WO2013038374A1 - Procédé de préparation d'un intermédiaire de synthèse - Google Patents

Procédé de préparation d'un intermédiaire de synthèse Download PDF

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Publication number
WO2013038374A1
WO2013038374A1 PCT/IB2012/054804 IB2012054804W WO2013038374A1 WO 2013038374 A1 WO2013038374 A1 WO 2013038374A1 IB 2012054804 W IB2012054804 W IB 2012054804W WO 2013038374 A1 WO2013038374 A1 WO 2013038374A1
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compound
formula
polar aprotic
mixture
solvents
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PCT/IB2012/054804
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English (en)
Inventor
Stefan Abele
Eike J. BERGNER
Christian BUKOVEC
Jacques-Alexis Funel
Christian Hubschwerlen
Azely MIRRE
Ivan SCHINDELHOLZ
Jean-Philippe Surivet
Cornelia Zumbrunn Acklin
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Actelion Pharmaceuticals Ltd
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Publication of WO2013038374A1 publication Critical patent/WO2013038374A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems

Definitions

  • the present invention relates to a new process for manufacturing known intermediates in the preparation of antibiotic compounds, as well as to new synthetic intermediates.
  • 1-6 is a synthetic intermediate commonly used in the preparation of antibiotic compounds.
  • the use of this synthetic intermediate for preparing antibiotic compounds is disclosed for example in WO 2007/081597, WO 2007/071936, WO 2008/003690, WO 2008/009700, WO 2008/116815, WO 2008/125594, WO 2009/128953, WO 2009/000945, WO 2010/067332 or WO 2010/116337.
  • the known methods for preparing the compound of formula 1-6 are however not most appropriate for large manufacturing, notably because of the use of an oxidation agent containing toxic heavy metals in the final step for obtaining the desired aldehyde (see e.g. WO 2007/071936 wherein Os0 4 is used). It is therefore desirable to achieve a cheaper, more efficient and more environmentally benign preparation method of such compounds (in particular, a method avoiding use of Os0 4 ).
  • the invention firstly relates to a new synthetic intermediate in the preparation of the compounds of formula 1-6 described previously, namely the compound of formula I-l below
  • the invention also relates to a process for manufacturing a compound of formula 1-1 as defined in embodiment 1), said process comprising the following two steps: a) the reaction of the compound of formula 1-0
  • a preferred base for step a) of the process according to embodiment 2) will be TEA, pyridine or DIPEA (and in particular DIPEA).
  • a preferred polar aprotic solvent or polar aprotic mixture of solvents will be one or more of DMF, MeCN, THF and DME, and notably a mixture of MeCN and THF (specially a mixture of 5 to 12 volumes of MeCN per volume of THF, for example from 7 to 10 volumes of MeCN per volume of THF).
  • a particularly preferred polar aprotic mixture of solvents will be a mixture of MeCN and THF containing from 5 to 15 L of MeCN per kg of compound of formula 1-0 and from 1 to 5 L of THF per kg of compound of formula 1-0 (notably a mixture of MeCN and THF containing about 7 L of MeCN per kg of compound of formula 1-0 and about 2 L of THF per kg of compound of formula 1-0).
  • Step a) of the process according to any of embodiments 2) to 5) will preferably be performed using from 1 to 1.25 equivalents of 2-mercaptoethanol per equivalent of compound of formula 1-0 and from 1.5 to 4 equivalents of base per equivalent of compound of formula 1-0, and notably using from 1 to 1.15 equivalents of 2-mercaptoethanol per equivalent of compound of formula 1-0 and from 1.5 to 2.5 equivalents of base per equivalent of compound of formula 1-0.
  • Step b) of the process according to any of embodiments 2) to 6) will preferably be performed using from 1 to 1.25 equivalents of triphenylphosphine per equivalent of intermediate obtained after step a) and from 1 to 1.25 equivalents of DIAD or DEAD per equivalent of intermediate obtained after step a), and notably using from 1 to 1.15 equivalents of triphenylphosphine per equivalent of intermediate obtained after step a) and from 1 to 1.15 equivalents of diisopropyl azodicarboxylate per equivalent of intermediate obtained after step a).
  • the process according to any of embodiments 2) to 7) will be such that its step a) is performed at a temperature between 50°C and the reflux temperature of the reaction mixture (and in particular at a temperature between 65 °C and the reflux temperature of the reaction mixture).
