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WO1999007367A1 - Reaction d'addition conjuguee asymetrique - Google Patents

Reaction d'addition conjuguee asymetrique Download PDF

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Publication number
WO1999007367A1
WO1999007367A1 PCT/US1998/016251 US9816251W WO9907367A1 WO 1999007367 A1 WO1999007367 A1 WO 1999007367A1 US 9816251 W US9816251 W US 9816251W WO 9907367 A1 WO9907367 A1 WO 9907367A1
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Prior art keywords
alkyl
aryl
alkoxy
cycloalkyl
alkenyl
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PCT/US1998/016251
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English (en)
Inventor
Paul N. Devine
Richard M. Heid, Jr.
Richard D. Tillyer
David M. Tschaen
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Merck & Co., Inc.
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Priority claimed from GBGB9810550.5A external-priority patent/GB9810550D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU86901/98A priority Critical patent/AU8690198A/en
Publication of WO1999007367A1 publication Critical patent/WO1999007367A1/fr

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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
    • 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
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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.
  • 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)). Three endothelin isopeptides (endothelin- 1, endothelin-2 and endothelin-3), 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. 1164-1168 (1988); Biochem. Biophys, Res. Commun., 155, 20 167-172 (1989); Proc. Natl. Acad. Sci. USA, 85 1 9797-9800 (1989); J. Cardiovasc. Pharmacol., 13, 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)).
  • endotoxin is one of potential candidates to promote the release of endothelin. Remarkable elevation of the endothelin levels in the blood or in the culture supernatant of endothelial cells was observed when endotoxin was exogenously administered to animals or added to the culture endothelial cells, respectively.
  • endothelin Such various effects of endothelin are caused by the binding of endothelin to endothelin receptors widely distributed in many tissues (Am. J. Physiol., 256, R856-R866 (1989)). It is known that vasoconstriction by the endothelins is caused via at least two subtypes of endothelin receptors (J. Cardiovasc. Pharmacol., 17(Suppl.7L SI 19- 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.
  • Ri is: aryl, C r C 8 alkyl, or heteroaryl
  • R2 is: OR4, N(R5)2, H, or OH;
  • R3 i s H, Cl-C8 alkyl, Cl-C8 alkoxy, halo, aryl, heteroaryl, or CHO;
  • R 4 is C1-C8 alkyl;
  • R 5 is H, C1-C8 alkyl or aryl
  • endothelin antagonists such as the compound below (Ishikawa et al. U.S. 5,389,620):
  • This invention relates to a key intermediate in the synthesis of an endothelin antagonist and the synthesis of this key intermediate via an asymmetric conjugate addition.
  • the instant invention relates to a compound of Formula I:
  • heterocyclyl is defined as a cyclic moiety containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, and the heterocyclyl is unsubstituted or substituted with one, two or three R substituents, wherein R is selected from the group consisting of: OH, CO2R 4 , Br, CI, F, I, CF3, N(R5)2, Cl- C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and b) 5- or 6-membered carbocyclyl, wherein carbocyclyl is defined as a cyclic moiety containing only carbon in the ring and containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substitute
  • C3-C8 cycloalkyl are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, CI, 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, OBenzyl, CO2R 4 , Br, CI, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, 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 a 5- or 6- membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO2R 6 , Br, CI, F, I, CF3, N(R7)2, C1-C8 al
  • Rl is: a) aryl, wherein aryl is as defined above, b) C r C 8 alkyl, 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, CI, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and CO(CH2) n CH2N(R5) 2 ,
  • R2 is: a) OR 4 , c) H, or d) OH;
  • R3 is: a) H, b) C1-C8 alkyl, C) Cl-C ⁇ alkoxy, ) Br, Cl, F, I, e) aryl, f) heteroaryl, g) C(OR )(OR ) , wherein R and R are independently (Cl-
  • C5)alkyl and may be connected to form a 5- or 6- membered heterocyclic ring containing two oxygens, or h) CHO;
  • n 0 to 5;
  • R 4 is Cl-C ⁇ alkyl
