl.
• R is H, C1-C12 alkyl (e.g., C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl), C2-C12 alkenyl (e.g., C2-C8, C2- C6, C2-C4, C3-C12, and C3-C6 alkenyl), C6-C20 aryl (e.g., C6-C15, C6-C10, C8-C20, and C8-C15 aryl), monocyclic C1-C6 heteroaryl (e.g., monocyclic C1-C4 and C2-C6 heteroaryl), C4-C19 heteroaryl (e.g., C4-C10 heteroaryl), (C6-C15)aryl
• alkyl is meant a straight or branched chain saturated cyclic (i.e., cycloalkyl) or acyclic hydrocarbon group of from 1 to 12 carbons, unless otherwise specified.
• exemplary alkyl groups include C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl. Specific examples include methyl, ethyl, 1- propyl, 2-propyl, 2-methyl-l -propyl, 1 -butyl, 2-butyl, and the like.
• alkyl groups used in any context herein, are optionally substituted with halogen, alkoxy, aryloxy, arylalkyloxy, oxo, alkylthio, alkylenedithio, alkylamino, [alkenyl]alkylamino, [aryl]alkylamino,
• alkylamino is meant -NHR, wherein R is alkyl.
• [alkenyljalkylamino” is meant -NRR', wherein R is alkyl, and R' is alkenyl.
• [aryl]alkylamino is meant -NRR', wherein R is alkyl, and R' is aryl.
• [arylalkyl] alkylamino is meant -NRR', wherein R is alkyl, and R' is arylalkyl.
• dialkylamino is meant -NR 2 , wherein each R is alkyl, selected independently.
• alkylene is meant a divalent alkyl group. Alkylene groups, used in any context herein, are optionally substituted in the same manner as alkyl groups. For example, a CI alkylene group is -CH 2 -. By “alkylenedithio” is meant -S-alkylene-S-.
• alkylthio is meant -SR., wherein R is alkyl.
• alkenyl is meant a straight or branched chain cyclic or acyclic hydrocarbon group of, unless otherwise specified, from 2 to 12 carbons and containing one or more carbon-carbon double bonds.
• alkenyl groups include C2-C8, C2-C7, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl. Specific examples include ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), and the like.
• Alkenyl groups, used in any context herein are optionally substituted in the same manner as alkyl groups. Alkenyl groups, used in any context herein, may also be substituted with an aryl group.
• alkoxy is meant -OR, wherein R is alkyl.
• aryl is meant a monocyclic or multicyclic ring system having one or more aromatic rings, wherein the ring system is carbocyclic or heterocyclic.
• Heterocyclic aryl groups are also referred to as heteroaryl groups.
• a heteroaryl group includes 1 to 4 atoms selected independently from O. N, and S.
• Exemplary carbocyclic aryl groups include C6-C20, C6-C15, C6-C10, C8-C20, and C8-C15 aryl.
• a preferred aryl group is a C6-10 aryl group.
• Specific examples of carbocyclic aryl groups include phenyl, indanyl, indenyl, naphthyl, phenanthryl, anthracyl, and fluorenyl.
• Exemplary heteroaryl groups include monocylic rings having from 1 to 4 heteroatoms selected independently from O, N, and S and from 1 to 6 carbons (e.g., C1-C6, C1-C4, and C2-C6).
• Monocyclic heteroaryl groups preferably include from 5 to 9 ring members.
• Other heteroaryl groups preferably include from 4 to 19 carbon atoms (e.g., C4-C10).
• Specific examples of heteroaryl groups include pyridinyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, quinazolinyl, dihydroquinazolyl, and tetrahydroquinazolyl.
• aryl groups are optionally substituted with alkyl, alkenyl, aryl, arylalkyl, halogen, alkoxy, aryloxy, arylalkyloxy, oxo, alkylthio, alkylenedithio, alkylamino, [alkenyljalkylamino, [aryljalkylamino, [arylalkyl]alkylamino, dialkylamino, silyl, sulfonyl, cyano, nitro, carboxyl, or azido.
• arylalkyl is meant -R'R", wherein R' is alkylene, and R" is aryl.
• arylalkyloxy is meant -OR, wherein R is arylalkyl.
• aryloxy is meant -OR, wherein R is aryl.
• carbamate is meant -OC(O)NR 2 , wherein each R is independently H, alkyl, alkenyl, aryl, or arylalkyl.
• carbonate is meant -OC(O)OR, wherein R is alkyl, alkenyl, aryl, or arylalkyl.