  • the process according to any of embodiments 2) to 8) will be such that its step b) is performed at a temperature between 50°C and the reflux temperature of the reaction mixture (and in particular at a temperature between 65°C and the reflux temperature of the reaction mixture).
  • step a) is not isolated and steps a) and b) are performed in the same reactor (that is, the 2-step process is performed as a so-called "one -pot process").
  • Performing the process according to any of embodiments 2) to 9) as a one -pot process has the advantage of avoiding the isolation of a malodorous intermediate sulphur derivative after step a) and being able to collect the compound of formula 1-1 by simple filtration (no other purification is required).
  • the invention furthermore relates to another new synthetic intermediate in the preparation of the compound of formula 1-6 described previously, namely the compound of formula 1-2 below
  • the invention also relates to a process for the preparation of the compound of formula 1-2 as defined in embodiment 11), said process comprising the reaction of the compound of formula I- 1 as defined in embodiment 1) with trifluoromethanesulfonic anhydride in the presence of pyridine in a polar aprotic solvent or a polar aprotic mixture of solvents.
  • the reaction of the compound of formula 1-1 with trifluoromethanesulfonic anhydride in the presence of pyridine will be performed using from 1 to 1.5 equivalents of trifluoromethanesulfonic anhydride per equivalent of compound of formula 1-1 and from 1 to 1.5 equivalents of pyridine per equivalent of compound of formula I- 1, and notably using from 1 to 1.2 equivalents of trifluoromethanesulfonic anhydride per equivalent of compound of formula I- 1 and from 1 to 1.2 equivalents of pyridine per equivalent of compound of formula 1-1.
  • the process according to embodiment 12) or 13) is performed at room temperature.
  • the polar aprotic solvent or polar aprotic mixture of solvents of the process of any of embodiments 12) to 14) will in particular be DCM.
  • the invention also relates to the use of the compound of formula 1-2 as defined in embodiment 11) in a process for the preparation of the compound of formula 1-3
  • said process comprising the reaction of the compound of formula 1-2 as defined in embodiment 11) with carbon monoxide and methanol, said reaction being performed in the presence of carbonylation palladium catalyst, bidentate phosphine ligand and base in a polar aprotic solvent or a polar aprotic mixture of solvents at a temperature of 40 to 80°C (notably at a temperature of 40 to 60°C and preferably at a temperature of 50 to 60°C).
  • the reaction of the compound of formula 1-2 with carbon monoxide and methanol will be performed using from 1 to 10 mol% of palladium carbonylation catalyst relative to the compound of formula 1-2 and from 1 to 15 mol% of bidentate phosphine ligand relative to the compound of formula 1-2, and notably using from 1 to 5 mol% of palladium carbonylation catalyst relative to the compound of formula 1-2 and from 4 to 8 mol% of bidentate phosphine ligand relative to the compound of formula 1-2.
  • the palladium carbonylation catalyst will be palladium(II) diacetate.
  • the bidentate phosphine ligand will be 1 , -3z ' s-(diphenylphosphino)ferrocene or l,3-3z ' s-(diphenylphosphino)propane.
  • the reaction of the compound of formula 1-2 with carbon monoxide and methanol will be performed using a pressure of carbon monoxide from at least 1 or 2 bars (for example from 1 or 2 to 100 bars, and notably at least 4 bars, in particular about 7 bars).
  • Preferred bases for the process according to any of embodiments 16) to 20) will be one or more of DIPEA, TEA, K 2 CO 3 , Na 2 C03, CS 2 CO 3 and NaOH (more preferably one or more of DIPEA and TEA, and in particular DIPEA).
  • a further preferred base for the process according to any of embodiments 16) to 20) is Pyr, alone or in mixture with one or more of DIPEA, TEA, K 2 CO 3 , Na 2 C0 3 , CS 2 CO 3 and NaOH (and more preferably one or more of DIPEA and Pyr).
  • Particularly preferred bases for the process according to any of embodiments 16) to 20) are thus one or more of DIPEA, Pyr and a mixture of DIPEA and Pyr.
  • the invention moreover relates to a further new synthetic intermediate in the preparation of compounds of formula I as defined in embodiment 1), namely the compound of formula 1-3
  • This invention also relates to the use of a compound of formula 1-3 as defined in embodiment 25) for manufacturing the compound of formula 1-6
  • a further object of this invention relates to a process for manufacturing a compound of formula 1-6
  • the reduction of the compound of formula 1-3 is performed by: a) reacting said compound of formula 1-3 with LiOH, NaOH or KOH, to obtain the compound of formula 1-4
