WO1999014210A1 - Elaboration de 5,6-dihydro-2h-pyran-2-ones substitues - Google Patents

Elaboration de 5,6-dihydro-2h-pyran-2-ones substitues Download PDF

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WO1999014210A1
WO1999014210A1 PCT/US1998/017081 US9817081W WO9914210A1 WO 1999014210 A1 WO1999014210 A1 WO 1999014210A1 US 9817081 W US9817081 W US 9817081W WO 9914210 A1 WO9914210 A1 WO 9914210A1
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carbons
heterocycle
cycloalkyl
cor
branched alkyl
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PCT/US1998/017081
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English (en)
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Ihoezo Victor Ekhato
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Warner-Lambert Company
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Priority to AU91986/98A priority Critical patent/AU9198698A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/36—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members

Definitions

  • the compounds disclosed in the above United States Patent Application are inhibitors of the virally encoded protease, an essential enzyme that processes the gag/pol polyproteins to generate viral enzymes and structural proteins of the developing virus.
  • the compounds have been shown to inhibit the HIV protease and are potential anti-HIV agents useful in treating AIDS.
  • Particularly valuable as an anti-AIDS agent is (S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl- phenylsulfanyl)-4-hydroxy-6- [2-(4-hydroxy-phenyl)-ethyl] -6-isopropyl-5 ,6- dihydro-pyran-2-one.
  • the object of the present invention is an improved, efficient, and economical process for the preparation of substituted 5,6-dihydro-pyran-2-ones.
  • the present method avoids the disadvantages of the prior method and is amenable to large-scale synthesis, as well as for the preparation of radio-labeled compounds. amenable to large-scale synthesis, as well as for the preparation of radio-labeled compounds.
  • a first aspect of the present invention is an improved process for the preparation of a compound of Formula I
  • R 1 is H, 2- or 3- or 4- (CH 2 ) n ' OR' or (CH 2 ) n ' N(R') 2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring;
  • R2 and R 3 are independently H, OR, N(R) 2 , a straight or branched alkyl of
  • NRSO 2 N(R) 2 , NRCON(R) 2 , or R 2 and R 3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms;
  • R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph
  • n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) 2 , CON(R) 2 , NRCOR,
  • R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph which comprises:
  • Step (a) treating a compound of Formula XrV
  • Step (b) treating a compound of Formula XII with an oxidizing reagent in a solvent to afford a compound of Formula XI
  • Step (c) treating a compound of Formula XI with a Wittig type reagent in a solvent to afford a compound of Formula X
  • R ⁇ is as defined above;
  • Step (d) treating a compound of Formula X with a compound of Formula DC
  • Rl, R 2 , R 3 , and R ⁇ are as defined above;
  • Step (e) treating a compound of Formula VIII with a hydride reagent in a solvent to afford a compound of Formula VII
  • Rl, R 2 , R 3 , and R ⁇ are as defined above;
  • Step (f) treating a compound of Formula VII with hydrogen in the presence of a catalyst in a solvent to afford a compound of Formula VI
  • R , R 2 , R 3 , and R ⁇ are as defined above;
  • Step (g) treating a compound of Formula VI with a hydroxyl activating moiety in a solvent followed by addition of an alkali metal cyanide in a solvent to afford a compound of Formula V
  • Rl, R 2 , R 3 , and R ⁇ are as defined above;
  • Step (h) treating a compound of Formula V with a hydride reagent in a solvent to afford a compound of Formula IV
  • Rl, R 2 , R 3 , and R4 are as defined above;
  • Step (i) treating a compound of Formula IV with an oxidizing reagent in a solvent to afford a compound of Formula III
  • Rl, R 2 , R 3 , and R ⁇ are as defined above;
  • Step (j) treating either a compound of Formula IV with the compound of Formula
  • Rl, R 2 , R 3 , and R ⁇ are as defined above;
  • Step (k) treating a compound of Formula II with a base in a solvent followed by acidification with an acid to afford a compound of Formula I.
