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WO1998006700A1 - Reaction de desoxygenation stereoselective - Google Patents

Reaction de desoxygenation stereoselective Download PDF

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Publication number
WO1998006700A1
WO1998006700A1 PCT/US1997/014045 US9714045W WO9806700A1 WO 1998006700 A1 WO1998006700 A1 WO 1998006700A1 US 9714045 W US9714045 W US 9714045W WO 9806700 A1 WO9806700 A1 WO 9806700A1
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Prior art keywords
alkyl
group
cycloalkyl
alkenyl
alkynyl
Prior art date
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PCT/US1997/014045
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English (en)
Inventor
Paul N. Devine
Ulf H. Dolling
Lisa F. Frey
Richard D. Tillyer
David M. Tschaen
Yoshiaki Kato
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MSD KK
Merck and Co Inc
Original Assignee
Banyu Phamaceutical Co Ltd
Merck and Co Inc
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Priority claimed from GBGB9617900.7A external-priority patent/GB9617900D0/en
Priority claimed from GBGB9625806.6A external-priority patent/GB9625806D0/en
Application filed by Banyu Phamaceutical Co Ltd, Merck and Co Inc filed Critical Banyu Phamaceutical Co Ltd
Priority to EP97937187A priority Critical patent/EP0923557A4/fr
Priority to CA002262676A priority patent/CA2262676A1/fr
Priority to JP10509915A priority patent/JPH11514676A/ja
Priority to AU39757/97A priority patent/AU711936B2/en
Publication of WO1998006700A1 publication Critical patent/WO1998006700A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel key intermediates in the synthesis of an endothelin antagonist and the method for preparing these key intermediates of formula I.
  • Two endothelin receptor subtypes ETA and ET ⁇ are known so far.
  • the compounds of the present invention possess high affinity to at least one of two receptor subtypes, responsible for the dilation of smooth muscle, such as blood vessels or in the trachea.
  • the endothelin antagonist compounds of the present invention provide a new therapeutic potential, particularly for the treatment of hypertension, pulmonary hypertension, Raynaud's disease, acute renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, arteriosclerosis, asthma, gastric ulcer, diabetes, restenosis, prostatauxe endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and/or cyclosporin-induced renal failure or hypertension.
  • Endothelin is a polypeptide composed of amino acids, and it is produced by vascular endothelial cells of human or pig. Endothelin has a potent vasoconstrictor effect and a sustained and potent pressor action (Nature, 332, 411-415 (1988)).
  • endothelin isopeptides which resemble one another in structure, exist in the bodies of animals including human, and these peptides have vasoconstriction and pressor effects (Proc. Natl. Acad, Sci, USA, 86. 2863-2867 (1989)).
  • the endothelin levels are clearly elevated in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, diabetes or atherosclerosis, or in the washing fluids of the respiratory tract or the blood of patients with asthmaticus as compared with normal levels (Japan, J. Hypertension, 12, 79, (1989), J. Vascular medicine Biology, 2, 207 (1990), Diabetologia, 33, 306-310 (1990), J. Am. Med. Association, 264, 2868 (1990), and The Lancet, ii, 747-748 (1989) and ii, 1144-1147 (1990)).
  • endothelin is secreted not only by endothelial cells but also by tracheal epithelial cells or by kidney cells (FEBS Letters, 255. 129-132 (1989), and FEBS Letters, 249, 42-46 (1989)).
  • Endothelin was also found to control the release of physiologically active endogenous substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A2, prostacyclin, noradrenaline, angiotensin II and substance P (Biochem. Biophys, Res. Commun., 157. 1 164-1168 (1988); Biochem. Biophys, Res. Commun., j ⁇ 5, 20 167-172 (1989); Proc. Natl. Acad. Sci. USA, &5_ 1 9797-9800 (1989); J. Cardiovasc. Pharmacol., ⁇ , S89-S92 (1989); Japan. J.
