WO1999055664A1 - Preparation de composes carboxyliques - Google Patents

Preparation de composes carboxyliques Download PDF

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Publication number
WO1999055664A1
WO1999055664A1 PCT/US1999/007378 US9907378W WO9955664A1 WO 1999055664 A1 WO1999055664 A1 WO 1999055664A1 US 9907378 W US9907378 W US 9907378W WO 9955664 A1 WO9955664 A1 WO 9955664A1
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WIPO (PCT)
Prior art keywords
typically
mol
mixture
methyl
carbon atoms
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PCT/US1999/007378
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English (en)
Inventor
Mark W. Becker
Harlan H. Chapman
Daphne E. Kelly
Kenneth M. Kent
Willard Lew
Michael S. Louie
Lawrence R. Mcgee
Ernest J. Prisbe
Michael J. Postich
John C. Rohloff
Lisa M. Schultze
Richard H. Yu
Lijun Zhang
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Gilead Sciences, Inc.
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Priority to AU36376/99A priority Critical patent/AU3637699A/en
Publication of WO1999055664A1 publication Critical patent/WO1999055664A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/14—Compounds containing azido groups with azido groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention is directed to methods of preparing carbocyclic compounds and intermediates therefore.
  • a principal object of the invention is to provide new synthetic methods and compositions.
  • An additional object of the invention is to provide new methods of preparing intermediates useful in the synthesis of neuraminidase inhibitors.
  • An additional object of the invention is to provide compositions useful as intermediates that are themselves useful in the synthesis of neuraminidase inhibitors.
  • An additional object of the invention is to provide compositions useful as neuraminidase inhibitors.
  • One aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • R 1 is a cyclic hydroxy protecting group
  • R 2 is a carboxylic acid protecting group
  • R 3 is a hydroxy protecting group; and each R 20 is independently H or an alkyl of 1 to 12 carbon atoms; which process comprises reaction of a compound of the formula:
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • each of R 2 , R 3 and R 20 are as defined above; R4 is -C(R 0 ) 3 ; each R 5 is independently H or R 3 ; each R 7 is independently H or an amino protecting group; each R 8 is independently H or R 2 ; each R 9 is independently H or a thiol protecting group; each R 21 is independently R 20 , Br, Cl, F, I, CN, N0 2 or N 3 ; each R 22 is independently F, Cl, Br, I, -CN, N 3 , -N0 2 , -OR 5 , -OR 20 , -N(R0) 2 , -N(R0)(R7), -N(R 7 ) 2 , -SR0, -SR9, -S(O)R0, -S(0) 2 R 20 , -S(O)OR 2 0, -S(0)OR8, -S(0) 2 OR°, -S(0) 2 OR8, -C(0)OR 2 «, -C(0)
  • R 31 is a ketal or acetal, with a lewis acid reagent; provided that R 4 , taken as a whole, contains:
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • R 2 , R 4 , R 7 , R ° and R 21 are as defined above. which process comprises reaction of a compound of the formula:
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • R 2 , R 4 , R 5 , R 20 and R 21 are as described above; and Y 1 is a mono-, di- or unsubstituted amino group; which process comprises reaction of a compound of the formula:
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • R 2 , R 4 , R 7 , R 20 , R 21 and Y 1 are as described above; which process comprises reaction of a compound of the formula:
  • the present invention is directed to methods of making the compositions described herein. Even though the compositions of the invention are prepared by any of the applicable techniques of organic synthesis, the present invention provides advantageous methods for accomplishing the preparations.
  • reaction conditions such as temperature, reaction time, solvents, workup procedures, and the like, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • the terms "treated”, “treating”, “treatment”, and the like, mean contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities.
  • treating compound one with compound two is synonymous with “allowing compound one to react with compound two", “contacting compound one with compound two”, “reacting compound one with compound two”, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was “treated”, “reacted”, “allowed to react”, etc., with compound two.
  • Treating indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures (-100°C to 250°C, typically -78°C to 150°C, more typically -78°C to 100°C, still more typically 0°C to 100°C), solvents (aprotic or protic), reaction times (typically 10 seconds to 10 days, more typically 1 min. to 10 hours, still more typically 10 min. to 6 hours), reaction vessels (typically glass, plastic, metal), pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions and apparatus for "treating" in a given process. In particular,
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20°C), although for metal hydride reductions frequently the temperature is reduced to 0°C to -100°C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0°C to -100°C) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
  • Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
  • Workup typically consists of quenching any unreacted reagents followed by partition between a water /organic layer system (extraction) and separating the layer containing the product.
  • extraction e.g. water /organic layer system
  • One aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • R 1 is a cyclic hydroxy protecting group.
  • Typical 1,2-diol protecting groups are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-f-Butylethylidene, 1-Phenylethylidene, (4- Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetor ⁇ de
  • 1,2-diol protecting groups include those shown in Table A, or ayalic ketals or acetals. Still more typically, cyclic ketals and acetals.
  • R la is C -C6 alkyl (as defined immediately below).
  • Alkyl as used herein, unless stated to the contrary, is C ⁇ -C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n- propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2)/ 1-butyl (n-Bu, n- butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH3CH
  • Typical carboxylic acid protecting groups are R 25 (described immediately below) or those described in Greene at pages 224-276.