• carboxyl is meant -C(O)OH, in free acid, ionized, or salt form.
• cyclic boronate is meant -OBRO-, wherein R is alkyl, alkenyl, aryl, arylalkyl, alkoxy, or 2,6-diacetamidophenyl.
• cyclic carbonate is meant -OC(O)O-.
• cyclic silylene is meant -OSiR 2 O-, wherein each R is
• dialkylsilylene is meant a cyclic silylene, wherein each R is alkyl.
• esters is meant -OC(O)R, where -C(O)R is an acyl group, as defined herein, that is bound to the oxygen atom of a protected hydroxyl, as defined below.
• ether is meant -OR, wherein R is alkyl, alkenyl, arylalkyl, silyl, or 2-tetrahydropyrany 1.
• halogen is meant fluoro, chloro, bromo, or iodo.
• ketal is meant >CR 2 (or - CR 2 -), wherein each R is independently alkyl, alkenyl, aryl, or arylalkyl, or both R groups are together alkylene.
• silyl is meant -S1R 3 , wherein each R is independently alkyl, alkenyl, aryl, or arylalkyl.
• silyl groups include tri(Cl-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6 heteroaryl)(Cl-C6 alkyl)silyl, and (C6-C10 aryl or C1-C6 heteroaryl)di(Cl-C6 alkyl)silyl.
• silyl group when a silyl group includes two or more alkyl, alkenyl, aryl, heteroaryl, or arylalkyl groups, these groups are independently selected. As defined herein, any heteroaryl group present in a silyl group has from 1 to 4 heteroatoms selected independently from O, N, and S.
• sulfonate is meant -OS(0) 2 R, wherein R is alkyl, alkenyl, aryl, or arylalkyl.
• R is CI -CI 2 alkyl (e.g., C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl), C2-C12 alkenyl (e.g., C2-C8, C2- C6, C2-C4, C3-C12, and C3-C6 alkenyl), carbocyclic C6-C20 aryl (e.g., C6- C15, C6-C10, C8-C20, and C8-C15 aryl), monocyclic C1-C6 heteroaryl (e.g., C1-C4 and C2-C6 heteroaryl), C4-C19 heteroaryl (e.g., C4-C10 heteroaryl), (C6-C15)
• any heteroaryl group present in a sulfonate group has from 1 to 4 heteroatoms selected independently from O, N, and S.
• sulfonyl is meant -S(0) 2 R, wherein R is alkyl, alkenyl, aryl, arylalkyl, or silyl.
• R is alkyl, alkenyl, aryl, arylalkyl, or silyl.
• Preferred R groups for sulfonyl are the same as those described above for sulfonates.
• hydroxyl protecting group is meant any group capable of protecting the oxygen atom to which it is attached from reacting or bonding. Hydroxyl protecting groups are known in the art, e.g., as described in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley- Interscience, 4 th
• Exemplary protecting groups are independently selected from esters, carbonates, carbamates, sulfonates, and ethers.
• R of the acyl group is C1-C12 alkyl (e.g., C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl), C2-C12 alkenyl (e.g., C2-C8, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl), carbocyclic C6-C20 aryl (e.g., C6-C15, C6-C10, C8-C20, and C8-C15 aryl), monocyclic C1-C6 heteroaryl (e.g., C1-C4 and C2-C6 heteroaryl), C4-C19 heteroaryl (e.g., C4-C10 heteroaryl), (C6-C15)aryl(Cl-C6)alkyl, (C4- C19)heteroaryl(Cl-C6)alkyl, or (
• acyl groups for use in esters include formyl, benzoylformyl, acetyl (e.g., unsubstituted or chloroacetyl, trifluoroacetyl, methoxyacetyl,
• any heteroaryl group present in an ester group has from 1 to 4 heteroatoms selected independently from O, N, and S.
• R is CI -C 12 alkyl
• C1-C8 C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl C2-C12 alkenyl (e.g., C2-C8, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl), carbocyclic C6-C20 aryl (e.g., C6-C15, C6-C10, C8-C20, and C8-C15 aryl), monocyclic C1-C6 heteroaryl (e.g., C1-C4 and C2-C6 heteroaryl), C4-C19 heteroaryl (e.g., C4-C10 heteroaryl), (C6-C15)aryl(Cl-C6)alkyl, (C4-C19)heteroaryl(Cl- C6)alkyl, or (Cl-C6)heteroaryl(Cl-C6)alkyl.