  • endothelin receptors are present in a high density not only in the peripheral tissues but also in the central nervous system, and the cerebral administration of endothelin induces a behavioral change in animals, endothelin is likely to play an important role for controlling nervous functions (Neuroscience Letters, 97, 276- 279 (1989)). Particularly, endothelin is suggested to be one of mediators for pain (Life Sciences, 49, PL61-PL65 (1991)). Internal hyperplastic response was induced by rat carotid artery balloon endothelial denudation. Endothelin causes a significant worsening of the internal hyperplasia (J. Cardiovasc.
  • endothelin is an important mediator for endotoxin- induced diseases (Biochem. Biophys. Commun., 161. 1220-1227 (1989); and Acta Physiol. Scand., 137, 317-318 (1989)).
  • vasoconstriction by the endothelins is caused via at least two subtypes of endothelin receptors (J. Cardiovasc. Pharmacol., 17(Suppl.7). S119-SI21 (1991)).
  • One of the endothelin receptors is ETA receptor Selective to ET-1 rather than ET-3, and the other is ET ⁇ receptor equally active to ET-1 and ET-3. These receptor proteins are reported to be different from each other (Nature, 348. 730- 735 (1990)).
  • endothelin receptors are differently distributed in tissues. It is known that the ETA receptor is present mainly in cardiovascular tissues, whereas the ET ⁇ receptor is widely distributed in various tissues such as brain, kidney, lung, heart and vascular tissues.
  • Substances which specifically inhibit the binding of endothelin to the endothelin receptors are believed to antagonize various pharmacological activities of endothelin and to be useful as a drug in a wide field. Since the action of the endothelins is caused via not only the ETA receptor but also the ET ⁇ receptor, novel non-peptidic substances with ET receptor antagonistic activity to either receptor subtype are desired to block activities of the endothelins effectively in various diseases.
  • Endothelin is an endogenous substance which directly or indirectly (by controlling liberation of various endogenous substances) induces sustained contraction or relaxation of vascular or non-vascular smooth muscles, and its excess production or excess secretion is believed to be one of pathogeneses for hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, restenosis, acute renal failure, myocardial infarction, angina pectoris, cerebral vasospasm and cerebral infarction.
  • endothelin serves as an important mediator involved in diseases such as restenosis, prostatauxe, endotoxin shock, endotoxin- induced multiple organ failure or disseminated intravascular coagulation, and cyclosporin-induced renal failure or hypertension.
  • Two endothelin receptors ETA and ET ⁇ are known so far.
  • An antagonistic agent against the ET ⁇ receptor as well as the ETA receptor is useful as a drug.
  • some non- peptidic compounds possessing antagonistic activity against endothelin receptors were already disclosed in patents (for example, EP 0526708 Al, WO 93/08799 Al). Accordingly, it is an object of the present invention to provide a novel therapeutics for the treatment of the above- mentioned various diseases by an invention of a novel and potent non- peptidic antagonist against either ETA or ET ⁇ receptor.
  • endothelin antagonists of the following structure:
  • Rl is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, aryl, or heteroaryl;
  • R 4 is C1-C8 alkyl
  • R5 is: H, C1 -C8 alkyl, or aryl.
  • This invention relates to a key intermediate in the synthesis of an endothelin antagonist, the synthesis of this key intermediate and the synthesis of an endothelin antagonist using this intermediate in a stereoselective deoxygenation reaction.
  • the instant invention relates to a compound of formula I:
  • C3-C8 cycloalkyl are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl -C ⁇ alkoxy, C3-C8 cycloalkyl, CO(CH2) n CH3, and aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, C l -C8 alkoxy, C 1 -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2)nCH2N(R5)2, and when two substituents are located on adjacent carbons they can join to form
  • n 0 to 5;
  • Rl is: a) C 1 -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, or c) heteroaryl;
  • heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1 , 2 or 3 heteroatoms selected from O, N and S , which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, Cl-C ⁇ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2) n CH2N(R5) 2 ,
  • R 3a is: a) -CO-C1-C8 alkyl, b) -CO-aryl, or c) -CO-heteroaryl;