  • Those described in Greene include Esters (Methyl); Substituted Methyl Esters (9-Fluorenylmethyl, Methoxymethyl, Methylthiomethyl, Tetrahydropyranyl, Tetrahydrofuranyl,
  • R 25 is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms, any one of which alkyl, alkenyl, or alkynyl is substituted with 0-3 R 22 groups (R 22 is described below). More typically R 25 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, any one of which alkyl, alkenyl, or alkynyl is substituted with 0- 3 R 22 groups. Still more typically, R 25 is alkyl of 1 to 8 carbon atoms substituted with 0-2 R 22 groups. Even more typically, R 25 is alkyl of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Most typically R 25 is methyl, ethyl, 1-propyl or 2- propyl.
  • Alkenyl as used herein, unless stated to the contrary, is C ⁇ -C6
  • Alkynyl as used herein, unless stated to the contrary, is Ci-C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are ethynyl (-C+CH), 1-prop-l-ynyl (-C+CCH3), l-prop-2-ynyl (-CH2C+CH), 1-but-l-ynyl (-C+CCH2CH3), l-but-2-ynyl (-CH2C+CCH3), 1- but-3-ynyl (-CH2CH2C+CH), 2-but-3-ynyl (CH(CH3)C+CH), 1-pent-l-ynyl (-C+CCH2CH2CH3), l-pent-2-ynyl (-CH2C+CCH2CH3), l-pent-3-ynyl (-CH2CH2C+CCH3) or l-pent-4-ynyl (-CH2CH2CH
  • R 3 is a hydroxy protecting group.
  • Typical R 3 hydroxy protecting groups described in Greene (pages 14-118) include Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t- Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p- Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t- Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl, 2- (Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl, 4-Methoxyt
  • Benzoylformate Acetate, Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate, p-Chlorophenoxyacetate, p-poly-Phenylacetate, 3-Phenylpropionate, 4- Oxopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate / Pivaloate, Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate (Mesitoate)); Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl, 2- (Triphenylphosphon
  • R 3 hydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, still more typically, trialkylsilyl ethers, tosylates, mesylates and acetates.
  • Each R 20 is independently H or an alkyl of 1 to 12 carbon atoms. Typically R 20 is H or alkyl of 1 to 6 carbon as described above. Still more typically, R 20 is H or methyl. More typically yet, R 20 is H.
  • hydroxy group at position 1 is eliminated without removing the cis-4,5-diol protecting group.
  • the hydroxy group at position 1 is eliminated to form an olefinic bond between positions 1 and 6.
  • the process comprises treating compound 4 with a suitable dehydrating agent, such as a mineral acid (HCl, H2SO4) or SO2CI2. More typically, compound 4 is treated with SO2CI2, followed by an alkanol. Still more typically, compound 4 is treated with SO2CI2 in a suitable polar, aprotic solvent, such as an amine to form an olefin. More typically yet, compound 4 is treated with SO2CI2 in pyridine/CH2Cl2 at a temperature between -100°C
  • a suitable dehydrating agent such as a mineral acid (HCl, H2SO4) or SO2CI2. More typically, compound 4 is treated with SO2CI2, followed by an alkanol. Still more typically, compound 4 is treated with SO2CI2 in a suitable polar, aprotic solvent, such as an amine to form an olefin. More typically yet, compound 4 is treated with SO2CI2 in pyridine/CH2Cl2 at a temperature between -100°C
  • a solution of compound 4 and pyridine in dichloromethane is cooled to -20° to -30°C and treated portionwise with sulfuryl chloride. After the exothermic reaction subsided, the resulting slurry is quenched with ethanol, warmed to 0°C, and washed successively with 16% sulfuric acid, water and 5% aqueous sodium bicarbonate.
  • Example 4 A detailed example of this embodiment is provided as Example 4 below.
  • the process of this embodiment further comprises purifying or separating compound 5 from any other reaction products or other containments such as other double bond isomers, halogenated side products or starting materials and reagents by treatment with a noble metal complex.
  • Noble metals include gold, silver, platinum, palladium, iridium, rhenium, mercury, ruthenium and osmium.
  • the noble metal complex of this embodiment is a complex of platinum or palladium. More typically the complex is a palladium (0) complex, still more typically, the complex is a tetrakis(triarylphosphine)palladium (0) complex.
  • the organic layer of the reaction contains a mixture of olefin and halogenated products as well as starting material. It is concentrated in vacuo and ethyl acetate is added. The solution is treated with pyrrolidine and tetrakis(triphenylphosphine)palladium(0) at ambient temperature, followed by washing with 16% sulfuric acid. The organic layer is filtered through a pad of silica gel and eluted with ethyl acetate. The filtrate is concentrated in vacuo . The residue is dissolved in ethyl acetate at reflux and hexane is added. Upon cooling, the product crystallizes and is separated by filtration and washed with 14% ethyl acetate in hexane. After drying in vacuo, 5 was obtained. A detailed example of this embodiment is provided as Example 4 below.
  • compound 5 is of the formula:
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • R 2 , R 3 and R 20 are as defined above.
  • R 4 is described below.
  • W is carbocycle or heterocycle wherein any one of which carbocycle or heterocycle is substituted with 0 to 3 R 29 groups (R 29 is described below).
  • W is a carbocycle or heterocycle, with the proviso that each W is independently substituted with 0 to 3 R 29 groups (R 29 is described below).
  • W carbocycles and heterocycles are stable chemical structures. Such structures are isolatable in measurable yield, with measurable purity, from reaction mixtures at temperatures from -78°C to 200°C.
  • Each W is independently substituted with 0 to 3 R 29 groups.
  • W is a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. More typically, W has 3 to 10 ring atoms, still more typically, 3 to 7 ring atoms, and ordinarily 3 to 6 ring atoms.
  • the W rings are saturated when containing 3 ring atoms, saturated or monounsaturated when containing 4 ring atoms, saturated, or mono- or diunsaturated when containing 5 ring atoms, and saturated, mono- or diunsaturated, or aromatic when containing 6 ring atoms.
