WO2007066181A2 - Methods of preparing a vegf-r inhibitor - Google Patents

Methods of preparing a vegf-r inhibitor Download PDF

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Publication number
WO2007066181A2
WO2007066181A2 PCT/IB2006/003331 IB2006003331W WO2007066181A2 WO 2007066181 A2 WO2007066181 A2 WO 2007066181A2 IB 2006003331 W IB2006003331 W IB 2006003331W WO 2007066181 A2 WO2007066181 A2 WO 2007066181A2
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WO
WIPO (PCT)
Prior art keywords
compound
formula
alkenyl
alkynyl
alkyl
Prior art date
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PCT/IB2006/003331
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French (fr)
Other versions
WO2007066181A3 (en
Inventor
Narubumi Fred Makino
Wolfgang Reinhard Ludwig Notz
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Pfizer Products Inc.
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.)
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Publication date
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Priority to CA002632384A priority Critical patent/CA2632384A1/en
Priority to JP2008543930A priority patent/JP2009518382A/en
Priority to EP06820962A priority patent/EP1963310A2/en
Publication of WO2007066181A2 publication Critical patent/WO2007066181A2/en
Publication of WO2007066181A3 publication Critical patent/WO2007066181A3/en

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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D405/12—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to methods for preparing a VEGF-R inhibitor, and to intermediates thereof.
  • This compound is a receptor protein kinase inhibitor and represents a synthetic, small molecule inhibitor of angiogenic receptor signaling.
  • the present invention relates to methods of preparing Compound 7, as well as pharmaceutically acceptable salts and intermediate compounds thereof. Such compounds are useful for the treatment of cancer and other diseases associated with angiogenesis or cellular proliferation mediated by protein kinases.
  • the present invention relates to methods of preparing a compound of formula 7, and intermediates thereof.
  • the present invention relates to a method of preparing a compound of formula 7,
  • X is any suitable leaving group, to form the compound of formula 7.
  • X is halogen, NO 2 or -OSO 2 R 1 wherein R 1 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 6 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 6 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • the reaction is carried out under conditions comprising a base.
  • the base is selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , KHCO 3 , NaH, an amine base, an alkoxide base, a hydroxide base, and an organometallic reagent.
  • X is Cl and the reaction is carried out at a temperature of 90 to 11O 0 C.
  • Another aspect of the present invention is a method of preparing a compound of formula 4,
  • X and Y are each any suitable leaving group, to form a compound of formula 4.
  • the compound of formula 30 is 2-(4-Morpholinyl)-ethyl chloride hydrochloride.
  • X and Y are each independently halogen, NO 2 , or -OSO 2 R 1 , wherein R 1 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • X is Cl and Y is Cl.
  • the reaction is carried out in the presence of a first base at a temperature of 70 to 9O 0 C, followed by the addition of an acid at a temperature of 20 to 3O 0 C, followed by the addition of a second base at a temperature of 20 to 3O 0 C.
  • the first base can be selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , KHCO 3 , NaH, an amine base, an alkoxide base, and a hydroxide base.
  • the base can be NaOtBu or KOtBu.
  • the acid is any acid that allows for pH adjustment to a pH of 3 or less.
  • the acid can be selected from the group consisting of HCI, HBr, H 2 SO 4 , and H 3 PO 4 .
  • the second base is any base that allows for pH adjustment to a pH of 12 or greater.
  • the second base can be NaOH or KOH.
  • the present invention also relates to a method of preparing a compound of formula 3
  • the method comprising the steps of; a) treating a compound of formula 2 with a suitable deprotecting agent; followed by
  • X is any suitable leaving group
  • R is (Ci to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to Ci 4 ) aryl group.
  • X is halogen, NO 2 or -OSO 2 R 1 , wherein R 1 is (C 1 to C 6 ) alkyl,
  • the deprotecting agent can be BBr 3 , BCI 3 , TMSCI, TMSBr, TMSI, HBr, HI, thioacetic acid, thioglycolic acid, or methanesulfonic acid.
  • the base can be any base that allows for pH adjustment to a pH of 11 or greater.
  • the base can be NaOH or KOH.
  • the acid is any acid that allows for pH adjustment to a pH of 7.
  • the acid is HCI, HBr, H 2 SO 4 , or H 3 PO 4 .
  • the present invention further relates to a method of preparing a compound of formula 6
  • the carboxylic acid activating agent is CDI, HATU, SOCI 2 , (COCI) 2 , DCC, EDC, HOBt, CDMT, BOP-CI, or PyBOP.
  • the method further comprises the addition of a catalyst, for example pyridine or DMAP.
  • the invention further relates to a method of preparing a compound of formula 6
  • R 1 is acyl, -SO 2 R 2 , (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl, wherein R 2 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C-
  • R 1 is -CH 3
  • the reaction is carried out at a temperature of 55 to 75 0 C
  • the deprotection agent is MSA
  • the scavenger is me
  • the invention further relates to a method of preparing a compound of formula 6
  • R 1 is acyl, -SO 2 R 3 , (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl
  • R 2 is H, (C 1 to C 6 ) alkyl, (Q 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl
  • R 3 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • R 1 is -CH 3 , or -CH 2 -phenyl
  • the reaction is carried out at a temperature of 55 to 75 0 C
  • the deprotection agent is an acid such as MSA and the scavenger is methionine.
  • the present invention further relates to a method of preparing a compound of formula 18
  • R 1 is acyl, -SO 2 R 3 , (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl
  • R 2 is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl
  • R 3 is (Ci to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to Ci 4 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • R 1 is -CH 3
  • R 2 is H
  • the reaction further comprises the addition of a suitable carboxylic acid activating agent.
  • the carboxylic activating agent is selected from the group consisting of CDI, HATU, SOCI 2 , (COCI) 2 , DCC, EDC, HOBt, CDMT, BOP-CI, and PyBOP.
  • R 1 is -CH 3
  • R 2 is -CH 3
  • the catalyst is NaCN.
  • the reaction is carried out at a temperature of 55 to 75 0 C.
  • R 1 is - CH 3
  • R 2 is -CH 2 CH 3
  • the catalyst is NaCN.
  • the present invention further relates to a method of preparing a compound of formula 24
  • R 1 is acyl, -SO 2 R 3 , (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl;
  • R 2 is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl;
  • R 3 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to , C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • the agent that enables rearrangement dehydration is an acid.
  • the acid is HCI, R 1 is -CH 3 , and R 2 is H.
  • the acid is MSA, the solvent is MeOH, R 1 is -CH 3 , and R 2 is -CH 3 .
  • the acid is MSA, the solvent is EtOH, R 1 is -CH 3 , and R 2 is -CH 2 CH 3 .
  • the present invention further relates to a method of preparing a compound of formula 14
  • R 1 is acyl, -SO 2 R 2 , (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl; and R 2 is (Ci to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • the base is selected from the group consisting of alkoxides, amides, NaH, and organometallic reagents.
  • R 1 is -CH 3 and the base is BuLi, LDA, LHMDS, NaHMDS, or KHMDS.
  • the acylating agent is an anhydride, an acid halide, or an ester of acetic acid.
  • the acylating agent is ethyl acetate, acetyl chloride, or acetic anhydride.
  • the present invention also relates to a method of preparing a compound of formula 13
  • R 1 is acyl, -SO 2 R 3 , (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl;
  • R 2 is H or a cationic counterion;
  • R 3 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • R 1 is -CH 3
  • R 2 is H 2 NCy 2
  • the activation agent is selected from the group consisting of CDI, HATU, SOCI 2 , (COCI) 2 , DCC, EDC, HOBt, CDMT, BOP-CI, and PyBOP
  • the base is selected from the group consisting of an amine, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , and KHCO 3
  • R 2 is H
  • the method further comprises the addition of a suitable nucleophile.
  • the step of treating a compound of formula 20 with the carboxylic acid activation agent, the base, and the nucleophile is carried out by (i) treating the compound of formula 20 with the carboxylic acid activation agent, the base, and the nucleophile to form an intermediate compound of formula 19;
  • R 1 is acyl, -SO 2 R 3 , (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl;
  • R 4 is (C-i to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group, and (ii) treating the intermediate compound of formula 19 with a base to form the compound of formula ⁇ 3.
  • R 1 is -CH 3
  • the carboxylic acid activation agent is selected from the group consisting of CDI, HATU, SOCI 2 , (COCI) 2 , DCC, EDC, HOBt, CDMT, BOP-CI 1 and PyBOP
  • the base in steps (i) and (ii) is independently selected from the group consisting of an amine, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , and KHCO 3
  • the nucleophile is an alcohol or an amine.
  • the carboxylic acid activation agent is SOCI 2
  • the base is pyridine
  • the nucleophile is MeOH, EtOH, or methylamine.
  • the present invention also relates to a method of preparing a compound of formula 20
  • R 1 is H, acyl, -SO 2 R 3 , (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl;
  • R 2 is H or a cationic counterion;
  • R 3 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • R 1 is -CH 3
  • R 2 is H
  • the sulfur source is S 8
  • the amine is NH 3 , piperidine, or morpholine.
  • step a) is carried out at a temperature of 120 to 14O 0 C.
  • the base is any base that allows for pH adjustment to a pH of 12 or greater.
  • the base can be NaOH or KOH.
  • the acid is any acid that allows for pH adjustment to a pH of 2 or less.
  • the acid can be HCI, HBr, H 2 SO 4 , or H 3 PO 4 .
  • the present invention also relates to a compound of formula 20
  • R 1 is acyl, -SO 2 R 3 , (C-i to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl;
  • R 2 is H or a cationic counterion;
  • R 3 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group; or a salt or solvate thereof.
  • R 1 is -CH 3 and R 2 is H or NH 2 Cy 2 .
  • the present invention also relates to a compound of formula 13
  • R 1 is acyl, -SO 2 R 2 , (C-i to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 8 ) alkynyl; and R 2 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C M ) aryl group; or a salt or solvate thereof.
  • R 1 is -CH 3 .
  • the present invention further relates to a compound of formula 14
  • R 1 is acyl, -SO 2 R 2 , (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 6 ) alkynyl; and R 2 is (C 1 to C 6 ) alkyl, (C2 to C8) alkenyl, (C 2 to C 6 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to Ci 4 ) aryl group " ; or a salt or solvate thereof.
  • R 1 is -CH 3 .
  • the present invention further relates to a compound of formula 24
  • R 1 is H, acyl, -SO 2 R , (C 1 to C 6 ) alkyl, (C2 to C8) alkenyl, or (C 2 to C 6 ) alkynyl
  • R 2 is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 6 ) alkynyl
  • R 3 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl; wherein any of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group; or a salt solvate thereof.
  • R 1 is -CH 3
  • R 2 is H, -CH
  • the present invention also relates to a compound of formula 18
  • R 1 is H, acyl, -SO 2 R 2 , (C 1 to C 6 ) alkyl, (C2 to C8) alkenyl, or (C 2 to C 6 ) alkynyl;
  • R 2 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to Ci 4 ) aryl group; or a salt or solvate thereof.
  • R 1 is -CH 3 .
  • the present invention also relates to a compound of formula 4
  • X is any suitable leaving group; or a salt or solvate thereof.
