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WO2013038374A1 - Process for manufacturing a synthetic intermediate - Google Patents

Process for manufacturing a synthetic intermediate 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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Prior art keywords
compound
formula
polar aprotic
mixture
solvents
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PCT/IB2012/054804
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French (fr)
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/en

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

Abstract

The invention relates to a process for manufacturing the compound of formula 1-6 which is a synthetic intermediate commonly used in the preparation of antibiotic compounds, or for manufacturing salts of that compound. The invention furthermore relates to intermediate compounds used in such process, namely 6,7-dihydro- [l,4]oxathiino[2,3-c]pyridazin-3(2H)-one, 6,7-dihydro-[l,4]oxathiino[2,3-c]pyridazin-3-yl trifluoromethanesulfonate and methyl 6,7-dihydro-[l,4]oxathiino[2,3-c]pyridazine- 3-carboxylate, and to salts thereof.

Description

PROCESS FOR MANUFACTURING A SYNTHETIC INTERMEDIATE
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.
The compound of formula 1-6
Figure imgf000002_0001
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 Os04 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 Os04).
The Applicants have now found an improved manufacturing route to obtain the compound of formula 1-6, which uses the new intermediates of formulae I-l, 1-2 and 1-3 below
Figure imgf000003_0001
I-l
1-2
Figure imgf000003_0002
1-3
Said manufacturing route starts from the already known compound of formula 1-0
Figure imgf000003_0003
1-0 which can be prepared by conventional methods well known to one skilled in the art. Various embodiments of the invention are presented hereafter:
1) 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
Figure imgf000003_0004
I-l or to a salt of this compound. 2) 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
Figure imgf000004_0001
1-0 with 2-mercaptoethanol in the presence of a base in a polar aprotic solvent or polar aprotic mixture of solvents; and b) the reaction of the intermediate obtained after step a) above with triphenylphosphine and diisopropyl azodicarboxylate or diethyl azodicarboxylate in a polar aprotic solvent or polar aprotic mixture of solvents.
3) A preferred base for step a) of the process according to embodiment 2) will be TEA, pyridine or DIPEA (and in particular DIPEA).
4) For step a) and for step b) of the process according to embodiment 2) or 3), 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).
5) For step a) and for step b) of the process according to embodiment 2) or 3), 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).
6) 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.
7) 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).
8) Preferably, 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). 9) Preferably, 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).
10) According to a preferred variant of the process according to any of embodiments 2) to 9), the product obtained after 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). 11) 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
Figure imgf000006_0001
1-2 or to a salt of this compound. 12) 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. 13) According to a preferred variant of the process according to embodiment 12), 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.
14) Preferably, the process according to embodiment 12) or 13) is performed at room temperature. 15) 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. 16) 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
Figure imgf000007_0001
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).
17) According to a preferred variant of the use according to embodiment 16), 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. 18) Preferably, in the use according to embodiment 16) or 17), the palladium carbonylation catalyst will be palladium(II) diacetate.
19) Preferably, in the process according to any of embodiments 16) to 18), the bidentate phosphine ligand will be 1 , -3z's-(diphenylphosphino)ferrocene or l,3-3z's-(diphenylphosphino)propane. 20) Preferably, in the process according to any of embodiments 16) to 19), 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). 21) Preferred bases for the process according to any of embodiments 16) to 20) will be one or more of DIPEA, TEA, K2CO3, Na2C03, CS2CO3 and NaOH (more preferably one or more of DIPEA and TEA, and in particular DIPEA).
22) 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, K2CO3, Na2C03, CS2CO3 and NaOH (and more preferably one or more of DIPEA and Pyr).
23) 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.
24) A preferred solvent for the process according to any of embodiments 16) to 23) will be
DMF.
25) 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
Figure imgf000008_0001
1-3 or a salt thereof.
26) 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
Figure imgf000008_0002
1-6 said compound of formula 1-6 being useful in the preparation of compounds of formula I as defined in embodiment 1).
27) A further object of this invention relates to a process for manufacturing a compound of formula 1-6
Figure imgf000009_0001
1-6 said process comprising the reduction of the compound of formula 1-3 as defined in embodiment 25).
28) According to a variant of the process according to embodiment 27), 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
Figure imgf000009_0002
1-4
reacting said compound of formula 1-4 with N,O-dimethylhydroxylamine or a salt thereof in the presence of a base, of an activating agent selected from the group consisting of N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-
3 -(3 -dimethyl aminopropyl)carbodiimide (EDCI), propylphosphonic anhydride (T3P),
0- (7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N'-disuccinimidyl carbonate (DSC), and optionally in the presence of
1- hydroxybenzotriazole (HOBT) or 1 -hydroxy-7-aza-benzotriazole (HO AT) in a polar aprotic solvent or a polar aprotic mixture of solvents, to obtain the compound of formula 1-5 a
Figure imgf000010_0001
I-5a or reacting said compound of formula 1-4 with morpholine or a salt thereof in the presence of a base, of an activating agent selected from the group consisting of N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-
3 -(3 -dimethyl aminopropyl)carbodiimide (EDCI), propylphosphonic anhydride (T3P),
0- (7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N'-disuccinimidyl carbonate (DSC), and optionally in the presence of
1- hydroxybenzotriazole (HOBT) or 1 -hydroxy-7-aza-benzotriazole (HO AT) in a polar aprotic solvent or a polar aprotic mixture of solvents, to obtain the compound of formula 1-5 b
Figure imgf000010_0002
1-56
or reacting said compound of formula 1-4 with oxalyl chloride or thionyl chloride and reacting the intermediate thus obtained with N,O-dimethylhydroxylamine in a polar aprotic solvent or a polar aprotic mixture of solvents, to obtain the compound of formula 1-5 a, or reacting said compound of formula 1-4 with oxalyl chloride or thionyl chloride and reacting the intermediate thus obtained with morpholine in a polar aprotic solvent or a polar aprotic mixture of solvents, to obtain the compound of formula l-5b, and c) reacting said compound of formula I-5a or l-5b with a reducing agent selected from diisobutylaluminium hydride (DIBAH), L1AIH4 and sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al) in a polar aprotic solvent or a polar aprotic mixture of solvents, to obtain the compound of formula 1-6.
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).
29) Preferably, 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.
30) Preferably, 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.
31) Preferably, step a) of the process according to any of embodiments 28) to 30) will be performed at room temperature.
32) Preferably, 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).
33) Preferably, in the process variants that do not involve the reaction of compound of formula 1-4 with oxalyl chloride or thionyl chloride, the base used for step b) of the process according to any of embodiments 28) to 32) will be TEA. 34) Preferably, step b) of the process according to any of embodiments 28) to 33) will be performed using:
• from 1.5 to 5 equivalents of base per equivalent of compound of formula 1-4, from 1 to 3 equivalents of N,O-dimethylhydroxylamine, morpholine or salt of N,O-dimethylhydroxylamine or morpholine per equivalent of compound of formula 1-4, from 1 to 3 equivalents of activating agent per equivalent of compound of formula 1-4 and optionally from 0.5 to 1 equivalent of HOBT or HO AT per equivalent of compound of formula 1-4 (and notably using from 1.5 to 3 equivalents of base per equivalent of compound of formula 1-4, from 1 to 2 equivalents of N,O-dimethylhydroxylamine, morpholine or salt of N,O-dimethylhydroxylamine or morpholine per equivalent of compound of formula 1-4, from 1 to 2 equivalents of activating agent per equivalent of compound of formula 1-4 and optionally from 0.7 to 0.9 equivalent of HOBT or HOAT per equivalent of compound of formula 1-4); or alternatively
· from 1 to 1.25 equivalents of oxalyl chloride or thionyl chloride per equivalent of compound of formula 1-4 and afterwards from 1 to 3 equivalents of N,O-dimethylhydroxylamine or morpholine per equivalent of compound of formula 1-4 (and notably using from 1 to 1.15 equivalents of oxalyl chloride or thionyl chloride per equivalent of compound of formula 1-4 and afterwards from 1 to 2 equivalents of N,O-dimethylhydroxylamine or morpholine per equivalent of compound of formula 1-4).