  • R 5 is H, C1-C8 alkyl, or aryl
  • R 6 is H, C1-C8 alkyl, and aryl
  • R7 is H, Cl-C8 alkyl, or aryl, when there are two R substituents on a nitrogen they can join to form a 3- through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 , Br, Cl, F, I, CF3, N(R5)2, Q-C8 alkoxy, Cl-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and
  • the instant invention relates to a compound of Formula I:
  • heterocyclyl is defined as a cyclic moiety containing one, two or three double bonds, but at least one double bond and 1 , 2 or 3 heteroatoms selected from O, N and S, and the heterocyclyl
  • R 10 is unsubstituted or substituted with one, two or three R substituents, where in R is selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl-
  • C3-C8 cycloalkyl CO(CH2) n CH3, and b) 5- or 6-membered carbocyclyl, wherein carbocyclyl is defined as a cyclic moiety containing only carbon in the ring and containing one or two double bonds, but at least one double bond, the carbocyclyl 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, -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and c) aryl, wherein aryl is as defined below,
  • 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(R , 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, OBenzyl, CO2R 4 , Br, Cl, F, I, CF3, N(R 5 )2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3,
  • 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, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and CO(CH2) n CH2N(R5) 2 ,
  • R2 is: a) OR 4 , c) H, or d) OH;
  • R3 is: a) H, b) C1-C8 alkyl, c) C1-C8 alkoxy, d) Br, Cl, F, I, e) aryl, f) heteroaryl, g) C(OR )(OR ) , wherein R and R are independently (Cl- C5)alkyl and may be connected to form a 5- or 6- membered heterocyclic ring containing two oxygens, or h) CHO;
  • n 0 to 5;
  • R 4 is C1-C8 alkyl
  • R 5 is H, C1-C8 alkyl, or aryl
  • R 6 is H, C1-C8 alkyl, and aryl
  • R is H, C1-C8 alkyl, or aryl, when there are two R7 substituents on a nitrogen they can join to form a 3- through 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, C1-C8 alkoxy, Cl-C ⁇ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and
  • R2 is : a) OR 4 , c) H, or d) OH;
  • R3 is ; a) H, b) Cl-C ⁇ alkyl, c) C1-C8 alkoxy, d) Br, Cl, F, I, e) aryl, f) heteroaryl, a b g) C C((OORR a ⁇ ))((OORR b )) , wherein R and R are independently (Cl-
  • C5)alkyl and may be connected to form a 5- or 6- membered heterocyclic ring containing two oxygens, or h) CHO;
  • R 4 is C1-C8 alkyl
  • R 5 is H, Cl-C ⁇ alkyl or aryl; and R 10 is: a) OH, b) CO2R 4 , c) halo, wherein halo is Br, Cl, F, or I, d) CF3, f) C1-C8 alkoxy, g) C1-C8 alkyl, h) C2-C8 alkenyl, i) C2-C8 alkynyl, j) C3-C8 cycloalkyl, ) CO(CH2) n CH3, or
  • heterocyclyl is defined as a cyclic moiety containing one, two or three double bonds, but at least one double bond and 1 , 2 or 3 heteroatoms selected from O, N and S, and the heterocyclyl is unsubstituted or substituted with one, two or three R , 10 substituents, wherein R 10 is selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl- C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and b) 5- or 6-membered carbocyclyl, wherein carbocyclyl is defined as a cyclic moiety containing only carbon in the ring and containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubsti
  • 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, OBenzyl, CO2R 4 , Br, Cl, F, I, CF3, N(R 5 )2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3,
  • Rl is: a) aryl, wherein aryl is as defined above, b) C r C 8 alkyl, 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, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and CO(CH2) n CH2N(R5) 2 ,
  • R3 is: a) H, b) C1-C8 alkyl, c) C1-C8 alkoxy, d) Br, Cl, F, I, e) aryl, f) heteroaryl, g) C(OR )(OR ) , wherein R and R are independently (Cl- C5)alkyl and may be connected to form a 5- or 6- membered heterocyclic ring containing two oxygens, or h) CHO;
  • n 0 to 5;
  • R 4 is C1-C8 alkyl
  • R5 is H, C1-C8 alkyl, or aryl
  • R 6 is H, C1-C8 alkyl,or aryl
  • R7 is H, Cl-C8 alkyl, or aryl, when there are two R7 substituents on a nitrogen they can join to form a 3- through 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-C ⁇ alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and
  • R8 and R9 are independently: a) aryl, wherein aryl is as defined in A(c) above, b) heteroaryl, wherein heteroaryl is as defined in R ⁇ (b) above, c) CH2OR 4 , d) aryl-SCH3, wherein aryl is as defined in A(c) above, e) C1-C8 alkyl, or f) H, so long as both R& and R9 are not both H at the same time.