  • R 3b is: a) C1-C8 alkyl, b) aryl, or c) heteroaryl;
  • R 4 is C1-C8 alkyl
  • R5 is: H, C1-C8 alkyl, or aryl.
  • the instant invention relates to a compound of formula I:
  • C3-C8 cycloalkyl are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2) n CH3, and aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl-C ⁇ alkoxy, Cl-C ⁇ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2)nCH2N(R5)2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6- member
  • n 0 to 5;
  • Rl is: a) C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, or c) heteroaryl;
  • heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S , which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl-C ⁇ alkoxy, Cl-C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C ⁇ alkynyl, or C3-C ⁇ cycloalkyl, CO(CH2) n CH3, and CO(CH2) n CH2N(R5) 2 ,
  • R 3b is: a) Cl-C ⁇ alkyl, b) aryl, or c) heteroaryl;
  • R 4 is C1-C8 alkyl
  • R5 is: H, C1-C8 alkyl, or aryl.
  • C3-C8 cycloalkyl are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl-C ⁇ alkoxy, C3-C8 cycloalkyl, CO(CH2) n CH3 , and aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl-C ⁇ alkoxy, C 1 -C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C ⁇ alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2)nCH2N(R 5 )2, and when two substituents are located on adjacent carbons they can join to form
  • n 0 to 5;
  • Rl is: a) Cl-C ⁇ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C ⁇ cycloalkyl, b) aryl, or c) heteroaryl;
  • heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S , which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, C l -C ⁇ alkoxy, Cl -C ⁇ alkyl, C2-C8 alkenyl, C2-C ⁇ alkynyl, or C3-C cycloalkyl, CO(CH2) n CH3, and CO(CH2) n CH2N(R5) 2 ,
  • R 4 is Cl-C ⁇ alkyl
  • R5 is: H, Cl-C ⁇ alkyl, or aryl
  • the strong base is selected from the group consisting of: LDA, LiHMDS, KHMDS, NaHMDS, KO J Bu, and sodium t-amylate, in about 2 to about 6 equivalents
  • the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), benzene, toluene, pentane, hexane, dioxane and a mixture of said solvents; and the temperature range is about -78°C to about 25°C, and preferably about -50°C to about 25°C.
  • the process conditions for the process recited above are wherein the strong base is LiHMDS, KHMDS, or NaHMDS, preferably in about 3 to about 4 equivalents, the aprotic solvent is tetrahydrofuran and the temperature range is preferably about 0°C to about 25 °C.
  • Cl-Cs alkoxy Cl-C ⁇ alkyl, C2-C alkenyl, C2-C ⁇ alkynyl, or
  • C3-C ⁇ cycloalkyl are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, C1 -C8 alkoxy, C3-C8 cycloalkyl, CO(CH2) n CH3, and aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, C 1 -C ⁇ alkoxy, C l -C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2)nCH2N(R 5 )2, and when two substituents are located on adjacent carbons they can join
  • Rl is: a) C 1 -C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C alkynyl, C3-C cycloalkyl, b) aryl, or c) heteroaryl;
  • heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S , which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, Cl-C ⁇ alkyl, C2-C alkenyl, C2-C ⁇ alkynyl, or C3-C8 cycloalkyl,
  • n 0 to 5;
  • R 4 is Cl-C ⁇ alkyl
  • R5 is: H, Cl-C ⁇ alkyl, or aryl
  • the reducing agent is selected from the group consisting of: a hydride, a borane, C5-C6 cycloalkene with a transition metal catalyst and H2 with a transition metal catalyst.
  • the reducing agents useful in this process in about 2 to about 20 equivalents and preferably about 2 to about 5 equivalents are: hydrides, such as R3S-H, R2SiH2, wherein R is Cl-C ⁇ alkyl or aryl, and NaBH4, boranes, such as BH3 « NHMe2, BH3 » SMe2, BH3 » pyridine, and BH3 » THF, C5-C6 cycloalkene with a transition metal catalyst, such as cyclohexene or cyclohexadiene with Pd/C, Pt-C, Rh/Al and Raney Ni, H2 with a transition metal catalyst, such as Pd-C, Pt-C, Rh/Al and Raney Ni, or S
  • the acid is a Lewis acid
  • the reducing agent when the reducing agent is a hydride, a borane or C5-C6 cycloalkene with a transition metal catalyst, a protic acid, when the reducing agent is H2 with a transition metal catalyst, or no acid, when the reducing agent is Sml2-