35) Preferably, 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). 36) Preferably, 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)).
37) Preferably, the reducing agent used for step c) of the process according to embodiment 28) to 36) will be DIBAH. 38) Preferably, 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.
39) Preferably, 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).
40) According to another variant of the process according to claim 27), the reduction of the compound of formula 1-3 into the compound of formula 1-6 is performed using DIBAH.
41) Preferably, the polar aprotic solvent or polar aprotic mixture of solvents used in the process according to embodiment 40) will be DCM.
42) Preferably, 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.
43) Preferably, 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). 44) According to a preferred variant of the process according to any of embodiments 28) to 43), 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").
Performing the process according to any of embodiments 28) to 43) as a one-pot process has the advantage of avoiding the isolation of two intermediates. Based on the dependencies of the different embodiments as disclosed hereinabove, the following embodiments are thus possible and intended and herewith specifically disclosed in individualized form:
• i ;
· 2, 3+2, 4+3+2, 4+2, 5+3+2, 5+2, 6+5+3+2, 6+5+2, 6+4+3+2, 6+4+2, 6+3+2, 6+2, 7+6+5+3+2, 7+6+5+2, 7+6+4+3+2, 7+6+4+2, 7+6+3+2, 7+6+2, 7+5+3+2, 7+5+2, 7+4+3+2, 7+4+2, 7+3+2, 7+2, 8+7+6+5+3+2, 8+7+6+5+2, 8+7+6+4+3+2, 8+7+6+4+2, 8+7+6+3+2, 8+7+6+2, 8+7+5+3+2, 8+7+5+2, 8+7+4+3+2, 8+7+4+2, 8+7+3+2, 8+7+2, 8+6+5+3+2, 8+6+5+2, 8+6+4+3+2, 8+6+4+2, 8+5+3+2, 8+5+2, 8+4+3+2, 8+4+2, 8+3+2, 8+2, 9+8+7+6+5+3+2, 9+8+7+6+5+2, 9+8+7+6+4+3+2, 9+8+7+6+4+2, 9+8+7+6+3+2, 9+8+7+6+2, 9+8+7+5+3+2, 9+8+7+5+2, 9+8+7+4+3+2, 9+8+7+4+2,
9+8+7+3+2, 9+8+7+2, 9+8+6+5+3+2, 9+8+6+5+2, 9+8+6+4+3+2, 9+8+6+4+2, 9+8+6+3+2, 9+8+6+2, 9+8+5+3+2, 9+8+5+2, 9+8+4+3+2, 9+8+4+2, 9+8+3+2, 9+8+2, 9+7+6+5+3+2, 9+7+6+5+2, 9+7+6+4+3+2, 9+7+6+4+2, 9+7+6+3+2, 9+7+6+2, 9+7+5+3+2, 9+7+5+2, 9+7+4+3+2, 9+7+4+2, 9+7+3+2, 9+7+2, 9+6+5+3+2, 9+6+5+2, 9+6+4+3+2, 9+6+4+2, 9+6+3+2, 9+6+2, 9+5+3+2, 9+5+2, 9+4+3+2, 9+4+2, 9+3+2, 9+2, 10+9+8+7+6+5+3+2, 10+9+8+7+6+5+2, 10+9+8+7+6+4+3+2,
10+9+8+7+6+4+2, 10+9+8+7+6+3+2, 10+9+8+7+6+2, 10+9+8+7+5+3+2, 10+9+8+7+5+2, 10+9+8+7+4+3+2, 10+9+8+7+4+2, 10+9+8+7+3+2, 10+9+8+7+2, 10+9+8+6+5+3+2, 10+9+8+6+5+2, 10+9+8+6+4+3+2, 10+9+8+6+4+2, 10+9+8+6+3+2, 10+9+8+6+2, 10+9+8+5+3+2, 10+9+8+5+2, 10+9+8+4+3+2, 10+9+8+4+2, 10+9+8+3+2, 10+9+8+2, 10+9+7+6+5+3+2, 10+9+7+6+5+2, 10+9+7+6+4+3+2, 10+9+7+6+4+2, 10+9+7+6+3+2, 10+9+7+6+2, 10+9+7+5+3+2, 10+9+7+5+2,
10+9+7+4+3+2, 10+9+7+4+2, 10+9+7+3+2, 10+9+7+2, 10+9+6+5+3+2, 10+9+6+5+2, 10+9+6+4+3+2, 10+9+6+4+2, 10+9+6+3+2, 10+9+6+2, 10+9+5+3+2, 10+9+5+2, 10+9+4+3+2, 10+9+4+2, 10+9+3+2, 10+9+2, 10+8+7+6+5+3+2, 10+8+7+6+5+2, 10+8+7+6+4+3+2, 10+8+7+6+4+2, 10+8+7+6+3+2, 10+8+7+6+2, 10+8+7+5+3+2, 10+8+7+5+2, 10+8+7+4+3+2, 10+8+7+4+2, 10+8+7+3+2, 10+8+7+2, 10+8+6+5+3+2, 10+8+6+5+2, 10+8+6+4+3+2, 10+8+6+4+2,
10+8+5+3+2, 10+8+5+2, 10+8+4+3+2, 10+8+4+2, 10+8+3+2, 10+8+2, 10+7+6+5+3+2, 10+7+6+5+2, 10+7+6+4+3+2, 10+7+6+4+2, 10+7+6+3+2, 10+7+6+2, 10+7+5+3+2, 10+7+5+2, 10+7+4+3+2, 10+7+4+2, 10+7+3+2, 10+7+2, 10+6+5+3+2, 10+6+5+2, 10+6+4+3+2, 10+6+4+2, 10+6+3+2, 10+6+2, 10+5+3+2, 10+5+2, 10+4+3+2, 10+4+2, 10+3+2, 10+2;
· 11 ;
• 12, 13+12, 14+13+12, 14+12, 15+14+13+12, 15+14+12, 15+13+12, 15+12;
• 16, 17+16, 18+17+16, 18+16, 19+18+17+16, 19+18+16, 19+17+16, 19+16, 20+19+18+17+16, 20+19+18+16, 20+19+17+16, 20+19+16, 20+18+17+16, 20+18+16, 20+17+16, 20+16, 21+20+19+18+17+16, 21+20+19+18+16, 21+20+19+17+16, 21+20+19+16, 21+20+18+17+16, 21+20+18+16, 21+20+17+16, 21+20+16, 21+19+18+17+16, 21+19+18+ 16, 21+19+17+16, 21+19+16,
21+18+17+16, 21+18+16, 21+17+16, 21+16, 22+20+19+18+17+16, 22+20+19+18+16, 22+20+19+17+16, 22+20+19+16, 22+20+18+17+16, 22+20+18+16, 22+20+17+16, 22+20+16, 22+19+18+17+16, 22+19+18+16, 22+19+17+16, 22+19+16, 22+18+17+16, 22+18+16, 22+17+16, 22+16, 23+20+19+18+17+16, 23+20+19+18+16, 23+20+19+17+16, 23+20+19+16, 23+20+18+17+16, 23+20+18+16, 23+20+17+16, 23+20+16, 23+19+18+17+16, 23+19+18+16, 23+19+17+16, 23+19+16, 23+18+17+16, 23+18+16, 23+17+16, 23+16, 24+23+20+19+18+17+16, 24+23+20+19+18+16, 24+23+20+19+17+16, 24+23+20+19+16, 24+23+20+18+17+16, 24+23+20+18+16, 24+23+20+17+16, 24+23+20+16, 24+23+19+18+17+16, 24+23+19+18+16, 24+23+19+17+16, 24+23+19+16, 24+23+18+17+16, 24+23+18+16, 24+23+17+16, 24+23+16, 24+22+20+19+18+17+16,