  • W When W is carbocyclic, it is typically a 3 to 7 carbon monocycle or a 7 to 12 carbon atom bicycle. More typically, W monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. W bicyclic carbocycles typically have 7 to 12 ring atoms arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, still more typically, 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, 1- cyclopent-1-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-1-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
  • a W heterocycle is typically a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). More typically, W heterocyclic monocycles have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S), still more typically, 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
  • W heterocyclic bicycles typically have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system, still more typically, 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
  • Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A.
  • heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydro quinolinyl,
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2- pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2- pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1- pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • W heterocycles are selected from pyridyl, pyridazinyl,
  • the heterocycle of W is bonded through a carbon atom or nitrogen atom thereof. Still more typically W heterocycles are bonded by a stable covalent bond through a carbon or nitrogen atom thereof. Stable covalent bonds are chemically stable structures as described above.
  • W optionally is selected from the group consisting of:
  • R5 is H or R 3 .
  • R 7 is H or an amino protecting group.
  • R 7 amino protecting groups are described by Greene at pages 315-385. They include Carbamates (methyl and ethyl, 9-fluorenylmethyl, 9(2-sulfo)fluoroenylmethyl, 9-(2,7- dibromo)fluorenylmethyl, 2,7-di-i-buthyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl, 4-methoxyphenacyl); Substituted Ethyl (2,2,2- trichoroethyl, 2-trimethylsilylethyl, 2-phenylethyl, l-(l-adamantyl)-l- methylethyl, l,l-dimethyl-2-haloethyl, l,l-dimethyl-2,2-dibromoethyl, 1,1- dimethyl-2,2,2-t
  • R 9 is H or a thiol protecting group.
  • R 9 amino protecting groups are described by Greene at pages 277-308. They include Thioethers (S-Benzyl, S-p- Methoxybenzyl, S-o- or p-Hydroxy- or Acetoxybenzyl, S-p-Nitrobenzyl, S-4- Picolyl, S-2-Picolyl N-Oxide, S-9-Anthrylmethyl, S-9-Fluorenylmethyl, S-
  • S-Diphenylmethyl Substituted S-Diphenylmethyl, and S- Triphenylmethyl Thioethers (S-Diphenylmethyl, S-Bis(4- methoxyphenyl)methyl, S-5-Dibenzosuberyl, S-Triphenylmethyl, S-Diphenyl- 4-pyridylmethyl, S-Phenyl, S-2,4-Dinitrophenyl, S-f-Butyl, S-1-Adamantyl); Substituted S-Methyl Derivatives Monothio, Dithio, and Aminothio Acetals (S- Methoxymethyl, S-Isobutoxymethyl, S-2-Tetrahydropyranyl, S- Benzylthiomethyl, S-Phenylthiomethyl, Thiazolidines, S-Acetamidomethyl, S- Trimethylacetamidomethyl, S-Benza
  • Each R 21 is independently R 20 , Br, Cl, F, I CN, N0 2 or N 3 .
  • R 21 is Cl, F or R 20 , more typically, R 20 , still more typically, H.
  • Each R 22 is independently F, Cl, Br, I, -CN, N 3 , -N0 2 , -OR 5 , -OR 2 0, -N(R 0 ) 2 , -N(R 0)(R 7 ), -N(R ) 2 , -SR 20 , -SR 9 , -S(0)R 20 , -S(0) 2 R 20 , -S(O)OR 0, -S(0)OR 8 , -S(0) 2 OR 20 , -S(0) 2 OR 8 , -C(O)OR 2 0, -C(0)OR 8 , -OC(0)R 20 ,
  • Each R 23 is independently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or alkynyl of 2 to 11 carbon atoms. More typically R 23 is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, or alkynyl of 2 to 8 carbon atoms, still more typically, R 23 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms. More typically yet, R 23 is R 5 . Each R 24 is independently R 23 wherein each R 23 is substituted with 0 to
  • R 23 and R 22 are typical of R 24 . More typically R 24 is substituted with 0, 1, 2, or 3 R 22 groups.
  • R 2 a is independently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 22 groups. More typically R 2 a is alkylene of 1 to 8 carbon atoms, alkenylene of 2 to 8 carbon atoms, or alkynylene of 2 to 8 carbon atoms, still more typically, R 24a is alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms, or alkynylene of 2 to 6 carbon atoms. More typically yet, R a is -CH -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -C(H)(CH 3 )-.
  • Each R 28 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms. More typically R 28 is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, or alkynyl of 2 to 8 carbon atoms, still more typically, R 28 is alkyl of 1 to 6 carbon atoms, alkenyl
  • R 28 is R 25 .
  • Each R 29 is independently R 22 or R 28 wherein each R 28 is substituted with 0 to 3 R 22 groups.
  • Each of the typical embodiments of R 28 and R 22 are typical of R 29 . More typically R 29 is substituted with 0, 1, 2, or 3 R 22 groups.
  • Each R 30 is independently H, R 24 , W or -R 2 a W.
  • R 4 is -C(R 30 ) 3 , provided that R 4 , taken as a whole, contains 0 to 1 W groups (W is described above) substituted with 0 to 3 R 29 groups (R 29 is described above); and, in addition, 1 to 12 carbon atoms substituted with 0 to 3 R 22 groups (R 22 is described above).
  • W is described above
  • R 29 is described above
  • R 22 is described above
  • Exemplary embodiments of R 4 are provided as Ui embodiments in the documents cited in the "Brief Description of Related Art" above.
