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WO1998030543A1 - Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive - Google Patents

Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive Download PDF

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Publication number
WO1998030543A1
WO1998030543A1 PCT/US1998/000263 US9800263W WO9830543A1 WO 1998030543 A1 WO1998030543 A1 WO 1998030543A1 US 9800263 W US9800263 W US 9800263W WO 9830543 A1 WO9830543 A1 WO 9830543A1
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Prior art keywords
alkyl
aryl
cycloalkyl
group
alkenyl
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PCT/US1998/000263
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French (fr)
Inventor
Richard D. Tillyer
Feng Xu
David M. Tschaen
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Merck & Co., Inc.
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Filing date
Publication date
Priority claimed from GBGB9705858.0A external-priority patent/GB9705858D0/en
Priority to EP98902416A priority Critical patent/EP0973742A1/en
Priority to SK934-99A priority patent/SK93499A3/en
Priority to CA002277161A priority patent/CA2277161A1/en
Priority to JP10531063A priority patent/JP2000507969A/en
Priority to PL98334318A priority patent/PL334318A1/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to BR9806875-0A priority patent/BR9806875A/en
Priority to AU59089/98A priority patent/AU728441B2/en
Priority to EA199900661A priority patent/EA002056B1/en
Priority to NZ336220A priority patent/NZ336220A/en
Priority to HU0001921A priority patent/HUP0001921A3/en
Publication of WO1998030543A1 publication Critical patent/WO1998030543A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/48—Aldehydo radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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.
  • the compound possessing a high affinity for at least one of two receptor subtypes are responsible for the dilation of smooth muscle, such as blood vessels or in the trachea.
  • the endothelin antagonist compounds provide a potentially new therapeutic target, 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, 41 1-415 (1988)).
  • endothelin- 1 endothelin-2 and endothelin-3
  • endothelin-2 endothelin-2 and endothelin-3
  • 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, V2, 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., J ⁇ 5, 20 167- 172 (1989); Proc. Natl. Acad. Sci. USA, 85 1 9797-9800 (1989); J. Cardiovasc. Pharmacol., J_3, 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.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.
  • EP 0526708 Al and WO 93/08799 Al are representative examples of patent applications disclosing non-peptidic compounds with alleged activity as endothelin receptor antagonists.
  • the present invention discloses an asymmetric conjugate addition for preparing the compound of Formula I,
  • R 1 is: Cl-C ⁇ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, aryl, or heteroaryl;
  • R is C1-C8 alkyl
  • R 5 is: C 1-C8 alkyl, or aryl.
  • the instant invention relates to a process for the preparation of 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(R 5 )2, -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 l -C8 alkoxy, C l -C_ alkyl, C2-C8 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 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 with one, two or three substituents selected from the group consisting of: H, OH, CO2R 6 , Br, Cl, F, I, CF3, N(R?)2, C1-C8 al
  • 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, C ⁇ -C$ 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 3 is a) H, b) C1-C8 alkyl, c) C1-C8 alkenyl, ) C1-C8 alkynyl, e) C1-C8 alkoxyl, f) C3-C7 cycloalkyl, g) S(0) t R5, h) Br, Cl, F, I, i) aryl, j) heteroaryl,
  • X and Y are independently: O, S, or NR ⁇ ;
  • n 0 to 5;
  • t 0, 1 or 2;
  • R 4 is: C1-C8 alkyl
  • R 5 is: C l-C ⁇ alkyl, or aryl
  • R6, is: H, C1-C8 alkyl, or aryl
  • R7 is: H, C1-C8 alkyl, aryl, 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, or C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2) n CH2N(R5) 2; or when two R ⁇ substutients are on the same nitrogen they can join to form a ring of 3 to 6 atom;
  • R A Li an organolithium compound, R A Li, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C.
  • heterocyclyl 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, the heterocyclyl 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, C1-C8 alkoxy, C 1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl,
  • 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-Cs 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, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 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 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, Cl, F, I, CF3, N(R?)2, Cl-C ⁇ alkoxy, Cl-Cs
  • 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, -C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl,
  • R 3 is a) H, b) C1-C8 alkyl, c) C1-C8 alkenyl, d) C1-C8 alkynyl, e) C1-C8 alkoxyl, f) C3-C7 cycloalkyl, g) S(0) t R5, h) Br, Cl, F, I, i) aryl, j) heteroaryl,
  • X and Y are independently: O, S, or NR ,
  • n 0 to 5;
  • t 0, 1 or 2;
  • R 4 is C1-C8 alkyl
  • R5 is: C 1-C8 alkyl, or aryl
  • R 6 is: H, C1-C8 alkyl, and aryl
  • R? are independently: H, Cl-C8 alkyl, and 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, C02R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl-C8 alkoxy, Cl-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3,
  • R 1 Li an organolithium compound, R 1 Li, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C.
  • the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N' ,N' -tetra(C 1 -C6)-alkyltrans- 1 ,2-diamino- cyclohexane, or
  • R and R9 are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R 8 and
  • R9 cannot simultaneously be H; and RlO is C1-C6 alkyl or aryl, are useful in this process. It is understood that the amino alcohol represented by the above noted structure has at least one, and potentially two chiral centers.
  • aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, and dioxane. or a mixture of said solvents.
  • the preferred aprotic solvent is toluene.
  • the solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
  • Cl-C ⁇ alkoxy Cl-C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C ⁇ alkynyl, or
  • 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,
  • 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,
  • Rl is: a) C1-C8 alkyl, C2-C8 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, Cl-C ⁇ alkoxy, C l -C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C alkynyl, or C3-C cycloalkyl, CO(CH2) n CH3, and CO(CH2) n CH2N(R5) 2 ,
  • R 3 is a) CHO, b) CH(OR )2;
  • n 0 to 5
  • t 0, 1 or 2;
  • X and Y are independently: O, S, or NR ,
  • R 4 is Cl-C ⁇ alkyl
  • R 5 is: Cl-C ⁇ alkyl, or aryl
  • R ⁇ is: H, Cl-C ⁇ alkyl, and aryl
  • R7 are independently: H, Cl-C ⁇ alkyl, and 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(R 5 )2, C1-C8 alkoxy, Cl-C ⁇ alkyl, C2-C alkenyl, C2-C ⁇ alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3,
  • R3 is CH(OR 4 )2; with an organolithium compound, R x Li, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C to give the conjugate adduct; and
  • the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N' ,N'-tetra(C l -C6)-alkyltrans- 1 ,2-diamino- cvclohexane, or
  • R and R9 are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R ⁇ and R9 cannot simultaneously be H; and R ⁇ 0 is C1-C6 alkyl or aryl, are useful in this process.
  • aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane. and dioxane. or a mixture of said solvents.
  • the preferred aprotic solvent is toluene.
  • the solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
  • the solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
  • organolithium compound in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about -20°C.
  • the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N' ,N'-tetra(C 1 -C6)-alkyltrans- 1 ,2-diamino- cyclohexane, or
  • aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether. MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, and dioxane, or a mixture of said solvents.
  • MTBE methyl t-butyl ether
  • toluene benzene
  • hexane hexane
  • pentane pentane
  • dioxane or a mixture of said solvents.
  • the solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
  • 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.
  • 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.
  • the heteroaryl substituent represents an carbazolyl, furanyl, thienvl, 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.
  • the protected aldehyde represents an acetal, such as -
  • R ⁇ is CHO
  • Z is a leaving group, such as Br. Cl, I, OTriflyl, OTosyl or OMesyl and R 2 is OR 4 or N(R 5 )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 treated with an alcohol (R 4 OH) and aqueous acid to give the acetal-acceptor 5a.
  • 1,2-amino indanol is acylated (propionyl choride. K2CO3) to give amide 8, which is then converted into the acetonide 9 (2-methoxypropene, pyridinium p-toluene-sulfonate (PPTS)).
  • Acetonide 9 is then alkylated with the bromide 13, (LiHMDS) to give 14, which is then hydrolyzed (H+, MeOH) to give a mixture of acid and methyl ester 15.
  • Reduction (LAH) of the ester/acid mixture provided the alcohol 16 in high yield and optical purity. Protection of the alcohol 16 (TBSC1, imidazole) provided bromide 17, the precursor to organolithium 17a.
  • Compound 17a and a chiral additive, such as sparteine, are added to the , ⁇ -unsaturated ester 5a at -78° to -50°C. Work up with water affords compounds 6a and 6b. Mixtures of compounds 6a and 6b are treated with TBAF or aqueous acid to deprotect the silylated alcohol or acetal and silylated alcohol.
  • Dissolve product of bromination reaction (MW 239.12, 27.6 mmol, 6.60 g) in 66 mL toluene and cool to -42°C. Slowly add DIBAL (1.5 M in toluene, 2 equ, 37 mL) and age 1 h at -42°C. Add HC1 (2 N, 10 equ, 134 mL) and stir vigorously for 30 min. Dilute with ethyl acetate, separate layers, and wash aqueous with ethyl acetate. Combine organic layers, dry (magnesium sulfate), and concentrate in vacuo to afford 90% (MW 242.11, 6.01 g) of 3.
  • Dissolve 3 (MW 242.11, 24.8 mmol, 6.01 g) in 75 mL toluene. Add sodium acetate (MW 82, 3 equ, 6.13 g), t-butyl acrylate (MW 128.17, d 0.875, 2.5 equ, 9.08 mL), P(o-tolyl)3 (MW 304.38, 10 mol %, 755 mg) and allyl palladium chloride dimer (MW 365.85, 5 mol %, 455 mg). Age at reflux for 24 h. Cool, filter and evaporate in vacuo. Isolate 4a (MW 289.37) by silica gel chromatography (92:8 hexanes:ethyl acetate) in 80% yield (5.74 g).
  • Step A Preparation of 6a and 6b
  • Step B Preparation of 6c and 6 ⁇ (Method A) A solution of 500 mg (0.8 mmol) of above products 6a and
  • 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.

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Abstract

This invention relates to a process for the preparation of a key intermediate in the synthesis of an endothelin antagonist, having formula (I) by using a chiral additive to effect an asymmetric conjugate addition.

Description

ENDOTHELIN INTERMEDIATES BY ASYMMETRIC CONJUGATE ADDITION REACTION USING A CHIRAL ADDITIVE
BACKGROUND OF THE INVENTION
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.
The compound possessing a high affinity for at least one of two receptor subtypes, are responsible for the dilation of smooth muscle, such as blood vessels or in the trachea. The endothelin antagonist compounds provide a potentially new therapeutic target, 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, 41 1-415 (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)).
As reported, 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, V2, 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)).
Further, an increased sensitivity of the cerebral blood vessel to endothelin in an experimental model of cerebral vasospasm (Japan. Soc. Cereb. Blood Flow & Metabol., 1, 73 (1989)), an improved renal function by the endothelin antibody in an acute renal failure model (J. Clin, invest., 83, 1762-1767 (1989), and inhibition of gastric ulcer development with an endothelin antibody in a gastric ulcer model (Extract of Japanese Society of Experimental Gastric Ulcer. 50 (1991)) have been reported. Therefore, endothelin is assumed to be one of the mediators causing acute renal failure or cerebral vasospasm following subarachnoid hemorrhage.
Further, 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., J^5, 20 167- 172 (1989); Proc. Natl. Acad. Sci. USA, 85 1 9797-9800 (1989); J. Cardiovasc. Pharmacol., J_3, S89-S92 (1989); Japan. J. Hypertension, 12, 76 (1989) and Neuroscience Letters, 102. 179-184 (1989)). Further, endothelin causes contraction of the smooth muscle of gastrointestinal tract and the uterine smooth muscle (FEBS Letters, 247, 337-340 (1989); Eur. J. Pharmacol., 154, 227-228 (1988); and Biochem. Biophys Res. Commun., 159, 317-323 (1989)). Further, endothelin was found to promote proliferation of rat vascular smooth muscle cells, suggesting a possible relevance to the arterial hypertrophy (Atherosclerosis, 78, 225- 228 (1989)). Furthermore, since the 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. Pharmacol., 22, 355 - 359 & 371 - 373(1993)). These data support a role of endothelin in the phathogenesis of vascular restenosis. Recently, it has been reported that both ETA and ETβ receptors exist in the human prostate and endothelin produces a potent contraction of it. These results suggest the possibility that endothelin is involved in the pathophysiology of benign prostatic hyperplasia (J. Urology, 151. 763 - 766(1994), Molecular PharmocoL, 45, 306 - 311(1994)).