24+22+20+19+18+16, 24+22+20+19+17+16, 24+22+20+19+16, 24+22+20+18+17+16, 24+22+20+18+16, 24+22+20+17+16, 24+22+20+16, 24+22+19+18+17+16, 24+22+19+18+16, 24+22+19+17+16, 24+22+19+16, 24+22+18+17+16, 24+22+18+16, 24+22+17+16, 24+22+16, 24+21+20+19+18+17+16, 24+21+20+19+18+16, 24+21+20+19+17+16, 24+21+20+19+16, 24+21+20+18+17+16, 24+21+20+18+16, 24+21+20+17+16, 24+21+20+16, 24+21+19+18+17+16,
24+21+19+18+16, 24+21+19+17+16, 24+21+19+16, 24+21+18+17+16, 24+21+18+16, 24+21+17+16, 24+21+16, 24+20+19+18+17+16, 24+20+19+18+16, 24+20+19+17+16, 24+20+19+16, 24+20+18+17+16, 24+20+18+16, 24+20+17+16, 24+20+16, 24+19+18+17+16, 24+19+18+16, 24+19+17+16, 24+19+16, 24+18+17+16, 24+18+16, 24+17+16, 24+16;
· 25;
• 26; and
• 27, 28+27, 29+28+27, 30+29+28+27, 30+28+27, 31+30+29+28+27, 31+30+28+27, 31+29+28+27, 31+28+27, 32+31+30+29+28+27, 32+31+30+28+27, 32+31+29+28+27, 32+31+28+27, 32+30+29+28+27, 32+30+28+27, 32+29+28+27, 32+28+27, 33+32+31+30+29+28+27, 33+32+31+30+28+27, 33+32+31+29+28+27, 33+32+31+28+27, 33+32+30+29+28+27,
33+32+30+28+27, 33+32+29+28+27, 33+32+28+27, 33+31+30+29+28+27, 33+31+30+28+27, 33+31+29+28+27, 33+31+28+27, 33+30+29+28+27, 33+30+28+27, 33+29+28+27, 33+28+27, 34+33+32+31+30+29+28+27, 34+33+32+31+30+28+27, 34+33+32+31+29+28+27,
34+33+32+31+28+27, 34+33+32+30+29+28+27, 34+33+32+30+28+27, 34+33+32+29+28+27, 34+33+32+28+27, 34+33+31+30+29+28+27, 34+33+31+30+28+27, 34+33+31+29+28+27,
34+33+31+28+27, 34+33+30+29+28+27, 34+33+30+28+27, 34+33+29+28+27, 34+33+28+27, 34+32+31+30+29+28+27, 34+32+31+30+28+27, 34+32+31+29+28+27, 34+32+31+28+27, 34+32+30+29+28+27, 34+32+30+28+27, 34+32+29+28+27, 34+32+28+27, 34+31+30+29+28+27, 34+31+30+28+27, 34+31+29+28+27, 34+31+28+27, 34+30+29+28+27, 34+30+28+27, 34+29+28+27, 34+28+27, 35+34+33+32+31+30+29+28+27, 35+34+33+32+31+30+28+27,
35+34+33+32+31+29+28+27, 35+34+33+32+31+28+27, 35+34+33+32+30+29+28+27,
35+34+33+32+30+28+27, 35+34+33+32+29+28+27, 35+34+33+32+28+27,
35+34+33+31+30+29+28+27, 35+34+33+31+30+28+27, 35+34+33+31+29+28+27,
35+34+33+31+28+27, 35+34+33+30+29+28+27, 35+34+33+30+28+27, 35+34+33+29+28+27, 35+34+33+28+27, 35+34+32+31+30+29+28+27, 35+34+32+31+30+28+27, 35+34+32+31+29+28+27,
35+34+32+31+28+27, 35+34+32+30+29+28+27, 35+34+32+30+28+27, 35+34+32+29+28+27, 35+34+32+28+27, 35+34+31+30+29+28+27, 35+34+31+30+28+27, 35+34+31+29+28+27, 35+34+31+28+27, 35+34+30+29+28+27, 35+34+30+28+27, 35+34+29+28+27, 35+34+28+27, 35+33+32+31+30+29+28+27, 35+33+32+31+30+28+27, 35+33+32+31+29+28+27, 35+33+32+31+28+27, 35+33+32+30+29+28+27, 35+33+32+30+28+27, 35+33+32+29+28+27, 35+33+32+28+27, 35+33+31+30+29+28+27, 35+33+31+30+28+27, 35+33+31+29+28+27, 35+33+31+28+27, 35+33+30+29+28+27, 35+33+30+28+27, 35+33+29+28+27, 35+33+28+27, 35+32+31+30+29+28+27, 35+32+31+30+28+27, 35+32+31+29+28+27, 35+32+31+28+27, 35+32+30+29+28+27, 35+32+30+28+27, 35+32+29+28+27, 35+32+28+27, 35+31+30+29+28+27,
35+31+30+28+27, 35+31+29+28+27, 35+31+28+27, 35+30+29+28+27, 35+30+28+27, 35+29+28+27, 35+28+27, 36+35+34+33+32+31+30+29+28+27, 36+35+34+33+32+31+30+28+27,
36+35+34+33+32+31+29+28+27, 36+35+34+33+32+31+28+27, 36+35+34+33+32+30+29+28+27, 36+35+34+33+32+30+28+27, 36+35+34+33+32+29+28+27, 36+35+34+33+32+28+27, 36+35+34+33+31+30+29+28+27, 36+35+34+33+31+30+28+27, 36+35+34+33+31+29+28+27,
36+35+34+33+31+28+27, 36+35+34+33+30+29+28+27, 36+35+34+33+30+28+27,
36+35+34+33+29+28+27, 36+35+34+33+28+27, 36+35+34+32+31+30+29+28+27,
36+35+34+32+31+30+28+27, 36+35+34+32+31+29+28+27, 36+35+34+32+31+28+27,
36+35+34+32+30+29+28+27, 36+35+34+32+30+28+27, 36+35+34+32+29+28+27, 36+35+34+32+28+27, 36+35+34+31+30+29+28+27, 36+35+34+31+30+28+27,
36+35+34+31+29+28+27, 36+35+34+31+28+27, 36+35+34+30+29+28+27, 36+35+34+30+28+27, 36+35+34+29+28+27, 36+35+34+28+27, 36+35+33+32+31+30+29+28+27,
36+35+33+32+31+30+28+27, 36+35+33+32+31+29+28+27, 36+35+33+32+31+28+27,
36+35+33+32+30+29+28+27, 36+35+33+32+30+28+27, 36+35+33+32+29+28+27, 36+35+33+32+28+27, 36+35+33+31+30+29+28+27, 36+35+33+31+30+28+27,
36+35+33+31+29+28+27, 36+35+33+31+28+27, 36+35+33+30+29+28+27, 36+35+33+30+28+27, 36+35+33+29+28+27, 36+35+33+28+27, 36+35+32+31+30+29+28+27, 36+35+32+31+30+28+27, 36+35+32+31+29+28+27, 36+35+32+31+28+27, 36+35+32+30+29+28+27, 36+35+32+30+28+27, 36+35+32+29+28+27, 36+35+32+28+27, 36+35+31+30+29+28+27, 36+35+31+30+28+27, 36+35+31+29+28+27, 36+35+31+28+27, 36+35+30+29+28+27, 36+35+30+28+27, 36+35+29+28+27,
36+35+28+27, 36+34+33+32+31+30+29+28+27, 36+34+33+32+31+30+28+27,
36+34+33+32+31+29+28+27, 36+34+33+32+31+28+27, 36+34+33+32+30+29+28+27,
36+34+33+32+30+28+27, 36+34+33+32+29+28+27, 36+34+33+32+28+27,
36+34+33+31+30+29+28+27, 36+34+33+31+30+28+27, 36+34+33+31+29+28+27, 36+34+33+31+28+27, 36+34+33+30+29+28+27, 36+34+33+30+28+27, 36+34+33+29+28+27,