• C2-C12 alkenyl e.
• any heteroaryl group present in a carbonate group has from 1 to 4 heteroatoms selected independently from O, N, and S.
• each R is independently H, C1-C12 alkyl (e.g., C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl), C2-C12 alkenyl (e.g., C2-C8, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl), carbocyclic C6-C20 aryl (e.g., C6-C15, C6-C10, C8-C20, and C8-C15 aryl), monocyclic C1-C6 heteroaryl (e.g., C1-C4 and C2-C6
• heteroaryl C4-C19 heteroaryl (e.g., C4-C10 heteroaryl), (C6-C15)aryl(Cl- C6)alkyl, (C4-C19)heteroaryl(Cl-C6)alkyl, or (Cl-C6)heteroaryl(C l-C6)alkyl.
• Specific examples include N-phenyl and N-methyl-N-(o-nitrophenyl) carbamates.
• any heteroaryl group present in a carbamate group has from 1 to 4 heteroatoms selected independently from O, N, and S.
• Exemplary ether hydroxy 1 protecting groups include CI -CI 2 alkylethers (e.g., C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkyl), C2-C12 alkenylethers (e.g., C2-C8, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl), (C6- C 15)aryl(C 1 -C6)alkylethers, (C4-C 19)heteroaryl(C 1 -C6)alkylethers, (C 1 - C6)heteroaryl(Cl-C6)alkylethers, (Cl-C6)alkoxy(Cl-C6)alkylethers, (Cl- C6)alkylthio(C 1 -C6)alky lethers, (C6-C 10)ary 1(C 1 -C6)alkoxy (C 1 - C6)alkylether
• alkylethers include methyl and t-butyl, and an example of an alkenyl ether is allyl.
• alkoxy alky lethers and alkylthioalkylethers include methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, and ⁇ - (trimethylsilyl)ethoxymethyl.
• arylalkylethers examples include benzyl, p- methoxybenzyl (MPM), 3,4-dimethoxybenzyl, triphenylmethyl (trityl), o- nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, naphthylmethyl, and 2- and 4-picolyl ethers.
• silylethers include trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS), t- butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), and triphenylsilyl (TPS) ethers.
• TMS trimethylsilyl
• TES triethylsilyl
• TBS t-butyldimethylsilyl
• TIPS triisopropylsilyl
• TPS triphenylsilyl
• TPS triphenylsilyl
• An example of an arylalkyloxyalkylether is benzyloxymethyl ether.
• any heteroaryl group present in an ether group has from 1 to 4 heteroatoms selected independently from O, N, and S.
• Adjacent hydroxyl groups may be protected with a diol protecting group, such as acetal (e.g., C1-C6 alkyl), ketal (e.g., C2-C6 alkyl or C3-C6 cycloalkyl), cyclic silylene, cyclic carbonate, and cyclic boronate.
• acetal and ketal groups include methylene, ethylidene, benzylidene, isopropylidene, cyclohexylidene, and cyclopentylidene.
• An example of a cyclic silylene is di-t- butylsilylene.
• Another diol protecting group is 1,1 ,3,3- tetraisopropylsiloxanediyl.
• cyclic boronates include methyl, ethyl, phenyl, and 2,6-diacetamidophenyl boronates.
• Protecting groups may be substituted as is known in the art; for example, aryl and arylalkyl groups, such as phenyl, benzyl, naphthyl, or pyridinyl, can be substituted with C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, carboxyl, or halogen.
• Alkyl groups such as methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, and sec-butyl, and alkenyl groups, such as vinyl and allyl, can also be substituted with oxo, arylsulfonyl, halogen, and trialkylsilyl groups.
• Preferred protecting groups are TBS and Piv. Protecting groups that are orthogonal are removed under different conditions, as in known in the art.
• leaving group is meant a group that is displaced during a chemical reaction.
• Suitable leaving groups are well known in the art, e.g., see, Advanced Organic Chemistry, March, 4th Ed., pp. 351-357, John Wiley and Sons, N.Y. (1992).