  • R 30 is H. More typically, one R 30 is H and the remaining two R 30 's are independently R 24 , W or -R 4a W. More typically yet, one R 30 is H, one R 30 is R 24 and the remaining R 30 is independently R 24 , W or -R 2 a W.
  • one R 30 is H, one R 30 is R 25 and one R 30 is R 24 , W or -R 2 a W. Typically, one R 30 is H and two R 30 's are R 25 . In another embodiment of R 4 , one R 30 is H, one R 30 is -R 2 a W and one R 30 is R 24 , W or - R 2 a W. Typically, one R 30 is H, one R 30 is -R 2 a W and one R 30 is R 24 . In another embodiment, one R 30 is H and two R 30 's are alkyl of 1 to 6 carbon atoms.
  • R 4 is:
  • R 26 R 26 .
  • R ⁇ is H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OAc (-O- C(0)CH3), -OH, -NH2, or -SH, typically H, -CH3 or -CH2CH3.
  • each R 4 (taken as a whole) contains 0-3 W groups each of which is independently substituted with 0-3 R 29 groups; and each R 4 (taken as a whole) in addition contains 1-12 carbon atoms, each carbon atom of which is independently substituted with 0-3 R 22 groups. More typically each R 4 contains 0, 1 or 2 such W groups, more typically yet, 0 or 1 such W group.
  • each R 30 group (taken as whole) of R 4 is not so electron withdrawing as to prevent the formation of compound 11.
  • each R 30 group (taken as whole) of R 4 has a Hammett CJpa ra value of less than about 1, typically less than about 0.75, more typically less than about 0.5.
  • each R 30 group (taken as whole) of R 4 has a Hammett a para value of -1.0 to 1.0, more typically -0.75 to 0.75, more typically yet -0.5 to 0.5.
  • R 31 is a ketal or acetal, with a lewis acid reagent.
  • R 31 is -C(R 0 ) 2 - wherein R 30 is as described above.
  • compound 10 is also treated with a reducing reagent.
  • Typical reducing reagents are of the form B(R 30 )3 such as BH 3 .
  • reducing reagents of the form B(R 30 )3 are complexed with common solvents such as diethylether and dimethylsulfide.
  • common solvents such as diethylether and dimethylsulfide.
  • Brown, H.C. “Boranes in Organic Chemistry", (Cornell Univ. Press, Ithaca, N.Y., 1972) (Brown) provides a very large number of examples such as is found in Part Four, Selective Reductions, pages 209-251, Part Five, Hydroboration, pages 255-297, and Part Six, Organoboranes, pages 301-446.
  • compound 10 is treated with a lewis acid in a nonprotic solvent. More typically, compound 10 is treated with a lewis acid and a reducing reagent in a nonprotic solvent.
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • R 7 31 in: R 2 , R 4 , R 7 , R 20 and R 21 are as defined above.
  • This process embodiment comprises reaction of a compound of the formula:.
  • the process comprises treating compound 30 with a reducing agent to form compound 31. More typically the process comprises treating compound 30 with hydrogen gas and a catalyst (such as platinum on carbon or Lindlar's catalyst), or reducing reagents (typically a trisubstituted phosphine such as trialkyl (P(R 25 ) 3 ) or triaryl phosphine (PW 3 , e.g. triphenylphosphine).
  • a catalyst such as platinum on carbon or Lindlar's catalyst
  • reducing reagents typically a trisubstituted phosphine such as trialkyl (P(R 25 ) 3 ) or triaryl phosphine (PW 3 , e.g. triphenylphosphine).
  • the process comprises treating compound 30 with triphenylphosphine and a base to form compound 31.
  • compound 30 is disolved in a suitable polar, aprotic solvent such as anhydrous acetonitrile.
  • a suitable polar, aprotic solvent such as anhydrous acetonitrile.
  • a solution of anhydrous triphenylphosphine in a suitable solvent such as anhydrous tetrahydrofuran or a mixture of solvents is added dropwise. The mixture is heated at reflux then concentrated in vacuo to leave compound 5.
  • a suitable polar, aprotic solvent such as anhydrous acetonitrile.
  • a suitable solvent such as anhydrous tetrahydrofuran or a mixture of solvents
  • compound 31 is of the formula:
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • R 2 , R 4 , R 5 , R 20 and R 21 are as described above.
  • Y 1 is a mono-, di- or unsubstituted amino group.
  • Y 1 is of the formula -N(R 30 ) 2 , a phthalimide or is a nitrogen containing heterocycle
  • Y 1 is a phthalimide, more typically yet, a phthalimide salt.
  • the amine reagent is of the formula HY 1 or a salt of HY 1 , such as, by way of example, NH 3 (McManns, et al., "Bull Soc.
  • HY 1 generally (Moussevon, M., et al., "Synth. Commun.” 3:177 (1973)) or phthalimide (Gabriel, et al, “Ber.” 20:2224 (1887) or Gibson, et al, "Angew. Chem. Int.”, 7:919-930 (1968)).
  • the process comprises treating compound 40 with the amine reagent to produce compound 32. More typically, compound 40 is treated with the amine reagent in a suitable polar a protic solvent (e.g. CH 3 CN, DMF or THF). Optionally compound 40 is treated with the amine reagent and a base. Typical details of this process embodiment can be found in March, "Advanced Organic Chemistry" 4th. ed., pp 425-427.
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • This process embodiment comprises reaction of a compound of the formula:
  • oxidizing reagent an oxidizing reagent.
  • suitable oxidation reagents include Cr0 3 , Na 2 Cr 2 ⁇ 7, KMn ⁇ 4 , PDC and PCC. Typical details of this process embodiment can be found in Larock, "Comprehensive Organic Transformations", pp. 604-
  • Solvents typically include inert polar solvents (e.g. CH 2 C1 2 , toluene or CH 3 CN).