  • a second aspect of the present invention is a novel intermediate of Formula XII
  • R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) , CON(R) , NRCOR, SO 2 R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph; and PG is a protecting group.
  • a third aspect of the present invention is a novel intermediate of Formula XI
  • R 4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) 2 , CON(R) 2 , NRCOR, SO 2 R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1 -3 carbons, or Ph.
  • a fourth aspect of the present invention is a novel intermediate of
  • R 4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) 2 , CON(R) 2 , NRCOR, SO 2 R, and COR;
  • a fifth aspect of the present invention is a novel intermediate of Formula VIII
  • R 1 is H, 2- or 3- or 4- (CH 2 ) n ' OR' or (CH ) n ' N(R') 2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring;
  • R 2 and R 3 are independently H, OR, N(R) 2 , a straight or branched alkyl of
  • 1-4 carbons, a cycloalkyl of 3-6 carbons, F, Cl, Br, NRCOR, COR, CON(R) 2 , OCOR, CO 2 R, NRSO 2 R, SO N(R) 2 , NRSO3R, NRSO 2 N(R) 2 , NRCON(R) 2 , or R 2 and R 3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms;
  • R 4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) 2 , CON(R) 2 , NRCOR, SO 2 R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1 -3 carbons, or Ph.
  • a sixth aspect of the present invention is a novel intermediate of Formula VII
  • R 1 is H, 2- or 3- or 4- (CH 2 ) n ' OR' or (CH 2 ) n ' N(R') 2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring;
  • R 2 and R 3 are independently H, OR, N(R) 2 , a straight or branched alkyl of
  • NRSO 2 N(R) 2 , NRCON(R) 2 , or R 2 and R 3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms;
  • R 4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) 2 , CON(R) 2 , NRCOR, SO 2 R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.
  • a seventh aspect of the present invention is a novel intermediate of Formula VI
  • R 1 is H, 2- or 3- or 4- (CH 2 ) n ' OR' or (CH 2 ) n ' N(R') where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring;
  • R 2 and R 3 are independently H, OR, N(R) 2 , a straight or branched alkyl of
  • NRSO 2 N(R) 2 , NRCON(R) 2 , or R 2 and R 3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms;
  • R 4 is a straight or branched alkyl of 1 -7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) , CON(R) , NRCOR, SO 2 R, and COR;
  • R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.
  • An eighth aspect of the present invention is a novel intermediate of Formula V
  • Rl is H, 2- or 3- or 4- (CH 2 ) n ' OR' or (CH ) n ' N(R') 2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring;
  • R 2 and R 3 are independently H, OR, N(R) 2 , a straight or branched alkyl of
  • 1-4 carbons, a cycloalkyl of 3-6 carbons, F, Cl, Br, NRCOR, COR, CON(R) 2 , OCOR, CO 2 R, NRSO 2 R, SO 2 N(R) 2 , NRSO3R, NRSO 2 N(R) 2 , NRCON(R) 2 , or R 2 and R 3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms;
  • R 4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) 2 , CON(R) 2 , NRCOR, SO R, and COR;
  • R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.
  • a ninth aspect of the present invention is a novel intermediate of Formula IV
  • R 1 is H, 2- or 3- or 4- (CH 2 ) n ' OR' or (CH 2 ) n ' N(R') 2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring;
  • R 2 and R 3 are independently H, OR, N(R) 2 , a straight or branched alkyl of 1-4 carbons, a cycloalkyl of 3-6 carbons, F, Cl, Br, NRCOR, COR,
  • NRSO 2 N(R) 2 , NRCON(R) 2 , or R 2 and R 3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms;
  • R 4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) , CON(R) 2 , NRCOR, SO 2 R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.