On the other hand, 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. These findings suggest that endothelin is an important mediator for endotoxin- induced diseases (Biochem. Biophys. Commun., 161. 1220-1227 ( 1989); and Acta Physiol. Scand., 137, 317-318 (1989)).
Further, it was reported that cyclosporin remarkably increased endothelin secretion in the renal cell culture (LLC-PKL cells) (Eur. J. Pharmacol., 180, 191-192 (1990)). Further, dosing of cyclosporin to rats reduced the glomerular filtration rate and increased the blood pressure in association with a remarkable increase in the circulating endothelin level. This cyclosporin-inducea renal failure can be suppressed by the administration of endothelin antibody (Kidney Int., 37, 1487-1491 (1990)). Thus, it is assumed that endothelin is significantly involved in the pathogenesis of the cyclosporin-induced diseases.
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.7 . S119-SI21 (1991)). One of the endothelin receptors is ETA receptor Selective to ET-1 rather than ET-3, and the other is ETβ 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)).
These two subtypes of endothelin receptors are differently distributed in tissues. It is known that the ETA receptor is present mainly in cardiovascular tissues, whereas the ETβ 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 ETβ 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. Further, it is suggested that 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 ETβ are known so far and antagonists of these receptors have been shown to be potential drug targets. EP 0526708 Al and WO 93/08799 Al are representative examples of patent applications disclosing non-peptidic compounds with alleged activity as endothelin receptor antagonists.
The present invention discloses an asymmetric conjugate addition for preparing the compound of Formula I,
Figure imgf000007_0001
a key intermediate in the synthesis of endothelin antagonists of the following structure:
Figure imgf000007_0002
wherein
Figure imgf000007_0003
represents: 5- or 6-membered heterocyclyl, 5- or 6- membered carbocyclyl, and aryl;
R1 is: Cl-Cδ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, aryl, or heteroaryl;
Figure imgf000007_0004
is aryl, or heteroaryl;
R is C1-C8 alkyl; and
R5 is: C 1-C8 alkyl, or aryl. SUMMARY OF THE INVENTION
The instant invention relates to a process for the preparation of a compound of formula I:
Figure imgf000008_0001
wherein
Figure imgf000008_0002
represents:
a) 5- or 6-membered heterocyclyl 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, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cg alkoxy, -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, b) 5- or 6-membered carbocyclyl 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, c) aryl, wherein aryl is as defined below, C1-C8 alkoxy, Cl-Cδ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or
C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, -C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and
Figure imgf000009_0001
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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C l -C8 alkoxy, C l -C_ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)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 with one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R?)2, C1-C8 alkoxy, Cl-Cδ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and
Figure imgf000009_0002
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,
CO2R4, Br, Cl, F, I, CF3, N(R5)2, C\-C$ alkoxy, Cl -Cδ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
Figure imgf000010_0001
R3 is a) H, b) C1-C8 alkyl, c) C1-C8 alkenyl, ) C1-C8 alkynyl, e) C1-C8 alkoxyl, f) C3-C7 cycloalkyl, g) S(0)tR5, h) Br, Cl, F, I, i) aryl, j) heteroaryl,
Figure imgf000010_0002
1) NH2, m) CHO, n) -CO-C1-C8 alkyl,
0) -CO-aryl,
P) -CO-heteroaryl, q) -CO2R4, or r) protected aldehyde;
X and Y are independently: O, S, or NR^;
n is: 0 to 5;
t is: 0, 1 or 2;
R4 is: C1-C8 alkyl; R5 is: C l-Cδ alkyl, or aryl;
R6, is: H, C1-C8 alkyl, or aryl;
R7 is: H, C1-C8 alkyl, aryl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl- C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)2; or when two R^ substutients are on the same nitrogen they can join to form a ring of 3 to 6 atom;
comprising reacting a ,β-unsaturated ester or amide
Figure imgf000011_0001
with an organolithium compound, RALi, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C.
DETAILED DESCRIPTION OF THE INVENTION The instant invention relates to a process for the preparation of a compound of formula I:
Figure imgf000011_0002
wherein
Figure imgf000012_0001
represents:
a) 5- or 6-membered heterocyclyl 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, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C 1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl,
CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, b) 5- or 6-membered carbocyclyl 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cs alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, c) aryl, wherein aryl is as defined below,
C1-C8 alkoxy, -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl. or
C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cs alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and
Figure imgf000012_0002
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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)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, CO2R6, Br, Cl, F, I, CF3, N(R?)2, Cl-Cδ alkoxy, Cl-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and
Figure imgf000013_0001
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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, -C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl,
CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
Figure imgf000013_0002
R3 is a) H, b) C1-C8 alkyl, c) C1-C8 alkenyl, d) C1-C8 alkynyl, e) C1-C8 alkoxyl, f) C3-C7 cycloalkyl, g) S(0)tR5, h) Br, Cl, F, I, i) aryl, j) heteroaryl,
Figure imgf000014_0001
1) NH2, m) CHO, n) -CO-C1-C8 alkyl, o) -CO-aryl,
P) -CO-heteroaryl, q) -C02R4, or r) protected aldehyde;
X and Y are independently: O, S, or NR ,
n is: 0 to 5;
t is: 0, 1 or 2;
R4 is C1-C8 alkyl;
R5 is: C 1-C8 alkyl, or aryl; and
R6 is: H, C1-C8 alkyl, and aryl; and
R? are independently: H, Cl-C8 alkyl, and 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, C02R4, Br, Cl, F, I, CF3, N(R5)2, Cl-C8 alkoxy, Cl-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3,
Figure imgf000014_0002
comprising reacting a .β-unsaturated ester or amide
Figure imgf000015_0001
with an organolithium compound, R 1 Li, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C.
The process as recited above, wherein the number of equivalents of the organolithium compound, R^Li, is 1 to about 4. and preferably about 1.5 to about 2.5.
The process as recited above, wherein the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N' ,N' -tetra(C 1 -C6)-alkyltrans- 1 ,2-diamino- cyclohexane, or
c)
Figure imgf000015_0002
2. wherein R and R9 are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R8 and
R9 cannot simultaneously be H; and RlO is C1-C6 alkyl or aryl, are useful in this process. It is understood that the amino alcohol represented by the above noted structure has at least one, and potentially two chiral centers.
The process as recited above, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, and dioxane. or a mixture of said solvents. The process as recited above, wherein the preferred aprotic solvent is toluene.
The solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
The process as recited above, wherein the temperature range is about -78°C to about -20°C, and preferably about -78°C to about -50°C.
An embodiment of this invention is the process for the preparation of a compound of formula I:
Figure imgf000016_0001
wherein
Figure imgf000016_0002
represents:
a) 5- or 6-membered heterocyclyl 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, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cs alkoxy, Cl-Cδ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, b) 5- or 6-membered carbocyclyl 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cδ alkoxy, Q-Cδ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, c) aryl, wherein aryl is as defined below,
Cl-Cδ alkoxy, Cl-Cδ alkyl, C2-Cδ alkenyl, C2-Cδ alkynyl, or
C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cδ alkoxy,
C3-Cδ cycloalkyl, CO(CH2)nCH3, and
Figure imgf000017_0001
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, CO2R4, Br, Cl, F, I, CF3,
N(R5)2, Cl-Cδ alkoxy, Cl-Cδ alkyl, C2-C8 alkenyl, C2-Cδ alkynyl, or C3-Cδ cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)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, CO2R6, Br, Cl, F, I, CF3, N R7)2, Cl-Cδ alkoxy, C l-Cδ alkyl. C2-C8 alkenyl, C2-C8 alkynyl, or C3-Cδ cycloalkyl, CO(CH2)nCH3, and
Figure imgf000017_0002
Rl is: a) C1-C8 alkyl, C2-C8 alkenyl, C2-Cδ alkynyl, C3-Cδ 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, CO2R4, Br, Cl. F, I, CF3, N(R5)2, Cl-Cδ alkoxy, C l -Cδ alkyl, C2-Cδ alkenyl, C2-C alkynyl, or C3-C cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
Figure imgf000018_0001
R3 is a) CHO, b) CH(OR )2;
n is: 0 to 5,
t is: 0, 1 or 2;
X and Y are independently: O, S, or NR ,
R4 is Cl-Cδ alkyl;
R5 is: Cl-Cδ alkyl, or aryl;
Rό is: H, Cl-Cδ alkyl, and aryl;
R7 are independently: H, Cl-Cδ alkyl, and 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, Cl-Cδ alkyl, C2-C alkenyl, C2-Cδ alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3,
Figure imgf000018_0002
comprising the steps of:
1) reacting an α,β-unsaturated ester or amide
Figure imgf000019_0001
where R3 is CH(OR4)2; with an organolithium compound, RxLi, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C to give the conjugate adduct; and
2) removing the aldehyde protecting group with an acid to give the compound of Formula I, where R3 is CHO.
The process as recited above, wherein the number of equivalents of the organolithium compound, RxLi, is 1 to about 4. and preferably about 1.5 to about 2.5.
The process as recited above, wherein the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N' ,N'-tetra(C l -C6)-alkyltrans- 1 ,2-diamino- cvclohexane, or
c)
Figure imgf000019_0002
wherein R and R9 are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R§ and R9 cannot simultaneously be H; and Rχ0 is C1-C6 alkyl or aryl, are useful in this process.
The process as recited above, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane. and dioxane. or a mixture of said solvents. The process as recited above, wherein the preferred aprotic solvent is toluene. The solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
The solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
The process as recited above, wherein the temperature range is about -78°C to about -20°C, and preferably about -78°C to about -50°C.
An embodiment of this invention is the process for the preparation of the protected aldehyde
Figure imgf000020_0001
OMe comprising reacting an ,β-unsaturated ester or amide
Figure imgf000020_0002
with an organolithium compound
Figure imgf000021_0001
in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about -20°C.
The process as recited above, wherein the number of equivalents of the organolithium compound, R ^Li, is 1 to about 4. and preferably about 1.5 to about 2.5.
The process as recited above, wherein the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N' ,N'-tetra(C 1 -C6)-alkyltrans- 1 ,2-diamino- cyclohexane, or
c)
Figure imgf000021_0002
?, wherein R& and R9 are independently: H,
C l-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R§ and R9 cannot simultaneously be H; and RlO is C1-C6 alkyl or aryl, are useful in this process.
The process as recited above, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether. MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, and dioxane, or a mixture of said solvents. The process as recited above, wherein the preferred aprotic solvent is tetrahydorfuran.
The solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran. The process as recited above, wherein the temperature range is about -78°C to about -20°C, preferably about -78°C to about - 50°C, and most preferably about -78°C to about -70°C.
It is further understood that the substituents recited above would include the definitions recited below.
The 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.
The 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.
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.
The heteroaryl substituent represents an carbazolyl, furanyl, thienvl, 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.
The protected aldehyde represents an acetal, such as -
CH(OCl-C8 alkyl)2,
The α,β-unsaturated ester or amide
Figure imgf000022_0002
can generally be prepared in two steps:
1 ) a coupling reaction at the one position of Ring A
Figure imgf000023_0001
wherein R^ is CHO, Z is a leaving group, such as Br. Cl, I, OTriflyl, OTosyl or OMesyl and R2 is OR4 or N(R5)2; and
2) the conversion of the aldehyde (R3 is CHO) to the desired protected aldehyde (R is CH(OR4)2 and R4 is Cl-Cδ alkyl).
Commercially available 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. The nitrile
3a is then reduced to the aldehyde 3 using diisobutyl aluminum hydride (DIBAL). 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 treated with an alcohol (R4OH) and aqueous acid to give the acetal-acceptor 5a.
Scheme 1
Figure imgf000024_0001
2
DIBAL
Figure imgf000024_0003
Figure imgf000024_0002
3a 3
Figure imgf000024_0004
Commericially available acid 10 is reduced with BH3»SMe2, to the alcohol 11, which is then converted into the bromidel3, via the mesylate 12 using mesyl chloride, triethylamine followed by the addition of NaBr and dimethylacetamide (DMAC).
Scheme 2
Figure imgf000025_0001
Commercial available 1,2-amino indanol is acylated (propionyl choride. K2CO3) to give amide 8, which is then converted into the acetonide 9 (2-methoxypropene, pyridinium p-toluene-sulfonate (PPTS)). Acetonide 9 is then alkylated with the bromide 13, (LiHMDS) to give 14, which is then hydrolyzed (H+, MeOH) to give a mixture of acid and methyl ester 15. Reduction (LAH) of the ester/acid mixture provided the alcohol 16 in high yield and optical purity. Protection of the alcohol 16 (TBSC1, imidazole) provided bromide 17, the precursor to organolithium 17a. Scheme 3
Figure imgf000026_0001
14
Figure imgf000026_0002
Compound 17a and a chiral additive, such as sparteine, are added to the ,β-unsaturated ester 5a at -78° to -50°C. Work up with water affords compounds 6a and 6b. Mixtures of compounds 6a and 6b are treated with TBAF or aqueous acid to deprotect the silylated alcohol or acetal and silylated alcohol.