  • compound 51 is of the formula:
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • This process embodiment comprises reaction of a compound of the formula:
  • the base is a hindered amine or hindered alkoxide or the salts of either. More typically the base is of the formula NaOR 25 , KOR 25 or NR 25 3 , more typically yet, DBN, DBU or diisopropyl ethyl amine.
  • compound 61 is of the formula:
  • Another aspect of the present invention is directed to processes for the preparation of compounds of the formula:
  • R 2 , R 4 , R 7 , R 20 , R 21 and Y 1 are as described above;
  • Schemes 1 and 2 depict embodiments of the invention. Detailed descriptions of the processes of Schemes 1 and 2 are provided in the Examples (below).
  • Additional individual process embodiments of the invention include any one or sequential combination of processes AA, AB, AC, AD, AE, AF, AG, AH, Al, AJ, or AK of Schemes 1 and 2.
  • Sequential combination as used herein means more than one process wherein the individual processes are performed one after the other in the order shown. Isolation, separation, purification is optionally performed prior to any of the individual processes.
  • Additional individual process embodiments of the invention include any one or sequential combination of the processes of Example 1, Example 2, Example 3, Example 4, Example 5, Example 6, Example 7, Example 8, Example 9, Example 10, Example 11, Example 12, Example 13, Example 14, Example 15, Example 16, Example 17, Example 18, Example 19, Example 20, Example 21, Example 22, Example 23, Example 24 or Example 25.
  • the construction of the 3-pentylether group was accomplished by reductive opening of a quinic or shikimic acid derived 3,4-pentylidene ketal 300 (Scheme 4).
  • 3,4-pentylidene ketal 300 was prepared in three steps and 80% yield from natural (-)-shikimic acid.
  • the quinic lactone acetonide 305 was prepared in 90% yield from by modification of the method of Shing (Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.;
  • the oily 3,4-pentylidene ketal 300 was isolated in nearly quantitative yield and was identical in all respects to the ketal 300 prepared from (-)- shikimic acid.
  • a more concise exemplary embodiment based on initial formation of the 3,4-pentylidene ketal analogs of 305, 307 and 308 from (-)- quinic acid 3 was found to be impractical for scale-up due to the lack of crystallinity in the 3,4-pentylidene series.
  • Epoxide 304 was heated at 70 °C with sodium azide and ammonium chloride in aqueous ethanol to afford an oily 10:1 mixture of isomeric azido-alcohols 313:314.
  • Intramolecular reductive cyclization (Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353 and references 276-282 cited therein) of the crude 313, 314 mixture with trimethylphosphine in anhydrous acetonitrile at 35°C cleanly afforded a single aziridine 315, of ca.
  • Trimethylphosphine is available from the Aldrich Chemical Company, 1001 West Saint Paul Ave., Milwaukee, WI 53233, or it can be prepared as described: Reier, F-W.; Wolfram, P.; Schumann, H.; German Offen. 1987, DE 3612629 Al). Triphenylphosphine, in the presence of catalytic triethylamine hydrochloride
  • azide reduction with substrate 317 was accomplished using catalytic hydrogenation with Raney nickel in ethanol (1 atm H2) at 35°C (see (a) Prisbe, E. J.; Verheyden, J. P. H.; Montgomery, W. W.;
  • the salt 116»H3P ⁇ 4 crystallized (The hydrochloride salt 116* HCl was a solid, but not crystalline in our hands. Screening of pharmaceutically-acceptable acids (Berge, S. M.; Bighley, L. D.; Monkhouse, D. C. /. Pharmaceutical Sci. 1977, 66, 1) revealed two which gave crystalline salts: citric (mp 123-6 °C, acetone) and phosphoric (mp 203-4 °C, ethanol). Both salts were 1:1 stoichiometry.) as feathery needles and it was isolated in 71% yield from 317.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example, size exclusion or ion exchange chromatography, high, medium, or low pressure liquid chromatography, small scale and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
  • the compounds of the invention are enriched or resolved optical isomers at any or all asymmetric atoms.
  • the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
  • racemic and diasteromeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention.
  • Stereospecific synthesis is described in the examples. Methods of this type conveniently are used when the appropriate chiral starting material is available and reaction steps are chosen do not result in undesired racemization at chiral sites.
  • One advantage of stereospecific synthesis is that it does not produce undesired enantiomers that must be removed from the final product, thereby lowering overall synthetic yield.
  • those skilled in the art would understand what starting materials and reaction conditions should be used to obtain the desired enantiomerically enriched or pure isomers by stereospecific synthesis. If an unexpected racemization occurs in a method thought to be stereospecific then one needs only to use one of the following separation methods to obtain the desired product.
  • a suitable stereospecific synthesis cannot be empirically designed or determined with routine experimentation then those skilled in the art would turn to other methods.
  • One method of general utility is chromotographic resolution of enantiomers on chiral chromatography resins. These resins are packed in columns, commonly called Pirkle columns, and are commercially available. The columns contain a chiral stationary phase. The racemate is placed in solution and loaded onto the column, and thereafter separated by HPLC. See for example, Proceedings Chromatographic Society - International Symposium on Chiral Separations, Sept. 3-4, 1987.
  • Enzymatic resolution is another method of potential value.
  • one prepares covalent derivatives of the enantiomers in the racemic mixture, generally lower alkyl esters (for example of carboxyl), and then exposes the derivative to enzymatic cleavage, generally hydrolysis.