  • Step a) of the process according to this embodiment has the advantage of being able to collect the compound of formula 1-4 by simple filtration or other operation commonly used for solid isolation like centrifugation (no other purification is required).
  • step a) of the process according to embodiment 28) will be performed in a mixture of water and a (Ci-C3)alkanol, and in particular in a mixture of water and methanol.
  • step a) of the process according to embodiment 28) or 29) will be performed using from 1 to 1.25 equivalents of LiOH, NaOH or KOH per equivalent of compound of formula 1-3, and notably using from 1 to 1.15 equivalents of LiOH, NaOH or KOH per equivalent of compound of formula 1-3.
  • step a) of the process according to any of embodiments 28) to 30) will be performed at room temperature.
  • the polar aprotic solvent or polar aprotic mixture of solvents used in step b) of the process according to any of embodiments 28) to 31) will be DCM, THF or EA (and notably DCM).
  • step b) of the process according to any of embodiments 28) to 32) will be TEA.
  • step b) of the process according to any of embodiments 28) to 33) will be performed using:
  • step b) of the process according to any of embodiments 28) to 34) will be performed at a temperature below 10°C, and in particular at a temperature below 0°C (for example at a temperature of about -5°C).
  • the polar aprotic solvent or polar aprotic mixture of solvents used in step c) of the process according to any of embodiments 28) to 35) will be DCM or a mixture of DCM with one or more of Hex, Hept, cyclohexane and toluene, and notably DCM (in particular when DIBAH is used as reducing agent in step c)).
  • the reducing agent used for step c) of the process according to embodiment 28) to 36) will be DIBAH.
  • step c) of the process according to any of embodiments 28) to 37) will be performed using from 1 to 1.4 equivalents of reducing agent per equivalent of compound of formula l-5a or l-5b, in particular 1 to 1.25 equivalents of reducing agent per equivalent of compound of formula I-5a or l-5b, and notably using from 1 to 1.15 equivalents of reducing agent per equivalent of compound of formula I-5a or l-5b.
  • step c) of the process according to any of embodiments 28) to 38) will be performed at a temperature below 10°C, and in particular at a temperature below 0°C (for example at a temperature from 0 to -10°C).
  • the reduction of the compound of formula 1-3 into the compound of formula 1-6 is performed using DIBAH.
  • the polar aprotic solvent or polar aprotic mixture of solvents used in the process according to embodiment 40) will be DCM.
  • the process according to embodiment 40) or 41) will be performed using from 1.25 to 1.75 equivalents of DIBAH per equivalent of compound of formula 1-3, and notably using from 1.4 to 1.6 equivalents of DIBAH per equivalent of compound of formula 1-3.
  • the process according to any of embodiments 40) to 42) will be performed at a temperature below -50°C, and in particular at a temperature below -70°C (for example at a temperature from -75 to -80°C).
  • the products obtained after steps a) and b) is not isolated and steps a), b) and c) are performed in the same reactor (that is, the 3-step process is performed as a so-called "one-pot process").
  • Red-Al 3 ⁇ 4z ' s(2-methoxyethoxy)aluminium hydride
  • polar aprotic solvent refers to a solvent which does not display hydrogen bonding, does not have an acidic hydrogen but is able to stabilise ions.
  • Representative examples of polar aprotic solvents include DCM, EA, iPrOAc, THF, 2-methyl- tetrahydrofurane, DMAC, DME, DMF, dioxane, diethyl ether, tert-butyl methyl ether or cyclopentyl methyl ether.
  • polar aprotic mixture of solvents refers to a mixture of solvents which includes at least one polar aprotic solvent as previously defined and at least another aprotic solvent (which may be polar or apolar).
  • Representative examples of polar aprotic mixtures of solvents include, but are not limited to: a mixture of two solvents selected from the group consisting of DCM, EA, iPrOAc, THF, DMAC, DME, DMF, dioxane and diethyl ether; a mixture of toluene with one or more of DCM, EA, iPrOAc, THF, 2-methyl-tetrahydrofurane, DMAC, DME, DMF, dioxane or diethyl ether; a mixture of Hex with one or more of DCM, EA, iPrOAc, THF, DMAC, DME, DMF, dioxane, diethyl ether, tert-but
  • alkanol refers to an aliphatic primary, secondary or tertiary alcohol containing from one to six carbon atoms and one hydroxy group.
  • (Ci-C x )alkanol refers to an aliphatic primary, secondary or tertiary alcohol containing 1 to x carbon atoms and one hydroxyl group. Examples of alkanols include methanol, ethanol and isopropanol.