  • a tenth aspect of the present invention is a novel intermediate of
  • Rl is H, 2- or 3- or 4- (CH ) n ' OR' or (CH 2 ) n ' N(R') 2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring;
  • R 2 and R 3 are independently H, OR, N(R) 2 , a straight or branched alkyl of
  • NRSO 2 N(R) 2 , NRCON(R) 2 , or R 2 and R 3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms;
  • R 4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) 2 , CON(R) 2 , NRCOR, SO 2 R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.
  • An eleventh aspect of the present invention is a novel intermediate of Formula II
  • Rl is H, 2- or 3- or 4- (CH 2 ) n ' OR' or (CH 2 ) n ' N(R') 2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring;
  • R 2 and R 3 are independently H, OR, N(R) 2 , a straight or branched alkyl of
  • NRSO 2 N(R) 2 , NRCON(R) 2 , or R 2 and R 3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms;
  • R 4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) 2 , CON(R) 2 , NRCOR, SO R, and COR;
  • R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.
  • alkyl means a straight or branched hydrocarbon radical having from 1-12 carbon atoms unless otherwise specified and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, and dodecyl.
  • the alkyl groups may contain one or more sites of unsaturation such as double or triple carbon-carbon bonds.
  • the alkyl group is unsubstituted or substituted by from 1-3 substituents selected from alkyl, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO-R, -CO-NH-, -CO 2 R, -COR, aryl, or heteroaryl wherein alkyl (R), aryl, and heteroaryl are as defined herein.
  • cycloalkyl means a hydrocarbon ring which contains from 3-12 carbon atoms unless otherwise specified, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Where possible, the cycloalkyl group may contain double bonds.
  • the cycloalkyl ring may be unsubstituted or substituted by from 1-3 substituents selected from alkyl, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO-R, -CO-NHR-, -CO 2 R, -COR, aryl, or heteroaryl wherein alkyl (R), aryl, and heteroaryl are as defined herein.
  • alkylcycloalkyl means a cycloalkyl group as defined above attached directly to an alkyl group as defined above.
  • alkoxy and thioalkoxy are O-alkyl or S-alkyl as defined above for alkyl.
  • spirocycle refers to a carbocyclic or heterocyclic ring whose ends meet at a single carbon in a chain or another ring.
  • heteroaryl and “heterocycle” mean a heterocyclic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isaxazolyl, 3- or 5- 1,2,4-triazolyl, 4- or 5- 1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7
  • aryl means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as
  • alkyl nitro, cyano, carboxy, SO3H, CHO, C-alkyl as defined
  • alkyl -C-NH 2 , -C-NH-alkyl, NH-C-alkyl, as defined above for O 11 alkyl, -C-N(alkyl) 2 as defined above for alkyl, -(CH 2 ) n 2-NH 2 wherein n 2 is an integer of 1 to 5, -(CH 2 ) n 2-NH-alkyl as defined above for alkyl and n 2 ,
  • Halogen is fluorine, chlorine, bromine, or iodine.
  • Alkali metal is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium and the like.
  • Alkaline-earth metal is a metal in Group IIA of the periodic table and includes, for example, calcium, barium, strontium, and the like.
  • silyl protecting group is a silyl ether commonly used to protect a hydroxyl functionality such as, for example, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tertiary-butyldimethylsilyl, and the like.
  • “Jones reagent” refers to oxidations using chromic acid and sulfuric acid in water in acetone.
  • compositions of Formula 1 are capable of further forming pharmaceutically acceptable acid-addition and/or base salts. All of these forms are within the scope of the present invention.
  • Pharmaceutically acceptable acid addition salts of the compounds of the present invention include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzensoulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M.,
  • the acid addition salt of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S.M., et al.,
  • the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration.
  • the present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof.