  • an enzyme must be chosen that is capable of stereospecific cleavage, so it is frequently necessary to routinely screen several enzymes. If esters are to be cleaved, then one selects a group of esterases, phosphatases, and Upases and determines their activity on the derivative. Typical esterases are from liver, pancreas or other animal organs, and include porcine liver esterase.
  • the enatiomeric mixture separates from solution or a melt as a conglomerate, i.e., a mixture of enantiomerically-pure crystals, then the crystals can be mechanically separated, thereby producing the enantiomerically enriched preparation.
  • This method is not practical for large scale preparations and is of no value for true racemic compounds.
  • Asymmetric synthesis is another technique for achieving enantiomeric enrichment. For example, a chiral protecting group is reacted with the group to be protected and the reaction mixture allowed to equilibrate. If the reaction is enantiomerically specific then the product will be enriched in that enantiomer.
  • compositions of this invention optionally comprise salts of the compounds herein, for example, Na + , Li+, KA Ca ++ and Mg ++ .
  • Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety.
  • Monovalent salts are preferred if a water soluble salt is desired.
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li + , Na + , and K + . A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoiochimetric amounts of
  • the salts of the parental compounds with one or more amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • a basic or acidic group e.g., lysine, arginine or glutamic acid
  • a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • the compounds of the invention are polyfunctional. As such they represent a unique class of monomers for the synthesis of polymers.
  • the polymers prepared from the compounds of this invention include polyamides, polyesters and mixed polyester- polyamides.
  • the present compounds are used as monomers to provide access to polymers having unique pendent functionalities.
  • the compounds of this invention are useful as comonomers with monomers which do not fall within the scope of the invention.
  • Polymers of the compounds of this invention will have utility as cation exchange agents (polyesters or polyamides) in the preparation of molecular sieves (polyamides), textiles, fibers, films, formed articles and the like.
  • Polymers are prepared by any conventional method, for example, by cross-linking an -OH or -NH 2 group of the compounds of the invention with a diacid comonomer. The preparation of these polymers from the compounds of the invention is conventional per se.
  • the compounds of the invention are also useful as a unique class of polyfunctional surfactants. Particularly when R 4 or R 2 do not contain hydrophilic substituents and are, for example, alkyl, the compounds have the properties of bi-functional surfactants. As such they have useful surfactant, surface coating, emulsion modifying, rheology modifying and surface wetting properties.
  • the compounds of the invention are useful as a unique class of phase transfer agents.
  • phase transfer agents For way of example and
  • the compounds of the invention are useful in phase transfer catalysis and liquid /liquid ion extraction (LIX).
  • LIX liquid /liquid ion extraction
  • the compounds of the invention optionally contain asymmetric carbon atoms.
  • they are a unique class of chiral auxiliaries for use in the synthesis or resolution of other optically active materials.
  • a racemic mixture of carboxylic acids can be resolved into its component enantiomers by: 1) forming a mixture of diastereomeric esters or amides with a compound of the invention containing an -OH or -NH 2 group; 2) separating the diastereomers; and 3) hydrolyzing the ester structure.
  • such a method can be used to resolve the compounds of the invention themselves if optically active acids are used instead of racemic starting materials.
  • the compounds of this invention are useful as linkers or spacers in preparing affinity absorption matrices, immobilized enzymes for process control, or immunoassay reagents.
  • the compounds herein contain a multiplicity of functional groups that are suitable as sites for cross-linking desired substances.
  • affinity reagents such as hormones, peptides, antibodies, drugs, and the like to insoluble substrates.
  • immobilized enzymes are used to perform catalytic conversions with facile recovery of enzyme.
  • Bifunctional compounds are commonly used to link analytes to detectable groups in preparing diagnostic reagents.
  • Suitable functional groups in the compounds of this invention are suitable for use in cross-linking.
  • -OH and -NH 2 groups Suitable protection of reactive groups will be used where necessary while assembling the cross-linked reagent to prevent polymerization of the bifunctional compound of this invention.
  • the compounds here are used by linking them through hydroxyl or amino groups to carboxylic or phosphonic acid groups of the first linked partner, then covalently bonding to the other binding partner through another -OH or -NH 2 group.
  • a first binding partner such as a steroid hormone is reacted to form an amide bond with the -NH 2 group of a compound of this invention and then this conjugate is cross-linked through a hydroxyl to cyanogen bromide activated Sepaharose,
  • aqueous layer was back-extracted with ethyl acetate (13 kg) and the combined organic layers were washed with 5% aqueous sodium bicarbonate (14 kg). Most of the ethyl acetate was distilled in vacuo to leave a pale yellow solid residue of 100 which was used directly in the next step.
  • Pentyl ketal 107 A solution of acetonide 104 (8.9 kg, 27.8 mol), 3- pentanone (24 kg, 279 mol) and 70% perchloric acid (0.056 kg, 0.39 mol) was stirred for 18 hours. The volatiles were distilled in vacuo at ambient temperature and fresh 3-pentanone (30 kg, 348 mol) was added gradually as the distillation progressed. The reaction mixture was filtered, toluene (18 kg) was added, and the resulting solution was washed successively with 6% aqueous sodium bicarbonate (19 kg), water (18 kg) and brine (24 kg). The organic layer was concentrated in vacuo and toluene (28 kg) was added gradually as the distillation progressed. When no more distilled, the residual orange oil was composed of pentyl ketal 107 (9.7 kg, 100% yield) and toluene (ca. 2 kg).