36+34+33+28+27, 36+34+32+31+30+29+28+27, 36+34+32+31+30+28+27, 36+34+32+31+29+28+27, 36+34+32+31+28+27, 36+34+32+30+29+28+27, 36+34+32+30+28+27, 36+34+32+29+28+27, 36+34+32+28+27, 36+34+31+30+29+28+27, 36+34+31+30+28+27, 36+34+31+29+28+27, 36+34+31+28+27, 36+34+30+29+28+27, 36+34+30+28+27, 36+34+29+28+27, 36+34+28+27, 36+33+32+31+30+29+28+27, 36+33+32+31+30+28+27, 36+33+32+31+29+28+27,
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44+36+35+33+30+28+27, 44+36+35+33+29+28+27, 44+36+35+33+28+27,
44+36+35+32+31+30+29+28+27, 44+36+35+32+31+30+28+27, 44+36+35+32+31+29+28+27, 44+36+35+32+31+28+27, 44+36+35+32+30+29+28+27, 44+36+35+32+30+28+27, 44+36+35+32+29+28+27, 44+36+35+32+28+27, 44+36+35+31+30+29+28+27,
44+36+35+31+30+28+27, 44+36+35+31+29+28+27, 44+36+35+31+28+27, 44+36+35+30+29+28+27, 44+36+35+30+28+27, 44+36+35+29+28+27, 44+36+35+28+27, 44+36+34+33+32+31+30+29+28+27, 44+36+34+33+32+31+30+28+27, 44+36+34+33+32+31+29+28+27, 44+36+34+33+32+31+28+27, 44+36+34+33+32+30+29+28+27, 44+36+34+33+32+30+28+27, 44+36+34+33+32+29+28+27,
44+36+34+33+32+28+27, 44+36+34+33+31+30+29+28+27, 44+36+34+33+31+30+28+27, 44+36+34+33+31+29+28+27, 44+36+34+33+31+28+27, 44+36+34+33+30+29+28+27,
44+36+34+33+30+28+27, 44+36+34+33+29+28+27, 44+36+34+33+28+27,
44+36+34+32+31+30+29+28+27, 44+36+34+32+31+30+28+27, 44+36+34+32+31+29+28+27, 44+36+34+32+31+28+27, 44+36+34+32+30+29+28+27, 44+36+34+32+30+28+27,
44+36+34+32+29+28+27, 44+36+34+32+28+27, 44+36+34+31+30+29+28+27,
44+36+34+31+30+28+27, 44+36+34+31+29+28+27, 44+36+34+31+28+27, 44+36+34+30+29+28+27, 44+36+34+30+28+27, 44+36+34+29+28+27, 44+36+34+28+27, 44+36+33+32+31+30+29+28+27, 44+36+33+32+31+30+28+27, 44+36+33+32+31+29+28+27, 44+36+33+32+31+28+27, 44+36+33+32+30+29+28+27, 44+36+33+32+30+28+27, 44+36+33+32+29+28+27,
44+36+33+32+28+27, 44+36+33+31+30+29+28+27, 44+36+33+31+30+28+27,
44+36+33+31+29+28+27, 44+36+33+31+28+27, 44+36+33+30+29+28+27, 44+36+33+30+28+27, 44+36+33+29+28+27, 44+36+33+28+27, 44+36+32+31+30+29+28+27, 44+36+32+31+30+28+27, 44+36+32+31+29+28+27, 44+36+32+31+28+27, 44+36+32+30+29+28+27, 44+36+32+30+28+27, 44+36+32+29+28+27, 44+36+32+28+27, 44+36+31+30+29+28+27, 44+36+31+30+28+27,
44+36+31+29+28+27, 44+36+31+28+27, 44+36+30+29+28+27, 44+36+30+28+27, 44+36+29+28+27, 44+36+28+27, 44+35+34+33+32+31+30+29+28+27, 44+35+34+33+32+31+30+28+27,
44+35+34+33+32+31+29+28+27, 44+35+34+33+32+31+28+27, 44+35+34+33+32+30+29+28+27, 44+35+34+33+32+30+28+27, 44+35+34+33+32+29+28+27, 44+35+34+33+32+28+27, 44+35+34+33+31+30+29+28+27, 44+35+34+33+31+30+28+27, 44+35+34+33+31+29+28+27,
44+35+34+33+31+28+27, 44+35+34+33+30+29+28+27, 44+35+34+33+30+28+27,
44+35+34+33+29+28+27, 44+35+34+33+28+27, 44+35+34+32+31+30+29+28+27,
44+35+34+32+31+30+28+27, 44+35+34+32+31+29+28+27, 44+35+34+32+31+28+27,
44+35+34+32+30+29+28+27, 44+35+34+32+30+28+27, 44+35+34+32+29+28+27, 44+35+34+32+28+27, 44+35+34+31+30+29+28+27, 44+35+34+31+30+28+27,
44+35+34+31+29+28+27, 44+35+34+31+28+27, 44+35+34+30+29+28+27, 44+35+34+30+28+27, 44+35+34+29+28+27, 44+35+34+28+27, 44+35+33+32+31+30+29+28+27,
44+35+33+32+31+30+28+27, 44+35+33+32+31+29+28+27, 44+35+33+32+31+28+27,
44+35+33+32+30+29+28+27, 44+35+33+32+30+28+27, 44+35+33+32+29+28+27, 44+35+33+32+28+27, 44+35+33+31+30+29+28+27, 44+35+33+31+30+28+27,
44+35+33+31+29+28+27, 44+35+33+31+28+27, 44+35+33+30+29+28+27, 44+35+33+30+28+27, 44+35+33+29+28+27, 44+35+33+28+27, 44+35+32+31+30+29+28+27, 44+35+32+31+30+28+27, 44+35+32+31+29+28+27, 44+35+32+31+28+27, 44+35+32+30+29+28+27, 44+35+32+30+28+27, 44+35+32+29+28+27, 44+35+32+28+27, 44+35+31+30+29+28+27, 44+35+31+30+28+27, 44+35+31+29+28+27, 44+35+31+28+27, 44+35+30+29+28+27, 44+35+30+28+27, 44+35+29+28+27, 44+35+28+27, 44+34+33+32+31+30+29+28+27, 44+34+33+32+31+30+28+27,
44+34+33+32+31+29+28+27, 44+34+33+32+31+28+27, 44+34+33+32+30+29+28+27,
44+34+33+32+30+28+27, 44+34+33+32+29+28+27, 44+34+33+32+28+27,
44+34+33+31+30+29+28+27, 44+34+33+31+30+28+27, 44+34+33+31+29+28+27, 44+34+33+31+28+27, 44+34+33+30+29+28+27, 44+34+33+30+28+27, 44+34+33+29+28+27,
44+34+33+28+27, 44+34+32+31+30+29+28+27, 44+34+32+31+30+28+27, 44+34+32+31+29+28+27, 44+34+32+31+28+27, 44+34+32+30+29+28+27, 44+34+32+30+28+27, 44+34+32+29+28+27, 44+34+32+28+27, 44+34+31+30+29+28+27, 44+34+31+30+28+27, 44+34+31+29+28+27, 44+34+31+28+27, 44+34+30+29+28+27, 44+34+30+28+27, 44+34+29+28+27, 44+34+28+27, 44+33+32+31+30+29+28+27, 44+33+32+31+30+28+27, 44+33+32+31+29+28+27,
44+33+32+31+28+27, 44+33+32+30+29+28+27, 44+33+32+30+28+27, 44+33+32+29+28+27, 44+33+32+28+27, 44+33+31+30+29+28+27, 44+33+31+30+28+27, 44+33+31+29+28+27, 44+33+31+28+27, 44+33+30+29+28+27, 44+33+30+28+27, 44+33+29+28+27, 44+33+28+27, 44+32+31+30+29+28+27, 44+32+31+30+28+27, 44+32+31+29+28+27, 44+32+31+28+27, 44+32+30+29+28+27, 44+32+30+28+27, 44+32+29+28+27, 44+32+28+27, 44+31+30+29+28+27,
44+31+30+28+27, 44+31+29+28+27, 44+31+28+27, 44+30+29+28+27, 44+30+28+27, 44+29+28+27, 44+28+27.
