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WO1999052899A1 - Procede d'oxydation au moyen d'acide periodique - Google Patents

Procede d'oxydation au moyen d'acide periodique Download PDF

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Publication number
WO1999052899A1
WO1999052899A1 PCT/US1999/007468 US9907468W WO9952899A1 WO 1999052899 A1 WO1999052899 A1 WO 1999052899A1 US 9907468 W US9907468 W US 9907468W WO 9952899 A1 WO9952899 A1 WO 9952899A1
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WIPO (PCT)
Prior art keywords
alkyl
aryl
cycloalkyl
alkoxy
formula
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PCT/US1999/007468
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English (en)
Inventor
Zhiguo Song
David M. Tschaen
Mangzu Zhao
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Merck & Co., Inc.
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Priority claimed from GBGB9810179.3A external-priority patent/GB9810179D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002327926A priority Critical patent/CA2327926A1/fr
Priority to AU33833/99A priority patent/AU3383399A/en
Priority to JP2000543457A priority patent/JP2002511464A/ja
Priority to EP99915282A priority patent/EP1070061A4/fr
Publication of WO1999052899A1 publication Critical patent/WO1999052899A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the present invention relates to an oxidation process which converts the penultimate intermediate to the target endothelin antagonist compound.
  • This oxidation method avoids the disposal issues associated with running a Jones oxidation reaction, as well as reducing the epimerization of any ⁇ -chiral centers and is a one step procedure .
  • the endothelin antagonist 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, 11-415 (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,
  • 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)).
  • 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.
  • vasoconstriction by the endothelins is caused via at least two subtypes of endothelin receptors (J. Cardiovasc. Pharmacol., 17(Suppl.7). S119-SI21 (1991)).
  • endothelin receptors J. Cardiovasc. Pharmacol., 17(Suppl.7). S119-SI21 (1991).
  • ETA receptor Selective to ET-1 rather than ET-3 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)).
  • 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 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 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.
  • Ci-C ⁇ alkyl, 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,
  • 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,
  • R 2 is: OR 4 or N(R5) 2;
  • R 3 is a) H, b) C1-C8 alkyl, c) C1-C8 alkoxyl, d) C3-C7 cycloalkyl, e) S(O) t R 5 , ) Br, Cl, F, I, g) aryl, h) heteroaryl, i) N(R5)2, j) NH 2 , k) -CHO,
  • - 7 - 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 , Ci-Cs alkoxy, Cl-Cs alkyl,
  • n 0 to 5;
  • t 0, 1 or 2;
  • R 4 is: H, or Cl-Cs alkyl
  • R 5 is: H, or Cl-C ⁇ alkyl, or aryl
  • R 6 is: H, Cl-Cs alkyl, or aryl
  • R is: H, Cl-Cs 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, Ci-C ⁇ alkoxy, Cl-Cs alkyl, C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2)nCH2N(R 5 )2; or when two R 7 substutients are on the same nitrogen they can join to form a ring of 3 to 6 atom; and
  • R8, R9, RIO an d R11 are independently: H, Cl-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Cl-C ⁇ alkoxy, C1-C8 alk lthio, aryl, each of 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, Ci-Cg alkoxy, Cl-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2) n CH3, or CO(CH2) n CH2N(R5) 2;
  • the present invention discloses a process for preparing a compound of Formula I:
  • C1-C8 alkoxy, C1-C8 alkyl, 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(R 5 )2, Cl-Cs alkoxy, C3-C8 cycloalkyl, CO(CH2) n CH3, and CO(CH2)nCH 2 N(R5)2,
  • 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(R 5 )2, Cl-C ⁇ alkoxy, Cl-Cs alkyl, or C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2) n CH2N(R 5 )2, or when aryl is substituted on adjacent carbons they can form a 5- or 6- membered fused ring having one, two or three heteroatoms selected from O, N, and S, this ring is unsubstituted or substituted on carbon or nitrogen with one, two or three substituents selected from the group consisting of: OH,