  • Pentyl ether 108 A solution of ketal 107 (8.6 kg, 25 mol) in dichloromethane (90 kg) was cooled to -30° to -20°C and treated with borane- methyl sulfide complex (2.1 kg, 27.5 mol) and trimethylsilyl trifluoromethanesulfonate (7.2 kg, 32.5 mol). After one hour, 10% aqueous sodium bicarbonate solution (40 kg) was slowly added. The mixture was warmed to ambient temperature and stirred for 12 hours. The organic layer was filtered and concentrated in vacuo to leave a ca. 8:1 mixture of 108:109 as a gray waxy solid (7.8 kg, 90% yield).
  • Epoxide 110 A ca. 8:1 mixture of isomeric pentyl ethers 108:109 (7.8 kg, 22.3 mol) in ethanol (26 kg) was treated with a solution of potassium hydrogen carbonate (3.52 kg, 35 mol) in water (22 kg). After heating at 55°-
  • Hydroxy azide 111 A mixture of epoxide 110 (548 g, 2.0 mol), sodium azide (156 g, 2.4 mol) and ammonium chloride (128.4 g, 2.4 mol) in water (0.265 L) and ethanol (1.065 L) was heated at 70°-75°C for eight hours. Aqueous sodium bicarbonate (0.42 L of 8% solution) was added and the ethanol was distilled in vacuo. The aqueous residue was extracted with ethyl acetate (1 L) and the extract was washed with water (0.5 L). The water wash was back-extracted with ethyl acetate (0.5 L).
  • Example 9 Aziridine 113: A ca. 10:1 mixture of hydroxy azides 111:112 (608 g, 2.0 mol) was three times co-evaporated in vacuo from anhydrous acetonitrile (3 x 0.3 L) and then dissolved in anhydrous acetonitrile (1 L). A solution of anhydrous triphenylphosphine (483 g, 1.84 mol) in anhydrous tetrahydrofuran (0.1 L) and anhydrous acetonitrile (0.92 L) was added dropwise over two hours.
  • Acetamido azide 115 A mixture of aziridine 113 (490 g, 1.93 mol) and triphenylphosphine oxide (ca. 108 g), sodium azide (151 g, 2.33 mol) and ammonium chloride (125 g, 2.33 mol) in dimethylformamide (1.3 L) was heated at 80°-85°C for five hours. Sodium bicarbonate (32.8 g, 0.39 mol) and water (0.66 L) were added. The amino azide 114 was isolated from the reaction mixture by six extractions with hexanes (6 x 1 L). The combined hexane extracts were concentrated in vacuo to ca. 4.5 L total volume and dichloromethane (1.04 L) was added.
  • Aqueous sodium bicarbonate (4.2 L of 8% solution, 3.88 mol) was added, followed by acetic anhydride (198 g, 1.94 mol). After stirring for one hour at ambient temperature, the aqueous layer was discarded. The organic phases were concentrated in vacuo to 1.74 kg total weight and dissolved with ethyl acetate (0.209 L) at reflux. Upon cooling, acetamido azide 115 crystallized and was isolated by filtration. After washing with cold 15% ethyl acetate in hexane (1 L) and drying in vacuo at ambient temperature, pure 115 was obtained as off-white crystals (361 g, 55% yield), mp 126-132°C.
  • Acetamido amine 116 A mixture of azide 115 (549 g, 1.62 mol) and Lindlar catalyst (50 g) in abs. ethanol (3.25 L) was stirred for eighteen hours while hydrogen (1 atm.) was bubbled through the mixture. Filtration through Celite and concentration of the filtrate vacuo afforded 116 as a foam which solidified on standing (496 g, 98% yield).
  • Phosphate salt of 116 A solution of acetamido amine 116 (5.02 g, 16.1 mmol) in acetone (75 mL) at reflux was treated with 85% phosphoric acid (1.85 g, 16.1 mmol) in abs. ethanol (25 mL). Crystallization commenced immediately and after cooling to 0°C for 12 hours the precipitate was collected
  • Example 15 Ethyl (-)-3,4-0-Isopropylidene Quinate (307).
  • a suspension of the crude lactone 305 (22.3 kg, 104.1 mol) in absolute ethanol (70.4 kg) under a nitrogen atmosphere was treated with 21% sodium ethoxide in denatured ethanol (340 g, 1.05 mol) and the resulting solution was stirred for 2 h.
  • the sodium ethoxide was quenched by the addition of glacial acetic acid (72 g, 1.2 mol) and the volatile components were removed by distillation in vacuo (50°C, 25 mm Hg).
  • Ethyl 3,4-0-Isopropylidene-5-0-methanesulfonyl Shikimate (309).
  • a solution of mesylate 308 (24.2 kg, 71.64 mol) and pyridine (34.0 kg, 430 mol) in dichloromethane (92 kg) was cooled to between -20 and -30°C and treated dropwise with sulfuryl chloride (14.5 kg, 107.4 mol) over 3.5 h.
  • Excess sulfuryl chloride was decomposed by dropwise addition of ethyl alcohol (5.7 kg) over 1 h.
  • the mixture was warmed to 0-5°C and washed with 2 M sulfuric acid (69 kg, 131 mol).
  • -56- composed of a mixture of 309:310:311 (ratio 4:1:1).
  • the mixture was dissolved in ethyl acetate (51 kg) and treated with pyrrolidine (5.33 kg, 74.9 mol) and tetrakis(triphenylphosphine)palladium(0) (165 g, 0.14 mol) at 35°C for 3.5 h.
  • the 1,6-olefin 310 was converted into the pyrrolidine substitution product 312.
  • the murky brown mixture was extracted three times with 2 M sulfuric acid (3 x 47 kg) to remove 312 and unreacted pyrrolidine.