  • X is halogen, NO 2 , or -OSO 2 R 1 wherein R 1 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • X is Cl.
  • the present invention also relates to a compound of formula 2
  • X is any suitable leaving group; and R is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl,
  • X is halogen, NO 2 , or
  • R 1 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to
  • each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • X is Cl
  • R is -CH 3 or -CH 2 -phenyl.
  • the present invention also relates to a compound of formula 31 wherein: R is H, acyl, -SO 2 R 1 , (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, or (C 2 to C 6 ) alkynyl; and R 1 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 8 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group; or a salt or solvate thereof.
  • treating refers to a chemical process or processes in which two or more reactants or chemical species are allowed to come into contact with each other to effect a chemical change or transformation. For example, when reactant A and reactant B are allowed to come into contact with each other to afford a new chemical compound(s) C, A is said to have been
  • protecting refers to a process in which a functional group in a chemical compound is selectively masked by a non-reactive functional group in order to allow a selective reaction(s) to occur elsewhere on said chemical compound.
  • protecting groups Such non-reactive functional groups are herein termed "protecting groups.”
  • hydroxyl protecting group refers to those groups that are capable of selectively masking the reactivity of a hydroxyl (-OH) group.
  • suitable protecting group refers to those protecting groups that are useful in the preparation of the compounds of the present invention. Such groups are generally able to be selectively introduced and removed using mild reaction conditions that do not interfere with other portions of the subject compounds.
  • Protecting groups that are suitable for use in the processes and methods of the present invention are known to those of ordinary skill in the art. The chemical properties of such protecting groups, methods for their introduction and their removal can be found, for example, in T. Greene and P.
  • deprotecting means to refer to the process of removing a protecting group, or agents that remove a protecting group, from a compound. Methods for deprotecting, including the appropriate conditions and reagents, are known to those of ordinary skill in the art.
  • solvate is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • solvates include, but are not limited to, compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
  • a "carboxylic acid activating agent” is anything suitable to activate a carboxylic acid for amide or ester formation.
  • Such agents are well known to those of skill in the art and include CDI, HATU, SOCI 2 , (COCI) 2 , DCC, EDC, HOBt, CDMT, BOP-CI, and PyBOP.
  • a "scavenger” is a chemical compound or functional group that can accept another group that is being removed from a chemical compound.
  • a "R1 scavenger” is any chemical compound or functional group that forms an interaction with the R1 group that is being removed from a chemical compound. Such scavengers are well known to those of skill in the art.
  • an "agent that enables rearrangement dehydration” is any agent that facilitates rearrangement dehydration as part of a chemical reaction.
  • agents are well known to those of skill in the art and include acids such as HCI, H 2 SO 4 , and MSA.
  • a "leaving group” refers to a chemical functional group that generally allows a nucleophilic substitution reaction to take place at the atom to which it is attached.
  • the -Cl group is generally referred to as a leaving group because it allows nucleophilic substitution reactions to take place at the carbonyl carbon to which it is attached.
  • Suitable leaving groups are known to those of ordinary skill in the art and can include halides, aromatic heterocycles, cyano, amino groups (generally under acidic conditions), ammonium groups, alkoxide groups, carbonate groups, formates, and hydroxy groups that have been activated by reaction with compounds such as carbodiimides.
  • suitable leaving groups can include, but are not limited to halogen, NO 2 , and -OSO 2 R 1 , where R 1 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 6 ) alkynyl, or (C 6 to C 14 ) aryl, and wherein each of said (C-i to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, and (C 2 to C 6 ) alkynyl is optionally substituted with at least one (C 6 to C 14 ) aryl group.
  • an "acylating agent” is any chemical compound capable of delivering an acyl group in an acylation reaction.
  • acylating agents are well known to those of skill in the art and include anhydrides of carboxylic acids, acid halides, and esters.
  • (C 1 to C 6 ) alkyl means a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 6 carbon atoms.
  • Examples of (C 1 to C 6 ) alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, /so-butyl, terf-butyl, pentyl, and the like.
  • (C 2 to C 8 ) alkenyl means an alkyl moiety comprising 2 to 8 carbons having at least one carbon-carbon double bond.
  • the carbon-carbon double bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound.
  • Such groups include both the E and Z isomers of said alkenyl moiety. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, ally!, and pentenyl.
  • (C 2 to C 8 ) alkynyl means an alkyl moiety comprising from 2 to 8 carbon atoms and having at least one carbon- carbon triple bond.
  • the carbon-carbon triple bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, and 3-hexynyl.
  • (C 6 to C 14 ) aryl means a group derived from an aromatic hydrocarbon containing from 6 to 14 carbon atoms.
  • Ph and -"phenyl as used herein, mean a -C 6 H 5 group.
  • benzyl as used herein, means a -CH 2 C 6 H 5 group.
  • halogen and/or “halo” refer to fluorine, chlorine, bromine or iodine.
  • the following processes illustrate the general preparation of Compound 7 according to methods of the present invention.
  • the present invention also encompasses novel intermediates that occur in the processes described herein.
  • the methods of preparing Compound 7, as well as intermediates thereof, are useful for preparing a compound that can be used for the treatment of cancer and other diseases associated with angiogenesis or cellular proliferation mediated by protein kinases.
  • any reference to a particular compound used in the methods described herein also encompass any salts of that particular compound.
  • Salts of the present invention include acid addition and base salts (including disalts). Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • a salt of the compounds described herein can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • Compounds described herein containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound contains an alkenyl or alkenylene group, geometric cis/trans (or ZlE) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. A single compound may exhibit more than one type of isomerism. Included within the scope of the invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds described herein, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • One aspect of the present invention is a process for preparing Compound 7 that is depicted by the following Scheme A:
  • a compound represented by formula 3 can be prepared as shown in steps a) and b) by treating a compound of either formula 1 or formula 2 with a deprotecting agent, a base, and an acid.
  • a deprotecting agent e.g., T.W. Greene, P. G. M. Wuts Protective Groups in Organic Synthesis, 3 rd ed. John-Wiley & Sons, 1999.
  • deprotecting agents suitable for this reaction step include Lewis acids such as BBr 3 , BCI 3 , or TMSX (where X is Cl, Br, or I), mineral acids such as HBr or HI, or other strong acids such as methanesulfonic acid.
  • suitable solvent can optionally be used in this step.
  • Solvents that can be used in this step include CH 2 CI 2 .
  • Suitable bases include NaOH, KOH, or an any base that allows for pH adjustment to a pH of about 11 or greater.
  • Suitable acids include HCI, HBr, H 2 SO 4 , H 3 PO 4 , or any acid that allows for pH adjustment to about 7.
  • this reaction step is carried out at elevated temperatures, for example 50 to 70 0 C.
  • step a) can be carried out in the presence of MSA and methionine at about 60 0 C, followed by aqueous NaOH where the pH is adjusted to greater than about 11 , followed by the addition of HCI to adjust the pH to about 7.
  • step b) can be carried out by first adding BBr 3 /CH 2 CI 2 , followed by reflux, then adding aqueous NaOH to adjust the pH to about 11 or greater, followed by the addition of HCI to adjust the pH to about 7.
  • a compound of formula 4 can be prepared as shown in step c) by treating a compound of formula 3 with 2-(4-morpholinyl)-ethyl chloride hydrochloride.
  • Suitable reaction conditions for this step comprise elevated temperatures (e.g. 70 to 90 0 C), a base in a suitable solvent such as acetonitrile, followed by the addition of an aqueous acid, followed by the addition of a base, and optionally followed by purification by recrystallizatjon from an appropriate solvent such as acetonitrile.
  • Suitable bases include Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , KHCO 3 , amines, alkoxides, and hydroxides.
  • Suitable acids include HCI, HBr, H 2 SO 4 , H 3 PO 4 , or any acid that allows for pH adjustment to an acidic pH, preferably to a pH of less than 3.
  • Suitable bases include NaOH, KOH, or any base that allows for pH adjustment to a pH of 12 or greater.
  • step c) can be carried out by adding 2-(4-morpholinyl)-ethyl chloride hydrochloride, NaOtBu, acetonitrile followed by reflux, then adding aqueous or concentrated HCI to adjust the pH to about 2 to 3, followed by the addition of aqueous NaOH to adjust the pH to about 12 to 13, followed by recrystallization from MeCN.
  • a compound of formula 6 can be prepared by treating a compound of formula 5 with a carboxylic acid activating agent and CH 3 NH 2 as indicated in step d).
  • suitable carboxylic activating agents include any agent that is able to activate a carboxylic acid for amide or ester formation, such as CDI, HATU, SOCI 2 , (COCI) 2 , DCC, EDC, HOBt, CDMT, BOP-CI, and PyBOP.
  • a catalyst may also be used, such as pyridine, DMAP, and the like.
  • the product 6 can optionally be purified by recrystallization from a suitable solvent such as methanol.
  • step d) can be carried out by using CDI in 2-MeTHF, followed by the addition of CH 3 NH 2 in H 2 O, followed by recrystallization from MeOH/H 2 O.
  • a compound of formula 7 can be prepared by treating a compound of formula 4 with a compound of formula 6 as indicated in step e).
  • Suitable reaction conditions include a base in an appropriate solvent at elevated temperatures (e.g. 90 to 11O 0 C).
  • Suitable bases include Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , KHCO 3 , amine bases, alkoxides, hydroxides, NaH, and organometallic reagents.
  • Suitable solvents include any polar aprotic solvent such as DMF, DMSO, and DMAc.
  • the product 7 can optionally be purified by precipitation by addition of antisolvent, such as water, followed by recrystallization from an appropriate solvent or solvent mixtures, such as ethanol/water.
  • antisolvent such as water
  • solvent or solvent mixtures such as ethanol/water.
  • step e) can be carried out by first adding NaOtBu in DMSO at 10O 0 C, followed by the addition of H 2 O, followed by the addition of DARCO G60, EtOH/CH 2 CI 2 , followed by recrystallization from EtOH/H 2 O.
  • Another aspect of the present invention is a process for preparing Compound 6 using a Claisen Condensation that is depicted by the following Scheme B:
  • a compound of formula 11 or 12 can be prepared by treating a compound of formula 9 with a sulfur source such as elemental sulfur S 8 , S x 2" , (NH 4 J 2 S x , and so forth, using a solvent with a high boiling point such as toluene, H 2 O, NMP, DMF and the like, and an amine, including primary or secondary amines, acyclic or cyclic, such as NH 3 , NHR 2 , piperidine, or morpholine.
  • This step is preferably carried out at elevated temperatures, preferably ⁇ 130 0 C.
  • Suitable bases include NaOH and KOH, or any base that allows for the pH adjustment to a pH of about 12 or greater.
  • Suitable aqueous acids include HCI, HBr, H 2 SO 4 , H 3 PO 4 , and the like, or any acid that allows for pH-adjustment to an acidic pH, preferably a pH of less than 2.
  • Salts of compound 11 can be formed using any compound that is capable of forming a salt of 11 , preferably amines, such as dicyclohexylamine.
  • step a) can be carried out using reaction conditions comprising elemental sulfur, morpholine, NMP at 130 0 C for 3 hours.
  • Step b) can then be carried out by adding aqueous NaOH, followed by concentrated HCI to adjust the pH to about O to form the compound of formula 11.