  • R2 is: OR 4 or N(R5)2;
  • R 3 is: a) H, b) Cl-Cs alkyl,
  • 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, CO 2 R 4 , Br, Cl, F, I, CF3, N(R5)2, Ci-C 8 alkoxy, Ci-C ⁇ alkyl, C3-C8 cycloalkyl, CO(CH2) n CH3, and CO(CH2) n CH2N(R5) 2 ,
  • n 0 to 5;
  • t 0, 1 or 2;
  • R 4 is: H, or Ci-Cs alkyl
  • R5 is: H, or Ci-Cs alkyl, or aryl
  • R 6 is: H, Cl-Cs alkyl, or aryl
  • R 7 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-Cs
  • R8, R9, RIO an d R11 are independently: H, Cl-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Cl-Cs alkoxy, Ci-Cs alkylthio, aryl, each of 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, Ci-Cs alkoxy, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH 2 ) n CH3, or CO(CH2) n CH2N(R5) 2;
  • the solvent is selected from the group consisting of: acetonitrile, tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), DME (dimethoxyethane), DIGLYME (2-methoxyethyl ether), TRIGLYME (triethylene glycol dimethyl ether), toluene, benzene, hexane, pentane, dioxane, or a mixture of said solvents, including a mixture of said solvents with water.
  • the solvent is selected from the group consisting of: acetonitrile, tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), DME (dimethoxyethane), DIGLYME (2-methoxyethyl ether), TRIGLYME (triethylene glycol dimethyl ether), toluene, benzene, hexane, pentane, dio
  • the periodic acid H 5 I0 6
  • the periodic acid is utilized in about 2.0 to about 4.0 equivalents, preferably about 3.5 equivalents.
  • a minimum of two equivalents of periodic acid are needed to carry out the oxidation from a primary alcohol to a carboxylic acid.
  • an additional equivalent of periodic acid for each basic functional group will be needed to carry out the oxidation.
  • the chromium reagent is selected from the group consisting of: CrO 3 , Na 2 Cr 2 O 7 , K 2 Cr 2 0 7 , CrX 3 , where X is Cl, Br, F, N0 2 , OAc, or C10 4 .
  • the chromium reagent is utilized in about 0.1 to about 10 mole percent, preferably about 1.0 to about 2.0 mole percent.
  • the temperature range is about -20°C to about 30°C, and preferably about -10°C to about 0°C.
  • the reaction time is about 15 minutes to about 24 hours and preferably between about 45 minutes and about 1.5 hours.
  • the protected aldehyde substitutent recited above denotes those aldehyde protecting groups outlined by Greene and Wuts in Chapter 4 of "Protective Groups in Organic Synthesis” 2nd Edition, John Wiley & Son, Inc. (1991).
  • 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.
  • 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, cyclobutyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
  • the alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.
  • the aryl substituent represents phenyl and 1-naphthyl or 2- naphthyl, including aryls substituted with a 5- or 6-membered fused ring, such as an unsubstituted and substituted methylenedioxy, oxazolyl, imidazolyl, or thiazolyl ring.
  • the heteroaryl substituent represents a 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.
  • R 3 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;
  • X and Y are independently: O, S, or NR 5 ; R 4 s Ci-C ⁇ alkyl; R5 is: Cl-Cs alkyl, or aryl; R c , R d , Re and R f are independently: H, Cl-Cs alkyl, and aryl, such that either R c and R are not the same and/or R e and Rf are not the same, or R c and R e or R & and R*can join to form a 5- or 6- membered ring, which is unsubstituted or substituted with
  • 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.
  • PBr3 a brominating agent
  • the nitrile 3a is then reduced to the aldehyde 3 using diisobutyl aluminum hydride (DIBAL).
  • 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 heated with pseudoephedrine, or alternatively, N-methyl-cis-aminoindanol (not shown in the schemes), and acetic acid in toluene to give the protected aldehyde 5.