  • the organic layer was filtered through a silica gel pad (Merck SG 60, 70-230 mesh, 24 kg) to remove catalyst residues and the pad was eluted with ethyl acetate (102 kg).
  • the eluent was washed with 5% aqueous sodium bicarbonate (24.2 kg, 14.3 mol) and the volatiles were removed by distillation in vacuo (60°C, 50 mm Hg).
  • the semi-solid residue was recrystallized from refluxing ethyl acetate (14.3 kg) and hexanes (13.0 kg) with vigorous stirring.
  • Example 18 Ethyl 3,4-0-Isopentylidene-5-0-methanesulfonyl Shikimate (300).
  • Example 19 Ethyl 3-0-(l-Ethylpropyl)-5-0-methanesulfonyl Shikimate (301).
  • a solution of pentylidene ketal 300 (10.3 kg, 29.6 mol) in dichloromethane (125 kg) was cooled to between -10 and -20°C and treated with borane*dimethylsulfide complex (2.47 kg, 32.6 mol), followed by trimethylsilyl trifluoromethanesulfonate (4.80 kg, 21.6 mol) over 0.5 h.
  • the reaction was treated in portions with 6.8% aqueous sodium bicarbonate (38.7 kg, 31.3 mol) over 3-6 h. The initial portions were added slowly, ca.
  • a ca. 10:1 mixture of azido-alcohols 313:314 (2.00 kg, 6.73 mol) was dissolved in anhydrous acetonitrile (2.1 kg) and dried by azeotropic distillation of acetonitrile in vacuo (50°C, 100 mm Hg).
  • the water content was determined to be ⁇ 0.1% by Karl Fischer titration, the solution was cooled and diluted to a total volume of 5 L with anhydrous acetonitrile.
  • a mixture of crude aziridine 315 (1.66 kg, 6.55 mol), dimethylformamide (3.3 kg), ammonium chloride (0.35 kg, 6.53 mol), and sodium azide (0.43 kg, 6.61 mol) was stirred and heated at 70-80°C under a nitrogen atmosphere.

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Abstract

L'invention concerne de nouveaux procédés synthétiques et des compositions, plus particulièrement de nouveaux procédés de préparation d'intermédiaires utiles dans la synthèse d'inhibiteurs de la neuraminidase et des compositions utiles en tant qu'intermédiaires qui sont, quant à eux, utiles dans la synthèse des inhibiteurs de la neuraminidase.
PCT/US1999/007378 1998-04-24 1999-04-23 Preparation de composes carboxyliques WO1999055664A1 (fr)

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Cited By (12)

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WO2001029020A2 (fr) * 1999-10-19 2001-04-26 Abbott Laboratories Inhibiteurs de la neuraminidase
JP2001354635A (ja) * 2000-04-10 2001-12-25 F Hoffmann La Roche Ag タミフル、ガロカルボン酸法
US6596870B2 (en) 2000-07-13 2003-07-22 Brandeis University Asymmetric synthetic methods based on phase transfer catalysis
EP1951654A1 (fr) * 2005-11-25 2008-08-06 Hetero Drugs Limited Procede ameliore de fabrication de phosphate d oseltamivir
US7473798B2 (en) 2005-12-28 2009-01-06 Roche Palo Alto Llc Derivatives of unsaturated, cyclic organic acids
CN105688987A (zh) * 2016-03-10 2016-06-22 南京大学 一种新型的手性磷酸催化剂及其合成方法与应用
CN110194728A (zh) * 2019-06-19 2019-09-03 湖南华腾制药有限公司 磷酸奥司他韦中间体的连续化合成方法
CN112125877A (zh) * 2020-09-28 2020-12-25 浙江得乐康食品股份有限公司 一种奎尼酸合成奥司他韦磺酸酯的工艺
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CN115417783A (zh) * 2022-08-18 2022-12-02 苏州匠化生物科技有限公司 一种合成奥司他韦对映异构体的方法
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001029020A2 (fr) * 1999-10-19 2001-04-26 Abbott Laboratories Inhibiteurs de la neuraminidase
WO2001029020A3 (fr) * 1999-10-19 2001-12-27 Abbott Lab Inhibiteurs de la neuraminidase
JP2001354635A (ja) * 2000-04-10 2001-12-25 F Hoffmann La Roche Ag タミフル、ガロカルボン酸法
US6596870B2 (en) 2000-07-13 2003-07-22 Brandeis University Asymmetric synthetic methods based on phase transfer catalysis
EP1951654A1 (fr) * 2005-11-25 2008-08-06 Hetero Drugs Limited Procede ameliore de fabrication de phosphate d oseltamivir
EP1951654A4 (fr) * 2005-11-25 2009-12-30 Hetero Drugs Ltd Procede ameliore de fabrication de phosphate d oseltamivir
EP2204359A1 (fr) * 2005-11-25 2010-07-07 Hetero Drugs Limited Procédé d'amélioré pour phosphate d'oseltamivir
US7473798B2 (en) 2005-12-28 2009-01-06 Roche Palo Alto Llc Derivatives of unsaturated, cyclic organic acids
CN105688987A (zh) * 2016-03-10 2016-06-22 南京大学 一种新型的手性磷酸催化剂及其合成方法与应用
CN110194728A (zh) * 2019-06-19 2019-09-03 湖南华腾制药有限公司 磷酸奥司他韦中间体的连续化合成方法
CN110194728B (zh) * 2019-06-19 2021-04-30 湖南华腾制药有限公司 磷酸奥司他韦中间体的连续化合成方法
CN112125877A (zh) * 2020-09-28 2020-12-25 浙江得乐康食品股份有限公司 一种奎尼酸合成奥司他韦磺酸酯的工艺
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