  • R3 is: a) H, b) C1-C8 alkyl, c) C1-C8 alkoxy, d) Br, Cl, F, I, e) aryl, f) heteroaryl, g) C(OR )(OR ) , wherein R and R are independently (Cl-
  • C5)alkyl and may be connected to form a 5- or 6- membered heterocyclic ring containing two oxygens, or h) CHO;
  • R 4 is C1-C8 alkyl
  • R 5 is H, C1-C8 alkyl or aryl
  • R8 and R9 are independently: a) aryl, wherein aryl is as defined in A(c) above, b) heteroaryl, wherein heteroaryl is as defined in Rl(b) above, c) CH2OR 4 , d) aryl-SCH3, wherein aryl is as defined in A(c) above, e) C1-C8 alkyl, or f ) H, so long as both R ⁇ and R9 are not both H at the same time; and
  • RlO is: a) OH, b) CO2R 4 , c) halo, wherein halo is Br, Cl, F, or I, d) CF 3 , f) C1-C8 alkoxy, g) C1-C8 alkyl, h) C2-C8 alkenyl, i) C2-C8 alkynyl, j) C3-C8 cycloalkyl, k) CO(CH2) n CH3, or
  • R 3 is I, Br, Cl, F, CHO or C(OR & )(OR ) , a b wherein R and R are independently (Cl-C5)alkyl and may be connected to form a 5- or 6- membered heterocyclic ring containing two oxygens.
  • heterocyclyl represents: a) 5- or 6-membered heterocyclyl, wherein heterocyclyl is defined as a cyclic moiety containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, and the heterocyclyl is unsubstituted or substituted with one, two or three R substituents, wherein R is selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Ci- C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and b) 5- or 6-membered carbocyclyl, wherein carbocyclyl is defined as a cyclic moiety containing only carbon in the ring and containing one or two double bonds, but at least one double bond, the carbocyclyl is unsub
  • 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(R , 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, OBenzyl, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl,
  • C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and Rl is: a) aryl, wherein aryl is as defined above, b) C,-C 8 alkyl, 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, C3-C8 cycloalkyl, CO(CH2) n CH3, and CO(CH2) n CH2N(R5)2 ;
  • R2 is ; a) OR 4 , c) H, or d) OH;
  • R3 is ; a) H, b) C1-C8 alkyl, c) C1-C8 alkoxy, d) Br, Cl, F, I, e) aryl, f) heteroaryl, or g) are independently (Cl- C5)alkyl and may be connected to form a 5- or 6- membered heterocyclic ring containing two oxygens;
  • n 0 to 5;
  • R 4 is Cl-C ⁇ alkyl
  • R 5 is H, Cl-C8 alkyl or aryl
  • R 6 is H, Cl-C ⁇ alkyl, or aryl
  • R7 is H, Cl-C8 alkyl, or aryl, when there are two R7 substituents on a nitrogen they can join to form a 3- through 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, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and comprising the steps of:
  • R8 and R are independently: a) aryl, wherein aryl is as defined in A(c) above, b) heteroaryl, wherein heteroaryl is as defined in R (b) above, c) CH2OR 4 , d) aryl-SCH3, wherein aryl is as defined in A(c) above, e) C1-C8 alkyl, or f ) H, so long as both R ⁇ and R9 are not both H at the same time;
  • aprotic solvents include tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), benzene, toluene, pentane, hexane, dioxane and a mixture of said solvents, in addition to aprotic solvents that would be readily apparent to a person skilled in the art; and the temperature range is about -100°C to about 25°C, and preferably about - 78°C to about 0°C.
  • a preferred embodiment of the invention is wherein the amount of R x Li added is between about 2 to about 3 equivalents, the aprotic solvent is tetrahydrofuran and the temperature range is between about -78°C to about 0°C.
  • a hydrolyzing reagent such as protic acid in an alcohol solvent, which is further defined as H2SO4 and isopropyl alcohol.
  • Suitable protic acids include H2SO4, H 2 N0 3 , HCl, acetic acid, trifluoroacetic acid, and other acids that would be readily apparent to those skilled in the art.
  • Suitable alcohol solvents are Ci -Cg straight- chain and branched alkyl alcohols, examples are methanol, ethanol, propanol, isopropanol, and butanol.
  • the hydrolysis step can be performed by treatment with other hydrolyzing reagents including, but not limited to, suitable electrophilic reagents, such as Lewis acids or alkylating agents.
  • suitable electrophilic reagents such as Lewis acids or alkylating agents.
  • Lewis acids include TiCl , BF 3 , BC1 3 , SnCl , AICI3, and TiCl2(OiPr) 2 .
  • Suitable alkylating agents include alkyl iodides, alkyl triflates, and anhydrides, examples of these electrophilic reagents include methyl iodide, methyl triflate, ethyl iodide, ethyl triflate and triflic anhydride.