  • a preferred compound of Formula I prepared by the improved process of the present invention is one wherein
  • Rl is H, 2- or 3- or 4- (CH 2 ) n ' OH' or (CH ) n ' NH 2 where n' is 0 or 1;
  • R 2 and R 3 are independently H, an alkyl of 1-3 carbons, F, Cl Br, or R 2 and R 3 may be taken together to form a 5-membered ring optionally containing 1 or 2 heteroatoms;
  • R 4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 2, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) , CON(R) 2 , NRCOR, SO 2 R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • Another preferred compound of Formula I prepared by the improved process of the present invention is one wherein
  • Rl is H, 3- or 4- (CH ) n ' OH or (CH 2 ) n ' NH 2 where n' is 0 or 1;
  • R 2 and R 3 are independently H, an alkyl of 1-3 carbons, F, Cl, or Br;
  • R 4 is a straight or branched alkyl of 1-5 carbons, a cycloalkyl of 3-6 carbons, a heterocycle of 5-6 carbons containing one heteroatom or Ph, all of which may be optionally substituted by OR, N(R) 2 , SO 2 R, and COR;
  • R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH 2 ) m -cycloalkyl wherein the cycloalkyl is of 3-6 carbons and wherein m is zero or an integer of 1 to 3, -(CH 2 ) m -Ph, a (CH 2 ) m -heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is as defined above, and wherein the (R) 2 in N(R) 2 may be a heterocycle containing the nitrogen, all optionally substituted by F, Cl, Br, -CN, -CF3, OR', COH, N(R') 2 , CON(R') 2 , or NR'COR'; and
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.
  • Another preferred compound of Formula I prepared by the improved process of the present invention is one wherein
  • Rl is H; R 2 and R 3 are H;
  • R 4 is phenyl or pyridinyl optionally substituted by OR, SR, N(R) 2 , CON(R) 2 ,
  • R is a (CH 2 ) m -heterocycle of 5-6 atoms with 1-2 heteroatoms optionally substituted by OR', N(R') 2 , CON(R') 2 , or NR'COR'; m is an integer of from 2 to 3 ; and
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.
  • a still further preferred compound of Formula I prepared by the improved process of the present invention is one wherein
  • Rl is 3- or 4- (CH 2 ) n 'OH or a (CH ) n 'NH 2 where n' is 0 or 1;
  • R 2 and R 3 are independently H, an alkyl of 1-3 carbons, F, Cl, or Br;
  • R 4 is a straight or branched alkyl of 1-6 carbons, or a cycloalkyl of 3-6 carbons.
  • Another preferred compound of Formula I prepared by the improved process of the present invention is one wherein R 1 is 3- or 4- (CH 2 ) n 'OH or a (CH 2 ) n 'NH where n' is 0 or 1;
  • R 2 and R 3 are H;
  • R 4 is a straight or branched alkyl of 1-6 carbons, or a cycloalkyl of 3-6 carbons.
  • a most preferred compound of Formula I prepared by the improved process of the present invention is one wherein
  • R is 4-OH orNH 2 ;
  • R 2 and R 3 are H;
  • R 4 is isopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • a second preferred compound of Formula I prepared by the improved process of the present invention is one wherein
  • Rl is 3-OH or H 2 ;
  • R 2 and R 3 are H;
  • R 4 is isopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Particularly preferred compounds of Formula I prepared by the improved process of the present invention are selected from the group consisting of:
  • the process of the present invention is a new, improved, economical, and commercially feasible method for preparing substituted 5,6-dihydro-2H-pyran-2- ones.
  • the process of the present invention is outlined in the following Scheme 1.
  • R 4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH 2 ) n Ph wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R) , CON(R) , NRCOR, SO 2 R and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph;
  • PG is an alcohol protecting group such as, for example, tert-butyldimethylsilyl, a tetrahydropyranyl protecting group, a ketal protecting group, a hemi-ketal protecting group and the like is treated with the compound of Formula XIII in a solvent such as, for example, diethyl ether, tetrahydrofuran, toluene and the like in the presence of a base such as, for example, sodium hydride and the like to afford a compound of Formula XII wherein R 4 and PG are as defined above.
  • the reaction is carried out in toluene in the presence of sodium hydride.
