WO2024252006A1 - Synthèse d'acyl sulfoximines cycliques - Google Patents

Synthèse d'acyl sulfoximines cycliques Download PDF

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WO2024252006A1
WO2024252006A1 PCT/EP2024/065831 EP2024065831W WO2024252006A1 WO 2024252006 A1 WO2024252006 A1 WO 2024252006A1 EP 2024065831 W EP2024065831 W EP 2024065831W WO 2024252006 A1 WO2024252006 A1 WO 2024252006A1
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formula
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Helmars Smits
Raphael Dumeunier
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Syngenta Crop Protection AG Switzerland
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Syngenta Crop Protection AG Switzerland
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Priority to IL324519A priority Critical patent/IL324519A/en
Priority to EP24732589.7A priority patent/EP4724447A1/fr
Priority to CN202480031686.2A priority patent/CN121175316A/zh
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Priority to MX2025014399A priority patent/MX2025014399A/es
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the enantioselective synthesis of cyclic acyl sulfoximines that are useful intermediates for the preparation of agrochemicals.
  • Pesticidally active heterocyclic sulfoximine derivatives have previously been described in the literature, for example, in WO 2015/071180, WO 2016/039441 , WO 2018/206348, WO 2019/219689, WO 10 2019/229089, WO 2019/234158, WO 2020/084075, W02020/141136 and WO2022253841 .
  • Such cyclic sulfoximines could in principle be prepared either by cyclization of acyclic sulfoximines as described below (pathway A, Scheme 2) or by an intramolecular nitrogen transfer on an adjacent sulfoxide (pathway B, Scheme 2).
  • pathway A has been the dominant method with an oxidative cyclization via pathway B being reported only for very specific compounds and under conditions not applicable for the preparation of enantiopure compounds (Russ. Chem. Bull. Int. Ed. 2004, 53, 916).
  • R 2 alkyl, aryl
  • R 1 alkyl, aryl
  • Hypervalent iodine is commonly used as a reagent, either in combination with a metal catalyst such as rhodium (Org. Lett., 2004, 6, 1305), copper (Tetrahedron Lett. 1998, 39, 4805), iron (Tetrahedron Lett., 1998, 39, 5015) or silver (Org. Lett., 2005,7, 4983) or without a catalyst as described by Bull and Luisi (Angew. Chem. Int. Ed. 2016, 51 , 7203).
  • a metal catalyst such as rhodium (Org. Lett., 2004, 6, 1305), copper (Tetrahedron Lett. 1998, 39, 4805), iron (Tetrahedron Lett., 1998, 39, 5015) or silver (Org. Lett., 2005,7, 4983) or without a catalyst as described by Bull and Luisi (Angew. Chem. Int. Ed. 2016, 51 , 7203).
  • pathway A Given the disadvantages of pathway A described above it would be advantageous to develop an alternative method going via pathway B (Scheme 2). This would potentially avoid handling dangerous reagents and expensive metal catalysts.
  • the present invention provides a process for the enantioselective preparation of cyclic acyl sulfoximines of formula (I) optionally in an enantiomerically pure, enantiomerically enriched or racemic form wherein
  • S* is a stereogenic sulfur atom in (R)- or (S)-configuration, in which said S* is in enantiomerically pure, enantiomerically enriched or racemic form;
  • Ri and R3 are independently hydrogen, halogen, haloalkyl, cycloalkyl, cyanocycloalkyl, cyanoalkoxy, cyanoalkyl or optionally substituted aryl;
  • R2 is alkyl, cycloalkyl, haloalkyl or optionally substituted aryl
  • G1 and G2 are independently CH or N provided that at least one of G1 or G2 is N.