  • pseudoephedrine or alternatively, N-methyl-cis-aminoindanol (not shown in the schemes)
  • acetic acid in toluene to give the protected aldehyde 5.
  • 1,2-aminoindanol 7 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 benzylchloride 13, (LiHMDS) to give 14, which is then hydrolyzed (6N HC1, dioxane) to give the carboxylic acid 15.
  • Reduction (NaBH4/BF3»Et2 ⁇ ) of the acid 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.
  • 19- Compound 17a is added to the ⁇ , ⁇ -unsaturated ester bearing a pseudoephedrine 5 (or the N-methyl-cis-aminoindanol chiral auxiliary, not shown) at -78° to -50°C. Work up with acid, THF and water (to remove the auxiliary) affords compound 6 in high yield and good stereoselectivity. Please note other chiral axillary groups can be utilized in this asymmetric addition. See WO 98/06698, published by the World Intellectual Property Organization on 19 February 1998.
  • the reaction must be controlled with intermittent cooling and by careful monitoring of the addition rate.
  • the mixture is aged for 30 min at 20-25°C.
  • Boron trifluoride etherate (36.9 g) is added over a period of 30 min at 30-35°C.
  • reaction mixture is cooled to 15°C and carefully quenched into a cold (10 °C) saturated ammonium chloride solution (150 mL) while maintaining the temperature ⁇ 25°C.
  • Ethyl acetate 500 mL is added and the layers are separated.
  • the organic layer is washed with water (100 mL) and then transfered to a 1L round bottom flask equipped for distillation.
  • the solution was concentrated and charged with fresh ethyl acetate. This is repeated until a solution with a volume of 200 mL has KF ⁇ 200
  • the addition funnel is charged with water (400 mL) which is added dropwise to the reaction mixture over a period of 30 min. while maintaining the temperture ⁇ 15°C.
  • the temperature is controlled by cooling and monitoring the rate of addition.
  • the initial addition of water is highly exothermic. Using large excess of thionyl chloride results in a more exothermic quench. If the quench temperture is not controlled, hydrolysis of the benzyl chloride back to the alcohol may result.
  • HPLC assay shows >99% amide formed.
  • Methanesulfonic acid (3 mL) is added to the reaction slurry.
  • 2- Methoxypropene 140 mL is charged to an addition funnel and added over 30 minutes at a temperature of 50°C.
  • the addition of 2-methoxypropene is mildly exothermic. The temperature is maintained by the rate of addition and a heating mantle. The reaction remains a slurry but does become less thick.
  • reaction slurry is aged for 1-2 hours at 50°C. HPLC assay at this point shows ⁇ 0.5A% of the amide remaining. The amide is not removed in the isolation so it is important to push the reaction to completion.
  • the reaction slurry is cooled to 0-5°C and quenched by addition of 5% aqueous sodium carbonate solution (1 L) and heptane (1 L). The layers are stirred and separated and the organic is washed with water (300 mL).
  • a THF solution (2L, KF ⁇ 200 ⁇ g/mL) of the acetonide (252 g) and the benzyl chloride (255 g) is cooled to -10°C.
  • Lithium bis(trimethylsilyl)amide (1.45 L) is added dropwise over 5 h at 0-2°C.
  • the mixture is then aged for 1.5 h and assayed by HPLC.
  • the reaction is quenched by adding aqueous saturated ammonium chloride solution (1 L).
  • the initial addition of the ammonium chloride should be slow in order to control the foaming. The rate can be increased when the foaming subsides.
  • the quenched reaction is then transfered into a mixture of aqueous ammonium chloride (1.5 L), water (0.5 L), and ethyl acetate (3 L). The mixture is then agitated for 15 min and the layers are separated. The organic layer is washed with water (1 L) and brine (0.5 L). The ethyl
  • - 28 - acetate solution is concentrated to a low volume and solvent switched to 1,4-dioxane.