  • the compound of formula 12 can then be formed by the addition of dicyclohexylamine.
  • a compound of formula 13 can be prepared by the addition of a carboxylic acid activation agent and a base to the compound of formula 12 as shown below.
  • Suitable carboxylic acid activation agents include any agent suitable to activate a carboxylic acid for amide or ester formation includung but not limited to CDI, HATU, SOCI 2 , (COCI) 2 , DCC, EDC, HOBt, CDMT, BOP-CI, PyBOP, and the like.
  • Suitable bases include Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , KHCO 3 , and amine bases.
  • step c) in Scheme B can be carried out using SOCI 2 , pyridine, and acetonitrile.
  • a compound of formula 13 can also be prepared from compound 11 by the addition of a suitable carboxylic acid activation agent, a base, and a nucleophile to form the intermediate compound 19, where CO 2 R' in compound 19 represents any suitable ester, such as the ethyl ester.
  • Compound 13 can then be prepared by the addition of a suitable base to compound 19.
  • Suitable nucieophiles include alcohols such as MeOH, and EtOH, or amines such as methylamine.
  • compound 14 can be prepared from compound 13 by using a base, an acylating agent, and a suitable solvent as indicated in step d).
  • Suitable bases include alkoxides, amides, and organometallic reagents.
  • bases may include methoxides, ethoxides, te/t-butoxides, LDA, BuLi and so forth.
  • Appropriate solvents include ethers and esters such as MTBE, THF, 2-MeTHF and EtOAc.
  • Appropriate acylating agents include anhydrides, acid halides, and esters.
  • acetic acid derivatives can be used as the acylating agent.
  • Preferred acylating agents include ethyl acetate, acetyl chloride, and acetic anhydride.
  • the reaction in step d) may be carried out at lower temperatures, preferably T ⁇ 25 0 C, more preferably T ⁇ O "C.
  • step d) can be carried out by adding BuLi as a base and 2-MeTHF as the solvent at a temperature of about O 0 C, followed by the addition of acetyl chloride as the acylating agent.
  • LDA can be used as the base and Ac 2 O can be used as the acylating agent.
  • compounds of formulas 15, 16, and 17 can be prepared from compound 14 as shown in step e) by using a rearrangement dehydration agent in a suitable solvent at an elevated temperature.
  • suitable rearrangement dehydration agents include acids such as HCI, H 2 SO 4 , and MSA
  • suitable solvents include alcohols, such as MeOH or EtOH, and water.
  • Elevated temperature means room temperature (e.g. 25 0 C) or greater.
  • compound 15 can be obtained using step e) where HCI is used and the temperature is 100 0 C.
  • Compound 16 can be obtained where MSA and EtOH are used, and compound 17 can be obtained where MSA and MeOH are used.
  • compound 18 can be prepared from compounds with formulas 15, 16, or 17 as indicated by steps f) and g) by adding CH 3 NH 2 .
  • compound 18 can be prepared from compound 15 by first using CDI and 2-MeTHF as the solvent, followed by the addition of aqueous MeNH 2 .
  • Compound 18 can also be prepared from compounds 16 or 17 by using a catalyst such as NaCN, MeNH 2 , and 2-MeTHF as the solvent.
  • compound 6 can be prepared from compound 18 as shown in step h).
  • compound 6 can be prepared by using a deprotection agent and a scavenger.
  • step h) can be carried out using MSA and methionine.
  • a compound of formula 6 can be formed using the Claisen Condensation as shown.
  • a further aspect of the present invention is a process of preparing a compound of formula 6 using the following Scheme D:
  • compositions may be formulated into pharmaceutical compositions in any pharmaceutical form recognizable to the skilled artisan as being suitable.
  • Pharmaceutical compositions comprise a therapeutically effective amount of a compound of formula 7, or a pharmaceutically acceptable salt or solvate thereof, and an inert, pharmaceutically acceptable carrier or diluent.
  • the mixture was granulated for at least 2 hours at 20 to 25°C, and then filtered.
  • the contents of the flask were rinsed forward with H 2 O and the filter cake was rinsed thoroughly with H 2 O (total amount for rising flask and wetcake: 3x1000 mL).
  • the collected solids were pulled dry and then dried in vacuo at 60 to 7O 0 C with a nitrogen bleed to afford 3 ⁇ a as an off-white solid.
  • the MeCN in the acidic aqueous solution was then removed by concentration of the reaction mixture to 250 to 300 mL by distillation under vacuum while maintaining an internal temperature of 30 to 35°C.
  • the resulting pale yellow-orange color slurry was .
  • the reaction mixture was cooled to -10 to -15 0 C, and 37% HCI (900 mL) was added carefully, maintaining the internal temperature below 25°C.
  • a bi-phasic mixture was obtained with pH ⁇ 1.
  • the phases were separated and the aqueous phase was extracted with 2-MeTHF (1x500 mL).
  • the organic phases were combined and washed with H 2 O (1x500 mL). After the wash, the organic phases were concentrated to -800 mL by atmospheric distillation.
  • the solution was then cooled to 25°C, MeOH (3000 mL) was charged to the flask, and concentration to -800 mL by atmospheric distillation was resumed.
  • the reaction mixture was transferred to a 2L separatory funnel and the contents of the flask were rinsed forward into the separatory funnel using H 2 O (-100 mL) and 2-MeTHF (-100 mL).
  • the layers were separated and the organic layer was washed with 3N HCI (2x150 mL). After extraction of the aqueous layer with 2-MeTHF (2x125 mL), amide 18-a could no longer be detected in the aqueous layer.
  • the organic layer was transferred to a 3L, 3-neck flask and methanesuifonic acid (730 mL) was added. 2-MeTHF was then removed by vacuum distillation.
  • the methanesuifonic acid mixture was then cooled to 0 to 5°C and DL- methionine (247 g, 1.6548 mol) was charged within 5 minutes.
  • the mixture was heated to 65 0 C and stirred for approximately 24 hours when complete consumption of methyl amide 18-a was obtained.
  • the reaction mixture was then cooled to ⁇ 20°C.
  • the cooled reaction mixture was then added in portions to a 5-L, 3-neck flask containing cold (0 to 5 0 C) H 2 O (1360 mL) at a rate sufficient to keep the internal temperature below 20°C.
  • the thick mixture was granulated at a slow stirring rate. More H 2 O (100O mL) was added and granulation continued.
  • a 3L, 3- neck flask was charged with dried phenylacetic acid amine salt 12 (369.8g, 1.0174 mol) and ethyl acetate (1000 mL) to give a brown slurry.
  • the slurry was then heated to reflux within 40 to 50 minutes and a blackish brown solution was obtained, which was cooled to room temperature. More ethyl acetate (1000 mL) was added and the mixture was reheated to reflux and then decanted from undissolved particles.
  • the still hot solution was cooled while stirring and after 45 minutes, a thick light-brown slurry was obtained which was granulated, filtered and rinsed with ethyl acetate ( ⁇ 800 mL).
  • the brown solids were dried at 5O 0 C in vacuo to afford 12 (246.9 g; 53% overall yield; 92% purity).
  • a 3L, 3-neck flask was charged with commercially available 2.0M LDA solution in THF (662 mL, 1.3249 mol) and cooled in an ice/acetone bath. Separately, a 2L flask was charged with the lactone 13-a (72.5g, 0.4416 mol) and 2-MeTHF (725 mL) to give a dark, reddish-brown solution. The -lactone 13-a solution was then transferred to an addition funnel and added carefully to the LDA solution, maintaining the internal temperature below 5 0 C. After complete addition of the lactone 13-a solution, the reaction was warmed to approximately 15 0 C within ⁇ 45 minutes.
  • the solution was cooled again to -2O 0 C and acetic anhydride (50 mL, 0.5300 mol) was added via addition funnel.
  • the reaction mixture containing 14-a was then transferred to a 4L separatory funnel containing H 2 O (800 mL) and 37% HCI (80 mL).
  • the aqueous layer was extracted with 2-MeTHF (2x150 mL) and the combined organic layers ( ⁇ 1.8 L) were transferred to a 3L, 3-neck flask.

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Abstract

The present invention relates to methods for preparing a compound of formula (7), which is useful as a modulator and/or inhibitor of protein kinases. The present invention also relates to intermediate compounds useful in the preparation of a compound of formula (7).

Description

METHODS OF PREPARING A VEGF-R INHIBITOR
This application claims priority to U.S. Provisional Application No. 60/742,847, filed on December 5, 2005, which is incorporated herein by reference in its entirety.
Field of the Invention
The present invention relates to methods for preparing a VEGF-R inhibitor, and to intermediates thereof.
Background of the Invention
The compound N,2-dimethyl-6-[7-(2-morpholinoethoxy)quinolin-4- yloxy]benzofuran-3-carboxamide (also referred to as "Compound 7"),
Figure imgf000002_0001
7
is described in the U.S. published patent application U.S. 2005-0137395, the disclosure of which is hereby incorporated by reference in its entirety. This compound is a receptor protein kinase inhibitor and represents a synthetic, small molecule inhibitor of angiogenic receptor signaling.
The present invention relates to methods of preparing Compound 7, as well as pharmaceutically acceptable salts and intermediate compounds thereof. Such compounds are useful for the treatment of cancer and other diseases associated with angiogenesis or cellular proliferation mediated by protein kinases.
Although a method of preparing Compound 7 is discussed in U.S. 2005-
0137395, there remains a need in the art for new synthetic routes that are efficient and cost effective. Summary
The present invention relates to methods of preparing a compound of formula 7, and intermediates thereof.
Figure imgf000003_0001
In one aspect, the present invention relates to a method of preparing a compound of formula 7,
Figure imgf000003_0002
or a salt or solvate thereof, the method comprising treating a compound of formula 4 with a compound of formula 6,
Figure imgf000003_0003
4 6
wherein X is any suitable leaving group, to form the compound of formula 7. In a particular embodiment, X is halogen, NO2 or -OSO2R1 wherein R1 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C6) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C6) alkynyl is optionally substituted with at least one (C6 to C14) aryl group. In a further embodiment the reaction is carried out under conditions comprising a base. For example the base is selected from the group consisting of Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, NaH, an amine base, an alkoxide base, a hydroxide base, and an organometallic reagent. In a further embodiment X is Cl and the reaction is carried out at a temperature of 90 to 11O0C.
Another aspect of the present invention is a method of preparing a compound of formula 4,
Figure imgf000004_0001
or a salt or solvate thereof, the method comprising treating a compound of formula 3 with a compound of formula 30
Figure imgf000004_0002
30 wherein X and Y are each any suitable leaving group, to form a compound of formula 4. In one embodiment the compound of formula 30 is 2-(4-Morpholinyl)-ethyl chloride hydrochloride. In a further embodiment X and Y are each independently halogen, NO2, or -OSO2R1, wherein R1 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group. For example X is Cl and Y is Cl. In a further embodiment the reaction is carried out in the presence of a first base at a temperature of 70 to 9O0C, followed by the addition of an acid at a temperature of 20 to 3O0C, followed by the addition of a second base at a temperature of 20 to 3O0C. For example the first base can be selected from the group consisting of Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, NaH, an amine base, an alkoxide base, and a hydroxide base. For example the base can be NaOtBu or KOtBu. In a further embodiment the acid is any acid that allows for pH adjustment to a pH of 3 or less. For example the acid can be selected from the group consisting of HCI, HBr, H2SO4, and H3PO4. In a still further embodiment the second base is any base that allows for pH adjustment to a pH of 12 or greater. For example the second base can be NaOH or KOH.