In the preceding lists the numbers refer to the embodiments according to their numbering provided hereinabove whereas "+" indicates the dependency from another embodiment. The different individualised embodiments are separated by commas. In other words, "4+3+2" for example refers to embodiment 4) depending on embodiment 3) depending on embodiment 2), i.e. embodiment "4+3+2" corresponds to embodiment 2) further limited by the features of embodiments 3) and 4).
ABBREVIATIONS AND TERMS USED IN THIS TEXT
Abbreyiations:.
The following abbreviations are used throughout the specification and the exampli
Ac acetyl
aq. aqueous
DAD diode array detection
DCC N,N'-dicyclohexylcarbodiimide
DCM dichloromethane DEAD diethyl azodicarboxylate
DIBAH diisobutylaluminium hydride
DIAD diisopropyl azodicarboxylate
DIPEA N,N-diisopropylethylamine
DMAC dimethylacetamide
DME 1 ,2-dimethoxyethane
DMF dimethylformamide
DMSO dimethylsulfoxide
d6-DMSO perdeuterated dimethylsulfoxide
dppf 1 , -¾z5-(diphenylphosphino)ferrocene
dppp 1 ,3-£zs-(diphenylphosphino)propane
EA ethyl acetate
EDCI 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide eq. equivalent(s)
Et ethyl
EtOH ethanol
ET external temperature
Hept heptane
Hex hexane
HATU 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HO AT 1 -hydroxy-7-aza-benzotriazole
HOBT 1-hydroxybenzotriazole
iPr iso -propyl
IT internal temperature
LC-MS liquid chromatography - mass spectroscopy
MS mass spectroscopy
Me methyl
MeCN acetonitrile MeOH methanol
mol% percent in moles
org. organic
Pyr pyridine
quant. quantitative
Red-Al ¾z's(2-methoxyethoxy)aluminium hydride
Rf retention factor
RT room temperature
sat. saturated
T3P propylphosphonic anhydride
TBME tert-butyl methyl ether
TEA triethylamine
Tf trifluoromethanesulfonyl
THF tetrahydrofurane
TLC thin layer chromatography
tR retention time
Wt% percent in weight
Definitions f.particular .terms used.in this text :.
The following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention as well as other particular terms used in this text and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader or narrower definition:
♦♦♦ The term "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.
♦♦♦ The term "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-butyl methyl ether or cyclopentyl methyl ether; a mixture of Hept with one or more of DCM, EA, iPrOAc, THF, 2-methyl-tetrahydrofurane, DMAC, DME, DMF, dioxane, diethyl ether, tert-butyl methyl ether or cyclopentyl methyl ether; and a mixture of toluene with Hex or Hept and one or more of DCM, EA, iPrOAc, THF, 2-methyl-tetrahydrofurane, DMAC, DME, DMF, dioxane, diethyl ether, tert-butyl methyl ether or cyclopentyl methyl ether.
The term "alkanol" refers to an aliphatic primary, secondary or tertiary alcohol containing from one to six carbon atoms and one hydroxy group. The term "(Ci-Cx)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.
The term "palladium carbonylation catalyst" as used herein 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.
The term "bidentate phosphine ligand" as used herein refers to any phosphine-based ligand able to assist a palladium carbonylation catalyst in a carbonylation reaction. Representative examples of 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),
1.2- /3z's(diphenylphosphino)ethane (dppe), the dimer of phenylanisylmethylphosphine (DIP AMP), l,4-/3z's(diphenylphosphino)butane (dppb),
2.3- /3z's(diphenylphosphino)butane (Chiraphos), 2,2'-/3z's(diphenylphosphino)- 1,1 '-binaphthyl (BINAP), 4,5-3z5(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 4,4,4 ' ,4 ' ,6,6 '-hexamethyl-2,2 '-spirobichromane-
8,8'-diyl¾z'5(diphenylphosphane) (SPANphos), 4,4'-bi-l,3-benzodioxole-
5,5'-diyl6w(diphenylphosphane) (SEGPHOS) and
1 ,2-¾z'5(2,5-dimethylphospholano)benzene (Me-DuPhos). ♦♦♦ The term "room temperature" as used herein refers to a temperature of from 20 to 30°C, and preferably 25°C.
❖ Unless used regarding temperatures, 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. In the particular case of temperatures, 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.
Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in any way.
EXAMPLES
All temperatures given are internal temperatures and are stated in °C. Compounds were characterized by 1H-NMR (400 MHz) or 13C-NMR (100 MHz) (Bruker; chemical shifts δ are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet; p = pentuplet, hex = hexet, hept = heptet, m = multiplet, br. = broad, coupling constants are given in Hz); by LC-MS methods 1 and 2 (Finnigan Navigator with HP 1100 Binary Pump and DAD). Unless stated otherwise, a yield is given as is. Purity data are determined based on the NMR assay using as internal standard 98%> pure 1 ,4-dimethoxybenzene. Parameters of LC-MS and TLC methods:
W-M.S met_hod_L
Injection volume: 2 Column: Zorbax SB-Aq, 3.5 μιη, 4.6 x 50 mm
Column flow: 4.5 ml/min
Eluent: Eluent A: water, 0.04% TFA
Eluent B: acetonitrile
Gradient: 1.0 min 95% B
1.5 min 95% B
2.0 min 5% B
Temperature: 40°C
Detection: 210 nm
LC-MS method 2:
Injection volume: 2 μΕ
Column: Waters Xbridge CI 8 5 μιη, 4.6 x 50 mm
Column flow: 4.5 ml/min
Eluent: Eluent A: water, NH3 with [NH3] = 13 mmol/1
Eluent B: acetonitrile
Gradient: 0.75 min 95% B
1.45 min 95% B
1.55 min 5% B
Temperature: 20°C
Detection: 210 nm
T_LC_ inetho_d Eluent: EA/MeOH 9/1 + 3 drops AcOH (for 5 mL EtOH). Detection with UV and KMn04 staining.
T.LC_ metho_d .2.;
Eluent: EA. Detection with UV and KMn04 staining. Example 1: 6,7-dihydro-[l,4]oxathiino[2,3-c]pyridazin-3(2H)-one:
Method A
In a 30 L Biichi reactor connected to a scrubber filled with 10% bleach, DIPEA (2460 mL, 19.0 mol, 2.0 eq.) was added to a solution of 4-bromo-l ,2-dihydropyridazine-3,6-dione (1881 g, 9.5 mol) in MeCN (13.2 L). The resulting mixture was stirred for 5 min at an IT of 70°C for complete dissolution. 2-mercaptoethanol (742 mL, 10.5 mol, 1.1 eq.) was then added over 15 min via polyethylene tubing under N2 overpressure (caution: stench!). After completion of the addition, the mixture was heated to reflux for 4 h. At this point, TLC (method 1) showed complete conversion. A solution of Ph3P (2742 g, 13.0 mol, 1.1 eq.) in THF (2700 mL) was added dropwise over 1 min. The mixture was cooled slightly below reflux temperature (ET = 70°C) and DIAD (2182 mL, 10.5 mol, 1.1 eq.) was added carefully over a period of 30 min. The mixture was then heated to reflux for 1 h. At this point, complete conversion was observed by TLC. MeCN (1 1.5 L) was added and the mixture was refluxed for 30 min. It was then cooled down to RT over 3 h. The obtained solid was filtered off, rinsed with MeCN (4.6 L) and dried at the rotavap under vacuum (50°C, 10 mbar) until constant weight to yield the title compound as a white solid (857 g, 53% yield; purity: 96.4 wt%).