• Such leaving groups include halogen, C1-C12 alkoxy (e.g., C1-C8, C1-C6, C1-C4, C2-C7, and C3-C6 alkoxy), C1-C12 alkylsulfonate (e.g., C1-C8, C1-C6, C1-C4, C2-C7, C3-C12, and C3-C6 alkylsulfonate), C2-C12
• alkenylsulfonate e.g., C2-C8, C2-C6, C2-C4, C3-C12, and C3-C6
• alkenylsulfonate carbocyclic C6-C20 arylsulfonatc (e.g., C6-C15, C6-C10, C8-C20, and C8-C15 arylsulfonate), C4-C19 heteroarylsulfonate (e.g., C4-C10 heteroarylsulfonate), monocyclic C1-C6 heteroarylsulfonate (e.g., C1-C4 and C2-C6 heteroarylsulfonate), (C6-C15)aryl(Cl-C6)alkylsulfonate, (C4- C 19)heteroaryl(C 1 -C6)alkylsulfonate, (C 1 -C6)heteroaryl(C 1 -C6)alkylsulfonate, and diazonium.
• heteroarylsulfonates, arylalkylsulfonates, and heteroarylalkylsulfonates can be optionally substituted with halogen (e.g., chloro, iodo, bromo, or fluoro), alkoxy (e.g., C1-C6 alkoxy), aryloxy (e.g., C6-C15 aryloxy, C4-C19
• halogen e.g., chloro, iodo, bromo, or fluoro
• alkoxy e.g., C1-C6 alkoxy
• aryloxy e.g., C6-C15 aryloxy, C4-C19
• heteroaryloxy and C1-C6 heteroaryloxy
• oxo alkylthio
• alkylthio alkylthio
• alkylenedithio e.g., C1-C6 alkylenedithio
• alkylamino e.g., Cl- C6 alkylamino
• [alkenyl] alkylamino e.g., [(C2-C6)alkenyl](Cl- C6)alkylamino
• [aryl] alkylamino e.g., [(C6-C10)aryl](Cl-C6)alkylamino, [(C 1 -C6)heteroaryl](C 1 -C6)alkylamino, and [(C4-C 19)heteroaryl](C 1 - C6)alkylamino
• [arylalkyl]alkylamino e.g., [(C6-C10)aryl(Cl-C6)alkyl](Cl- C6)alkyiamino, [(C 1 -C6)he
• dialkylamino e.g., di(Cl-C6 alkyl)amino
• silyl e.g., tri(Cl-C6 alkyl)silyl, tri(C6-C10 ary
• Alkenylsulfonates can be optionally substituted with carbocyclic aryl (e.g., C6-C15 aryl), monocyclic C1-C6 heteroaryl, or C4-C19 heteroaryl (e.g., C4-C10 heteroaryl).
• Arylsulfonates can be optionally substituted with alkyl (e.g., C1-C6 alkyl) or alkenyl (e.g. C2-C6 alkenyl).
• any heteroaryl group present in a leaving group has from 1 to 4 heteroatoms selected independently from O, N, and S.
• Suitable leaving groups include chloro, iodo, bromo, fluoro, methanesulfonate (mesylate), 4-toluenesulfonate (tosylate), trifluoromethanesulfonate (triflate, OTf), nitro-phenylsulfonate (nosylate), and bromo-phenylsulfonate (brosylate). Leaving groups may also be further substituted as is known in the art.
• pharmaceutically acceptable salt is meant a salt within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and commensurate with a reasonable benefit/risk ratio.
• salts are well known in the art.
• pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley- VCH, 2008.
• Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate,
• the present invention provides compounds and methods of their use in the synthesis of halichondrin B analogs.
• the compounds are useful for the synthesis of the C14-C35 portion of halichondrin B analogs.
• ER- 804028 is a C14-C35 fragment that has been employed in the synthesis of eribulin:
• Halichondrin B analogs e.g., eribulin or pharmaceutically acceptable salts thereof, can be synthesized from the C14-C35 fragment as described in U.S. Patent No. 6,214,865 and International Publication No. WO 2005/118565.
• the C14-C35 portion, e.g., ER- 804028, of the molecule is coupled to the C1-C13 portion, e.g., ER-803896, to produce ER-804029, and additional reactions are carried out to produce eribulin (Scheme 1):
• CI -CI 3 aldehyde fragment furnishes a mixture of diastereomeric alcohols (ER- 804029). Additional protecting group manipulation and oxidation followed by removal of the sulfonyl group and an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction affords an intermediate, which, when oxidized and treated with tetrabutylammonium fluoride, undergoes intramolecular oxy-Michael ring closure. Pyridinium -toluenesulfonate mediated ketal formation and conversion of the terminal alcohol to an amine furnishes eribulin.