  • the Lewis acids in about 2 to about 5 equivalents, such as T-CI4, BF3, BCI3, SnC-4, AICI3, and TiCl2(OiPr)2 are useful in this process.
  • Protic acids such as trifluoroacetic acid, HCl, and H2SO4 are useful in this process.
  • the solvent is an aprotic solvent
  • the acid when the acid is a Lewis acid and the reducing agent is a hydride, a borane or C5-C6 cycloalkene with a transition metal catalyst, a protic solvent, when the acid is a protic acid and the reducing agent is H2 with a transition metal catalyst, or a solvent system consisting of an aprotic solvent and a protic solvent when the reducing agent is Sml2- Aprotic solvents such as tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), dioxane, CH2CI2, CHCI3, nitromethane, toluene, and dichlorobenzene, and protic solvents such as ethanol, methanol or isopropanol, are solvents within the scope of the invention.
  • temperature range is about -78°C to about 20°C and preferably about -20°C to about 10°C, when the acid is a Lewis acid and the reducing agent is a hydride or a borane, about 0°C to about 100°C and preferably about 0°C to about 40°C, when the acid is a Lewis acid or a protic acid and the reducing agent is a C5-C6 cycloalkene with a transition metal catalyst or H2 with a transition metal catalyst, or about 0°C to about 30°C, when the reducing agent is Sml2-
  • the preferred conditions for the process recited above are wherein the hydride is R3SiH, the Lewis acid is TiCl4, the aprotic solvent is nitromethane and the temperature range is about -5°C to about 5°C.
  • alkyl substituents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, tert-butyl, neopentyl, isopentyl, etc.
  • alkenyl-substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon double bond such as vinyl, allyl and 2-butenyl.
  • alkynyl- substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon triple bond such as ethynyl,and propynyl.
  • Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each of which may be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
  • the alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.
  • alkyl, alkenyl, akynyl, cycloalkyl and alkoxy can be substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl-C ⁇ alkoxy, C3-C ⁇ cycloalkyl, CO(CH2) n CH3, and CO(CH2)nCH2N(R5)2.
  • the heteroaryl substituent represents an carbazolyl, furanyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl.
  • the heterocyclyl substituent represents a pyridyl, pyrimidyl, thienyl, furanyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, imidazolyl, imidazoldinyl, thiazolidilnyl, isoxazolyl, oxadiazolyl, thiadiazolyl, mo ⁇ holinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrrolidinyl.
  • R- 5 chiral auxiliary (R- 5 ), wherein X and Y are independently: O, S, or NR 5 ; R 4 is Cl -Cs alkyl; R5 is: H, Cl -C ⁇ alkyl, or aryl; and R6, R7, R8 and R9 are independently: H, Cl-C ⁇ alkyl, and aryl, such that either R6 and R ⁇ are not the same and/or R& and R9 are not the same, or R6 and R8 or R?
  • R9 can join to form a 5- or 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl- C8 alkoxy, Cl-C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2) n CH2N(R5) 2 .
  • pyridone 1 is alkylated via its dianion with propyl bromide, and the product is then converted into the bromopyridine 3a using a brominating agent such as PBr3.
  • a brominating agent such as PBr3.
  • DIBAL diisobutyl aluminum hydride
  • the aldehyde then undergoes a Heck reaction with t-butyl acrylate using NaOAc, (allyl)2PdCl2, tri-o-tolylphosphine, toluene, reflux to provide the unsaturated ester 4a in high yield.
  • the unsaturated ester 4a is then reacted with a chiral auxiliary to give the acceptor 5a.
  • Examples of chiral auxiliaries useful in this method are the enantiomers of pseudoephedrine, ephedrine, 1 N,2N-dimethyl- diaminocyclohexane, diphenylprolinol, N-methylaminoindanol, and 1 N,2N-diethyldiaminocyclohexane.
  • Organolithium reagent 17a was reacted with the acceptor a (-78°C to -50°C). Workup (acetic acid-THF- water) to remove the chiral auxiliary affords aldehyde 6a in high yield and good selectivity (Scheme 4).
  • the de-oxygenation step can be carried out using a reducing agent including but not limited to trialkylsilyl hydride or samarian iodide, using an acid with the hydride reducing agent.