1H-NMR (d6-DMSO): δ = 12.0 (br. s, 1H), 6.79 (s, 1H), 4.45-4.43 (m, 2H), 3.21-3.19 (m, 2H).
TLC (method 1): Rf = 0.8 (LC-MS: [M+l]+ = 171). Method B
2-mercaptoethanol (2.0 mL, 27.4 mmol, 1.1 eq.) was added to a solution of 4-bromo- l ,2-dihydropyridazine-3,6-dione (5 g, 25.0 mol) and DIPEA (8.5 mL, 50 mmol, 2.0 eq.) at 20°C. The resulting mixture was heated under reflux for 4 h. A solution of ΡΡ1¾ (7.2 g, 27.4 mmol, 1.1 eq.) in THF (5 mL) was added dropwise followed by the careful addition of a 40% solution of DEAD in toluene (12.5 mL, 27.4 mmol, 1.1 eq.). It was stirred under reflux for 2 h. During this time, precipitation occurred. It was cooled down to 20°C, filtered, washed with EA and dried under reduced pressure (50°C, 10 mbar) to yield the title compound as a white solid (2.5 g, 60% yield).
The product has NMR data equivalent to those obtained for the product of Example 1 , Method A. Example 2: 6,7-dihydro-[l,4]oxathiino[2,3-c]pyridazin-3-yl
tr ifluoromethanesu lfonate :
Method A
Pyr (618 mL, 7.68 mol, 1.1 eq.) was added to a solution of the compound of Example 1 (1287 g, 6.98 mol) in DCM (13 L) at 20°C. The resulting mixture was cooled down to 0°C and Tf20 (1292 mL, 7.68 mL, 1.1 eq.) was added dropwise over 15 min so that IT did not exceed 20°C. It was stirred at RT for 20 min. At this point, TLC (method 2) showed complete conversion. Water (6.5 L) was added. The layers were separated and the org. phase was again washed with water (6.5 L). The org. layer was concentrated to dryness (50°C, 10 mbar) until constant weight to yield the title compound as an off-white powder (2153 g, quant, yield, 94% wt% purity) which was used as such without further purification.
Method B
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).
1H-NMR (d6-DMSO): δ = 8.07 (br. s, 1H), 4.70-4.67 (m, 2H), 3.37-3.35 (m, 2H).
TLC (method 2): Rf = 0.55.
Method C
Pyr (42 mL, 0.52 mol, 1.05 eq.) was added to a solution of the compound of Example 1 (85.1 g, 0.50 mol) in DCM (425 mL) and the mixture was cooled to 0-4°C. Tf20 (155.1 g, 0.55 mol, 1.10 eq.) was slowly added and the reaction mixture was allowed to warm up to 20°C on its own. Water was added (300 mL) followed by a 1.5 M aqueous solution of HC1 (150 mL). Water (150 mL) was then added. The crude product solution was concentrated under vacuum (40°C, 800 mbar) to two thirds of its volume. Hept (600 mL) was added and the mixture was stirred 1 h at 0-4°C. The solid obtained was filtered off and dried overnight at 40°C (light yellow solid, 143 g, 95% yield). The product has NMR data equivalent to those obtained for the product of Example 2, Method B.
Example 3: methyl 6,7-dihydro-[l,4]oxathiino[2,3-c]pyridazine-3-carboxylate:
Method A
In a 50 L autoclave, a solution of the compound of Example 2 (1000 g, 3.30 mol), Pd(OAc)2 (22.4 g, 0.1 mol, 0.03 eq.), dppf (0.2 mol, 0.06 eq.) and DIPEA (636 mL, 6.6 mol, 2 eq.) in MeOH (12 L) and DMF (24 L) was stirred under 7 bars of carbon monoxide at 55°C for 4.5 h. The reaction mixture was cooled to RT, the pressure was released and the autoclave was purged with nitrogen. It was filtered off and evaporated to constant weight (55°C, 10 mbar). The resulting dark solid was dissolved in DCM (6 L) and washed three times with water (4 L). The combined organic extracts were concentrated to dryness (40°C, 800 mbar). The residue was slurried in THF (4 L). THF was distilled off (2 L) and the mixture was cooled down to 5-8°C whereupon product crystallised. It was filtered off, rinsed 3 times with cold (4°C) THF (0.5 L) and dried under reduced pressure (40°C, 10 mbar) to yield the title compound as a light yellow powder (477 g, 68% yield). 1H-NMR (d6-DMSO): δ = 8.07 (br. s, 1H), 4.70-4.68 (m, 2H), 3.90 (s, 3H), 3.36-3.33 (m, 2H).
LC-MS (method 1): tR = 0.53 min; [M+l]+ = 213. Method B
In a 100 mL autoclave, a solution of the compound of Example 2 (2.5 g, 8.3 mmol), Pd(OAc)2 (56 mg, 0.25 mmol, 0.03 eq.), dppp (206 mg, 0.5 mmol, 0.06 eq.) and TEA (2.5 mL, 18.3 mol, 2.2 eq.) in MeOH (39 mL) and DMF (26 mL) was stirred under 10 bars of carbon monoxide at 70°C for 4.5 h. The reaction mixture was cooled to RT, the pressure was released and the autoclave was purged with nitrogen. It was filtered off and evaporated to constant weight (55°C, 10 mbar). The resulting dark solid was slurried in EA, filtered and purified by flash chromatography on silica gel eluting with DCM as solvent to yield the title compound as a light yellow powder (0.44 g, 25% yield).
The product has NMR data equivalent to those obtained for the product of Example 3, Method A. Method C
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. It was cooled down to 20°C and extracted with DCM (2 x 50 mL). The combined org. phases were filtered through a plug of silica gel (20 g) using EA (50 mL) as eluent. The org. phase was concentrated to dryness. EA was added (15 mL) and the mixture was stirred at 0-4°C. The solid was filtered off and dried overnight at 40°C. A white solid (3.9 g, 65% yield) was obtained.
The product has NMR data equivalent to those obtained for the product of Example 3, Method A. Example 4: 6,7-dihydro-[l,4]oxathiino[2,3-c]pyridazine-3-carbaldehyde:
4.A.I. 6, 7-dihydro-[l,4]oxathiino[2,3-c]pyridazine-3-carboxylic acid:
A solution of LiOH.H20 (250 g, 5.95 mol, 1.1 eq.) in water (1.8 L) was added to a suspension of the compound of Example 3 (1215 g, 5.41 mol) in MeOH (6 L) at RT over 15 min so that IT < 30°C. After stirring for 2 min, a clear solution was obtained. After stirring for additional 10 min, a suspension was obtained. A sample testing (LC-MS) showed complete conversion. Aq. 2M HC1 (3.25 L, 6.50 mol, 2 eq.) was added and the mixture was stirred for 10 min. It was filtered off and rinsed with water (6 L) followed by acetone (3 L). It was dried under reduced pressure (50°C, 10 mbar) until constant weight to yield the title compound as a white solid (1088 g, quant, yield, 93 wt% purity).
1H-NMR (d6-DMSO): δ = 13.6 (br. s, 1H), 8.04 (br. s, 1H), 4.69-4.67 (m, 2H), 3.35-3.33 (m, 2H).