  • palladium carbonylation catalyst refers to any catalyst comprising a form palladium able to catalyse a carbonylation reaction.
  • Representative examples of palladium carbonylation catalysts include palladium(II) diacetate, palladium(II) diacetylacetonate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), allylpalladium(II) chloride dimer and palladium(II) chloride.
  • bidentate phosphine ligand refers to any phosphine-based ligand able to assist a palladium carbonylation catalyst in a carbonylation reaction.
  • bidentate phosphine ligands include dppf, dppp, 1 , 1 -£z ' s(diphenylphosphino)methane (dppm), 1 ,2-£z ' s(dimethylphosphino)ethane (dmpe), l,2-/3z ' s(diisopropylphosphino)ethane (dippe),
  • room temperature refers to a temperature of from 20 to 30°C, and preferably 25°C.
  • the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C.
  • Injection volume 2 Column: Zorbax SB-Aq, 3.5 ⁇ , 4.6 x 50 mm
  • T_LC_ inetho_d Eluent EA/MeOH 9/1 + 3 drops AcOH (for 5 mL EtOH). Detection with UV and KMn0 4 staining.
  • Example 2 6,7-dihydro-[l,4]oxathiino[2,3-c]pyridazin-3-yl
  • Variant A The protocol of Variant A was used to obtain the crude title compound. This time however the latter was purified as described hereafter. 10 g of the crude product were suspended at 20°C in EA (20 mL) and TBME (20 mL). The mixture was heated to reflux and TBME (80 mL) was added until turbidity was observed. It was allowed to cool down to 20°C on its own. The solid obtained was filtered off, washed with Hept (20 mL) and dried under reduced pressure (50°C, 10 mbar) until constant weight to yield a white powder (7.1 g, 71% yield).
  • Example 2 The compound of Example 2 (10 g, 33 mmol), Pd(OAc) 2 (0.225 g, 1 mmol, 0.03 eq.) and dppf (0.929 g, 1.7 mmol, 0.05 eq.) were dissolved in MeOH (50 mL), DMF (100 mL) and Pyr (4.5 mL; 55.7 mmol; 1.7 eq.). The autoclave was pressurized under 7-8 bar of CO. The reaction mixture was stirred at 55°C for 24 h. The reaction mixture was then concentrated to dryness under vacuum (10 mbar, 60°C). Water (100 mL) was added and the mixture was heated to reflux for 1 h. The reaction mixture was decanted for 1 h.
  • Example 4 6,7-dihydro-[l,4]oxathiino[2,3-c]pyridazine-3-carbaldehyde:
  • the pH was adjusted to 8.5 by addition of a 50% aq. solution of NaOH.
  • the phases were separated and the aq. phase was extracted with DCM (2 x 12.5 mL).
  • the combined org. phases were dried over Na 2 S0 4 , filtered and evaporated to dryness under vacuum (10 mbar, 50°C).
  • the residue was dissolved in EA (7.5 mL) and 25 mL of Hept were added. The resulting suspension was stirred overnight at RT, filtered off and washed with Hept. It was dried overnight at 40°C to yield the title intermediate as a light brown solid (2.7 g, 90% yield).
  • the product has NMR data equivalent to those obtained for the product of step 4.A.2, Method A. 4.A.3. 6, 7-dihydro-[l,4]oxathiino[2,3-c]pyridazine-3-carbaldehyde: VARIANT A:
  • the product has NMR data equivalent to those obtained for the product of step 4.
  • the product has NMR data equivalent to those obtained for the product of step 4.
  • the product has NMR data equivalent to those obtained for the product of step 4.
  • the reaction mixture was warmed to 20°C and stirred for at least 5 h.
  • the layers were separated and the aq. layer was extracted with EA (1000 mL).
  • the combined org. phases were washed with brine (1000 mL) and concentrated under vacuum (>300 mbar, 50°C).
  • EA (300 mL) was added and the mixture was concentrated under vacuum (>300 mbar, 50°C).
  • EA (300 mL) was added and the mixture was concentrated to a total volume of 500 mL.
  • the mixture was cooled to 5-10°C and stirred for 1 h. It was filtered off and washed with EA (4 x 30 mL). It was dried overnight at 40°C to give the title product as an off-white solid (55.6 g, 74% yield).
  • the product has NMR data equivalent to those obtained for the product of step 4.
  • the product has NMR data equivalent to those obtained for the product of step 4.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé de préparation du composé de formule 1-6 ou de sels de celui-ci, ce composé étant un intermédiaire de synthèse fréquemment utilisé pour préparer des composés antibiotiques. L'invention concerne également les composés intermédiaires utilisés dans ce procédé, c'est-à-dire la 6,7-dihydro-[1,4]oxathiino[2,3-c]pyridazin-3(2H)-one, le trifluorométhanesulfonate de 6,7-dihydro-[1,4]oxathiino[2,3-c]pyridazin-3-yle et le 6,7-dihydro-[1,4]oxathiino[2,3-c]pyridazine-3-carboxylate de méthyle, et leurs sels.
PCT/IB2012/054804 2011-09-16 2012-09-14 Procédé de préparation d'un intermédiaire de synthèse WO2013038374A1 (fr)