  • This aldol reaction and de-oxygenation sequence can be carried out with a variety of ketones, such as -COaryl and -COheteraryl.
  • Oxidation of the side chain hydroxyl 21 to the carboxyiic acid 22 was effected using standard conditions (cat RuCl3-NaI ⁇ 4, CH3CN, or two steps involving i) Sulfur trioxide pyridine complex- dimethyl sulfoxide, ii) sodium chlorite-tert butanol). Subsequent hydrolysis (NaOH-MeOH) of 22 provided the target compound 23 cleanly. The iH and 13c NMR spectrum of this material was identical with that of the authentic target compound (Scheme 8).
  • Scheme 9 describes the preparation of the isopropyl ester analog of compound 23 described in Scheme 8.
  • Unsaturated oxazoline 25 was prepared via the Horner-Emmons reaction of phosphonate 24 with the bromopyridine aldehyde 3.
  • Conjugate addition of the lithium anion of 4-bromo-l,2-(methylenedioxy)benzene to 25 produced the desired adduct 26 with in high diastereomeric excess.
  • Hydrolysis of oxazoline 26 was accomplished by refluxing in isopropyl alcohol with concentrated sulfuric acid to yield the isopropyl ester (not shown in scheme).
  • Compound 1 is a commericially available starting material, for example, see Aldrich Chemical Company, Milwaukee, WI, USA 53201.
  • Dissolve 17 (see Example 17, MW 373.41, 2 equ, 14.79 g) in 85 mL THF. Cool to -78°C and add t-BuLi (1.7 M in pentane, 4 equ, 46.6 mL), maintaining temperature below -70°C. Age 15 min, then slowly add solution of 5c (MW 436.59, 19.8 mmol, 8.64 g) in 65 mL THF. Age 1 h at -78°C, then cannula into cold aq NH4CI (100 mL). Add ethyl acetate and separate layers. Wash aqueous with ethyl acetate.
  • Dissolve 17 (see Example 17, MW 373.41, 2 equ, 12.99 g) in 70 mL THF. Cool to -78°C and add t-BuLi (1.7 M in pentane, 4 equ, 40.9 mL), maintaining temperature below -70°C. Age 15 min, then slowly add solution of 5b (MW 384.57, 17.4 mmol, 6.69 g) in 55 mL THF. Age 1 h at -78°C, then cannula into cold aq NH4CI (100 mL). Add ethyl acetate and separate layers. Wash aqueous with ethyl acetate.
  • Compound 7 is a commericially available starting material, for example, see DSM Andeno, Grubbenvorsterweg 8, P.O. Box 81 , 5900 AB Venlo,The Netherlands.
  • Compound 10 is a commericially available starting material, for example, see Lancaster Synthesis, P.O. Box 1000, Windham, NH 03087-9977 or Ryan Scientific, Inc., P.O. Box 845, Isle of Palms, SC 29451-0845.
  • Ar represents:
  • Dissolve 19 (MW 703.99, 13.6 mmol, 9.58 g) in 75 mL THF and cool to -50°C. Slowly add LiHMDS (1.0 M in THF, 5 equ, 68.0 mL) and age 25°C for 16 h. Quench into aqueous NH4CI and add ethyl acetate. Wash organic with brine, dry (magnesium sulfate) and evaporate in vacuo to afford 20 (MW 703.99).
  • Dissolve 20 (MW 703.99, 13.6 mmol) in 125 ml nitromethane and add Et3SiH (MW 1 16.28, d 0.728, 10 equ, 21.7 mL). Cool to 0°C and slowly add TiCl4 (1.0 M in CH2CI2, 4 equ, 54.4 mL) and age 1 h at 0°C. Quench into 2N HCl and dilute with ethyl acetate. Wash aqueous with ethyl acetate, then combine organics and wash with brine. Dry (magnesium sulfate) and evaporate in vacuo.
  • Step B Preparation of 26 51.1 g (215 mmol) of compound 25 from Example 23,
  • Step A were dissolved in IL of THF and cooled to 0° C. 24.7 g (224 mmol) of sodium t-pentoxide was then added. The mixture was aged at 0 - 5° C for about 30 mins. 13.9 mL (224 mmol) of Mel were then added dropwise and the solution allowed to warm to room temperature. After 4 hours, the reaction was quenched with water and extracted with ethylacetate. The organic layer was dried over MgSO/J., filtered and concentrated under reduced pressure to yield 54.04 g (100%) of crude product, 26.
  • Example 17 To a solution of 2.62 g (7.02 mmol) of the arylbromide 17, Example 17 in 15 mL THF was added 3.3 mL (7.1 mmol) of nBuLi (2.15 M in hexanes) while maintaining an internal temperature below -70° C. After 10 minutes, the solution was transferred via cooled cannula (dry ice) to a solution of the diester, 31 produced in Example 27 in 35 mL of THF. The solution was observed to turn a green-black color. The mixture was stirred for an additional 0.5 hours and then quenched with aqueous NaHC ⁇ 3. The aqueous layer was extracted with ethylacetate (2X) and the combined organic layers dried over MgS ⁇ 4.
  • nBuLi 2.15 M in hexanes

