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WO2010055138A1 - Nouveau procédé stéréospécifique pour la préparation de composés de dioxabicyclooctane - Google Patents

Nouveau procédé stéréospécifique pour la préparation de composés de dioxabicyclooctane Download PDF

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Publication number
WO2010055138A1
WO2010055138A1 PCT/EP2009/065147 EP2009065147W WO2010055138A1 WO 2010055138 A1 WO2010055138 A1 WO 2010055138A1 EP 2009065147 W EP2009065147 W EP 2009065147W WO 2010055138 A1 WO2010055138 A1 WO 2010055138A1
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WO
WIPO (PCT)
Prior art keywords
formula
group
compound
alkyl
thp
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2009/065147
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English (en)
Inventor
Francisco Pubill Coy
Anna Modolell Saladrigas
José Repollés Moliner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lacer SA
Original Assignee
Lacer SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP08380318A external-priority patent/EP2149577B1/fr
Application filed by Lacer SA filed Critical Lacer SA
Publication of WO2010055138A1 publication Critical patent/WO2010055138A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • C2-6-alkenyl refers to a straight or branched hydrocarbon chain radical, having 2 to 6 carbon atoms and at least one double bond of either E or Z stereochemistry where applicable, e.g., vinyl, allyl, 1-butenyl, 2-butenyl, and 2-methyl-2-propenyl .
  • Czi-g-cycloalkenyl refers to an alicyclic group having 4 to 8 carbon atoms, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl .
  • Aryl refers to an aromatic hydrocarbon radical, preferably with 6 to 14 carbon atoms, e.g., phenyl, naphthyl, fluorenyl, or phenanthryl, whereby said radicals are un s ub s t i t u t e d or substituted by one or more substituents independently of one another, preferably up to three, primarily one or two substituents, especially those selected from unsubstituted, mono- or di-substituted amino, halogen, unsubstituted or substituted alkyl, free, etherified or esterified hydroxy, nitro, cyano, free or esterified carboxy, alkanoyl, unsubstituted, N-mono- or N, N-di-substituted carbamoyl, amidino, guanidino, mercapto, phenylthio, phenylsulfinyl, phenylsulf
  • heteroaryl-C]__6- alkyl relates to thienylmethyl, furylmethyl, pyranylmethyl, imidazolylmethyl, pyridylmethyl, and pyridylpropyl, whereof pyridylmethyl is most preferred.
  • formula (Ilia) represents bromomethyl-methylether and formula (HIb) represents 3, 4-dihydro-2H-pyran or methyl-vinyl- ether.
  • compound (7) represents another aspect of the invention:
  • novel dioxa-bicycloctane compounds can be prepared.
  • These new compounds form a further aspect of the present invention and are represented by the following formula (I) : wherein both the nitrate and the thiocarboxylate are trans or both are cis with regard to the bridgehead hydrogens, i.e. compounds according to formula (IA) ("isoidide derivative") and formula (IB) ("isomannide derivative”):
  • (IB) are those wherein Z represents a C1-C2 alkyl group or a C3 alkenyl group.
  • a particularly preferred representative of compounds (IA) is a compound wherein Z is a methyl group:
  • the Nuclear Magnetic Resonance spectra were recorded using a Varian Gemini-2000 apparatus.
  • the operating frequency and the solvent used to record the spectra are indicated in the 1 H-NMR spectra.
  • the signal's positions are indicated in ⁇ (ppm) and the signal from the solvent's protons is taken as a reference.
  • the reference values were 7.24 ppm for deuterated chloroform and 2.49 ppm for hexadeuterated dimethyl sulfoxide.
  • the signal obtained for tetramethylsilane' s (TMS) protons is occasionally taken as an internal standard, with a reference value of 0 ppm.
  • brackets are indicated the number of protons corresponding to each signal measured by electronic integration and the type of signal using the following abbreviations: s (singlet), d (doublet), t (triplet), q (quadruplet) , dd (doublet of doublets) , ddd (doublet of doublet of doublets) , bs (broad signal) , m (multiplet) , cs (complex signal), s.a. D 2 O (simplifies upon deuteration) , d.a. D 2 O (disappears upon deuteration).
  • the 13 C-NMR spectra indicate the working frequency and the solvent used to run the spectrum.
  • the position of the signals is indicated in ⁇ (ppm) , using the central signal of the solvent as reference.
  • the reference values are 77.00 ppm for deuterated chloroform and 39.50 ppm for hexadeuterated dimethyl sulfoxide.
  • the filtered solid is mixed with 102 L of toluene and heated to 90 0 C until total dissolution. Between 10 and 20 L of toluene are distilled. The toluenic solution is cooled at 3-5 0 C for 2 h, filtered and washed with a volume between 6 and 9 L of toluene. The solid obtained is dried in a vacuum oven at 40 0 C yielding 22.8 Kg (74%) of isomannide monotosylate (2), which is identified by its spectroscopic data.
  • Step 2 Preparation of 5- (tetrahydropyran-2-yl) -2- (4- toluenesulfonyl) isomannide (3)
  • the aqueous phase is separated and the organic phase is washed with 17 L of sodium bicarbonate saturated aqueous solution and 17 L of water.
  • the aqueous phase is decanted and the toluene is distilled under reduced pressure, maintaining the internal temperature at 50 0 C.
  • Addition of 21.5 L of N, N-dimethylformamide is followed by distillation to eliminate the remaining toluene.
  • the solution of the title compound in N, N-dimethylformamide (27.5 Kg of (3) estimated by HPLC) obtained is used in the next step without purification . After subjecting 15.3 g of the crude reaction product (isolated after drying at reduced pressure) to silica gel flash chromatography (Hx/AcOEt 2:1), 13.38 g of the title compound are obtained.
  • the aqueous phase is separated (62 L) and the organic phase is washed with 43 L of water.
  • the aqueous phase is decanted
  • Step 4 Preparation of 2-acetylthio-isosorbide 5- mononitrate (5) .
  • reaction control is performed by thin layer chromatography Hx/AcOEt 4:6).
  • the toluenic phase is washed with 20.6 L of sodium chloride saturated aqueous solution.
  • the aqueous phase is decanted (55 L), MeOH is added (5.0 L) and the solution is stirred for 20 min.
  • the mixture is washed with 4 x 20.6 L of sodium bicarbonate saturated aqueous solution and the organic phase is distilled at reduced pressure maintaining the internal temperature at 50 0 C.
  • 10 L of isopropyl alcohol are added and distilled at reduced pressure.
  • the organic phase is washed with 55 mL of a saturated solution of NaHC ⁇ 3 containing 15 mL of MeOH and then with 4 x 50 mL of a saturated solution of NaHC ⁇ 3.
  • the organic phase is dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. 0.52 g of the crude product are obtained in which the title compound is identified as the major product.
  • Step 1 Preparation of 5- (1-ethoxyethyl) -2- (4- toluenesulfonyl) isomannide (8)
  • Step 2 Preparation of 5- (1-ethoxyethyl) -2-acetylthio- isosorbide (9)
  • Step 1 Preparation of 2- (4-toluenesulfonyl) isosorbide (11) and 5- (4-toluenesulfonyl) isosorbide (12)
  • Step 2 Preparation of 5- (tetrahydropyran-2-yl) -2- (4- toluenesulfonyl) isosorbide (13)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Cette invention porte sur un nouveau procédé pour la thiocarboxylation stéréospécifique de composés organiques pour la préparation de composés répondant à la formule (I) dans lequel un composé de formule (II) est mis à réagir avec un composé de formule (IIIa) ou (IIIb), puis le produit obtenu est traité avec un acide thiocarboxylique ou un sel de celui-ci et une réaction de nitration est par la suite effectuée.
PCT/EP2009/065147 2008-11-14 2009-11-13 Nouveau procédé stéréospécifique pour la préparation de composés de dioxabicyclooctane Ceased WO2010055138A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08380318A EP2149577B1 (fr) 2008-07-22 2008-11-14 Nouveau procédé stéréospécifique pour la préparation de composés de dioxa-bicyclooctane
EP08380318.9 2008-11-14