  • the dioxane solution is adjusted to a final volume of 1.8 L.
  • the dioxane solution of the coupled product is charged to a 12 L round bottom flask and 6 M HC1 (1.5 L) is charged. The mixture is heated to reflux and monitored by HPLC.
  • the mixture is cooled to 20°C and MTBE (3 L) is added.
  • the mixture is agitated for 15 min and the layers are separated.
  • the organic layer is washed with water (1 L).
  • the MTBE solution of the crude acid is extracted with 0.6 M sodium hydroxidize (2 L).
  • the aqueous solution of the sodium salt of the acid is combined with MTBE (2.5 L) and cooled to 10°C.
  • the two phase mixture is acidified with 5.4 M sulfuric acid (250 mL), agitated for 15 min, settled and the layers separated.
  • the MTBE solution of the acid is washed with water (0.5 L).
  • the MTBE solution of the acid is dried by distilation and then solvent switched to THF.
  • the final volume of the THF is 2 L with a KF ⁇ 250 ⁇ g/mL.
  • THF solution (2 L) of the acid is added to the sodium borohydride slurry over 1 h while maintaining the temperature at 20-25°C.
  • reaction is controlled with a cooling bath and by carefully monitoring the addition rate. A nitrogen sweep and proper venting of the hydrogen is also important.
  • the mixture is aged for 30 min at 20-25 °C.
  • Boron trifluoride etherate (152 g) is added over 1 h at 30-35 °C. The addition produces a delayed exotherm and should be carefully monitored in order to control the reaction temperature.
  • the resulting milky white slurry is aged for 1 h at 30 °C and sampled for HPLC assay.
  • the reaction mixture is cooled to 15 °C and carefully quenched in a cold (10°C) ammonium chloride solution (1.5 L) while maintaing the temperature at 25 °C.
  • the rate of hydrogen evolution is controlled by the rate of the addition of the mixture into the ammonium chloride.
  • the quenched mixture is distilled in vacuo to remove the THF.
  • the aqueous layer is extracted with MTBE (1.5 L) and the organic layer is dried by flushing with additional MTBE.
  • the MTBE solution is then solvent switched to hexanes and adjusted to a volume of 350 mL and seeded.
  • the slurry is aged for 2 h at 20 °C and then cooled to 0-5 °C aged for 1 h and filtered.
  • the cake is washed with cold hexanes (200 mL).
  • the solid is dried under a nitrogen sweep.
  • the isolated solid (164 g) is > 99A% by HPLC and > 99%ee.
  • Imidazole (1.6 g, 0.023 mol) is added to a solution of the alcohol (5.0 g, 0.019 mol) in DMF (15 mL) at 20 °C.
  • the addition of imidazole is endothermic and results in a 4-5 °C drop in temperature.
  • TBSCl (3.0 g, 0.020mol) is dissolved in DMF (5 mL) and is added slowly to the above solution while maintaining the temperature 20-25 °C using a cooling bath. The reaction is monitored by HPLC.
  • a HPLC assay of an aliquot indicates that all starting Heck product has been consumed.
  • the reaction is then cooled to 40 °C and pumped into a 50 L extractor and diluted with MTBE (10.67 kg).
  • the organic layer is washed with saturated NaHC0 3 ( 12.10 kg ) and then with water ( 23.64 kg).
  • the organic layer is concentrated to a volume ⁇ 10 L and a KF ⁇ 120 ⁇ g/mL.
  • the MTBE is removed prior to flushing with toluene. Typically 8-10 L of toluene is required as flush to obtain the desired KF.
  • the dry toluene solution was stored under nitrogen until needed.
  • Assay by HPLC indicates that the lithiation is complete after addition of the n-BuLi.
  • the lithiation reaction is instantaneous at the reaction temperature. The purpose of checking an aliquot is to insure that the proper amount of n-BuLi is charged.