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  • Steroid Compounds (AREA)

Abstract

L'invention concerne un intermédiaire clé dans la synthèse d'un antagoniste de l'endothéline, la synthèse dudit intermédiaire clé et la synthèse d'un antagoniste de l'endothéline réalisées par l'emploi dudit intermédiaire dans une réaction de désoxygénation stéréosélective.
PCT/US1997/014045 1996-08-09 1997-08-08 Reaction de desoxygenation stereoselective Ceased WO1998006700A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP97937187A EP0923557A4 (fr) 1996-08-09 1997-08-08 Reaction de desoxygenation stereoselective
CA002262676A CA2262676A1 (fr) 1996-08-09 1997-08-08 Reaction de desoxygenation stereoselective
JP10509915A JPH11514676A (ja) 1996-08-09 1997-08-08 立体選択的脱酸素化反応
AU39757/97A AU711936B2 (en) 1996-08-09 1997-08-08 Stereoselective deoxygenation reaction

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US2361496P 1996-08-09 1996-08-09
US60/023,614 1996-08-09
GB9617900.7 1996-08-28
GBGB9617900.7A GB9617900D0 (en) 1996-08-28 1996-08-28 Stereoselective deoxygenation reaction
US2843896P 1996-10-10 1996-10-10
US60/028,438 1996-10-10
GB9625806.6 1996-12-12
GBGB9625806.6A GB9625806D0 (en) 1996-12-12 1996-12-12 Stereoselective deoxygenation reaction

Publications (1)

Publication Number Publication Date
WO1998006700A1 true WO1998006700A1 (fr) 1998-02-19

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/014045 Ceased WO1998006700A1 (fr) 1996-08-09 1997-08-08 Reaction de desoxygenation stereoselective

Country Status (5)

Country Link
EP (1) EP0923557A4 (fr)
JP (1) JPH11514676A (fr)
AU (1) AU711936B2 (fr)
CA (1) CA2262676A1 (fr)
WO (1) WO1998006700A1 (fr)