• NHK Nozaki-Hiyama-Kishi
• ER- 804029 As described in WO 2005/118565 (Example 6), ER- 804029:
• ER 804029 is reacted, e.g., oxidized, to produce ER-804030:
• mixture ER- 118047/118048 the mixture ER- 118047/118048 is reacted, e.g., oxidized, to produce ER- 118046:
• eribulin e.g., eribulin mesylate
• eribulin mesylate can be formed by methods known in the art, e.g., in situ during the final isolation and purification of the compound or separately by reacting the free base group with a suitable organic acid.
• eribulin is treated with a solution of MsOH and NH 4 OH in water and acetonitrile. The mixture is concentrated. The residue is dissolved in DCM-pentane, and the solution is added to anhydrous pentane. The resulting precipitate is filtered and dried under high vacuum to provide eribulin mesylate, as shown in Scheme 2.
• (-)-quinic acid is converted to Compound A through stages 1-13 as described in International Publication Nos. WO 2009/046308 and WO
• the scheme is also advantageous as the C14-C26 starting material and CI 4- C35 product of the NHK coupling of this scheme exhibit greater stability than the starting material and product of previous methods.
• the C14-C26 starting material and C14-C35 product of the NHK coupling are stable indefinitely at room temperature, allowing for a flexible manufacturing schedule.
• hydroxyl protecting groups employed in particular reactions may be varied.
• the leaving groups employed may be altered; for example, triflate groups can be replaced with halogens such as iodine or bromine.
• the invention provides compounds having the formula: (I), e.g., Compound O, Compound AI, and
• Yj and Y 2 are present, they may be the same or different.
• Compounds of this formula include those having the formula: wherein is H, pivaloyl, benzoyl, p- bromobenzoyl, 1 -naphthoyl, 2-naphthoyl, p-methoxybenzoyl, or o-phthaloyl (including salts such as triethylamine and potassium).
• Compound AF Compound AK, Compound AL, and Compound AM, wherein X is halogen or oxo;
• R is H or - OY 2 ;
• n is 1 or 2;
• Y 1; Y 2 , Y 3 , and Y 4 are each independently H or a hydroxyl protecting group;
• T is oxo or -OY 5 ;
• Y 5 is H or a hydroxyl protecting group, or Y 5 , together with the oxygen atom to which it is bound, is a leaving group.
• Y 3 and Y 4 are together a divalent hydroxyl protecting group.
• Yj, Y 3 , and Y 4 are protecting groups, and Yj is orthogonal to Y 3 and Y 4 .
• Y 1? Y 3 , Y 4 , and Y 5 are protecting groups; Y 3 and Y 4 are orthogonal to Yi and Y 5 ; and Y 1 is orthogonal g the formula:
• the invention also features compounds having the formula:
• R is H or -OY 2 ;
• n is 1 or 2;
• Y,, Y 2 , Y 3 , and Y 4 are each independently H or a hydroxyl protecting group;
• U is halogen or -OY 6 ;
• Y 5 is H or a hydroxyl protecting group or Y 5 , together with the oxygen atom to which it is bound, is a leaving group; and
• Y 6 is H or a hydroxyl protecting group or Y 6 , together with the oxygen atom to which it is bound, is a leaving group, provided that when Q is -C(R)H(CH 2 ) n OY !
• Y 3 and Y 4 are together a divalent hydroxyl protecting group.
• Y l5 Y 3 , and Y 4 are protecting groups, and Yj is orthogonal to Y 3 and Y 4 .
• Y l5 Y 3 , Y 4 , and Y 5 are protecting groups; Y 3 and Y 4 are orthogonal to Yi and Y 5 ; and Y ⁇ is orthogonal to Y 5 .
• the compounds of the invention can be used in the synthesis of ER-804028 and in turn eribulin, or a pharmaceutically acceptable salt thereof, e.g., eribulin mesylate.
• the reaction mixture was diluted with MTBE (23 ml), sequentially washed with: 1) 20 wt% citric acid (aqueous solution, 12 g, 12 mmol, 2.1 eq) and 2) saturated NaHC0 3 (aqueous solution, 4.6 g, 5.5 mmol, 0.95 eq), and concentrated to give crude product as pale yellow oil.
• the crude was purified by Biotage (Uppsala, Sweden) 40M (heptane-MTBE 7:3 v/v) to give Compound E as pale yellow oil (2.79 g, 5.04 mmol, 87% yield).