Scheme 4
Figure imgf000028_0001
The instant invention can be understood further by the following examples, which do not constitute a limitation of the invention.
EXAMPLE 1
Figure imgf000029_0001
Preparation of 1 Compound 1 is a commericially available starting material, for example, see Aldrich Chemical Company, Milwaukee, WI, USA 53201.
EXAMPLE 2
Figure imgf000029_0002
Preparation of 2
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 1 (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 2. EXAMPLE 3
Figure imgf000030_0001
Preparation of 3
Mix 2 (MW 176.22, 46 mmol) and PBr3 (MW 270.70, d
2.880, 2.5 equ, 10.8 mL) and age at 160°C. After 2 h, cool to 25°C and add some CH2CI2. Slowly quench by adding water. Separate layers and wash aqueous two times with CH2CI2. Combine organic layers and dry (magnesium sulfate). Concentrate and isolate solid by silica gel chromatography (90: 10 hexanes:ethyl acetate) in 60% yield (MW 239.12, 6.60 g).
Dissolve product of bromination reaction (MW 239.12, 27.6 mmol, 6.60 g) in 66 mL toluene and cool to -42°C. Slowly add DIBAL (1.5 M in toluene, 2 equ, 37 mL) and age 1 h at -42°C. Add HC1 (2 N, 10 equ, 134 mL) and stir vigorously for 30 min. Dilute with ethyl acetate, separate layers, and wash aqueous with ethyl acetate. Combine organic layers, dry (magnesium sulfate), and concentrate in vacuo to afford 90% (MW 242.11, 6.01 g) of 3.
EXAMPLE 4a
Figure imgf000030_0002
Preparation of 4a
Dissolve 3 (MW 242.11, 24.8 mmol, 6.01 g) in 75 mL toluene. Add sodium acetate (MW 82, 3 equ, 6.13 g), t-butyl acrylate (MW 128.17, d 0.875, 2.5 equ, 9.08 mL), P(o-tolyl)3 (MW 304.38, 10 mol %, 755 mg) and allyl palladium chloride dimer (MW 365.85, 5 mol %, 455 mg). Age at reflux for 24 h. Cool, filter and evaporate in vacuo. Isolate 4a (MW 289.37) by silica gel chromatography (92:8 hexanes:ethyl acetate) in 80% yield (5.74 g).
EXAMPLE 4b
Figure imgf000031_0001
3 4b
Preparation of 4 b
Dissolve 3 (MW 242.11, 24.8 mmol, 6.01 g) in 75 mL toluene. Add sodium acetate (MW 82, 3 equ, 6.13 g), dimethylacrylamide (MW 99.13, d 0.962, 1 equ, 2.55 mL), PPh3 (MW
262.29, 10 mol %, 653 mg) and allyl palladium chloride dimer (MW 365.85, 5 mol %, 455 mg). Age at 140°C in sealed tube for 24 h. Cool, filter and evaporate in vacuo. Isolate 4b (MW 260.34) by silica gel chromatography (80:20 hexanes:ethyl acetate) in 70% yield (4.52 g).
EXAMPLE 5a
Figure imgf000031_0002
Preparation of 5a
A solution of 16.0 g (55.36 mmol) of aldehyde 4a and 1.4 g (5.54 mmol) of PPTS in 280 mL of MeOH was heated at reflux for 2.5 h. After cooling to room temperature, the solvents were evaporated in vacuo. The residue was dissolved into EtOAc and washed with satd. sodium bicarbonate solution. Concentration of the organic layer gave 18.2 g of the desired product 5a. 98% yield. Η NMR (CDCL3) δ: 7.95 (d, 1 H), 7.80 (d, 1 H), 7.12 (d, 1 H), 7.04 (d, 1 H), 5.09 (1 H), 3.45 (s, 6 H), 2.80 (t, 2 H), 1.73 (m, 2 H), 1.54 (s, 9 H), 1.40 (m, 2 H), 0.95 (t, 3 H) ppm.
EXAMPLE 6
Figure imgf000033_0001
Step A: Preparation of 6a and 6b
To a solution of 17 (2.23 g, 5.97 mmol), (-)-sparteine (1.37 mL, 5.97 mmol), and THF (73 μL, 0.896 mmol) in 20 mL of toluene at -78 °C was added t-BuLi (1.7 M in Hexane, 7.0 mL, 11.94 mmol) dropwise. The solution was aged for 30 min. at -78 °C. A solution of the unsaturated t-butyl ester 5a (1.0 g, 2.98 mmol) in 5 mL of toluene was added dropwise over 10 min. at -78 °C. After 20 min at - 78 °C, the reaction was quenched with water. The organic phase was separated and dried over anhydrous sodium sulfate. Purification of the crude product by silica gel chromatography (EtO Ac/Hex, 2:98) gave 1.52 g of the desired products 6a and 6b. 81% yield. For major diasteromer 6b: Η NMR (CDCL3) δ: 7.24 (dd, 1 H), 7.00 (d, 1 H), 6.84 (d, 1 H), 6.70 (d, 1 H), 6.55 (dd, 1 H), 5.74 (s, 1 H). 5.02 (m, 1 H), 3.72 (s, 3 H), 3.55 (m, 4 H), 3.22 (s, 3 H), 2.92 (s, 3 H). 2.80 (t, 2 H), 2.50 (m, 2 H), 2.12 (m, 1 H), 1.75 (m, 2 H), 1.40 (m, 2 H), 1.28 (s, 9 H), 0.95 (m, 6 H), 0.90 (s, 9 H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm. In order to determine the ratio of the two diasteroisomers
6a and 6b, the above compounds were further deprotected by treatment with TBAF in THF or with either HCl or pTSA in aqueous acetone.