  • a compound of Formula XII Treatment of a compound of Formula XII with an oxidizing reagent such as, for example, Swern reagent, pyridinium dichromate, pyridinium chromate and the like in a solvent such as, for example, methylene chloride, dimethylformamide, pyridine, and the like to afford a compound of Formula XI wherein R 4 is as defined above.
  • an oxidizing reagent such as, for example, Swern reagent, pyridinium dichromate, pyridinium chromate and the like in a solvent such as, for example, methylene chloride, dimethylformamide, pyridine, and the like to afford a compound of Formula XI wherein R 4 is as defined above.
  • the reaction is carried out using Swern oxidation conditions in methylene chloride.
  • a Wittig type reagent such as, for example, zinc-diiodomethane or methylene dibromide-titanium tetrachloride, aNysted reagent ( ⁇ cyclo-dibromodi ⁇ -methylene[ ⁇ - (tetrahydrofuran)jtrizinc ⁇ ), a Wittig reagent, a Peterson reagent, and the like in a solvent such as, for example, diethyl ether, tetrahydrofuran, methylene chloride and the like to afford a compound of Formula X wherein R 4 is as defined above.
  • the reaction is carried out with zinc-diiodomethane-titanium tetrachloride in tetrahydrofuran.
  • Rl is H, 2- or 3- or 4- (CH ) n ' OR' or (CH 2 ) n ' N(R') 2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring;
  • R 2 and R 3 are independently H, OR, N(R) 2 , a straight or branched alkyl of
  • NRSO N(R) 2 , NRCON(R) 2 , or R 2 and R 3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms;
  • R is independently H, a straight or branched alkyl of 1-5 carbons, a
  • R' is H, a straight or branched alkyl of 1-3 carbons, or Ph in the presence of a base such as, for example, a trialkylamine, for example, triethylamine and the like in a solvent such as, for example, hexane, cyclohexane, toluene, diethyl ether and the like to afford a compound of Formula VIII wherein
  • Rl, R 2 , R 3 , and R 4 are as defined above.
  • R 2 , and R 3 are as defined above.
  • the reaction is carried out with L-selectride in tetrahydrofuran.
  • a compound of Formula VI Treatment of a compound of Formula VI with a hydroxyl activating moiety such as, for example, mesyl chloride, tosyl chloride, triphenyl phosphine and the like in a solvent such as, for example, methylene chloride, tetrahydrofuran and the like in the presence of a base such as, for example, diisopropylethylamine and the like followed by the addition of an alkali metal cyanide such as, for example, sodium cyanide, potassium cyanide or ammonium cyanide and the like in a solvent such as, for example, dimethylsulfoxide, dimethylformamide, acetonitrile and the like to afford a compound of Formula V wherein Rl, R 2 , R 3 , and R 4 are as defined above.
  • a hydroxyl activating moiety such as, for example, mesyl chloride, tosyl chloride, triphenyl phosphine and the like in a solvent
  • the reaction is carried out with mesyl chloride in methylene chloride in the presence of diisopropylethylamine followed by optional removal of the solvent and isolation of the mesylate followed by addition of potassium cyanide in dimethylsulfoxide.
  • a compound of Formula V Treatment of a compound of Formula V with a hydride reagent such as, for example, diisobutylaluminum hydride and the like in a solvent such as, for example, toluene, tetrahydrofuran, methylene chloride and the like to afford a compound of Formula IV wherein Rl, R 2 , R 3 , and R 4 are as defined above.
  • a hydride reagent such as, for example, diisobutylaluminum hydride and the like in a solvent such as, for example, toluene, tetrahydrofuran, methylene chloride and the like to afford a compound of Formula IV wherein Rl, R 2 , R 3 , and R 4 are as defined above.
  • the reaction is carried out with diisobutylaluminum hydride in tetrahydrofuran.