  • R4 is alkyl or substituted aryl; preferably, R4 is methyl, p-tosyl, 4-chlorophenyl, 4-cyanophenyl, 4- nitrophenyl or 2,4-dinitrophenyl;
  • R1 , R2, R3, G1, G2 and S* are as defined for compounds of formula (I) and X is halogen (preferably, Cl) or SO2R4 wherein R4 is as defined for a compound of formula (III)
  • a compound of formula (Va) could be produced by adding an appropriate base and used in step (C)
  • R1, R2, R3, G1, G2 and S* are as defined for compounds of formula (I) And C) Hydrolyzing the compound of formula (V)
  • R1 , R2, R3, G1, G2 and S* are as defined for compounds of formula (I) and X is halogen (preferably, Cl) or SO2R4 wherein R4 is as defined for a compound of formula (III); With water at appropriate temperature and in the presence of an appropriate co-solvent to produce compound of formula (I)
  • Ri, R2, R3, G1, G2 and S* are as defined previously.
  • the process for the enantioselective preparation of cyclic acyl sulfoximines of formula (I) is carried out in one pot without isolating intermediate compound of formula (IV) (i.e., without the hydrolysis step C)) by direct rearrangement of the compound of formula (IV) obtained from step B)
  • R1, R2, R3, G1, G2 and S* are as defined for compounds of formula (I) and R4 is as defined for a compound of formula (III); in the presence of water and an appropriate co-solvent to produce a compound of formula (I)
  • R1, R2, R3, G1, G2 and S* are as defined previously.
  • the enantioselectivity of the inventive process results in the enantiomeric character of the stereogenic sulfur atom S* being fully preserved during the synthesis of compounds of formula (I) when starting from an enantiomerically pure, enantiomerically enriched or racemic compound of formula (II).
  • a compound of formula (II) with an (R) stereogenic center at sulfur S* leads to compound of formula (I) with an (R) stereogenic center at sulfur S* with no erosion of enantiomeric purity.
  • starting with a sulfoxide enriched in (S) enantiomer at sulfur S* leads to a compound of formula (I) enriched in (S) enantiomer.
  • step (A) comprises
  • the ratio of the compound of formula (III) used, compared to the compound of formula (II), is in the range from 3:1 to 1 :1 , preferably between 1.5:1 and 1 :1 , more preferably between 1.2:1 and 1 :1.
  • Example of suitable and preferred bases for step A are trialkylamines such as triethylamine and tributylamine, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxide such as potassium hydroxide and sodium hydroxide.
  • the base is a trialkylamine, more preferably triethylamine.
  • the ratio of a base used, compared to sulfonyl chloride of formula (III), is from 1 .5:1 to 1 :1 , more preferably between 1 .2:1 and 1 :1.
  • Suitable and preferred solvents (or diluents) for step A are esters, nitriles, ethers, and aliphatic, aromatic or halogenated hydrocarbons.
  • Examples include but are not limited to: tetrahydrofuran, 2-methyl tetra hydrofuran, acetonitrile, butyronitrile, dichloromethane, 1 ,2-dichloroethane, chlorobenzene, ethyl acetate, toluene, xylenes, dioxane, cyclopentylmethyl ether, t-butylmethyl ether, diethyl ether, anisole, fluorobenzene
  • the solvent is an ether, nitrile or a halogenated hydrocarbon, for example: tetrahydrofuran, 2- methyl tetrahydrofuran, acetonitrile, dichloromethane and chlorobenzene
  • Step (B) comprises
  • Suitable solvents are polar aprotic solvents, nitriles, esters, ketones, alcohols, aromatic hydrocarbons, carbonates and ethers or mixtures thereof.
  • solvents examples include but are not limited to: acetonitrile, butyronitrile, benzonitrile, ethylene glycol, methanol, ethanol, methyl isobutyl ketone, nitrobenzene, trifluorotoluene, polyethelene glycol, chlorobenzene, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1 ,4-dioxane, anisole, N,N- dimethyl formamide, N-methyl pyrrolidine, sulfolane, 2,5-dimethyl isosorbide, dimethyl acetamide, cyrene, or mixture thereof.