Step B: Preparation of 6c and 6ά (Method A) A solution of 500 mg (0.8 mmol) of above products 6a and
6b and 0.96 mL of TBAF (1.0 M in THF) in 6 mL of THF was allowed to stir for 4 h. at room temperature. The reaction solution was then washed with water and dried over sodium sulfate. The product was analyzed by H NMR. Integration of the singlet peaks at 5.42 ppm (major diasteromer) and 5.38 ppm (minor diasteromoer) was used to determine the ratio of the two diasteromers.
Step C: Preparation of 6e and 6f (Method B
A solution of 100 mg (0.16 mmol) of above products 6a and 6b in 3 mL of acetone and 1 mL of 5% HCl or 45 mg pTS A in 3 mL of acetone and 1 mL of water was allowed to stir for 5 h. at room temperature. The solvents were evaporated in vacuo. The residue was dissolved in EtOAc and washed with 10% sodium carbonate. The product was concentrated and analyzed by H NMR. Integration of the singlet peaks at 10.35 ppm (major diasteromer) and 10.20 ppm (minor diasteromoer) was used to determine the ratio of the two diasteromers.
EXAMPLE 7
Figure imgf000035_0001
Preparation of 7
Compound 7 is a commericially available starting material, for example, see DSM Andeno, Grubbenvorsterweg 8, P.O. Box 81, 5900 AB Venlo,The Netherlands.
EXAMPLE 8
Figure imgf000035_0002
8
Preparation of 8
Na2C03 (MW 105.99, 1.5 equ, 8.8 g) dissolved in 82 mL water. Add a solution of (1R,2S) amino indanol 7 (MW 149.19, 55.0 mmol, 8.2 g) in 160 mL CH2CI2. Cool to -5°C and add propionyl chloride (MW 92.53, d 1.065, 1.3 equ, 6.2 mL). Warm to 25°C and age 1 h. Separate layers and dry organic (magnesium sulfate). Concentrate in vacuo to afford 8 (MW 205.26, 10 g) in 89% isolated yield. EXAMPLE 9
Figure imgf000036_0001
8 9
Preparation of 9
To a solution of 8 (MW 205.26, 49.3 mmol, 10 g) in 200 mL THF, add pyridinium -toluenesulfonate (PPTS) (MW 251.31, 0.16 equ, 2g) then methoxypropene (MW 72.11, d 0.753, 2.2 equ, 10.4 mL). Age 2 h at 38°C, then add aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried (magnesium sulfate). After concentration in vacuo, 9 (MW 245.32, 12.09 g) was formed in quantitative yield.
EXAMPLE 10
Figure imgf000036_0002
Preparation of 10
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. EXAMPLE 11
Figure imgf000037_0001
Preparation of 1 1
10 (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 11 (MW 217.06, 25.5 g).
EXAMPLE 12
Figure imgf000037_0002
Preparation of 12
Dissolve 11 (MW 217.06, 47.2 mmol, 10.24 g) in 55 mL CH2CI2 and cool to -20°C. Add DIEA (MW 129.25, d 0.742, 1.3 equ,
10.69 mL) then methane sulfonyl chloride (MsCl) (MW 114.55, d 1.480, 1.2 equ, 4.38 mL). Age -5°C to 0°C for 1 h then quench into 55 mL water. Extract with CH2CI2 then wash with IN H2SO4 (40 mL), then brine. Dry organic layers (magnesium sulfate) and concentrate in vacuo to afford 12 (MW 295.15, 13.23 g) in 95% yield. EXAMPLE 13
Figure imgf000038_0001
Preparation of 13
12 (MW 295.15, 44.8 mmol, 13.23 g) in 44 mL dimethylacetamide (DMAC). Add NaBr (MW 102.90, 2 equ, 9.22 g) and age lh. Add 88 mL water and collect solid by filtration. Wash cake with water and dry by suction. Quantitative yield of 13 (MW 279.96, 12.54 g) is obtained.
EXAMPLE 14
Figure imgf000038_0002
Preparation of 14
9 (MW 245.32, 1.1 equ, 89.1 g) in 1 L THF, cooled to - 50°C. Add LiHMDS (1.0 M in THF, 1.5 equ, 545 mL) and age 1.5 h, warming to -30°C. Add 13 (MW 279.96, 327 mmol, 91.3 g) in 300 mL THF, and age -35°C for 1 h. Warm to -10°C over 1 h, then quench into aqueous NH4CI. Separate layers and extract with ethyl acetate. Dry organic and concentrate in vacuo to afford crude 14 (MW 444.37).
EXAMPLE 15
Figure imgf000039_0001
Preparation of 15
14 in 1 L MeOH and cooled to 10°C. Bubble in HCl gas for 1 h until reaction is complete. 2 L H2O added and the product was filtered. The cake was washed with H2O and dried to give the product hydroxyamide, which was then dissolved in 1 L MeOH and 1.5 L 6N HCl and refluxed overnight. The mixture was cooled to 25°C and extracted with CH2CI2 to give, after concentration, compounds 15 (60 g, 64% from bromide 13).
EXAMPLE 16
Figure imgf000039_0002
15 16 Preparation of 16
15 (mixture of acid and ester, 26.88 mmol) in 150 mL THF at -78°C. Add lithium aluminum hydride (UAIH4) (1 M in THF,
2 equ, 53.76 mL) over 30 min. Warm to 25°C over 1 h, then quench into aqueous NH4CI. Add ethyl acetate, extract ethyl acetate. Wash organics with brine, dry (magnesium sulfate), and concentrate in vacuo to afford 95% yield of 16 (MW 259.14, 6.62 g).
EXAMPLE 17
Figure imgf000040_0001
Preparation of 17
16 (MW 259.14, 25.54 mmol, 6.62 g) in 35 mL CH2CI2 and cool to 0°C. Add imidazole (MW 68.08, 2.5 equ, 4.35 g) and then tert-butyldimethylsilyl chloride (TBSC1) (MW 150.73, 1 equ, 3.85 g). Age 1 h at 25°C then quench with aqueous NaHCθ3 and add ethyl acetate. Extract with ethyl acetate, then dry organic layer (magnesium sulfate) and concentrate in vacuo to afford a quantitative yield of 17 (MW 373.41, 9.54 g). H NMR (CDCI3) : 7.41 (d, 7=8.74, 1H), 6.77 (d, J=3.04, 1H), 6.63 (dd, 7=8.73, 3.06, 1H), 3.78 (s, 3 H), 3.50 (d, 7=5.75, 2 H), 2.89 (dd, 7=13.31, 6.15, 1 H), 2.45 (dd, 7=13.30, 8.26, 1 H), 2.03 (m, 1 H), 0.94 (s, 9 H), 0.92 (d, 7=5.01, 3 H), 0.07 (s, 6 H).