  • oxidizing reagent such as, for example, Jones reagent, sodium chlorite and hydrogen peroxide and the like in a solvent such as, for example, acetone, acetonitrile and water, pyridine, acetic acid and the like to afford a compound of Formula III wherein Rl, R 2 , R 3 , and R 4 are as defined above.
  • the reaction is carried out with Jones reagent in acetone.
  • a compound of Formula II Treatment of a compound of Formula III with l,l'-carbonyldiimidazole in a solvent such as, for example, tetrahydrofuran and the like followed by the addition of ethyl magnesium malonate to afford a compound of Formula II wherein Rl, R 2 , R 3 , and R 4 are as defined above.
  • the reaction is carried out in tetrahydrofuran.
  • a compound of Formula II is obtained by treating a compound of Formula IV with ethyl diazoacetate in a solvent such as, for example, methylene chloride.
  • a compound of Formula XVI Treatment of a compound of Formula XVI with a hydride reagent such as, for example, diisobutylaluminum hydride in a solvent such as, for example, methylene chloride and the like followed by oxidation of the aldehyde with an oxidizing reagent such as, for example, hydrogen peroxide and sodium chlorite and the like to afford a compound of Formula XV wherein R 4 is as defined above.
  • the reaction is carried out with diisobutylaluminum hydride in methylene chloride followed by hydrogen peroxide and sodium chlorite oxidation.
  • a compound of Formula IX or the compound of Formula XIII can be obtained from commercial sources or prepared by methods generally known to one skilled in the art.
  • Step B Preparation of 2-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-butyric acid 2-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-butyronitrile (15.0 g) was dissolved in CH 2 C1 2 and cooled to -78°C under argon atmosphere.
  • DIBAL-H Diisobutylaluminum hydride
  • Step B Preparation of l-r(lR)-10.10-Dimethyl-3,3-dioxo-3 ⁇ 6 -thia-4-aza- tricyclo 5.2.1.pi ⁇ dec-4-yl)-3-methyl-butane-l .2-dione
  • Step C Preparation of l- (lR -10.10-Dime ⁇ hyl-3.3-dioxo-3 ⁇ 6 -thia-4-aza- tricyclo[ " 5.2.1.01 ⁇ ]dec-4-yl]-2-isopropyl-prop-2-en- 1 -one
  • Zinc dust 2.16 g (8.7 eq.), was suspended in dry THF under argon atmosphere and stirred.
  • Diiodomethane 1.53 mL (5 eq.), was added, and after 30 minutes at room temperature, it was cooled to -40°C and ⁇ CI4, 720 mg (1.0 eq.), was added cautiously. It was maintained at this temperature for
  • Step D Preparation of [(5R)-3-(4-Benzyloxy-phenyl -5-isopropyl-4-5- dihvdro-isoxazol-5-yl]-[(lR)10,10-dimethyl-3,3-dioxo-3 ⁇ -thia-4-aza- tricyclo[5.2.1.Ql>5]dec-4-yl]-methanone l-[(lR)-10,10-Dimethyl-3,3-dioxo-3 ⁇ 6 -thia-4-aza-tricyclo[5.2.1. ⁇ l' 5 ]dec- 4-yl]-2-isopropyl-prop-2-en-l-one (820 mg) in hexane (20 mL) under argon atmosphere was stirred and p-benzyloxyaldoximinoyl chloride, 3.85 g (5 eq.), was added, followed by triethylamine, 2.05 mL (5 eq.).
  • Step E Preparation of (5R)-[3-(4-Benzyloxy-phenyl)-5-isopropyl-4.5-dihydro- isoxazoI-5 -yl] -methanol
  • Step F Preparation of (lR)-2- 2-(4-Benzyloxy-phenyl)-ethyl]-3-methyl-butane- 1.2-diol
  • isoxazoline 5R-[3-(4-benzyloxy-phenyl)-5-isopropyl-4,5-dihydro- isoxazol-5-yl] -methanol (500 mg) in methanol (50 mL)
  • methanol 50 mL
  • a balloon of hydrogen was placed on it, and the reaction vessel was degassed. Hydrogen was admitted into the reaction vessel, and the degassing process was repeated twice.