  • the solvent is N-methyl pyrrolidine, sulfolane, acetonitrile, ethylene glycol, ethanol, or mixtures thereof.
  • the rearrangement is advantageously carried out in a temperature range from 0 °C to 150 °C.
  • the preferred temperature is dependent on the electronic nature of R4 substituent. If R4 is highly electron withdrawing (for example 2,4-dinitro phenyl) the appropriate reaction temperature is in the range from 0 °C to 40 °C. Whereas, if R4 is neutral (for example methyl) or moderately electron withdrawing (for example tosyl) the preferred temperature is between 60 °C and 100 °C.
  • steps (A) and (B) could be advantageously carried out in one pot without isolating intermediate compound of formula (IV). This is most preferable when R4 in sulfonyl chloride of formula (III) is highly electron withdrawing (for example 2,4-dinitrophenyl).
  • Step (C) comprises
  • Hydrolysing compounds of formula (V) by heating in an aqueous media using a suitable cosolvent (or diluent) optionally in a presence of an appropriate acid.
  • Suitable co-solvents are water miscible alcohols, ethers and nitriles.
  • Examples of appropriate and preferred co-solvents include but are not limited to: methanol, ethanol, tetra hydrofuran, acetonitrile, 1 ,4-dioxane.
  • the amount of water used is in the range from a stoichiometric amount to 80%, preferably in the range from 1 :3 to 1 :1 relative to the co-solvent.
  • acids include but are not limited to: sulfuric, hydrochloric, trifluoracetic, acetic, trifluormethansulfonic, methansulfonic. Most preferably the acid is sulfuric or hydrochloric.
  • the hydrolysis is advantageously carried out in a temperature range from 0 °C to 100 °C, more preferably between 20 °C and 60 °C.
  • steps (B) and (C) could be advantageously carried out in one pot without isolating intermediate compounds of formula (V). This is accomplished by directly heating compounds of formula (IV) in an aqueous media using an appropriate cosolvent as described above for steps (B) and (C) and optionally in a presence of an appropriate acid.
  • acids include but are not limited to: sulfuric, hydrochloric, trifluoracetic, acetic, trifluormethansulfonic, methansulfonic. Most preferably the acid is sulfuric or hydrochloric.
  • alkyl as used herein, in isolation or as part of a chemical group, represents straight-chain or branched hydrocarbons, preferably with 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, 1 - methylbutyl, 2-methylbutyl, 3-methylbutyl, 1 ,2-dimethylpropyl, 1 ,1 -dimethylpropyl, 2,2- dimethylpropyl, 1 -ethylpropyl, hexyl, 1 -methylpentyl, 2-methylpentyl, 3- methylpentyl, 4- methylpentyl, 1 ,2-dimethylpropyl, 1 ,3-dimethylbutyl, 1 ,4-dimethylbutyl,2,3-dimethylbutyl,
  • Alkyl groups with 1 to 4 carbon atoms are preferred, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl.
  • alkoxy refers to a straight-chain or branched saturated alkyl radical preferably with 1 to 6 carbon atoms (as mentioned above) which is attached via an oxygen atom, i.e., for example, any one of methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, 1 -methylpropoxy, 2-methylpropoxy or 1 , 1 -dimethylethoxy.
  • cyanoalkyl refers to a straight chain or branched saturated alkyl radicals (as mentioned above) which is substituted by a cyano group, for example cyanomethylene, cyanoethylene,
  • cyanoalkoxy refers to a straight chain or branched saturated alkyloxy radicals (as mentioned above) which is substituted by a cyano group.
  • cycloalkyl refers to a 3-6 membered cycloalkyl group such as cyclopropane, cyclobutane, cyclopropane, cyclopentane and cyclohexane.
  • cyanocycloalkyl refers to a 3-6 membered cycloalkyl group (as mentioned above) which is substituted by a cyano group.