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WO1999037639A1 (fr) * 1998-01-21 1999-07-29 Banyu Pharmaceutical Co., Ltd. Derive de 5-(2,2-difluoro-1,3-benzodioxol-5-yl) cyclopentenopyridine substitue
WO1999052900A1 (fr) * 1998-04-09 1999-10-21 Merck & Co., Inc. Procede d'oxydation au moyen de tempo
EP0923556A4 (fr) * 1996-08-09 1999-12-15 Merck & Co Inc Reaction d'addition par conjugue asymetrique
US6031101A (en) * 1998-04-09 2000-02-29 Merck & Co., Inc. Oxidation process using tempo
US6046327A (en) * 1998-04-09 2000-04-04 Merck & Co., Inc. Phosphate-mediated cyclization
US6172235B1 (en) 1996-08-09 2001-01-09 Merck & Co., Inc. Asymmetric conjugate addition reaction
EP1070041A4 (fr) * 1998-04-09 2001-05-16 Merck & Co Inc Cyclisation par l'intermediaire d'un phosphate
EP1070061A4 (fr) * 1998-04-09 2001-11-07 Merck & Co Inc Procede d'oxydation au moyen d'acide periodique
WO2002002527A1 (fr) * 2000-07-05 2002-01-10 Ishihara Sangyo Kaisha, Ltd. Derive de benzoylpyridine ou sel de ce derive, fongicide le renfermant comme ingredient actif, son procede de production, et produit intermediaire pour sa production
AP1286A (en) * 2000-07-05 2004-06-26 Ishihara Sangyo Kaisha Benzoylpyridine derivative or its salt, Fungicide containing it as an active ingredient, its production process and intermediate for producing it.
US8071311B2 (en) 2001-03-09 2011-12-06 Nugen Technologies, Inc. Methods and compositions for amplification of RNA sequences
US8314252B2 (en) 2008-07-30 2012-11-20 Intervet Inc. Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol
US8481564B2 (en) 2006-04-20 2013-07-09 Janssen Pharmaceutica, N.V. Inhibitors of c-fms kinase
US8497376B2 (en) 2007-10-17 2013-07-30 Janssen Pharmaceutica N.V. Inhibitors of c-fms kinase
US8557847B2 (en) 2005-06-10 2013-10-15 Janssen Pharmaceutica, N.V. Synergistic modulation of FLT3 kinase using a FLT3 inhibitor and a farnesyl transferase inhibitor
US8697716B2 (en) 2006-04-20 2014-04-15 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US8859602B2 (en) 2006-04-20 2014-10-14 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9029352B2 (en) 2012-08-07 2015-05-12 Janssen Pharmaceutica Nv Process for the preparation of C-FMS kinase inhibitors
US9303046B2 (en) 2012-08-07 2016-04-05 Janssen Pharmaceutica Nv Process for the preparation of heterocyclic ester derivatives

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JP4608140B2 (ja) * 2000-07-05 2011-01-05 石原産業株式会社 ベンゾイルピリジン誘導体またはその塩、それらを有効成分として含有する殺菌剤、それらの製造方法ならびにそれらを製造するための中間体

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US5389620A (en) * 1993-08-18 1995-02-14 Banyu Pharmaceutical Co., Ltd. Endothelin antagonistic heteroaromatic ring-fused cyclopentene derivatives

