# US 6,723,854 B2 · Synthesis of epothilones, intermediates thereto, analogues and uses thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 6,723,854 B2 - Document ID: US6723854B2 - Status: Granted - Kind: B2 - Application number: 10/374,805 - Filed: 2003-02-25 - Published: 2004-03-04 - Granted: 2004-04-20 - Earliest claimed: 1996-12-03 - Assignees: Sloan-Kettering Institute for Cancer Research - Inventors: Samuel J. Danishefsky; Peter Bertinato; Dai-Shi Su; Dang Fang Meng; Ting-Chao Chou; Ted Kamenecka; Erik J Sorensen; Aaron Balog; Kenneth A. Savin - Web page: https://patentgrep.com/patent/US6723854B2 ## CPC - A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} - A61K 31/335: having oxygen as the only ring hetero atom, e.g. fungichromin - A61K 31/337: having four-membered rings, e.g. taxol - A61K 31/425: Thiazoles - A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375) - A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047) - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 35/00: Antineoplastic agents - A61P 35/02: specific for leukemia - C07C 69/007: Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom - C07D 277/24: Radicals substituted by oxygen atoms - C07D 313/00: Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom - C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 417/14: containing three or more hetero rings - C07D 493/04: Ortho-condensed systems - C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)} - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22) ## Abstract The present invention provides convergent processes for preparing epothilone A and B, desoxyepothilones A and B, and analogues thereof. Also provided are analogues related to epothilone A and B and intermediates useful for preparing same. The present invention further provides novel compositions based on analogues of the epothilones and methods for the treatment of cancer and cancer which has developed a multidrug-resistant phenotype. ## Claims ### Claim 1 A compound of formula wherein X is a halogen; Y is S or O; R1 is hydrogen, methyl, ethyl, n-propyl, n-hexyl, —CH2OTBS, or —(CH2)3-OTBDPS; and R2 is hydrogen, linear or branched alkyl, alkyoxyalkyl, substituted or unsubstituted aryloxylalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, or protecting group. ### Claim 2 (depends on 1) The compound of claim 1, wherein X is I. ### Claim 3 (depends on 1) The compound of claim 1, wherein X is Br. ### Claim 4 (depends on 1) The compound of claim 1, wherein R1 is hydrogen. ### Claim 5 (depends on 1) The compound of claim 1, wherein R1 is methyl. ### Claim 6 (depends on 1) The compound of claim 1, wherein R2 is hydrogen. ### Claim 7 (depends on 1) The compound of claim 1, wherein R2 is acetyl. ### Claim 8 (depends on 1) The compound of claim 1, wherein R2 is trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl. ### Claim 9 (depends on 1) The compound of claim 1, wherein R2 is TMS. ### Claim 10 (depends on 1) The compound of claim 1, wherein R2 is TBDMS. ### Claim 11 (depends on 1) The compound of claim 1, wherein R2 is Troc. ### Claim 12 (depends on 1) The compound of claim 1, wherein R2 is TES. ### Claim 13 (depends on 1) The compound of claim 1, wherein X is I, Y is S, R1 is methyl, and R2 is TBDMS. ### Claim 14 (depends on 1) The compound of claim 1, wherein X is I, Y is S, R1 is methyl, and R2 is acetyl. ### Claim 15 (depends on 1) The compound of claim 1, wherein X is I, Y is S, R1 is hydrogen, and R2 is TBDMS. ### Claim 16 (depends on 1) The compound of claim 1, wherein X is I, Y is S, R1 is hydrogen, and R2 is aetyl. ### Claim 17 (depends on 1) The compound of claim 1, wherein Y is S. ### Claim 18 (depends on 1) The compound of claim 1, wherein Y is O. ### Claim 19 (depends on 1) The compound of claim 1, wherein X is I, Y is O, R1 is methyl, and R2 is TBDMS. ### Claim 20 (depends on 1) The compound of claim 1, wherein X is I, Y is O, R1 is methyl, and R2 is acetyl. ### Claim 21 (depends on 1) The compound of claim 1, wherein X is I, Y is O, R1 is methyl, and R2 is TES. ### Claim 22 (depends on 1) The compound of claim 1, wherein X is I, Y is O, R1 is hydrogen, and R2 is TBDMS. ### Claim 23 (depends on 1) The compound of claim 1, wherein X is I, Y is O, R1 is hydrogen, and R2 is acetyl. ### Claim 24 (depends on 1) The compound of claim 1, wherein X is I, Y is O, R1 is hydrogen, and R2 is TES. ### Claim 25 A method of preparing a compound having the structure: wherein X is a halogen; Y is S or O; R1 is hydrogen, methyl, ethyl, n-propyl, n-hexyl, —CH2OTBS, or —(CH2)3-OTBDPS; and R2 is hydrogen, linear or branched alkyl, alkyoxyalkyl, substituted or unsubstituted aryloxylalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, or protecting group, which comprises (a) oxidatively cleaving a compound having the structure: using periodate to form an aldehyde intermediate; and (b) condensing the aldehyde intermediate with a halomethylene transfer agent under basic conditions to form the desired compound. ### Claim 26 (depends on 25) The method of claim 25, wherein X is iodine. ### Claim 27 (depends on 25) The method of claim 25, wherein Y is S. ### Claim 28 (depends on 25) The method of claim 25, wherein Y is O. ### Claim 29 (depends on 25) The method of claim 25, wherein the halomethylene transfer agent is Ph3P═CR1I or (Ph3P+CHR1I)I−. ### Claim 30 A method of preparing a haloalkene having the structure: wherein X is a halogen; Y is S or O; and R2 is hydrogen, linear or branched alkyl, alkyoxyalkyl, substituted or unsubstituted aryloxylalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, or protecting group, which comprises (a) coupling a compound having the structure: with a methyl ketone having the structure: wherein R′ is independently a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryl or benzyl, under suitable conditions to form a compound having the structure: (b) treating the compound formed in step (a) under basic conditions to form a Z-iodoalkene having the structure: and (c) optionally, deprotecting and acylating the Z-iodoalkene formed in step (b) with N-iodosuccinimide in the presence of a reducing agent to form the desired compound. ### Claim 31 (depends on 30) The method of claim 30, wherein X is iodine. ### Claim 32 (depends on 30) The method of claim 30, wherein Y is S. ### Claim 33 (depends on 30) The method of claim 30, wherein Y is O.