Publications (1)

Publication Number Publication Date
WO2010055138A1 true WO2010055138A1 (fr) 2010-05-20

Family

ID=41561671

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/065147 Ceased WO2010055138A1 (fr) 2008-11-14 2009-11-13 Nouveau procédé stéréospécifique pour la préparation de composés de dioxabicyclooctane

Country Status (1)

Country Link
WO (1) WO2010055138A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7205786A (fr) * 1971-04-29 1972-10-31
EP0403185A2 (fr) * 1989-06-12 1990-12-19 A.H. Robins Company, Incorporated Composés ayant au moins un groupement aminosulfonyloxy, utilisables comme médicaments
EP1120419A1 (fr) * 1998-10-07 2001-08-01 Lacer, S.A. Derives de mononitrate d'isosorbide et leur utilisation en tant qu'agents vasodilatateurs a tolerance reduite
WO2005037842A1 (fr) * 2003-10-03 2005-04-28 Lácer, S.A. Derives de disulfure, sulfure, sulfoxyde et sulfone de sucres cycliques et utilisations associees
EP1941876A1 (fr) * 2006-12-28 2008-07-09 Lacer, S.A. Derivés du mononitrite de l'isosorbide destinées au traitement de l'inflammation et l'hypertension oculaire
US7635782B1 (en) * 2008-07-22 2009-12-22 Lacer, S.A. Stereospecific method for the preparation of dioxa-bicyclooctane compounds

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7205786A (fr) * 1971-04-29 1972-10-31
EP0403185A2 (fr) * 1989-06-12 1990-12-19 A.H. Robins Company, Incorporated Composés ayant au moins un groupement aminosulfonyloxy, utilisables comme médicaments
EP1120419A1 (fr) * 1998-10-07 2001-08-01 Lacer, S.A. Derives de mononitrate d'isosorbide et leur utilisation en tant qu'agents vasodilatateurs a tolerance reduite
WO2005037842A1 (fr) * 2003-10-03 2005-04-28 Lácer, S.A. Derives de disulfure, sulfure, sulfoxyde et sulfone de sucres cycliques et utilisations associees
EP1941876A1 (fr) * 2006-12-28 2008-07-09 Lacer, S.A. Derivés du mononitrite de l'isosorbide destinées au traitement de l'inflammation et l'hypertension oculaire
US7635782B1 (en) * 2008-07-22 2009-12-22 Lacer, S.A. Stereospecific method for the preparation of dioxa-bicyclooctane compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DAVID J. CLAFFEY, MARY F. CASEY, PATRICK A. FINAN: "Glycosylation of 1,4:3,6-dianhydro-D-glucidol (isosorbide)", CARBOHYDRATE RESEARCH, vol. 339, 2004, pages 2433 - 2440, XP002535979 *

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