The present invention also relates to a method of preparing a compound of formula 3
Figure imgf000004_0003
or a salt or solvate thereof, the method comprising the steps of; a) treating a compound of formula 2 with a suitable deprotecting agent; followed by
Figure imgf000005_0001
2
b) adding a base; followed by c) adding an acid; to form a compound of formula 3, wherein X is any suitable leaving group; and R is (Ci to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to Ci4) aryl group. In a particular embodiment, X is halogen, NO2 or -OSO2R1, wherein R1 is (C1 to C6) alkyl,
(C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C-, to C8) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one
(C6 to C14) aryl group. In a particular embodiment X is Cl, R is -CH3 or -CH2-phenyl, and step a) is carried out at a temperature of 50 to 7O0C. In a further embodiment, the deprotecting agent can be BBr3, BCI3, TMSCI, TMSBr, TMSI, HBr, HI, thioacetic acid, thioglycolic acid, or methanesulfonic acid. In a further embodiment, the base can be any base that allows for pH adjustment to a pH of 11 or greater. For example the base can be NaOH or KOH. In a further embodiment the acid is any acid that allows for pH adjustment to a pH of 7. For example the acid is HCI, HBr, H2SO4, or H3PO4.
The present invention further relates to a method of preparing a compound of formula 6
Figure imgf000005_0002
i
or a salt or solvate thereof, the method comprising treating a compound of formula 5
Figure imgf000005_0003
5
with a suitable carboxylic acid activating agent and CH3NH2, to form a compound of formula 6. In one particular embodiment the carboxylic acid activating agent is CDI, HATU, SOCI2, (COCI)2, DCC, EDC, HOBt, CDMT, BOP-CI, or PyBOP. In a further embodiment the method further comprises the addition of a catalyst, for example pyridine or DMAP.
The invention further relates to a method of preparing a compound of formula 6
Figure imgf000006_0001
or a salt or solvate thereof, the method comprising treating a compound of formula 1j8
Figure imgf000006_0002
18
with a deprotection agent and a R1 scavenger, to form a compound of formula 6, wherein R1 is acyl, -SO2R2, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl, wherein R2 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C-|4) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to Ci4) aryl group. For example R1 is -CH3, the reaction is carried out at a temperature of 55 to 750C, the deprotection agent is MSA and the scavenger is methionine.
The invention further relates to a method of preparing a compound of formula 6
Figure imgf000006_0003
or a salt or solvate thereof, the method comprising treating a compound of formula 24
Figure imgf000006_0004
24
with an deprotection agent and a R1 scavenger to form a compound of formula 32
Figure imgf000007_0001
32
which can then be treated with a catalyst and CH3NH2 to form a compound of formula 6, wherein R1 is acyl, -SO2R3, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; R2 is H, (C1 to C6) alkyl, (Q2 to C8) alkenyl, or (C2 to C8) alkynyl; and R3 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group. In one embodiment R1 is -CH3, or -CH2-phenyl, the reaction is carried out at a temperature of 55 to 750C, the deprotection agent is an acid such as MSA and the scavenger is methionine.
The present invention further relates to a method of preparing a compound of formula 18
Figure imgf000007_0002
18
or a salt or solvate thereof the method comprising treating a compound of formula 24
Figure imgf000007_0003
24
with CH3NH2 and optionally a catalyst, to form a compound of formula 18, wherein: R1 is acyl, -SO2R3, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; R2 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; and R3 is (Ci to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to Ci4) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group. In one particular embodiment R1 is -CH3, R2 is H, and the reaction further comprises the addition of a suitable carboxylic acid activating agent. In a further embodiment the carboxylic activating agent is selected from the group consisting of CDI, HATU, SOCI2, (COCI)2, DCC, EDC, HOBt, CDMT, BOP-CI, and PyBOP. In a further embodiment R1 is -CH3, R2 is -CH3, and the catalyst is NaCN. In a further embodiment the reaction is carried out at a temperature of 55 to 750C. In a further embodiment R1 is - CH3, R2 is -CH2CH3, and the catalyst is NaCN.
The present invention further relates to a method of preparing a compound of formula 24
Figure imgf000008_0001
24
or a salt or solvate thereof, the method comprising treating a compound of formula 14
Figure imgf000008_0002
14
with an agent that enables rearrangement dehydration and a suitable solvent to form a compound of formula 24, wherein: R1 is acyl, -SO2R3, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; R2 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; and R3 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to , C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group. In one embodiment the agent that enables rearrangement dehydration is an acid. For example the acid is HCI, R1 is -CH3, and R2 is H. Further, for example, the acid is MSA, the solvent is MeOH, R1 is -CH3, and R2 is -CH3. Even further for example, the acid is MSA, the solvent is EtOH, R1 is -CH3, and R2 is -CH2CH3.
The present invention further relates to a method of preparing a compound of formula 14
Figure imgf000008_0003
14
or a salt or solvate thereof, the method comprising treating a compound of formula 13
Figure imgf000009_0001
13
with a base, followed by the addition of an acylating agent, to form a compound of formula 14, wherein: R1 is acyl, -SO2R2, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; and R2 is (Ci to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group. In one particular embodiment the base is selected from the group consisting of alkoxides, amides, NaH, and organometallic reagents. In a further embodiment R1 is -CH3 and the base is BuLi, LDA, LHMDS, NaHMDS, or KHMDS. In a further embodiment the acylating agent is an anhydride, an acid halide, or an ester of acetic acid. In a further embodiment the acylating agent is ethyl acetate, acetyl chloride, or acetic anhydride.
The present invention also relates to a method of preparing a compound of formula 13
Figure imgf000009_0002
13
or a salt or solvate thereof, the method comprising treating a compound of formula 20
Figure imgf000009_0003
20
with a suitable carboxylic acid activation agent and a suitable base, to form a compound of formula 13, wherein: R1 is acyl, -SO2R3, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; R2 is H or a cationic counterion; and R3 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group. In one particular embodiment, R1 is -CH3, R2 is H2NCy2, the activation agent is selected from the group consisting of CDI, HATU, SOCI2, (COCI)2, DCC, EDC, HOBt, CDMT, BOP-CI, and PyBOP, and the base is selected from the group consisting of an amine, Na2CO3, K2CO3, Cs2CO3, NaHCO3, and KHCO3. In a further embodiment R2 is H, and the method further comprises the addition of a suitable nucleophile. In a further embodiment, the step of treating a compound of formula 20 with the carboxylic acid activation agent, the base, and the nucleophile is carried out by (i) treating the compound of formula 20 with the carboxylic acid activation agent, the base, and the nucleophile to form an intermediate compound of formula 19;
Figure imgf000010_0001
19
wherein: R1 is acyl, -SO2R3, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; R4 is (C-i to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group, and (ii) treating the intermediate compound of formula 19 with a base to form the compound of formula ^3. In one particular embodiment R1 is -CH3, the carboxylic acid activation agent is selected from the group consisting of CDI, HATU, SOCI2, (COCI)2, DCC, EDC, HOBt, CDMT, BOP-CI1 and PyBOP, the base in steps (i) and (ii) is independently selected from the group consisting of an amine, Na2CO3, K2CO3, Cs2CO3, NaHCO3, and KHCO3, and the nucleophile is an alcohol or an amine. In a further embodiment the carboxylic acid activation agent is SOCI2, the base is pyridine, and the nucleophile is MeOH, EtOH, or methylamine.
The present invention also relates to a method of preparing a compound of formula 20
Figure imgf000010_0002
20
or a salt or solvate thereof, the method comprising the steps of: a) treating a compound of formula 9
Figure imgf000010_0003
with a sulfur source and an amine; followed by b) adding a base and then an acid, to form a compound of formula 20, wherein: R1 is H, acyl, -SO2R3, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; R2 is H or a cationic counterion; and R3 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group. In one particular embodiment R1 is -CH3, R2 is H, the sulfur source is S8, and the amine is NH3, piperidine, or morpholine. In a further embodiment step a) is carried out at a temperature of 120 to 14O0C. In a further embodiment the base is any base that allows for pH adjustment to a pH of 12 or greater. For example the base can be NaOH or KOH. In another embodiment the acid is any acid that allows for pH adjustment to a pH of 2 or less. For example the acid can be HCI, HBr, H2SO4, or H3PO4.
The present invention also relates to a compound of formula 20
Figure imgf000011_0001
20
wherein; R1 is acyl, -SO2R3, (C-i to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; R2 is H or a cationic counterion; and R3 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group; or a salt or solvate thereof. In one particular embodiment R1 is -CH3 and R2 is H or NH2Cy2.
The present invention also relates to a compound of formula 13
Figure imgf000011_0002
IS
wherein: R1 is acyl, -SO2R2, (C-i to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; and R2 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to CM) aryl group; or a salt or solvate thereof. In one particular embodiment R1 is -CH3.
The present invention further relates to a compound of formula 14
Figure imgf000011_0003
14
wherein: R1 is acyl, -SO2R2, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C6) alkynyl; and R2 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C6) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to Ci4) aryl group"; or a salt or solvate thereof. In one embodiment R1 is -CH3. The present invention further relates to a compound of formula 24
Figure imgf000012_0001
24
wherein: R1 is H, acyl, -SO2R , (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C6) alkynyl, R2 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C6) alkynyl; and R3 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl; wherein any of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group; or a salt solvate thereof. In one particular embodiment R1 is -CH3, and R2 is H, -CH3, or -CH2CH3.
The present invention also relates to a compound of formula 18
Figure imgf000012_0002
18
wherein: R1 is H, acyl, -SO2R2, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C6) alkynyl; R2 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to Ci4) aryl group; or a salt or solvate thereof. In one embodiment R1 is -CH3.
The present invention also relates to a compound of formula 4
Figure imgf000012_0003
wherein X is any suitable leaving group; or a salt or solvate thereof. In one embodiment X is halogen, NO2, or -OSO2R1 wherein R1 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group. In a further embodiment X is Cl.
The present invention also relates to a compound of formula 2
Figure imgf000013_0001
2
wherein: X is any suitable leaving group; and R is H, (C1 to C6) alkyl, (C2 to C8) alkenyl,
(C2 to C8) alkynyl, or (C6 to Ci4) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group; or a salt or solvate thereof. In one particular embodiment X is halogen, NO2, or
-OSO2R1 wherein R1 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to
C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group. In a further embodiment X is Cl, and R is -CH3 or -CH2-phenyl.
The present invention also relates to a compound of formula 31
Figure imgf000013_0002
wherein: R is H, acyl, -SO2R1, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C6) alkynyl; and R1 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group; or a salt or solvate thereof.
Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below.
As used in describing the present invention, the terms "comprising" and
"including" are used in their open, non-limiting sense.
The term "treating," as used in describing the present invention, refers to a chemical process or processes in which two or more reactants or chemical species are allowed to come into contact with each other to effect a chemical change or transformation. For example, when reactant A and reactant B are allowed to come into contact with each other to afford a new chemical compound(s) C, A is said to have been
"treated" with B to produce C.