  • aryl represents a mono-, bi- or polycyclical aromatic system with preferably 6 to 14, more preferably 6 to 10 ring-carbon atoms, for example phenyl, naphthyl, anthryl, phenanthrenyl, preferably phenyl.
  • Aryl also represents polycyclic systems, for example tetrahydronaphtyl, indenyl, indanyl, fluorenyl, biphenyl.
  • Arylalkyls are examples of substituted aryls, which may be further substituted with the same or different substituents both at the aryl or alkyl part. Benzyl and 1 — phenylethyl are examples of such arylalkyls.
  • halogen represents fluoro, chloro, bromo or iodo, particularly fluoro, chloro or bromo.
  • the chemical groups which are substituted with halogen for example haloalky I, are substituted one or up to the maximum number of substituents with halogen. If “alkyl” is substituted with halogen, the halogen atoms can be the same or different and can be bound at the same carbon atom or different carbon atoms.
  • the term “optionally substituted” means that the group in question can be substituted with zero up to the maximum number of substituents with groups independently selected from: halogen, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, trifluoromethyl, difluoromethyl, chlorodifluoromethyl, trichloromethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, nitro, cyano, hydroxy, sulfhydryl, acetyl, acetoxy, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, amino, methlamino, dimethylamino, phenyl.
  • enantiomerically enriched means that one of the enantiomers of the compound is present in excess in comparison to the other enantiomer. This excess will hereafter be referred to as enantiomeric excess or ee.
  • the ee may be determined by chiral GC, HPLC or SFC analysis.
  • the ee is equal to the difference between amounts of enantiomers divided by the sum of the amounts of the enantiomers, which quotient can be expressed as a percentage after multiplication by 100.
  • the ee can also be referred to as the absolute difference between the mole fraction of each enantiomer in the mixture.
  • the term "enantiomerically enriched” also refers to an enantiomeric excess (e.e.) of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.
  • Embodiment 1 provides a process for the enantioselective preparation of cyclic acyl sulfoximines of formula (I) as defined above optionally in an enantiomerically pure, an enantiomerically enriched or a racemic form as set out in the detailed description above.
  • Embodiment 2 provides a process for the enantioselective preparation of a compound of formula (I) according to embodiment 1 which process comprises:
  • step (B) thermally rearranging a compound of formula (IV) to produce a compound of formula (V) in a suitable solvent (or diluent) at an appropriate temperature and, optionally, producing a compound of formula (Va) by adding an appropriate base; and (C) hydrolysing the compound of formula (V), or compound of formula (Va), by heating in an aqueous media using a suitable cosolvent (or diluent) optionally in a presence of an appropriate acid, to produce a compound of formula (I) as defined above; wherein steps (B) and (C) are optionally carried out in one pot without isolating intermediate compounds of formula (V) or formula (Va).
  • Embodiment 3 provides a process for the enantioselective preparation of a compound of formula (I) according to embodiments 1 - 2, wherein the preferred alternatives of steps (A) - (C) including the base and solvent (or diluent) used in step (A), the solvent (or diluent), temperature and base of step (B); and the temperature, cosolvent (or diluent) and optional acid of step (C) that are used in the process of embodiments 1 - 2 and which are, in any combination thereof, as set out in the detailed description above.
  • Embodiment 4 provides a process according to embodiments 1 - 3, wherein a compound of formula (V) is prepared when steps (A) and (B) are carried out in one pot without isolating the intermediate compound of formula (IV). This is most preferable when R4 in sulfonyl chloride of formula (III) is highly electron withdrawing (for example 2,4-dinitrophenyl).