13c NMR (CDCI3) : 159.1, 141.6, 133.2, 117.0, 115.4, 113.2, 67.4, 55.4, 39.7, 36.3, 26.0 (3C), 18.4, 16.5, -5.3 (2C). EXAMPLE 18-22 Following the procedure described in Example 6 the listed chiral additive resulted in the indicated diastereomeric ratios of compounds 6a to 6b.
Example No. Chiral Additive Diastereomeric
Ratio ( 6a:6b)
6 (-)sparteine 1:5
18 N-methyl ephedrine 1: 1
Figure imgf000041_0001
20 Ph
Ph* t 1: 1.3
MeO OMe
21 3.7: 1
Figure imgf000041_0002
Figure imgf000041_0003

Claims

WHAT IS CLAIMED IS:
A process for the preparation of a compound of formula I:
Figure imgf000042_0001
wherein
Figure imgf000042_0002
represents:
a) 5- or 6-membered heterocyclyl 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, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cδ alkoxy, Cl-Cδ alkyl, C2-Cδ alkenyl, C2-C alkynyl, or C3-Cδ cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, b) 5- or 6-membered carbocyclyl 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cδ alkoxy, Cl-Cδ alkyl, C2-Cδ alkenyl, C2-C8 alkynyl, or C3-Cδ cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, c) aryl, wherein aryl is as defined below,
Cl-Cδ alkoxy, Cl-Cδ alkyl, C2-Cδ alkenyl, C2-Cδ alkynyl, or
C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R , Cl-Cδ alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and
Figure imgf000043_0001
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, CO2R4, Br, Cl, F, I, CF3,
N(R5)2, C1-C8 alkoxy, Cl-Cδ alkyl, C2-C alkenyl, C2-C alkynyl, or C3-C cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)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, CO2R6, Br, Cl, F, I, CF3, N(R?)2,
C1-C8 alkoxy, Cl-Cδ alkyl, C2-Cδ alkenyl, C2-Cδ alkynyl, or C3-Cδ cycloalkyl, CO(CH2)nCH3, and
Figure imgf000043_0002
Rl is: a) Cl-Cδ alkyl, C2-Cδ alkenyl, C2-Cδ alkynyl, C3-Cδ 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cδ alkoxy, Cl-Cδ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl,
CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
Figure imgf000044_0001
R3 is a) H, b) Cl-C8 alkyl, c) Cl-Cδ alkenyl, ) Cl-Cδ alkynyl, e) Cl-C8 alkoxyl, f) C3-C7 cycloalkyl, g) S(0)tR5, h) Br, Cl, F, I, i) aryl, j) heteroaryl,
Figure imgf000044_0002
1) NH2, m) CHO, n) -CO-C1-C8 alkyl, o) -CO-aryl,
P) -CO-heteroaryl, q) -CO2R4, or r) protected aldehyde;
X and Y are independently: O, S, or NR >
n is: 0 to 5;
t is: 0, 1 or 2;
R4 is Cl-Cs alkyl;
R5 is: Cl-Cs alkyl, or aryl; and
R6 is: H, Cl-Cs alkyl, and aryl; and R7 are independently: H, -Cδ alkyl, and 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3,
Figure imgf000045_0001
comprising reacting a α,β-unsaturated ester or amide
Figure imgf000045_0002
with an organolithium compound, RlLi, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C.
2. The process as recited in Claim 1, wherein the number of equivalents of the organolithium compound, R^Li, is 1 to about 4.
3. The process as recited in Claim 2, wherein the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N',N'-tetra(Cl-C6)-alkyltrans-l,2-diamino- cyclohexane, or c)
Figure imgf000046_0001
wherein R0* and R9 are independently: H,
Cl-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R§ and R9 cannot simultaneously be H; and R*0 is H, C1-C6 alkyl or aryl.
4. The process as recited in Claim 3, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, hexane, pentane, and dioxane, or a mixture of said solvents.
5. The process as recited in Claim 4, wherein the temperature range is about -78°C to about -20°C.
A process for the preparation of a compound of formula I:
Figure imgf000046_0002
wherein
Figure imgf000046_0003
represents:
a) 5- or 6-membered heterocyclyl 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, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cδ alkoxy, Cl -Cδ alkyl, C2-Cδ alkenyl, C2-Cδ alkynyl, or C3-Cδ cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, b) 5- or 6-membered carbocyclyl 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cδ alkoxy, Cl-Cδ alkyl, C2-Cδ alkenyl, C2-Cδ alkynyl, or C3-Cδ cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, c) aryl, wherein aryl is as defined below,
Cl-Cδ alkoxy, Cl-Cδ alkyl, C2-Cδ alkenyl, C2-Cδ alkynyl, or
C3-C cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cs alkoxy,
C3-C8 cycloalkyl, CO(CH2)nCH3, and
Figure imgf000047_0001
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, CO2R4, Br, Cl, F, I, CF3,
N(R5)2, C1-C8 alkoxy, Cl-Cs alkyl, C2-Cδ alkenyl, C2-Cδ alkynyl, or C3-Cδ cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)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, CO2R6, Br, Cl, F, I, CF3, N(R?)2, Cl-Cδ alkoxy, C1-C8 alkyl, C2-C alkenyl, C2-Cδ alkynyl, or C3-Cδ cycloalkyl, CO(CH2)nCH3, and
Figure imgf000047_0002
Rl is: a) Cl-Cδ alkyl, C2-Cδ alkenyl, C2-C alkynyl, C3-Cδ 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cδ alkoxy, Cl-Cδ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
Figure imgf000048_0001
R3 is a) CHO, b) CH(OR4)2;
n is: 0 to 5,
t is: 0, 1 or 2;
X and Y are independently: O, S, or NR ,
R4 is Cl-Cδ alkyl;
R5 is: Cl-Cδ alkyl, or aryl;
R6 is: H, Cl-Cδ alkyl, and aryl;
R7 are independently: H, Cl-Cδ alkyl, and 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, Cl-Cδ alkoxy, Cl-Cδ alkyl, C2-Cδ alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3,
Figure imgf000049_0001
comprising the steps of:
1) reacting an ,β-unsaturated ester or amide
Figure imgf000049_0002
where R3 is CH(OR4)2; with an organolithium compound, R^Li, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C to give the conjugate adduct; and
2) removing the protecting group with an acid to give the compound of Formula I, where R3 is CHO.