The term "protecting," as used herein, refers to a process in which a functional group in a chemical compound is selectively masked by a non-reactive functional group in order to allow a selective reaction(s) to occur elsewhere on said chemical compound.
Such non-reactive functional groups are herein termed "protecting groups." For example, the term "hydroxyl protecting group," as used herein refers to those groups that are capable of selectively masking the reactivity of a hydroxyl (-OH) group. The term "suitable protecting group," as used herein refers to those protecting groups that are useful in the preparation of the compounds of the present invention. Such groups are generally able to be selectively introduced and removed using mild reaction conditions that do not interfere with other portions of the subject compounds. Protecting groups that are suitable for use in the processes and methods of the present invention are known to those of ordinary skill in the art. The chemical properties of such protecting groups, methods for their introduction and their removal can be found, for example, in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999). The terms "deprotecting", "deprotected", "deprotect", "deprotecting agent", or "deprotection agent" as used herein, are meant to refer to the process of removing a protecting group, or agents that remove a protecting group, from a compound. Methods for deprotecting, including the appropriate conditions and reagents, are known to those of ordinary skill in the art.
A "solvate" is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include, but are not limited to, compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
As used in describing the present invention, a "carboxylic acid activating agent" is anything suitable to activate a carboxylic acid for amide or ester formation. Such agents are well known to those of skill in the art and include CDI, HATU, SOCI2, (COCI)2, DCC, EDC, HOBt, CDMT, BOP-CI, and PyBOP.
As used in describing the present invention, a "scavenger" is a chemical compound or functional group that can accept another group that is being removed from a chemical compound. For example, as used herein, a "R1 scavenger" is any chemical compound or functional group that forms an interaction with the R1 group that is being removed from a chemical compound. Such scavengers are well known to those of skill in the art.
As used herein, an "agent that enables rearrangement dehydration" is any agent that facilitates rearrangement dehydration as part of a chemical reaction. Such agents are well known to those of skill in the art and include acids such as HCI, H2SO4, and MSA.
As used in describing the present invention, a "leaving group" refers to a chemical functional group that generally allows a nucleophilic substitution reaction to take place at the atom to which it is attached. For example, in acid chlorides of the formula CI-C(O)R, wherein R is alkyl, aryl, or heterocyclic, the -Cl group is generally referred to as a leaving group because it allows nucleophilic substitution reactions to take place at the carbonyl carbon to which it is attached. Suitable leaving groups are known to those of ordinary skill in the art and can include halides, aromatic heterocycles, cyano, amino groups (generally under acidic conditions), ammonium groups, alkoxide groups, carbonate groups, formates, and hydroxy groups that have been activated by reaction with compounds such as carbodiimides. For example, suitable leaving groups can include, but are not limited to halogen, NO2, and -OSO2R1, where R1 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C6) alkynyl, or (C6 to C14) aryl, and wherein each of said (C-i to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C6) alkynyl is optionally substituted with at least one (C6 to C14) aryl group.
As used in describing the present invention, an "acylating agent" is any chemical compound capable of delivering an acyl group in an acylation reaction. Such acylating agents are well known to those of skill in the art and include anhydrides of carboxylic acids, acid halides, and esters.
As used in describing the present invention, the following acronyms are defined as follows: "Et" means ethyl, "Ac" means acetyl, "Me" means methyl, "Cy" means cyclohexyl, "EtOAc" means ethyl acetate, "THF" means tetrahydrofuran, "HOBt" means hydroxy benzotriazole, "MeOH" means methanol, "EtOH" means ethanol, "2-MeTHF" means 2-methyl tetrahydrofuran, "NaOtBu" means sodium tert-butoxide, "DMSO" means dimethylsulfoxide, "LDA" means lithium diisopropyl amide, "LHMDS" means lithium hexamethyldisilazide, "NaHMDS" means sodium hexamethyldisilazide, "KHMDS" means potassium hexamethyldisilazide, "H2NCy2" means dicyclohexylamine, "AcCI" means acetyl chloride, "MTBE" means methyl t-butyl ether, "DMF" means N,N-dimethyl formamide, "DMA" means N,N-dimethylacetamide, "Ac2O" means acetic anhydride, "THP" means tetrahydropyran, "DMSO" means dimethyl sulfoxide, "DMAc" means dimethyl acetamide, "TMSCI" means trimethylsilyl chloride, "TMSBr" means trimethylsilyl bromide, "TMSI" means trimethylsilyl iodide, "MSA" means methane sulfonic acid, "CDI" means 1 ,1'-carbonyldiimidazole, "HATU" means (7-Aazabenzotriazol-1-yl)-1 ,1 ,3,3, tetra- methyluronium hexafluorophosphate, "DCC" means dicyclohexylcarbodiimide, "EDC" means 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, "CDMT" means 2-chloro-4,6- dimethoxy-1 ,3,5-triazine, "BOP-Cl" means bis(2-oxo-3-oxazoiidinyl)phosphinic chloride, "PyBOP" means (Benzotriazol-i-yloxy)tripyrrolidino-phosphonium Hexafluorophosphate, "HOBt" means 1 -hydroxy benzotriazole, and "DMAP" means 4-dimethylaminopyridine.
As used in describing the present invention, the term "(C1 to C6) alkyl" means a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 6 carbon atoms. Examples of (C1 to C6) alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, /so-butyl, terf-butyl, pentyl, and the like.
As used in describing the present invention, the term "(C2 to C8) alkenyl" means an alkyl moiety comprising 2 to 8 carbons having at least one carbon-carbon double bond. The carbon-carbon double bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Such groups include both the E and Z isomers of said alkenyl moiety. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, ally!, and pentenyl.
As used in describing the present invention, the term "(C2 to C8) alkynyl" means an alkyl moiety comprising from 2 to 8 carbon atoms and having at least one carbon- carbon triple bond. The carbon-carbon triple bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, and 3-hexynyl.
As used in describing the present invention, the term "(C6 to C14) aryl" means a group derived from an aromatic hydrocarbon containing from 6 to 14 carbon atoms.
Examples of such groups include, but are not limited to, phenyl or naphthyl. The terms
"Ph" and -"phenyl," as used herein, mean a -C6H5 group. The term "benzyl," as used herein, means a -CH2C6H5 group.
As used in describing the present invention, the term "halogen" and/or "halo" refer to fluorine, chlorine, bromine or iodine.
Detailed Description of the Invention
The following processes illustrate the general preparation of Compound 7 according to methods of the present invention. The present invention also encompasses novel intermediates that occur in the processes described herein. The methods of preparing Compound 7, as well as intermediates thereof, are useful for preparing a compound that can be used for the treatment of cancer and other diseases associated with angiogenesis or cellular proliferation mediated by protein kinases.
Unless otherwise indicated, the substituent variables of the compounds according to the following processes are as defined herein. Starting materials, the synthesis of which are not specifically described herein or provided with reference to published references, are either commercially available or can be prepared using methods known to those of ordinary skill in the art. Certain synthetic modifications may be done according to methods familiar to those of ordinary skill in the art.
It should be understood that, in the context of the present invention, any reference to a particular compound used in the methods described herein also encompass any salts of that particular compound. Salts of the present invention include acid addition and base salts (including disalts). Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
For a review on suitable salts, see Handbook of Pharmaceutical Salts:
Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002), the disclosure of which is incorporated herein by reference in its entirety.
A salt of the compounds described herein can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
In the case of agents that are solids, it is understood by those skilled in the art that the compounds, agents and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.
Compounds described herein containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound contains an alkenyl or alkenylene group, geometric cis/trans (or ZlE) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. A single compound may exhibit more than one type of isomerism. Included within the scope of the invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds described herein, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
One aspect of the present invention is a process for preparing Compound 7 that is depicted by the following Scheme A:
Figure imgf000018_0001
Scheme A
In one aspect of Scheme A above, a compound represented by formula 3 can be prepared as shown in steps a) and b) by treating a compound of either formula 1 or formula 2 with a deprotecting agent, a base, and an acid. Those of skill in the art will recognize those deprotecting agents that are suitable for this transformation (see, e.g., T.W. Greene, P. G. M. Wuts Protective Groups in Organic Synthesis, 3rd ed. John-Wiley & Sons, 1999). For example, deprotecting agents suitable for this reaction step include Lewis acids such as BBr3, BCI3, or TMSX (where X is Cl, Br, or I), mineral acids such as HBr or HI, or other strong acids such as methanesulfonic acid. Those of skill in the art will recognize that any suitable solvent can optionally be used in this step. Solvents that can be used in this step include CH2CI2. Suitable bases include NaOH, KOH, or an any base that allows for pH adjustment to a pH of about 11 or greater. Suitable acids include HCI, HBr, H2SO4, H3PO4, or any acid that allows for pH adjustment to about 7. Preferably this reaction step is carried out at elevated temperatures, for example 50 to 70 0C. For example, step a) can be carried out in the presence of MSA and methionine at about 60 0C, followed by aqueous NaOH where the pH is adjusted to greater than about 11 , followed by the addition of HCI to adjust the pH to about 7. Step b) can be carried out by first adding BBr3/CH2CI2, followed by reflux, then adding aqueous NaOH to adjust the pH to about 11 or greater, followed by the addition of HCI to adjust the pH to about 7. In a further aspect of Scheme A, a compound of formula 4 can be prepared as shown in step c) by treating a compound of formula 3 with 2-(4-morpholinyl)-ethyl chloride hydrochloride. Suitable reaction conditions for this step comprise elevated temperatures (e.g. 70 to 900C), a base in a suitable solvent such as acetonitrile, followed by the addition of an aqueous acid, followed by the addition of a base, and optionally followed by purification by recrystallizatjon from an appropriate solvent such as acetonitrile. Suitable bases include Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, amines, alkoxides, and hydroxides. Suitable acids include HCI, HBr, H2SO4, H3PO4, or any acid that allows for pH adjustment to an acidic pH, preferably to a pH of less than 3. Suitable bases include NaOH, KOH, or any base that allows for pH adjustment to a pH of 12 or greater. For example, step c) can be carried out by adding 2-(4-morpholinyl)-ethyl chloride hydrochloride, NaOtBu, acetonitrile followed by reflux, then adding aqueous or concentrated HCI to adjust the pH to about 2 to 3, followed by the addition of aqueous NaOH to adjust the pH to about 12 to 13, followed by recrystallization from MeCN.
In a further aspect of Scheme A, a compound of formula 6 can be prepared by treating a compound of formula 5 with a carboxylic acid activating agent and CH3NH2 as indicated in step d). Suitable carboxylic activating agents include any agent that is able to activate a carboxylic acid for amide or ester formation, such as CDI, HATU, SOCI2, (COCI)2, DCC, EDC, HOBt, CDMT, BOP-CI, and PyBOP. A catalyst may also be used, such as pyridine, DMAP, and the like. The product 6 can optionally be purified by recrystallization from a suitable solvent such as methanol. For example, step d) can be carried out by using CDI in 2-MeTHF, followed by the addition of CH3NH2 in H2O, followed by recrystallization from MeOH/H2O.