  • S* is a stereogenic sulfur atom in (R)- or (S)-configuration, in which said S* is in enantiomerically pure, enantiomerically enriched or racemic form;
  • S* is a stereogenic sulfur atom in (R)- or (S)-configuration, in which said S* is in racemic form;
  • S* is a stereogenic sulfur atom in (R)-configuration, in which said S* is in enantiomerically pure or enantiomerically enriched form (as defined above); and Further preferred is when S* is a stereogenic sulfur atom in (S)-configuration, in which said S* is in enantiomerically pure or enantiomerically enriched form (as defined above).
  • R1 and R3 are independently hydrogen, halogen, haloalkyl, cycloalkyl, cyanocycloalkyl, cyanoalkoxy, cyanoalkyl or optionally substituted aryl;
  • R1 and R3 are independently hydrogen, halogen, Ci-Ce-haloalkyl, Ci-Ce-cyanoalkyl, C1- Ce-cyanoalkoxy, Cs-Ce-cycloalkyl, Cs-Ce-cyanocycloalkyl or optionally substituted aryl; and Most preferably, R1 and R3 are independently hydrogen, chloro, bromo, trifluoromethyl, cyclopropyl, cyanocyclopropyl, cyanoisopropoxy, cyanoisopropyl, phenyl or halophenyl.
  • R2 is alkyl, cycloalkyl, haloalkyl or optionally substituted aryl;
  • R2 is Ci-Ce-alkyl, Cs-Ce-cycloalkyl, Ci-Ce-haloalkyl, phenyl or halophenyl; and Most preferably, R2 is ethyl, cyclopropyl, trifluoromethyl, phenyl or fluorophenyl.
  • G1 and G2 are independently CH or N provided that at least one of G1 or G2 is N. Also preferred is when Gi is N and G2 is CH; or when G1 is CH and G2 is N; or when both G1 and G2 are N.
  • R4 is alkyl or substituted aryl
  • R4 is methyl, p-tosyl, 4-chlorophenyl, 4-cyanophenyl, 4-nitrophenyl or 2,4-dinitrophenyl.
  • X is halogen
  • X is chloro
  • Racemic amidine oximes of formula (II) were prepared by either of the three general methods (A, B and C).
  • step 1 To a solution of starting sulfide in acetic acid was added Na2WO4.2H2O (5-10 mol%) followed by a slow addition of 30% aq H2O2 (1.1 eq). The reaction mixture was stirred at ambient temperature till the fully consumption of the starting material. The reaction was quenched by pouring into aq NaOH. The resulting mixture was extracted with EtOAc (2x). The combined organic layer was washed with 10% aq NaHSOs and brine, then dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure yielded the crude product which was purified via silica gel chromatography to yield the desired sulfoxide in a pure form. 3-ethylsulfinyl-5-(trifluoromethyl)pyridine-2-carbonitrile
  • Oxidation with hydrogen peroxide in acetic acid is replaced with an iron catalyzed oxidation with hydrogen peroxide in the presence of a chiral ligand.
  • the second step is analogous to the racemic version. In this case specific oxidation procedures are provided.
  • a single crystal grown from di-isopropyl ether was selected for X-ray data analysis.
  • the crystal sample mounted had dimensions of 0.4 mm x 0.3 mm x 0.3 mm and was a colorless prism.
  • Data collection was performed on a Rigaku Oxford Diffraction Supernova diffractometer at 293 K.
  • the unit cell was determined to be orthorhombic (space group P212121), and the structure contained one molecule in the crystal asymmetric unit ( Figure 1 , a thin stick representation labelled by chirality).
  • Flare software package (Cresset). The stereochemistry was unambiguously determined to be the R isomer, with a Flack parameter of 0.02 +/- 0.03. Crystallographic data is summarized in Table 1 and selected geometric parameters are listed in Table 2. Crystal data and structure refinement for 5-bromo-3- [(R)-ethylsulfinyl]pyridine-2-carbonitrile. Table 1 . Crystal data and structure refinement for 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile
  • the resulting reaction mixture was stirred for further 20 h at the same temperature.