  • To the above solution (re- cooled to approximately -80°C) is added the pre-cooled (approximately - 65°C) toluene solution (KF ⁇ 150 ⁇ g/mL) of the enoate. The addition is done very rapidly with the aid of a pump (addition time ⁇ 5min.) and the reaction typically exotherms to -32°C.
  • the enoate solution was diluted with an additional 3-4L of toluene.
  • reaction is re-cooled to -60 °C and quenched carefully with 2.9 L of acetic acid. (Warning: exothermic reaction.)
  • the reaction is re-cooled to -60 °C and quenched carefully with 2.9 L of acetic acid. (Warning: exothermic reaction.)
  • the phases are cut and the aqueous layer is extracted with MTBE (14.23kg).
  • the combined organic layers are washed twice with 5% NaHC0 3 (2 x 23 kg).
  • the organic layer is then washed with water (20.55 kg).
  • the pH of the water wash should be neutral to slightly basic.
  • the oganic layer is dried under reduced pressure to a volume ⁇ 7 L and a KF ⁇ 100 ⁇ g/mL.
  • the MTBE is removed prior to flushing with toluene. Approximately 30 kg of toluene is needed as flush to obtain the desired KF value.
  • the dry toluene solution is then pumped into a plastic carboy.
  • the 100 L extractor and pump are then flushed with 2.5 kg of THF.
  • HPLC assay indicates a yield of 4.2 kg (72% from the Heck Product, 3 steps). The ee of the product is determined to be 92%.
  • the ArBr should be added very carefully! No more than 10% of the ArBr should be added before the reaction is initiated as indicated by the exotherm (the batch temperature will be higher than that of the bath) and color change from colorless to pale yellow. Cooling maybe required to control the reaction temperature. Once the reaction is initiated, the heating is stopped and the remaining ArBr is added slowly maintaining a gentle reflux. The reaction mixture is then aged at 50 °C for 2 hours to
  • Step B Addition of the Grignard Reagent to the Aldehyde
  • a dry solution of the crude Michael addition product (4.22 kg in -4.7 L toluene and 2.5 L THF, KF ⁇ 200 ⁇ g/mL) is charged into a 72 L flask.
  • Dry THF (20 L, KF ⁇ 100 ug/mL) is added and the mixture is degassed by a vacuum/N 2 cycle.
  • the ArMgBr prepared above is added slowly maintaining the batch below -65 °C.
  • the mixture is aged at -70 °C for 1 hour and the completion of the reaction is confirmed by HPLC ( ⁇ 1A% aldehyde ).
  • the reaction mixture is aged for two more hours then pumped into aqueous NH 4 C1 (14 L 20w%) to quench the reaction.
  • Assay by HPLC indicates the presence of 4.67 Kg (91% yield) of the product in solution. It is dried with ⁇ 2 kg of anhydrous Na 2 S0 4 overnight to remove the bulk of the water then filtered and concentrated to 15 L under vacuum. The KF of the residue should be below 150 ug/mL (flush with additional toluene as needed). It is used directly for the cyclization.
  • the slurry is aged at 0-10 °C for 4 hrs. More diethyl chlorophosphate and LiN(TMS)2 may be added as required to complete the reaction. The reaction is monitored by
  • the temperature is contolled by controlling the rate of addition and by using a cooling bath. After the two layers are separated, the organic layer is washed with 14 L brine. The organic layer is concentrated under vacuum to minimum volume of 10-12 L and mixed with 20 L acetonitrile and then cooled to 0 °C. Concentrated HC1 (13.2 kg) is added slowly while keeping the reaction temperature ⁇ 25 °C. The mixture is aged at 20-25 °C overnight.
  • the product is a mixture of the acid alcohol and the lactone.
  • HPLC standard column and eluents
  • Water (6 L) is also added. When the pH of the aqueous layer reaches 3, the two layers are separated.
  • the top organic layer is then mixed with 3.3 kg 40% NaOH (5 eq) and 12 L water.