In a further aspect of Scheme A, a compound of formula 7 can be prepared by treating a compound of formula 4 with a compound of formula 6 as indicated in step e). Suitable reaction conditions include a base in an appropriate solvent at elevated temperatures (e.g. 90 to 11O0C). Suitable bases include Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, amine bases, alkoxides, hydroxides, NaH, and organometallic reagents. Suitable solvents include any polar aprotic solvent such as DMF, DMSO, and DMAc. The product 7 can optionally be purified by precipitation by addition of antisolvent, such as water, followed by recrystallization from an appropriate solvent or solvent mixtures, such as ethanol/water. Such mixtures can be used in a variety of ratios, for example ethanohwater = 3:4 (vol/vol). For example, step e) can be carried out by first adding NaOtBu in DMSO at 10O 0C, followed by the addition of H2O, followed by the addition of DARCO G60, EtOH/CH2CI2, followed by recrystallization from EtOH/H2O.
Another aspect of the present invention is a process for preparing Compound 6 using a Claisen Condensation that is depicted by the following Scheme B:
Figure imgf000020_0001
Scheme B
In one aspect of Scheme B above, a compound of formula 11 or 12 can be prepared by treating a compound of formula 9 with a sulfur source such as elemental sulfur S8, Sx 2", (NH4J2Sx, and so forth, using a solvent with a high boiling point such as toluene, H2O, NMP, DMF and the like, and an amine, including primary or secondary amines, acyclic or cyclic, such as NH3, NHR2, piperidine, or morpholine. This step is preferably carried out at elevated temperatures, preferably ~130 0C. Once the intermediate compound of formula 10 is formed, the addition of an aqueous base, followed by an aqueous acid produces the compound of formula 11. Suitable bases include NaOH and KOH, or any base that allows for the pH adjustment to a pH of about 12 or greater. Suitable aqueous acids include HCI, HBr, H2SO4, H3PO4, and the like, or any acid that allows for pH-adjustment to an acidic pH, preferably a pH of less than 2. Salts of compound 11 can be formed using any compound that is capable of forming a salt of 11 , preferably amines, such as dicyclohexylamine. For example, step a) can be carried out using reaction conditions comprising elemental sulfur, morpholine, NMP at 130 0C for 3 hours. Step b) can then be carried out by adding aqueous NaOH, followed by concentrated HCI to adjust the pH to about O to form the compound of formula 11. The compound of formula 12 can then be formed by the addition of dicyclohexylamine.
In a further aspect of Scheme B, a compound of formula 13 can be prepared by the addition of a carboxylic acid activation agent and a base to the compound of formula 12 as shown below. Suitable carboxylic acid activation agents include any agent suitable to activate a carboxylic acid for amide or ester formation includung but not limited to CDI, HATU, SOCI2, (COCI)2, DCC, EDC, HOBt, CDMT, BOP-CI, PyBOP, and the like. Suitable bases include Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, and amine bases. For example, step c) in Scheme B can be carried out using SOCI2, pyridine, and acetonitrile.
Figure imgf000021_0001
As shown above, a compound of formula 13 can also be prepared from compound 11 by the addition of a suitable carboxylic acid activation agent, a base, and a nucleophile to form the intermediate compound 19, where CO2R' in compound 19 represents any suitable ester, such as the ethyl ester. Compound 13 can then be prepared by the addition of a suitable base to compound 19. Suitable nucieophiles include alcohols such as MeOH, and EtOH, or amines such as methylamine.
In a further aspect of Scheme B shown above, compound 14 can be prepared from compound 13 by using a base, an acylating agent, and a suitable solvent as indicated in step d). Suitable bases include alkoxides, amides, and organometallic reagents. For example, such bases may include methoxides, ethoxides, te/t-butoxides, LDA, BuLi and so forth. Appropriate solvents include ethers and esters such as MTBE, THF, 2-MeTHF and EtOAc. Appropriate acylating agents include anhydrides, acid halides, and esters. For example, acetic acid derivatives can be used as the acylating agent. Preferred acylating agents include ethyl acetate, acetyl chloride, and acetic anhydride. The reaction in step d) may be carried out at lower temperatures, preferably T<25 0C, more preferably T < O "C. For example, step d) can be carried out by adding BuLi as a base and 2-MeTHF as the solvent at a temperature of about O 0C, followed by the addition of acetyl chloride as the acylating agent. Alternatively, LDA can be used as the base and Ac2O can be used as the acylating agent.
In a further aspect of Scheme B, compounds of formulas 15, 16, and 17 can be prepared from compound 14 as shown in step e) by using a rearrangement dehydration agent in a suitable solvent at an elevated temperature. For example, suitable rearrangement dehydration agents include acids such as HCI, H2SO4, and MSA, and suitable solvents include alcohols, such as MeOH or EtOH, and water. Elevated temperature means room temperature (e.g. 250C) or greater. For example, compound 15 can be obtained using step e) where HCI is used and the temperature is 100 0C. Compound 16 can be obtained where MSA and EtOH are used, and compound 17 can be obtained where MSA and MeOH are used.
In a further aspect of Scheme B, compound 18 can be prepared from compounds with formulas 15, 16, or 17 as indicated by steps f) and g) by adding CH3NH2. For example, compound 18 can be prepared from compound 15 by first using CDI and 2-MeTHF as the solvent, followed by the addition of aqueous MeNH2. Compound 18 can also be prepared from compounds 16 or 17 by using a catalyst such as NaCN, MeNH2, and 2-MeTHF as the solvent.
In another aspect of Scheme B, compound 6 can be prepared from compound 18 as shown in step h). In particular, compound 6 can be prepared by using a deprotection agent and a scavenger. For example, step h) can be carried out using MSA and methionine.
Another aspect of the present invention is a process for preparing Compound 6 that is depicted by the following Scheme C:
Figure imgf000022_0001
cyclization see Scheme B dehydration
Figure imgf000022_0002
Figure imgf000022_0003
Figure imgf000022_0004
24 23
Scheme C
As indicated in Scheme C, a compound of formula 6 can be formed using the Claisen Condensation as shown.
A further aspect of the present invention is a process of preparing a compound of formula 6 using the following Scheme D:
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
Scheme D
The compound of formula 7, or a pharmaceutically acceptable salt or solvate thereof, may be formulated into pharmaceutical compositions in any pharmaceutical form recognizable to the skilled artisan as being suitable. Pharmaceutical compositions comprise a therapeutically effective amount of a compound of formula 7, or a pharmaceutically acceptable salt or solvate thereof, and an inert, pharmaceutically acceptable carrier or diluent.
Examples
In the examples described below, unless otherwise indicated, all temperatures in the following description are in degrees Celsius (0C) and all parts and percentages are by weight, unless indicated otherwise.
Various starting materials and other reagents were purchased from commercial suppliers, such as Aldrich Chemical Company, Regis Chemical Company, and EM Science, and used without further purification, unless otherwise indicated.
The reactions set forth below were performed under a positive pressure of nitrogen, argon or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents. Analytical thin-layer chromatography was performed on glass- backed silica gel 6O0F 254 plates (Analtech (0.25 mm)) and eluted with the appropriate solvent ratios (v/v). The reactions were assayed by high-pressure liquid chromotagraphy (HPLC) or thin-layer chromatography (TLC) and terminated as judged by the progress of the reaction. The TLC plates were visualized by UV, phosphomolybdic acid stain, or iodine stain.
1H-NMR spectra were recorded on a Bruker instrument operating at 300 MHz and 13C-NMR spectra were recorded at 75 MHz. NMR spectra are obtained as DMSOd6 or CDCI3 solutions (reported in ppm), using DMSO or chloroform, respectively, as the reference standard (7.25 ppm and 77.00 ppm) or DMSOd6 (2.50 ppm and 39.52 ppm). Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplets. Coupling constants, when given, are reported in Hertz.
The examples and' preparations provided below further illustrate and exemplify the methods of the present invention. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples.
Example 1 :
Figure imgf000024_0001
A 5-L, 3-neck flask was charged with MSA (600 mL), and external cooling was initially set to 21 to 22°C. DL-methionine (220 g, 1.4830 mol) was then added in 4 to 5 portions over approximately 45 minutes. After complete addition of methionine, the reaction mixture was stirred for 1 to 2 hours at ~20°C. A compound of formula ^a
(100.00 g, 0.3707 mol) was then added, and the thick suspension was heated at 60 to
650C for 60 to 90 minutes. The mixture was then cooled to 20 to 25°C, and a cold (- 50C) solution of NaOH (490 g) in H2O (1500 mL) was added until pH~7. The suspension was then granulated, filtered, rinsed with H2O (1000 mL), and pulled dry by suction. The collected solids were recharged to the reaction flask, H2O (1800 mL) was added, and the contents of the flask were cooled to 20 to 25°C. The pH was then adjusted to pH=1 to 2 by addition of 37% HCI. A clear yellow/orange solution was obtained. This solution was neutralized to pH~7 by addition of 10% aqueous NaOH solution (~400 mL). Once pH~7 was obtained, the mixture was granulated for at least 2 hours at 20 to 25°C, and then filtered. The contents of the flask were rinsed forward with H2O and the filter cake was rinsed thoroughly with H2O (total amount for rising flask and wetcake: 3x1000 mL). The collected solids were pulled dry and then dried in vacuo at 60 to 7O0C with a nitrogen bleed to afford 3±a as an off-white solid.
1H NMR of 3-a (300MHz1 d6-DMSO): 10.46 (s, 1 H, OH); 8.68 (d, J = 4.8 Hz, 1 H); 8.06 (d, J = 9.6 Hz, 1 H); 7.49(d, J = 4.8 Hz, 1 H); 7.30-7.34 (m, 2 H).
13C NMR of 3-a (75 MHz, d6-DMSO): 159.8, 151.0, 150.9, 141.3, 125.4, 121.1 , 120.0, 118.9, 110.9.
Figure imgf000025_0001
3-a 4-a
A 500-mL, 3-neck flask was charged with 3-a (16.3 g, 0.0908 mol) and 2-(4- morpholinyl)-ethyl chloride hydrochloride (40.9 g, 0.220 mol), followed by MeCN (163 ml_). The resulting mixture was stirred vigorously at 20 to 25°C until a fine and homogeneous suspension was obtained. This suspension was cooled to an internal temperature of approximately -200C, followed by the addition of solid NaOtBu (36.8 g, 0.383mol) in 4 portions, maintaining the internal temperature below -50C. After the addition of NaOtBu was complete, the mixture was heated to reflux within approximately 60 minutes, and then stirred for another 25 to 35 minutes at reflux. The mixture was then cooled to 20 to 25°C, and to the yellow-brown slurry was added deionized H2O (326 mL, 20 vol), followed by 37% HCI (25 mL) until pH=2 to 3 was obtained. The MeCN in the acidic aqueous solution was then removed by concentration of the reaction mixture to 250 to 300 mL by distillation under vacuum while maintaining an internal temperature of 30 to 35°C. The resulting aqueous solution was cooled in an ice bath to an internal temperature of 5 to 1O0C. To this cold solution was charged 50% NaOH solution (16.5 mL) until pH=12 to 13 while keeping the internal temperature below 200C. The resulting pale yellow-orange color slurry was . warmed to 20 to 250C and granulated. The precipitate was collected by filtration, rinsed with H2O (5x16 mL), followed by MeCN (2x16 mL) and dried thoroughly in vacuo at 60 to 700C, affording 4-a (23.76 g, 0.081 mol, 89 %) as a slightly yellow solid.