LC-MS (method 1): tR = 0.38 min; [M+l]+ = 199. 4.A.2. N-methoxy-N-methyl-6, 7-dihydro-[ 1, 4]oxathiino[ 2, 3-cj 'pyridazine-3-carboxamide: Method A
Intermediate 4.A.1 (1 kg, 4.71 mol) was suspended in DCM (5 L). Et3N (1.31 L, 9.41 mol, 2 eq.) was then added dropwise. A clear solution was obtained after stirring for 5-10 min at 20°C. N,0-dimethylhydroxylamine hydrochloride (689 g, 7.06 mol, 1.5 eq.) was then added followed by HOBT (509 g, 3.77 mol, 0.8 eq.) at 20°C. EDCI (1354 g, 7.06 mol, 1.5 eq.) was then added. An rise of the IT up to 30°C was noticed. The resulting mixture was stirred at 20°C for 15 h. Sat. aq. NaHC03 (5 L) was added over 10 min. Water (5 L) was added and the mixture was stirred vigorously for 20 min at 20°C. The layers were separated. Sat. aq. NaHC03 (10 L) was added to the org. phase and the mixture was stirred at 20°C for 1 h. At this point, sample testing of the org. layer shows that there were no more residual HOBT present. The layers were separated. The aq. phase was extracted again with DCM (2 L). The combined org. extracts were then concentrated to dryness at the rotating evaporator (40°C, 800 mbar) to yield 850 g of crude product. The latter was dissolved in refluxing EA (6.8 L). Hept (1.7 L) was added. It was cooled down to 60°C, seeded and stirred at IT = 60°C for 30 min. The mixture was then cooled down to 20°C over 3 h. It was filtered off (10 L filter, 3 min filtration time). The filter cake was washed with Hept (4.5 L) and dried overnight under positive pressure of nitrogen, later on at the rotavap (50°C, 10 mbar) until constant weight to yield the title intermediate as a light beige powder (775 g). An additional crop (120 g) was obtained after additional DCM extraction of the aq. phase and crystallisation. 895 g (75% yield, 96 % wt% purity) of the title intermediate were thus obtained.
1H-NMR (d6-DMSO): δ = 7.79 (br. s, 1H), 4.67-4.64 (m, 2H), 3.66 (br. s, 3H), 3.36-3.33 (m, 2H), 3.29 (br. s, 3H).
LC-MS (method 1): tR = 0.50 min; [M+l]+ = 242.
Method B
Intermediate 4.A.1 (2.5 g, 12.6 mmol) dissolved in DMF (12.5 mL) was cooled to 0-4°C and N,0-dimethylhydroxylamine hydrochloride (1.25 g, 12.6 mmol, 1 eq.) was added. Propylphosphonic anhydride (50 wt% in DMF) was added slowly so that IT did not exceed 5°C. TEA (3.75 g, 37.0 mmol, 3 eq.) was added slowly and the suspension was allowed to warm to 20°C on its own over 2 h. The reaction mixture was concentrated to dryness under vacuum (10 mbar, 60°C). The residue was dissolved in DCM (25 mL) and water was added (12.5 mL). 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 Na2S04, 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:
Intermediate 4.A.2 (717 g, 2.85 mol) was suspended in THF (3.6 L) at 20°C. It was cooled down to IT = -5°C. A \M solution of DIBAH in DCM (3.14 L, 3.14 mol, 1.1 eq.) was added dropwise over 45 min so that IT did not exceed -5°C. The mixture was stirred at IT = -5°C for 1 h. At this point, TLC (method 2) showed that trace of starting material remained (Rf = 0.3). More \M DIBAH in DCM was added (100 mL; 0.1 mol, 0.03 eq.). After 10 min, TLC indicated complete conversion. A mixture of water (720 mL) and EtOH (3.6 L) was then added dropwise so that IT did not exceed 10°C. After stirring for 25 min at 20°C, a gel-like (stirrable) mixture was obtained. A solution of a 25 wt% aq. solution of sodium potassium tartrate salt (7.2 L) was added dropwise so that IT did not exceed 25°C. The resulting mixture was stirred vigorously for at least 4 h at 20°C so that a clear phase split was observed. The layers were separated and the aq. phase was extracted with EA / DCM (4 L/ 1 L). The combined org. extracts were washed with brine (3.5 L) and concentrated to dryness (40°C, 800 mbar) to yield the crude material as a beige solid (536 g, quant, yield, 88%> wt%> purity). The latter was suspended in EtOH (10 L) and heated to reflux. The minimum amount of water (4 L) was added to observe a clear solution. It was cooled down to 65°C, seeded and stirred at IT = 65°C for 30 min. The mixture was then cooled down to 0°C over 4 h. It was filtered off (10 L filter, 1 min filtration time) and dried overnight under positive pressure of nitrogen, later on at the rotative evaporator (50°C, 10 mbar) until constant weight to yield the title compound as a light grey powder (275 g, 53%> yield, 98 wt%> purity). 1H-NMR (d6-DMSO): δ = 10.0 (s, 1H), 7.99 (br. s, 1H), 4.73-4.71 (m, 2H), 3.36-3.35 (m, 2H).
TLC (method 2): Rf = 0.5.
LC-MS (method 2): tR = 0.51 min; [M+l]+ = 183. VARIANT B:
Intermediate 4.A.2 (40 g, 0.15 mol) was suspended in THF (200 mL) at 20°C. It was cooled down to IT = -5°C. A \M solution of DIBAH in DCM (160 mL, 0.16 mol, 1.1 eq.) was added dropwise over 45 min so that IT did not exceed -5°C. The mixture was stirred at IT = -5°C for 30 min to lh. At this point, TLC (method 2) showed that trace of starting material remained (Rf = 0.3). More \M DIBAH in DCM was added (16 mL; 16 mmol, 0.1 eq.). After 10 min, TLC indicated complete conversion. A mixture of water (40 mL) and EtOH (200 mL) was then added dropwise so that the IT did not exceed 10°C. After stirring for 25 min at 20°C, a gel-like (stirrable) mixture was obtained. A solution of a 25 wt% aq. solution of sodium potassium tartrate salt (400 mL) was added dropwise so that the IT did not exceed 25°C. The resulting mixture was stirred vigorously for at least 4 h at 20°C so that a clear phase split was observed. The layers were separated and the aq. phase was extracted with EA (300 mL). The combined org. extracts were washed with brine (200 mL) and concentrated to dryness (40°C, 800 mbar) to yield the crude material as a beige solid (30.5 g). This material was suspended in EA (300 mL) and heated to reflux for 1 h. It was cooled down to 5°C, filtered and dried under reduced pressure (50°C, 10 mbar) to yield the title compound as a beige solid (23 g, 87% yield, 88 wt% purity).
The product has NMR data equivalent to those obtained for the product of step 4. A.3, Variant A.
YARIAN .Q.
To a solution of intermediate 4.A.1 (1 g, 4.6 mmol) in DCM (10 mL) was added DMF (40 μί, 0.46 mmol, 0.1 eq.). It was cooled down to 4°C. Oxalyl chloride (430 μί, 4.6 mmol, 1 eq.) was then added to the suspension causing gas evolution. The resulting mixture was stirred at 20°C for 15 h. Morpholine (800 μί, 9.2 mmol, 2 eq.) was then added at 20°C. It was stirred for 30 min at 20°C. A \M solution of DIBAH in DCM (9.2 mL, 9.2 mol, 2.0 eq.) was added dropwise so that the IT did not exceed -5°C. The mixture was stirred at IT = -5°C for 30 min to 1 h. More \M DIBAH in DCM was then added (2.3 mL; 2.3 mmol, 0.5 eq.). After 20 min, TLC indicated complete conversion. A mixture of water (1 mL) and EtOH (5 mL) was then added dropwise so that the IT did not exceed 10°C. After stirring for 25 min at 20°C, a gel-like (stirrable) mixture was obtained. A solution of a 25 wt% aq. solution of sodium potassium tartrate salt (5 mL) was added dropwise so that the IT did not exceed 25°C. The resulting mixture was stirred vigorously for at least 4 h at 20°C so that a clear phase split was observed. The layers were separated and the aq. phase was extracted with EA (5 mL). The combined org. extracts were washed with brine (5 mL) and concentrated to dryness (40°C, 800 mbar) to yield the crude material as a beige solid (300 mg).