  • the reaction mixture was poured into EtOAc (23 ml) and quenched by addition of 1 .0M NaHSOs (2.4 ml). Phases were separated and the organic phase was washed with 1 .0M HCI (2.3 ml) and aq NaHCOs.
  • the organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure.
  • the crude material was purified by a reverse phase HPLC (water/MeCN/0.1 % formic acid mobile phase) to yield the title compound (230 mg, >99.5%ee, 93% yield) as a white powder.
  • the resulting reaction mixture was stirred vigorously for further 22 h at the same temperature.
  • the reaction was quenched by addition of 40% aq NaHSO3 (10.6 ml) and diluted with PhOMe (53 ml). Phase were separated and the organic phase was washed with 1 M H2SO4 (21 ml), aq saturated NaHCOs (21 ml) and brine (21 ml).
  • the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • the crude material was purified by a reverse phase HPLC (water/MeCN as a mobile phase) to yield the title compound (10.44 g, >99.5% ee, 93% yield) as a white powder.
  • the resulting deep red solution was cooled to 10 °C and 30% aq H2O2 (7.9 ml, 77.0 mmol) was dosed over 1 h via a syringe pump while stirring vigorously (300 rpm). After the end of dosing the reaction mixture was stirred at the same temperature for further 14 h (full conversion by LC/MS). The reaction was quenched by addition of aq 40% NaHSOs (10.6 ml) in two portions (exothermic). After 15 min the reaction temperature was raised to 20 °C and stirred vigorously (600 rpm) for 30 min (reaction color turns bright yellow). Phases were separated and 1 M H2SO4 (10.6 ml) was added to the organic phase.
  • the resulting white powder was resuspended in water (51 ml) and stirred vigorously for 1 .5 h to yield a stable white suspension.
  • the precipitate was filtered, washed on filter with water (20 ml) and dried under high vacuum overnight to yield the title compound (10.42 g, 97% assay, >99.5% ee, 80% isolated yield over two steps) as a white powder.
  • the reaction mixture was stirred for further 5 h and then quenched by adding aq saturated sodium thiosulphate at 0 °C.
  • the organic layer was separated, and aqueous layer extracted with ethyl acetate.
  • the combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure to get the crude compound.
  • the crude material was purified by silica gel chromatography using cyclohexane and ethyl acetate as an eluent to yield the title compound (1 .55 g, 89% purity, >99.5% ee, 79% yield).
  • the reaction mixture was stirred for 2 h at 24°C and then quenched by adding saturated Na2S20s at 0 °C.
  • the organic layer was separated and aqueous layer extracted with ethyl acetate.
  • the combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product.
  • the crude material was purified by column chromatography using cyclohexane and ethyl acetate as an eluent to yield the title compound (5.48 g, 91 % purity, 97% ee, 81 % yield).
  • amidine oxime being formed first by addition of hydroxylamine to a functionalized nitrile followed by oxidation of sulfide with hydrogen peroxide.
  • Step 1 To a solution of starting nitrile in EtOH (2 ml/mmol) was added a 50% aq NH2OH (1.1 eq). The reaction mixture was stirred at ambient temperature until a full consumption of starting material. The reaction mixture was then evaporated to dryness and the desired product purified either by trituration with diisopropyl ether or via silica gel chromatography.’
  • starting amidine oxime is commercially available and could also be prepared as described in CN101029023.
  • nucleophilic aromatic substitution with thiols in the presence of base produces corresponding sulfides which are oxidized using hydrogen peroxide as described for Method B.
  • Step 1 To a suspension of NaH (1 .1-3.1 eq) in dry 2-methyl tetrahydrofuran (5 ml/mmol) was added the corresponding thiol (1 .1-3.1 eq). After stirring for 10 min at ambient temperature heteroaryl hydroxylamine was added. The reaction mixture was stirred at 80 °C until the full conversion of starting material. The reaction was then cooled to ambient temperature and solvent was evaporated under reduced pressure. The residue was taken up in EtOAc and water. Phase were separated and aqueous phase extracted with EtOAc (3x). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure yielded a crude product. The crude product was further purified eitherby trituration with diisopropyl ether or by silica gel chromatography.