1H NMR of 4-a (300MHz, d6-DMSO): 8.74 (d, J = 4.8 Hz, 1 H); 8.07 (d, J = 9.0 Hz, 1 H); 7.56 (d, J = 4.8 Hz, 1 H); 7.48 (m, 1 H); 7.39 (m, 1 H); 4.28 (m, 2H); 3.59 (m, 4H); 2.76 (m, 2 H); 2.50 (m, 4H).
13C NMR of 4-a (75 MHz, d6-DMSO): 160.5, 151.2, 150.8, 141.2, 125.3, 121.3, 120.9, 119.7, 109.0, 66.5, 66.3, 57.2, 54.0. Example 3:
Figure imgf000026_0001
A 5-L, 3-neck flask was charged with the compound 5 (201.65 g, 1.0493 mol) followed by CD! (403.80 g, 2.4907 mol). Then, 2-MeTHF (2000 mL) was charged at 20 to 25°C while agitating. After ~30 minutes, the white suspension was cooled to -150C, and 40% aqueous MeNH2-solution (800 mL) was added carefully via addition funnel, maintaining the internal temperature at <5°C. After the addition was complete, the reaction mixture was warmed to 20 to 250C and stirred for at least 2 hours at 20 to 250C. The reaction mixture was cooled to -10 to -150C, and 37% HCI (900 mL) was added carefully, maintaining the internal temperature below 25°C. A bi-phasic mixture was obtained with pH~1. The phases were separated and the aqueous phase was extracted with 2-MeTHF (1x500 mL). The organic phases were combined and washed with H2O (1x500 mL). After the wash, the organic phases were concentrated to -800 mL by atmospheric distillation. The solution was then cooled to 25°C, MeOH (3000 mL) was charged to the flask, and concentration to -800 mL by atmospheric distillation was resumed. Upon concentration of the reaction mixture to ~800 mL, the solution was cooled to 25°C, MeOH (3000 mL) was recharged to the flask, and the solution in the flask was again concentrated to ~800 mL by atmospheric distillation. H2O (400 mL) was then added to the hot solution, the mixture was reheated to reflux briefly, then cooled to ~20°C while stirring gently, and stirred for at least 12 hours at ~20°C. The precipitated solids were filtered, rinsed with cold (0 to 50C) MeOH/H2O (1:1 , 1000 mL), and dried in vacuo at ~50°C to afford the compound 6 (167. 68 g, 0.8171 mol, 78 %) as an off-white solid. 1H NMR of 6: (300MHz, d6-DMSO): 9.50 (s, 1H); 7.72 (m, 1H); 7.52 (d, J = 8.4 Hz, 1H); 6.88 (Cl1 J = 2.1 Hz, 1 H); 6.76 (dd, J = 2.1 Hz, 8.4 Hz, 1H); 2.79 (d, J = 4.5 Hz, 3H); 2.55 (s, 3H).
13,
C NMR of 6: (75 MHz, d6-DMSO): 164.0, 155.9, 155.6, 154.3, 120.9, 118.2, 112.8,
112.5, 97.7, 26.3, 13.8.
Figure imgf000026_0002
A 2L, 3-neck flask was charged with 15 (85.3 g, 0.4137 mol), and CDI (113.3 g, 0.6987 mol), followed by 2-MeTHF (900 mL) to give a turbid brown solution. After complete consumption of benzofuran 15, the reaction mixture was then cooled in an ice bath and 40% aqueous MeNH2 (300 mL) was added via addition funnel at a rate sufficient to keep the internal temperature below 45°C. Once the amide formation was complete, the reaction mixture was cooled in an ice bath to an internal temperature <5°C and acidified to pH~7 with 37% HCI (-150 mL). The reaction mixture was transferred to a 2L separatory funnel and the contents of the flask were rinsed forward into the separatory funnel using H2O (-100 mL) and 2-MeTHF (-100 mL). The layers were separated and the organic layer was washed with 3N HCI (2x150 mL). After extraction of the aqueous layer with 2-MeTHF (2x125 mL), amide 18-a could no longer be detected in the aqueous layer. The organic layer was transferred to a 3L, 3-neck flask and methanesuifonic acid (730 mL) was added. 2-MeTHF was then removed by vacuum distillation. The methanesuifonic acid mixture was then cooled to 0 to 5°C and DL- methionine (247 g, 1.6548 mol) was charged within 5 minutes. The mixture was heated to 650C and stirred for approximately 24 hours when complete consumption of methyl amide 18-a was obtained. The reaction mixture was then cooled to ~20°C. The cooled reaction mixture was then added in portions to a 5-L, 3-neck flask containing cold (0 to 50C) H2O (1360 mL) at a rate sufficient to keep the internal temperature below 20°C. The thick mixture was granulated at a slow stirring rate. More H2O (100O mL) was added and granulation continued. 10% w/w aqueous NaOH solution (500 mL) was then added followed by 50% w/w NaOH solution (200 mL), and the mixture was granulated for 19 hours. The fine dark brown precipitates were filtered, rinsed with H2O (1000 mL), and dried at 500C in vacuo to afford crude 6 (54.5 g), which was further purified by recrystallization.
1H NMR of 6: (300MHz, d6-DMSO): 9.50 (s, 1H); 7.72 (m, 1H); 7.52 (d, J = 8.4 Hz, 1 H); 6.88 (d, J = 2.1 Hz, 1 H); 6.76 (dd, J = 2.1 Hz, 8.4 Hz, 1 H); 2.79 (d, J = 4.5 Hz, 3H); 2.55 (s, 3H).
13C NMR of 6: (75 MHz, d6-DMSO): 164.0, 155.9, 155.6, 154.3, 120.9, 118.2, 112.8, 112.5, 97.7, 26.3, 13.8.
Example 5:
Figure imgf000027_0001
A 3-L, 3-neck flask was charged with 6 (76.15 g, 1.0493 mol) and 4-a (119.47 g, 0.4081 mol). DMSO (760 ml_) was then charged at 20 to 25°C while agitating, followed by NaOtBu (44.11 g, 0.4452 mol) and the suspension was heated to 1000C. After stirring at this temperature for at least 12 hours, the mixture was cooled to ~30°C, and H2O (1520 mL) was charged at room temperature within -45 minutes upon which a precipitate formed. The suspension was granulated for 6 hours while cooling to 20 to 25 0C. The suspension was filtered, the collected solids were rinsed with H2O (2x840 mL) and then pulled dry. The solids were dried in vacuo at 60 to 70 0C affording crude product (-150 g). For further purification, crude 7 was dissolved in EtOH (750 mL) upon heating to reflux (80 to 82 0C), and then H2O (100O mL) was added to the refluxing solution within ~5 minutes. Shortly after complete addition of water, a precipitate formed and the mixture became a very thick suspension, yet easy to stir. This suspension was briefly heated to reflux, then cooled to 20 to 250C and granulated for at least 12 hours. The precipitated solids were filtered, rinsed with EtOH/H2O (3:4; 700 mL), pulled dry and then dried in vacuo at 60 to 70°C, affording 7 (135.74 g, 0.2941 mol, 79 %) as an off- white to yellow solid.
1H NMR of 7: (300MHz, d6-DMSO): 8.59 (d, J = 5.1 Hz1 1 H); 8.22 (d, J = 9.0 Hz, 1 H); 7.94 (m, 1 H); 7.86 (d, J = 8.7 Hz, 1 H); 7.59 (d, J = 2.1 Hz, 1 H); 7.44 (d, J = 2.4 Hz, 1 H); 7.30 (dd, J = 9.0 Hz, J = 2.4 Hz, 1 H); 7.22 (dd, J = 8.4 Hz, J = 2.1 Hz, 1 H); 6.46 (d, J = 5.4 Hz, 1 H); 4.29 (m, 2 H); 3.60 (m, 4 H); 2.77-2.84 (m, 5 H); 2.65 (s, 3 H); 2.50-2.54 (m, 4 H)
13C NMR of 7: (75 MHz, d6-DMSO): 163.5, 161.7, 160.2, 158.7, 153.6, 152.2, 151.6, 151.2, 124.2, 123.2, 122.0, 119.3, 117.2, 115.5, 113.1 , 108.5, 104.8, 103.2, 66.6, 66.1 , 57.3, 54.0, 26.4, 14.0
Example 6:
Figure imgf000028_0001
A 3L, 3-neck flask was charged with 2-hydroxy-4-methoxyacetophenone 9-a (210.90 g, 1.2692 mol), sulfur (81.40 g, 2.5390 mol), morpholine (220 mL, 2.5367 mol), and NMP (630 mL) to give a reddish-brown suspension. The suspension was heated to -13O0C for -4.5 hours affording 10 as intermediate. After cooling to 20 to 250C, a solution of NaOH (260 g) in H2O (260 mL) was added. Upon completion of addition, the mixture was heated to ~100°C and kept at this temperature for 2.5 to 3 hours. The reaction mixture was cooled below 400C with an external ice bath. A NaOH/NaOCI scrubber system and was installed. 37% HCI (~700 ml.) was then added carefully targeting a pH~O. The mixture was diluted with H2O (~5.4 L) and filtered through filter paper to remove elemental sulfur. The aqueous solution was extracted with 2-MeTHF (4x500 ml_ and 1x225 mL). The combined organic layers were transferred to a 3L, 3- neck flask and the 2-MeTHF solution containing 11 was concentrated to 850 to 900 mL by atmospheric distillation. The mixture was then cooled to ~50°C, and MTBE (875 mL) was added, lowering the internal temperature to ~38°C. Dicyclohexylamine (253 mL, 1.2711 mol) was added over ~10 min. After ~5 min into the addition, the mixture was seeded with 12. Additional dicyclohexylamine (20 mL, 0.1005 mol) was added to initiate the precipitation of amine salt 12. After granulation for -19 hours, the yellow brown slurry was filtered and rinsed with MTBE (1000 mL). The collected solids were pulled dripless and then dried in vacuo at 60 to 70°C to afford crude 12 (370 g, 81 % yield, ~50% purity) which was further purified by recrystallization. For that purpose, a 3L, 3- neck flask was charged with dried phenylacetic acid amine salt 12 (369.8g, 1.0174 mol) and ethyl acetate (1000 mL) to give a brown slurry. The slurry was then heated to reflux within 40 to 50 minutes and a blackish brown solution was obtained, which was cooled to room temperature. More ethyl acetate (1000 mL) was added and the mixture was reheated to reflux and then decanted from undissolved particles. The still hot solution was cooled while stirring and after 45 minutes, a thick light-brown slurry was obtained which was granulated, filtered and rinsed with ethyl acetate (~800 mL). The brown solids were dried at 5O0C in vacuo to afford 12 (246.9 g; 53% overall yield; 92% purity).