  • the mixture is vigorously stirred for 3 hrs until all the lactone is consumed (organic layer sample).
  • the two layers are then separated and to the organic layer is added 20 L MTBE and 20 L water and 200 g 40% NaOH.
  • the two layers are separated again after mixing.
  • the organic layer is mixed with 100 g 40% NaOH, 10 L water and 20 L heptane. The layers are separated and the organic layer discarded.
  • a solution of H 5 I0 6 /Cr0 3 is prepared by adding water (1.1 mL) and MeCN to 15.95 g of H 5 I0 6 to a volume of 160 mL. An aqueous solution of Cr0 3 (0.16 mL 200 mg/mL) is then added and the mixture is stirred until all the solid dissolved.
  • the mixture is aged for 0.5 hour at 0 °C and the completion of the reaction is confirmed by HPLC ( ⁇ 2A% of the SM).
  • the reaction is quenched with Na 2 HP0 4 solution (8.52 g in 150 mL H 2 0), then brine (50 mL). Some inorganic solid remains and is filtered off.
  • the pH of the aqueous layer should be 3-4.
  • Toluene (150 mL) is added and organic layer is separated and washed with 1:1 brine-water mixture (2 x 100 mL), then aqueous NaHS0 3 (2.15g uin 50 mL H 2 0.
  • the organic layer is concentrated to 160 mL to remove most of the acetonitrile (40 mmHg, 30 °C bath).
  • the mixture is treated with 0.30 N NaOH (150 mL) for 0.5 hour and the organic layer is separated and discarded.
  • the organic layer is separated and washed with water (2 x 50 mL), brine (50 mL) then concentrated to give the crude product as a brown foam.

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Abstract

L'invention concerne une oxydation à l'acide périodique permettant de convertir l'avant-dernier intermédiaire portant un alcool primaire en composé ciblé antagoniste d'endothéline représenté par la formule (I) et possédant un acide carboxylique.
PCT/US1999/007468 1998-04-09 1999-04-05 Procede d'oxydation au moyen d'acide periodique WO1999052899A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002327926A CA2327926A1 (fr) 1998-04-09 1999-04-05 Procede d'oxydation au moyen d'acide periodique
AU33833/99A AU3383399A (en) 1998-04-09 1999-04-05 Oxidation process using periodic acid
JP2000543457A JP2002511464A (ja) 1998-04-09 1999-04-05 過ヨウ素酸を使用する酸化方法
EP99915282A EP1070061A4 (fr) 1998-04-09 1999-04-05 Procede d'oxydation au moyen d'acide periodique

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US8144698P 1998-04-09 1998-04-09
US60/081,446 1998-04-09
GB9810179.3 1998-05-13
GBGB9810179.3A GB9810179D0 (en) 1998-05-13 1998-05-13 Oxidation processing using periodic acid

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WO1999052899A1 true WO1999052899A1 (fr) 1999-10-21

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JP (1) JP2002511464A (fr)
AU (1) AU3383399A (fr)
CA (1) CA2327926A1 (fr)
WO (1) WO1999052899A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5389620A (en) * 1993-08-18 1995-02-14 Banyu Pharmaceutical Co., Ltd. Endothelin antagonistic heteroaromatic ring-fused cyclopentene derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU711936B2 (en) * 1996-08-09 1999-10-28 Banyu Pharmaceutical Co., Ltd. Stereoselective deoxygenation reaction

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5389620A (en) * 1993-08-18 1995-02-14 Banyu Pharmaceutical Co., Ltd. Endothelin antagonistic heteroaromatic ring-fused cyclopentene derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1070061A4 *

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JP2002511464A (ja) 2002-04-16
EP1070061A4 (fr) 2001-11-07
EP1070061A1 (fr) 2001-01-24
AU3383399A (en) 1999-11-01
CA2327926A1 (fr) 1999-10-21

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