  • halo is Br, Cl, F, or I
  • CF3 f) C1-C8 alkoxy, g) C1-C8 alkyl, h) C2-C8 alkenyl, i) C2-C8 alkynyl, j) C3-C8 cycloalkyl, k) CO(CH2) n CH3, or
  • R8 and R9 are as defined above; with an amount of an organolithium compound of Formula VIII:
  • a subembodiment of the invention is the process as recited above wherein the amount of the organolithium compound of Formula VIII used in step 1 is between about 2 to about 3 equivalents relative to the chiral oxazoline.
  • Another subembodiment is the process as recited above wherein the aprotic solvent used in step 1 is chosen from a group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), benzene, toluene, pentane, hexane, dioxane and a mixture of said solvents.
  • step 2 is H 2 S0 4 .
  • R and R are independently (Cl-C5)alkyl and may be connected to form a 5- or 6- membered heterocyclic ring containing two oxygens, which comprises reacting a vinyl-substituted, chiral oxazoline of Formula X
  • 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, C1-C8 alkoxy, C3-C8 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, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrrolidinyl.
  • VI can generally be prepared by the following protocol.
  • Scheme 1 below outlines the synthesis of the chiral auxiliary.
  • Scheme 2 describes the addition of the chiral auxiliary 4 to form a vinyl-substituted, chiral oxazolines of Formula II.
  • Unsaturated oxazoline 6 was prepared via the Horner-Emmons reaction of phosphonate 4 with bromopyridine aldehyde 5.
  • Compound 16 is a commericially available starting material, for example, see Aldrich Chemical Company, Milwaukee, WI, USA 53201.
  • Diisopropyl amine (MW 101.19, d 0.772, 2.1 equ, 20.54 mL) in 200 mL THF. Cool to -50°C and add n-BuLi (1.6 M in hexanes, 2.05 equ, 96 mL), allowing solution to warm to -20°C. Age 0-3°C for 15 min, then cool to -30°C and add 16 (MW 134.14, 75 mmol, 10.0 g). Age 0°C to 43°C for 2 h. Cool to -50°C and add bromopropane (MW 123.00, d 1.354, 1.0 equ, 6.8 mL). Warm to 25°C over 30 min, and age 30 min. Add NH4CI and CH2CI2. Dry organic (magnesium sulfate) then evaporate in vacuo to afford 61% of 17.
  • Compound 18A 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.
  • 18A (MW 231.05, 130 mmol, 30.0 g) in 300 mL CH2CI2 at 0°C.
  • Add BH3-SMe2 (3 equ, 25.2 mL) and age for 2 h at 25°C. Quench into aqueous 2 N HCl and separate layers. Dry organic (magnesium sulfate) and concentrate in vacuo to obtain 94% yield of 18 (MW 217.06, 25.5 g).
  • Compound 21A is a commercially available starting material, for example, see DSM Andeno, Grubbenvorsterweg 8, P.O. Box 81, 5900 AB Venlo,The Netherlands.
  • Step C Preparation of Compound 4 132 mL (946 mmol) of diisopropylamine were dissolved in
  • the reaction was aged 0.5 h, warmed to 0 °C and quenched with water.

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Abstract

L'invention concerne un intermédiaire clé dans la synthèse d'un antagoniste d'endothéline, ainsi que la synthèse de cet intermédiaire clé par une réaction d'addition conjuguée asymétrique.
PCT/US1998/016251 1997-08-08 1998-08-04 Reaction d'addition conjuguee asymetrique WO1999007367A1 (fr)

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US5525997P 1997-08-08 1997-08-08
US60/055,259 1997-08-08
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GBGB9810550.5A GB9810550D0 (en) 1998-05-15 1998-05-15 Asymmetric conjugate addition reaction
US8703998P 1998-05-28 1998-05-28
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US6465664B1 (en) 1999-09-15 2002-10-15 Massachusetts Institute Of Technology Asymmetric 1,4-reductions of and 1,4-additions to enoates and related systems
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6465664B1 (en) 1999-09-15 2002-10-15 Massachusetts Institute Of Technology Asymmetric 1,4-reductions of and 1,4-additions to enoates and related systems
US6787655B2 (en) 1999-09-15 2004-09-07 Massachusetts Institute Of Technology Asymmetric 1,4-reductions of and 1,4-additions to enoates and related systems
JP2002356474A (ja) * 2000-07-05 2002-12-13 Ishihara Sangyo Kaisha Ltd 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
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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