1H NMR of 12: (300MHz, d6-DMSO): 6.82 (d, J = 9.0 Hz, 1 H); 6.19-6.25 (m, 2 H); 3.65 (s, 3 H); 2.91-3.06 (m, 2 H); 2.05-1.86 (m, 4 H); 1.81-1.63 (m, 4 H); 1.63-1.51 (m, 2 H); 1.39-1.14 (m, 9 H); 1.14-0.95 (m, 2 H)
13C NMR of 12: (75 MHz, d6-DMSO): 176.33, 159.36, 159.13, 130.71 , 117.20, 103.83, 102.93, 55.13, 52.30, 43.08, 29.44, 25.26, 24.39 Example 7:
Figure imgf000029_0001
13-a
A 3L, 3-neck flask was charged with pulverized 12 (242.80 g, 0.6680 mol) and acetonitrile (1.991 L) to afford a light brown suspension. Thionyl chloride (53.6 mL, 0.7348 mol) was added slowly via addition funnel without any external cooling. Once the reaction was complete, the dicyclohexylamine-hydrochloride salt was filtered and rinsed with ethyl acetate (1.8 L). The filtrate was transferred to a 4L separatory funnel and washed sequentially with 0.1 M HCI (500 mL), 0.01 M KOH (425 mL, 1.75 vol), and water (500 mL, 2.06 vol). The organic solution was then concentrated in vacuo to a viscous oil, which eventually solidified to give a waxy, reddish brown solid. The solids were dried at 500C in a vacuum oven to afford 13-a (105 g) in 96% yield.
1H NMR of 13-a: (300MHz, d6-DMSO): 7.25 (d, J = 9.0 Hz, 1 H); 6.84 (d, J = 3.0 Hz 1 H); 6.71 (dd, J = 3.0 Hz, 9.0 Hz, 1 H); 3.82 (s, 2 H); 3.76 (s, 3 H)
13C NMR of 13-a: (75 MHz, d6-DMSO): 175.27, 160.07, 155.35, 125.53, 115.98, 109.78, 97.50, 55.93, 32.51
Example 8:
Figure imgf000030_0001
13-a 14-a 15
A 3L, 3-neck flask was charged with commercially available 2.0M LDA solution in THF (662 mL, 1.3249 mol) and cooled in an ice/acetone bath. Separately, a 2L flask was charged with the lactone 13-a (72.5g, 0.4416 mol) and 2-MeTHF (725 mL) to give a dark, reddish-brown solution. The -lactone 13-a solution was then transferred to an addition funnel and added carefully to the LDA solution, maintaining the internal temperature below 50C. After complete addition of the lactone 13-a solution, the reaction was warmed to approximately 150C within ~45 minutes. The solution was cooled again to -2O0C and acetic anhydride (50 mL, 0.5300 mol) was added via addition funnel. The reaction mixture containing 14-a was then transferred to a 4L separatory funnel containing H2O (800 mL) and 37% HCI (80 mL). The layers were separated and to the aqueous layer (possessing pH~6) was added 37% HCI (~ 100 mL) until pH=0. The aqueous layer was extracted with 2-MeTHF (2x150 mL) and the combined organic layers (~1.8 L) were transferred to a 3L, 3-neck flask. Methanol (2100 mL) was added and the 2-MeTHF was replaced with methanol by azeotropic distillation. Upon complete solvent switch, the methanol solution was concentrated to 650 mL and cooled to 21 to 250C. Methanesulfonic acid (130 mL, 2.0048 mol, 17% by vol) was then added via addition funnel without external cooling, and subsequently heated to reflux for several hours until the reaction was complete. In preparation for the hydrolysis step, the internal temperature was adjusted to < 5°C using an external ice bath. A solution of NaOH (10Og, 2.5000 mol) dissolved in H2O (500 mL) was then added via an addition funnel and the mixture subsequently heated to 35 to 5O0C. Additional NaOH (52g, 1.3000 mol) was added and stirring was continued until the reaction was complete. After cooling the reaction mixture to 20 to 25°C, it was decanted into a 2L Erienmeyer flask. Separately, H2O (340 mL) followed by 37% HCI (160 mL, 1.92 mol) was charged to the 3L, 3-neck flask that contained the original reaction mixture and the HCI-solution thus obtained was cooled to < 50C using an ice bath. The reaction mixture was transferred from the Erienmeyer flask to an addition funnel and then added to the cooled aqueous HCI solution at such a rate to keep the internal temperature < 2O0C. After completion of the addition, more 37% HCI (20 mL, 0.0067 mol) was added to adjust to pH<2. The slurry was then granulated for approximately 21 hours, and the solids were filtered and rinsed with H2O (500 mL). The solids were then dried in a vacuum oven at 6O0C to afford 6- methoxy-2-methylbenzofuran-3-carboxylate 15 (85.8 g; 94% overall yield) as a dark brown solid.
1H NMR of 15: (300MHz, d6-DMSO): 12.83 (s, broad, 1 H); 7.74 (d, J = 8.7 Hz, 1 H); 7.19 (Cl1 J = 2.1 Hz, 1 H); 6.93 (dd, J = 2.3 Hz, 8.6 Hz, 1 H); 3.80 (s, 3 H); 2.69 (s, 3 H)
13C NMR of 15: (75 MHz, d6-DMSO): 165.40, 162.14, 157.89, 154.34, 121.77, 119.59, 112.64, 109.21 , 96.23, 55.95, 14.27

Claims

Claims We claim:
1. A method of preparing a compound of formula 7,
Figure imgf000032_0001
or a salt or solvate thereof, the method comprising treating a compound of formula 4 with a compound of formula 6,
Figure imgf000032_0002
4 6
wherein X is any suitable leaving group, to form the compound of formula 7.
2. The method of claim 1 wherein X is Cl and the reaction is carried out at a temperature of 90 to 110°C.
3. A method of preparing a compound of formula 4,
Figure imgf000032_0003
or a salt or solvate thereof, the method comprising treating a compound of formula 3 with a compound of formula 30
Figure imgf000033_0001
3 30
wherein X and Y are each independently any suitable leaving group, to form a compound of formula 4.
4. , The method of claim 3, wherein the compound of formula 30 is 2-(4- Morpholinyl)-ethyl chloride hydrochloride.
5. The method of claim 3 wherein the reaction is carried out in the presence of a first base at a temperature of 70 to 9O0C, followed by the addition of an acid at a temperature of 20 to 300C, followed by the addition of a second base at a temperature of 20 to 3O0C.
6. A method of preparing a compound of formula 6
Figure imgf000033_0002
or a salt or solvate thereof, the method comprising treating a compound of formula 5
Figure imgf000033_0003
with a suitable carboxylic acid activating agent and CH3NH2, to form a compound of formula 6.
7. A method of preparing a compound of formula 6
Figure imgf000034_0001
or a salt or solvate thereof, the method comprising treating a compound of formula 18
Figure imgf000034_0002
18
with a deprotection agent and a R1 scavenger, to form a compound of formula 6, wherein:
R1 is acyl, -SO2R2, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl, wherein:
R2 is (C1 to C6) alky], (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group.
8. The method of claim 7, wherein R1 is -CH3, the reaction is carried out at a temperature of 55 to 75°C, the deprotection agent is MSA and the scavenger is methionine.
9. A method of preparing a compound of formula 18
Figure imgf000034_0003
18
or a salt or solvate thereof the method comprising treating a compound of formula 24
Figure imgf000034_0004
24
with CH3NH2 and optionally a catalyst, to form a compound of formula 18, wherein:
R1 is acyl, -SO2R3, (C-, to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; R2 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl;
R3 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group.
10. The method of claim 9 wherein R1 is -CH3, R2 is H, and the reaction further comprises the addition of a suitable carboxylic acid activating agent.
11. The method of claim 9 wherein R1 is -CH3, R2 is -CH3 or -CH2CH3, and the catalyst is NaCN.
12. A method of preparing a compound of formula 24
Figure imgf000035_0001
24
or a salt or solvate thereof, the method comprising treating a compound of formula 14
Figure imgf000035_0002
14
with an agent that enables rearrangement dehydration and a suitable solvent to form a compound of formula 24, wherein:
R1 is acyl, -SO2R3, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl;
R2 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; and
R3 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group.
13. A method of preparing a compound of formula 14
Figure imgf000036_0001
14
or a salt or solvate thereof, the method comprising treating a compound of formula 13
Figure imgf000036_0002
13
with a base, followed by the addition of an acylating agent, to form a compound of formula
14, wherein:
R1 is acyl, -SO2R2, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; and R2 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to Cβ) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group.
14. A method of preparing a compound of formula 13
Figure imgf000036_0003
11
or a salt or solvate thereof, the method comprising treating a compound of formula 20
Figure imgf000036_0004
20
with a suitable carboxylic acid activation agent and a suitable base, to form a compound of formula 13, wherein:
R1 is acyl, -SO2R3, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl;
R2 is H or a cationic counterion; and
R3 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 'to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to Cn) aryl group.
15. The method of claim 14, where R2 is H, and the method further comprises the addition of a suitable nucleophile.
16. The method of claim 15 wherein the step of treating a compound of formula 20 with the carboxylic acid activation agent, the base, and the nucleophile is carried out by (i) treating the compound of formula 20 with the carboxylic acid activation agent, the base, and the nucleophile to form an intermediate compound of formula 19;
Figure imgf000037_0001
19
wherein:
R1 is acyl, -SO2R3, (C1 to C6) alky!, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; R4 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group,
and (ii) treating the intermediate compound of formula 19 with a base to form the compound of formula 13.
17. A method of preparing a compound of formula 20
Figure imgf000037_0002
20
or a salt or solvate thereof, the method comprising the steps of:
a) treating a compound of formula 9
Figure imgf000037_0003
9
with a sulfur source and an amine; followed by
b) adding a base and then an acid, to form a compound of formula 20, wherein:
R1 is H, acyl, -SO2R3, (C1 to C6) alkyl, (C2 to C8) alkenyl, or (C2 to C8) alkynyl; R is H or a cationic counterion; and
R3 is (C1 to C6) alky!, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group.
18. A compound of formula 4
Figure imgf000038_0001
wherein X is any suitable leaving group;
or a salt or solvate thereof.
19. The compound of claim 18, wherein X is halogen, NO2, or -OSO2R1 and wherein R1 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, and (C2 to C8) alkynyl is optionally substituted with at least one (C6 to C14) aryl group.
20. The compound of claim 70 wherein X is Cl.
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CN112724110A (en) * 2021-01-13 2021-04-30 广州安岩仁医药科技有限公司 Synthesis method of VEGFR inhibitor furoquintinib and benzofuran intermediate thereof

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
US7829574B2 (en) 2008-05-09 2010-11-09 Hutchison Medipharma Enterprises Limited Substituted quinazoline compounds and their use in treating angiogenesis-related diseases
US8212033B2 (en) 2008-05-09 2012-07-03 Hutchison Medipharma Enterprises Limited Use of substituted quinazoline compounds in treating angiogenesis-related diseases
US8497372B2 (en) 2008-05-09 2013-07-30 Hutchison Medipharma Enterprises Limited Use of substituted quinazoline compounds in treating age-related macular degeneration
CN112724110A (en) * 2021-01-13 2021-04-30 广州安岩仁医药科技有限公司 Synthesis method of VEGFR inhibitor furoquintinib and benzofuran intermediate thereof
CN112724110B (en) * 2021-01-13 2021-10-26 广州安岩仁医药科技有限公司 Synthesis method of VEGFR inhibitor furoquintinib and benzofuran intermediate thereof

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