The product has NMR data equivalent to those obtained for the product of step 4. A.3, Variant A.
VARIANTD:_
A \M solution of DIBAH in DCM (67.1 mL, 67.1 mmol, 1.5 eq.) was added dropwise to a solution of the compound of Example 3 (10 g, 44.8 mmol) in DCM (200 mL) at -70°C over 30 min so that the IT did not exceed -70°C. After stirring for 5 h at -70°C, it was quenched by the addition of EtOH (12.5 mL) / water (2.5 mL), causing a rise of the IT up to -35°C. The mixture was then allowed to warm up to 20°C over 1 h with vigourous stirring. An aq. 25% solution of sodium potassium tartrate salt (100 mL) was added and the mixture was vigorously stirred overnight at 20°C. The layers were separated and the aqueous layer was extracted with EA (100 mL). The combined org. layers were concentrated under reduced pressure (50°C, 250 mbar) to yield the crude expected product. The crude residue was suspended in EtOH (60 mL). H20 (21 mL) was added until a clear solution was obtained. 26 mL of solvents were distilled off and the mixture was allowed to cool down to 20°C on its own overnight. It was filtered, washed with cold (4°C) EtOH and dried under reduced pressure (50°C, 10 mbar) to give a beige solid (4.5 g, 55% yield).
The product has NMR data equivalent to those obtained for the product of step 4. A.3, Variant A.
VARIANTEi
Intermediate 4.A.2 (100 g, 0.41 mol) was dissolved in THF (1000 mL) and DCM (1000 mL) and cooled to -5-0°C. A 20% solution of DIBAH in Hept (490 mL; 0.51 mol; 1.22 eq.) was added slowly, so that IT did not exceed 0°C. It was stirred at this temperature for 1 h. A mixture of water (100 mL) and EtOH (400 mL) was added slowly (IT max = 5°C). After stirring for 30 min, the resulting mixture was added to a solution of sodium potassium tartrate (250 g) in water (850 mL), so that IT did not exceed 5°C. 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. A.3, Variant A.
VARIANTFi A 2M solution of lithium aluminium hydride in THF (7 mL; 14 mmol, 0.35 eq.) was added carefully (gas evolution) to a cold (4°C) solution of intermediate 4.A.2 (10 g, 39.8 mmol) in THF (50 mL) and DCM (50 mL). After 30 min, water (0.5 mL) was carefully added followed by a 15% aq. solution of NaOH (0.5 mL). Water (1.5 ml) was then added and the mixture was stirred vigorously at 20°C. It was filtered over Celite and concentrated to dryness. The crude residue was suspended in EtOH (70 mL) and heated to reflux. Water (20 mL) was added. The mixture was allowed to cool down to 4°C. It was filtered off to give the title product as an off-white solid (1.6 g, 20%> yield).
The product has NMR data equivalent to those obtained for the product of step 4. A.3, Variant A.

Claims

Claims
1. The compound of formula I-l
Figure imgf000066_0001
I-l or a salt of said compound.
2. A process for manufacturing the compound of formula I-l as defined in claim 1, said process comprising the following two steps: a) the reaction of the compound of formula 1-0
Figure imgf000066_0002
1-0 with 2-mercaptoethanol in the presence of a base in a polar aprotic solvent or polar aprotic mixture of solvents; and b) the reaction of the intermediate obtained after step a) above with triphenylphosphine and diisopropyl azodicarboxylate or diethyl azodicarboxylate in a polar aprotic solvent or polar aprotic mixture of solvents.
3. A process according to claim 2, wherein the base used in step a) is triethylamine, pyridine or N,N-diisopropylethylamine.
4. A process according to claim 2 or 3, wherein the polar aprotic solvent or polar aprotic mixture of solvents used for step a) and for step b) is a mixture of acetonitrile and tetrahydrofurane .
5. The compound of formula 1-2
Figure imgf000067_0001
1-2 or a salt of said compound.
6. A process for manufacturing the compound of formula 1-2 as defined in claim 5, said process comprising the reaction of the compound of formula I-l as defined in claim 1 with trifluoromethanesulfonic anhydride in the presence of pyridine in a polar aprotic solvent or a polar aprotic mixture of solvents.
7. A process according to claim 6, wherein the polar aprotic solvent or a polar aprotic mixture of solvents is dichloromethane.
8. The compound of formula 1-3
Figure imgf000067_0002
1-3 or a salt of said compound.
9. A process for manufacturing the compound of formula 1-3 as defined in claim 8, said process comprising the reaction of the compound of formula 1-2 as defined in claim 5 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.
10. A process according to claim 9, wherein the carbonylation palladium catalyst is palladium(II) diacetate and the bidentate phosphine ligand is 1 , 1 '-¾z'5-(diphenylphosphino)ferrocene or 1 ,3-£z's-(diphenylphosphino)propane.
11. A process according to claim 9 or 10, wherein the reaction is performed in dimethylformamide .
12. A process according to one of claims 9 to 11, wherein the base is selected from N,N-diisopropylethylamine, pyridine and a mixture of N,N-diisopropylethylamine and pyridine.
13. A process for manufacturing the compound of formula 1-6
Figure imgf000068_0001
1-6 said process comprising the reduction of the compound of formula 1-3 as defined in claim 8.
14. A process according to claim 13, wherein 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
Figure imgf000068_0002
1-4 b) reacting said compound of formula 1-4 with N,O-dimethylhydroxylamine or a salt thereof in the presence of a base, of an activating agent selected from the group consisting of N,N'-dicyclohexylcarbodiimide, 1-ethyl-
3-(3-dimethylaminopropyl)carbodiimide, propylphosphonic anhydride,
0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,A/ -disuccinimidyl carbonate, and optionally in the presence of 1-hydroxybenzotriazole or l-hydroxy-7-aza-benzotriazole in a polar aprotic solvent or a polar aprotic mixture of solvents, to obtain the compound of formula l-5a
Figure imgf000069_0001
I-5a or reacting said compound of formula 1-4 with morpholine or a salt thereof in the presence of a base, of an activating agent selected from the group consisting of N,N'-dicyclohexylcarbodiimide, 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide, propylphosphonic anhydride, 0-(7-azabenzotriazol-l-yl)-
N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N'-disuccinimidyl carbonate, and optionally in the presence of 1-hydroxybenzotriazole or 1-hydroxy- 7-aza-benzotriazole in a polar aprotic solvent or a polar aprotic mixture of solvents, to obtain the compound of formula 1-5 b
Figure imgf000069_0002
1-56
or reacting said compound of formula 1-4 with oxalyl chloride or thionyl chloride and reacting the intermediate thus obtained with N,O-dimethylhydroxylamine in a polar aprotic solvent or a polar aprotic mixture of solvents, to obtain the compound of formula 1-5 a, or reacting said compound of formula 1-4 with oxalyl chloride or thionyl chloride and reacting the intermediate thus obtained with morpholine in a polar aprotic solvent or a polar aprotic mixture of solvents, to obtain the compound of formula l-5b, and reacting said compound of formula I-5a or l-5b with a reducing agent selected from diisobutylaluminium hydride, L1AIH4 and sodium bis(2-methoxyethoxy)aluminium hydride in a polar aprotic solvent or a polar aprotic mixture of solvents, to obtain the compound of formula 1-6.
15. A process according to claim 14, wherein the reduction of the compound of formula 1-3 is performed using diisobutylaluminium hydride.
16. A process according to claim 15, wherein the polar aprotic solvent or polar aprotic mixture of solvents used in step c) is selected from dichloromethane and mixtures of dichloromethane with one or more of hexane, heptane, cyclohexane and toluene.
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