  • Example 44 Preparation of (1 R)-6-bromo-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridin-3-one
  • the crude starting material (1 .024 g) prepared in Example 43 was dissolved in a mixture of THF (8.0 ml) and water (2.0 ml). The resulting yellow solution was heated in a closed vial at 80 °C for 7 h.
  • the reaction mixture was cooled to ambient temperature and diluted with brine (20 ml). Phases were separated and the aqueous phase was extracted with EtOAc (2 x 30 ml). The combined organic phase was washed with aq NaHCOs, dried over anhydrous Na2SO4 and evaporated under reduced pressure.
  • a single crystal grown from di-isopropyl ether/acetonitrile was selected for X-ray data analysis.
  • the crystal sample mounted had dimensions of 0.8 mm x 0.05 mm x 0.05 mm and was a colorless needle.
  • Data collection was performed on a Rigaku Oxford Diffraction Supernova diffractometer at 293 K.
  • the unit cell was determined to be orthorhombic (space group P212121), and the structure contained one molecule in the crystal asymmetric unit (Figure 2, a thin stick representation labelled by chirality).
  • Figure generated in Flare software package (Cresset). The stereochemistry was unambiguously determined to be the R isomer, with a Flack parameter of -0.04 +/- 0.04. Crystallographic data is summarized in Table 3 and selected geometric parameters are listed in Table 4.
  • Example 45 6-chloro-1 -isopropyl-1 -oxo-isothiazolo[4,5-b]pyridin-3-one
  • 5-chloro-N'-hydroxy-3-isopropylsulfinyl-pyridine-2-carboxamidine 222 mg, 95% purity, 0.806 mmol
  • EtsN 0.12 ml, 0.886 mmol
  • 2,4- dinitrobenzene sulfonyl chloride 0.241 g, 0.886 mmol
  • Example 50a 6-chloro-1-oxo-1-phenyl-isothiazolo[4,5-b]pyridin-3-one
  • Example 50c 6-chloro-1 -oxo-1 -phenyl-isothiazolo[4,5-b]pyridin-3-one
  • Example 56 1-oxo-1-phenyl-6-(trifluoromethyl)isothiazolo[4,5-b]pyridin-3-one
  • 3-(benzenesulfinyl)-N'-hydroxy-5-(trifluoromethyl)pyridine-2-carboxamidine 515 mg, 99% purity, 1 .55 mmol
  • EtaN 0.24 ml, 1 .70 mmol
  • 2,4- dinitrobenzene sulfonyl chloride 0.63 g, 1.70 mmol
  • Example 69b Preparation of 1 -[(1 R)-1 -ethyl-1 ,3-dioxo-isothiazolo[4,5-b]pyridin-6- yl] cyclopropanecarbonitrile
  • the crude material was purified by silica gel chromatography using cyclohexane and ethyl acetate as an eluent to yield the title compound (0.100 g, 99% purity, >99.5% ee, 80% yield) as white solid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un composé de formule I : (I) R1, R2, R3, G1 et G2 étant tels que définis dans la description.
PCT/EP2024/065831 2023-06-07 2024-06-07 Synthèse d'acyl sulfoximines cycliques Ceased WO2024252006A1 (fr)

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EP24732589.7A EP4724447A1 (fr) 2023-06-07 2024-06-07 Synthèse d'acyl sulfoximines cycliques
CN202480031686.2A CN121175316A (zh) 2023-06-07 2024-06-07 环状酰基亚砜亚胺的合成
MX2025014399A MX2025014399A (es) 2023-06-07 2025-12-01 Sintesis de acil sulfoximinas ciclicas

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IL324519A (en) 2026-01-01

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