7. The process as recited in Claim 6, wherein the number of equivalents of the organolithium compound, R Li, is 1 to about 4.
8. The process as recited in Claim 7, wherein the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N' ,N' -tetra(C 1 -C6)-alkyltrans- 1 ,2-diamino- cyclohexane, or c)
Figure imgf000050_0001
and R9 are independently: H,
C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R§ and R9 cannot simultaneously be H; and Rχ0 is H, C1-C6 alkyl or aryl.
9. The process as recited in Claim 8, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, hexane, pentane, and dioxane, or a mixture of said solvents.
10. The process as recited in Claim 9, wherein the temperature range is about -78°C to about -20°C.
11. A process for the preparation of
Figure imgf000050_0002
comprising reacting an α,β-unsaturated ester or amide
Figure imgf000050_0003
with an organolithium compound
Figure imgf000051_0001
in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about -20°C.
12. The process as recited in Claim 11, wherein the number of equivalents of the organolithium compound, RxLi, is 1 to about 4.
13. The process as recited in Claim 11, wherein the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N' ,N'-tetra(C l -C6)-alkyltrans- 1 ,2-diamino- cyclohexane, or
c)
Figure imgf000051_0002
wherein R8 and R9 are independently: H,
Cl-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R& and R cannot simultaneously be H; and RlO is C1-C6 alkyl or aryl.
14. The process as recited in Claim 13, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, pentane, hexane, and dioxane, or a mixture of said solvents.
15. The process as recited in Claim 14, wherein the temperature range is about -78°C to about -50°C.
16. The process as recited in Claim 15, wherein the number of equivalents of the organolithium compound, RlLi, is 1.5 to about 2.5.
17. The process as recited in Claim 16, wherein the aprotic solvent is toluene or a toluene-hexane-(catalytic) tetrahydrofuran mixture.
18. The process as recited in Claim 17, wherein the temperature range is about -78°C to about -70°C.
PCT/US1998/000263 1997-01-14 1998-01-09 Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive WO1998030543A1 (en)

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HU0001921A HUP0001921A3 (en) 1997-03-21 1998-01-09 Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive
SK934-99A SK93499A3 (en) 1997-01-14 1998-01-09 Process for the preparation of intermediates
CA002277161A CA2277161A1 (en) 1997-01-14 1998-01-09 Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive
JP10531063A JP2000507969A (en) 1997-01-14 1998-01-09 Endothelin intermediate by asymmetric conjugate addition reaction using chiral additive
PL98334318A PL334318A1 (en) 1997-01-14 1998-01-09 Method of obtaining intermediate products for use in synthesising antagonists of endotheline by dissymmetrical addition employing a chiral additive
EP98902416A EP0973742A1 (en) 1997-01-14 1998-01-09 Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive
BR9806875-0A BR9806875A (en) 1997-01-14 1998-01-09 Process for the preparation of a compound.
AU59089/98A AU728441B2 (en) 1997-01-14 1998-01-09 Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive
EA199900661A EA002056B1 (en) 1997-01-14 1998-01-09 Endothelin intermediates by asymmetric conjugate addution reaction using a chiral additive
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US6313364B1 (en) 1999-10-28 2001-11-06 Merck & Co., Inc. Synthesis of cyclopropaneacetylene using a catalytic decarboxylation reaction
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
US6552239B1 (en) 1999-10-28 2003-04-22 Merck & Co., Inc. Synthesis of cyclopropaneacetylene by a one-pot process
US7060294B2 (en) 1998-05-27 2006-06-13 Merck & Co., Inc Compressed tablet formulation
US8115032B2 (en) 2009-04-09 2012-02-14 Lonza Ltd. Process for the synthesis of a propargylic alcohol
WO2012048884A1 (en) 2010-10-14 2012-04-19 Lonza Ltd Process for the synthesis of cyclic carbamates
WO2012048887A1 (en) 2010-10-14 2012-04-19 Lonza Ltd Process for the synthesis of chiral propargylic alcohols
US8283502B2 (en) 2009-04-09 2012-10-09 Lonza Ltd. Autocatalytic process for the synthesis of chiral propargylic alcohols

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WO1993008799A1 (en) * 1991-11-05 1993-05-13 Smithkline Beecham Corporation Endothelin receptor antagonists

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Publication number Priority date Publication date Assignee Title
EP0526708A1 (en) * 1991-06-13 1993-02-10 F. Hoffmann-La Roche Ag Sulfonamide, preparation and use thereof as medicine and intermediate
WO1993008799A1 (en) * 1991-11-05 1993-05-13 Smithkline Beecham Corporation Endothelin receptor antagonists

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7060294B2 (en) 1998-05-27 2006-06-13 Merck & Co., Inc Compressed tablet formulation
US7595063B2 (en) 1998-05-27 2009-09-29 Merck & Co., Inc. Compressed tablet formulation
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
US6313364B1 (en) 1999-10-28 2001-11-06 Merck & Co., Inc. Synthesis of cyclopropaneacetylene using a catalytic decarboxylation reaction
US6552239B1 (en) 1999-10-28 2003-04-22 Merck & Co., Inc. Synthesis of cyclopropaneacetylene by a one-pot process
US8115032B2 (en) 2009-04-09 2012-02-14 Lonza Ltd. Process for the synthesis of a propargylic alcohol
US8283502B2 (en) 2009-04-09 2012-10-09 Lonza Ltd. Autocatalytic process for the synthesis of chiral propargylic alcohols
WO2012048884A1 (en) 2010-10-14 2012-04-19 Lonza Ltd Process for the synthesis of cyclic carbamates
WO2012048887A1 (en) 2010-10-14 2012-04-19 Lonza Ltd Process for the synthesis of chiral propargylic alcohols
EP2447247A1 (en) 2010-10-14 2012-05-02 Lonza Ltd. Process for the synthesis of chiral propargylic alcohols
EP2447255A1 (en) 2010-10-14 2012-05-02 Lonza Ltd. Process for the synthesis of cyclic carbamates
US8957204B2 (en) 2010-10-14 2015-02-17 Lonza Ltd. Process for the synthesis of cyclic carbamates

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