  • the reaction was allowed to stir overnight under a hydrogen atmosphere, and filtered through a pad of Celite.
  • Step G Preparation of (3 SV3 - [2-(4-Benzyloxy-phenyl)-ethyl] -3 -hydroxy-4- methyl-pentanenitrile
  • Step I Preparation of(5S)-5- 2-(4-Benzyloxy-phenyl)-ethyl] -5 -hydroxy-6- methyl-3-oxo-heptanoic acid ethyl ester To a stirred solution of (3S)-3-[2-(4-benzyloxy-phenyl)-ethyl]-3-hydroxy-
  • Step J Preparation of (6S -6-

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Abstract

La présente invention concerne un perfectionnement de l'élaboration de 5,6-dihydro-2h-pyran-2-ones substitués. En l'occurrence, on obtient le produit attendu par une conversion, en dix opérations, d'un chlorure d'acide hydroxylé. L'invention concerne également des intermédiaires intéressants pour le procédé.
PCT/US1998/017081 1997-09-15 1998-08-18 Elaboration de 5,6-dihydro-2h-pyran-2-ones substitues WO1999014210A1 (fr)

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WO2007026965A1 (fr) 2005-09-02 2007-03-08 Nissan Chemical Industries, Ltd. Composé de benzamide à substitution isoxazoline et agent de lutte contre les organismes nuisibles
WO2007105814A1 (fr) 2006-03-10 2007-09-20 Nissan Chemical Industries, Ltd. Compose isoxazoline substitue et agent antiparasite
US7662972B2 (en) 2004-03-05 2010-02-16 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
CN107915754A (zh) * 2017-10-30 2018-04-17 浙江工业大学上虞研究院有限公司 一种纳斯特试剂的催化合成方法及其应用

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Cited By (17)

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WO2003095441A1 (fr) * 2002-05-10 2003-11-20 Pfizer Inc. Inhibiteurs de l'arn polymerase arn-dependante du virus de l'hepatite c et compositions et traitements utilisant cette polymerase
US8022089B2 (en) 2004-03-05 2011-09-20 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US10874645B2 (en) 2004-03-05 2020-12-29 Nissan Chemical Corporation Isoxazoline-substituted benzamide compound and pesticide
US7662972B2 (en) 2004-03-05 2010-02-16 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US10045969B2 (en) 2004-03-05 2018-08-14 Nissan Chemical Industries, Inc. Isoxazoline-substituted benzamide compound and pesticide
US8138213B2 (en) 2004-03-05 2012-03-20 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US10596157B2 (en) 2004-03-05 2020-03-24 Nissan Chemical Corporation Isoxazoline-substituted benzamide compound and pesticide
US8492311B2 (en) 2004-03-05 2013-07-23 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US8946492B2 (en) 2004-03-05 2015-02-03 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
WO2007026965A1 (fr) 2005-09-02 2007-03-08 Nissan Chemical Industries, Ltd. Composé de benzamide à substitution isoxazoline et agent de lutte contre les organismes nuisibles
US7951828B1 (en) 2005-09-02 2011-05-31 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US8673951B2 (en) 2005-09-02 2014-03-18 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US8987464B2 (en) 2005-09-02 2015-03-24 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
US7947715B2 (en) 2006-03-10 2011-05-24 Nissan Chemical Industries, Ltd. Isoxazoline compound and pesticide
US8242283B2 (en) 2006-03-10 2012-08-14 Nissan Chemical Industries, Ltd. Isoxazoline compound and pesticide
WO2007105814A1 (fr) 2006-03-10 2007-09-20 Nissan Chemical Industries, Ltd. Compose isoxazoline substitue et agent antiparasite
CN107915754A (zh) * 2017-10-30 2018-04-17 浙江工业大学上虞研究院有限公司 一种纳斯特试剂的催化合成方法及其应用

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