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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6172235B1 (en) 1996-08-09 2001-01-09 Merck & Co., Inc. Asymmetric conjugate addition reaction
EP0923556A4 (fr) * 1996-08-09 1999-12-15 Merck & Co Inc Reaction d'addition par conjugue asymetrique
WO1999037639A1 (fr) * 1998-01-21 1999-07-29 Banyu Pharmaceutical Co., Ltd. Derive de 5-(2,2-difluoro-1,3-benzodioxol-5-yl) cyclopentenopyridine substitue
EP1070041A4 (fr) * 1998-04-09 2001-05-16 Merck & Co Inc Cyclisation par l'intermediaire d'un phosphate
US6046327A (en) * 1998-04-09 2000-04-04 Merck & Co., Inc. Phosphate-mediated cyclization
US6031101A (en) * 1998-04-09 2000-02-29 Merck & Co., Inc. Oxidation process using tempo
EP1070061A4 (fr) * 1998-04-09 2001-11-07 Merck & Co Inc Procede d'oxydation au moyen d'acide periodique
WO1999052900A1 (fr) * 1998-04-09 1999-10-21 Merck & Co., Inc. Procede d'oxydation au moyen de tempo
WO2002002527A1 (fr) * 2000-07-05 2002-01-10 Ishihara Sangyo Kaisha, Ltd. Derive de benzoylpyridine ou sel de ce derive, fongicide le renfermant comme ingredient actif, son procede de production, et produit intermediaire pour sa production
AP1286A (en) * 2000-07-05 2004-06-26 Ishihara Sangyo Kaisha Benzoylpyridine derivative or its salt, Fungicide containing it as an active ingredient, its production process and intermediate for producing it.
US6770662B2 (en) 2000-07-05 2004-08-03 Ishihara Sangyo Kaisha, Ltd. Benzoylpyridine derivative or its salt, fungicide containing it as an active ingredient, its production process and intermediate for producing it
CN100336807C (zh) * 2000-07-05 2007-09-12 石原产业株式会社 苯甲酰吡啶衍生物或其盐、含有它作为活性成分的杀真菌剂、它的产生方法以及用于产生它的中间体
KR100760124B1 (ko) * 2000-07-05 2007-09-18 이시하라 산교 가부시끼가이샤 벤조일피리딘 유도체 또는 그의 염, 활성 성분으로서 그를포함하는 살진균제, 그의 제조 방법 및 그의 제조를 위한중간체
US8071311B2 (en) 2001-03-09 2011-12-06 Nugen Technologies, Inc. Methods and compositions for amplification of RNA sequences
US8557847B2 (en) 2005-06-10 2013-10-15 Janssen Pharmaceutica, N.V. Synergistic modulation of FLT3 kinase using a FLT3 inhibitor and a farnesyl transferase inhibitor
US8895584B2 (en) 2006-04-20 2014-11-25 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US8933091B2 (en) 2006-04-20 2015-01-13 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US8481564B2 (en) 2006-04-20 2013-07-09 Janssen Pharmaceutica, N.V. Inhibitors of c-fms kinase
US8697716B2 (en) 2006-04-20 2014-04-15 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US8759347B2 (en) 2006-04-20 2014-06-24 Janssen Pharmaceutica Nv Inhibitors of C-FMS kinase
US8859602B2 (en) 2006-04-20 2014-10-14 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9526731B2 (en) 2006-04-20 2016-12-27 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US9403804B2 (en) 2006-04-20 2016-08-02 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9394289B2 (en) 2006-04-20 2016-07-19 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9266866B2 (en) 2006-04-20 2016-02-23 Janssen Pharmaceutica Nv Inhibitors of C-FMS kinase
US9296726B2 (en) 2006-04-20 2016-03-29 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US8497376B2 (en) 2007-10-17 2013-07-30 Janssen Pharmaceutica N.V. Inhibitors of c-fms kinase
US8314252B2 (en) 2008-07-30 2012-11-20 Intervet Inc. Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol
US9303046B2 (en) 2012-08-07 2016-04-05 Janssen Pharmaceutica Nv Process for the preparation of heterocyclic ester derivatives
US9029352B2 (en) 2012-08-07 2015-05-12 Janssen Pharmaceutica Nv Process for the preparation of C-FMS kinase inhibitors

Also Published As

Publication number Publication date
CA2262676A1 (fr) 1998-02-19
EP0923557A4 (fr) 1999-12-08
EP0923557A1 (fr) 1999-06-23
AU711936B2 (en) 1999-10-28
JPH11514676A (ja) 1999-12-14
AU3975797A (en) 1998-03-06

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