• Zinc powder (1.54 g, 23.6 mmol, 50 eq) was suspended in water (1.1 ml) and cooled to 0 °C.
• AcOH (0.40 ml, 7.1 mmol, 15 eq) was added at 0 °C.
• a solution of Compound AF (530 mg, 0.473 mmol, 1 eq) in THF (2.7 ml) was added at 0 °C, and the mixture was allowed to warm to 20 °C. After 3 h, the reaction mixture was filtered for removal of zinc powder. The reactor was rinsed with a mixture of THF (1.1 ml) and water (1.1 ml).
• the filtrate was diluted with MTBE (10.6 ml), sequentially washed with: 1) 20 wt% Rochelle salt (aqueous solution, 2.7 g, 4.0 eq), 2) saturated NaHC0 3 (6.0 g), and 3) 20 wt% NaCl (aqueous solution, 2.6 g), and concentrated to give crude product as colorless oil.
• the crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 1 : 1 v/v) to give Compound AE (393 mg, 0.394 mmol, 83% yield) as colorless oil.
• the crude was azeotropically dried with heptane (3 ml ⁇ 2) and re-dissolved in THF (7.0 ml).
• the mixture was cooled to 0 °C and treated with 25 wt% NaOMe (0.13 ml). After 10 min, the reaction was allowed to warm to room temperature, and stirring was continued for an additional 30 min. The mixture was treated with additional 25 wt% NaOMe (0.045 ml), and stirring was continued for an additional 20 min.
• the reaction mixture was diluted with heptane (7.0 ml) and washed with water (1.4 ml).
• the organic layer was separated, sequentially washed with: 1) 20 wt% NH 4 C1 (0.84 g) and 2) 20 wt% NaCl (3 g), and concentrated to give crude product as brownish oil.
• the crude was purified by Biotage (Uppsala, Sweden) 12M (heptane-MTBE 2:3 v/v) to give ER-804028 (209 mg, 0.245 mmol, 87%) as pale yellow oil.
• the reaction mixture was diluted with MTBE (10 ml), sequentially washed with: 1) 20 wt% citric acid (aqueous solution, 3.0 g, 1.5 eq) and 2) saturated NaHC0 3 (aqueous solution, 3.0 g), and concentrated to give crude product as orange- colored oil.
• the crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 7:3 v/v) to give Compound F (0.920 g, 1.52 mmol, 72% overall yield) as colorless oil.
• Zinc dust (982 mg, 15.0 mmol, 10.0 eq) was suspended in THF (1.8 ml), and MsOH (0.0097 ml, 0.15 mmol, 0.10 eq) was added. The resultant mixture was heated at reflux for 30 min and then cooled to 20 °C. A solution of
• Zinc (1.06 g, 16.2 mmol, 10 eq) was suspended in THF (2.3 ml). MsOH (0.010ml, 0.02 mmol, 0.1 eq) was added at room temperature, and the resultant slurry was heated at reflux for 30 min. After cooling down, a mixture of Compound X (780 mg, 1.62 mmol, 1 eq) and benzhydryl bromoacetatc (0.74 g, 2.4 mmol, 1.5 eq; Kume et al., Tetrahedron, 1997, 53, 1635) in THF (3.9 ml) was added, and the reaction was heated to reflux.
• Example 2 by iodo-etherification with N-iodosuccinimide in acetonitrile.
• Compound AD was prepared in the process of producing a mixture of Compound P with its C27 diastereomcr.
• Compound P (50.2 mg, 0.0465 mmol, 1 eq) was dissolved in CH 2 C1 2 (0.50 ml).
• Dess-Martin periodinane (23.6 mg,
• Compound P can also be obtained from reduction of Compound AD, made by any means.
• Compound AD (33 mg, 0.031 mmol) was dissolved in toluene (0.50 ml) and cooled to 0 °C.
• 2.0 M LiBH 4 (solution in THF, 8 ⁇ ) was added at 0 °C, and stirring was continued at 0 °C for 10 min.
• 2.0 M LiBH 4 (solution in THF, 8 ⁇ ) was added, and stirring was continued for an additional 10 min.
• the reaction mixture was diluted with MTBE (1.0 ml), sequentially washed with 20 wt% citric acid (aqueous solution, 0.20 g) and saturated NaHC0 3 (aqueous solution, 0.20 g), and concentrated to give crude product.
• the crude was purified by preparative TLC (heptane-MTBE 2:3) to give Compound P (24mg, 72% yield, C27 -dr 5:1).

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