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IBPCT/IB2011/054061 2011-09-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020179859A1 (fr) 2019-03-06 2020-09-10 第一三共株式会社 Dérivé de pyrrolopyrazole

Citations (10)

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Publication number Priority date Publication date Assignee Title
WO2007071936A1 (fr) 2005-12-22 2007-06-28 Glaxo Group Limited Composés hétérocycliques, leur synthèse et leur utilisation en tant qu'antibactériens
WO2007081597A2 (fr) 2005-10-21 2007-07-19 Glaxo Group Limited Composés
WO2008003690A1 (fr) 2006-07-03 2008-01-10 Glaxo Group Limited Composés azatricycliques et leur utilisation
WO2008009700A1 (fr) 2006-07-20 2008-01-24 Glaxo Group Limited Dérivés et analogues de n-éthylquinolones et de n-éthylazaquinolones
WO2008116815A2 (fr) 2007-03-23 2008-10-02 Glaxo Group Limited Composés
WO2008125594A1 (fr) 2007-04-13 2008-10-23 Glaxo Group Limited Dérivés de pyrrolo (3, 2, 1-ij) quinoline-4-one pour traiter la tuberculose
WO2009000945A1 (fr) 2007-06-22 2008-12-31 Josep Sarmiento Gavalda Dispositif perfectionné d'ouverture de muselière pour animaux
WO2009128953A2 (fr) 2008-04-18 2009-10-22 University Of Maryland, Baltimore Variants génétiques dans un gène stk39 de susceptibilité à l’hypertension et leurs utilisations
WO2010067332A1 (fr) 2008-12-12 2010-06-17 Actelion Pharmaceuticals Ltd Dérivés de 5-amino-2-(1-hydroxyéthyl)tétrahydropyrane
WO2010116337A1 (fr) 2009-04-09 2010-10-14 Actelion Pharmaceuticals Ltd Dérivés 2-hydroxyéthyl-1h-quinoline-2-ones et leurs analogues azaisostériques avec une activité antibactérienne

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007081597A2 (fr) 2005-10-21 2007-07-19 Glaxo Group Limited Composés
WO2007071936A1 (fr) 2005-12-22 2007-06-28 Glaxo Group Limited Composés hétérocycliques, leur synthèse et leur utilisation en tant qu'antibactériens
WO2008003690A1 (fr) 2006-07-03 2008-01-10 Glaxo Group Limited Composés azatricycliques et leur utilisation
WO2008009700A1 (fr) 2006-07-20 2008-01-24 Glaxo Group Limited Dérivés et analogues de n-éthylquinolones et de n-éthylazaquinolones
WO2008116815A2 (fr) 2007-03-23 2008-10-02 Glaxo Group Limited Composés
WO2008125594A1 (fr) 2007-04-13 2008-10-23 Glaxo Group Limited Dérivés de pyrrolo (3, 2, 1-ij) quinoline-4-one pour traiter la tuberculose
WO2009000945A1 (fr) 2007-06-22 2008-12-31 Josep Sarmiento Gavalda Dispositif perfectionné d'ouverture de muselière pour animaux
WO2009128953A2 (fr) 2008-04-18 2009-10-22 University Of Maryland, Baltimore Variants génétiques dans un gène stk39 de susceptibilité à l’hypertension et leurs utilisations
WO2010067332A1 (fr) 2008-12-12 2010-06-17 Actelion Pharmaceuticals Ltd Dérivés de 5-amino-2-(1-hydroxyéthyl)tétrahydropyrane
WO2010116337A1 (fr) 2009-04-09 2010-10-14 Actelion Pharmaceuticals Ltd Dérivés 2-hydroxyéthyl-1h-quinoline-2-ones et leurs analogues azaisostériques avec une activité antibactérienne

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020179859A1 (fr) 2019-03-06 2020-09-10 第一三共株式会社 Dérivé de pyrrolopyrazole

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