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WO2024112764A1 - Synthèse de pyrrolo [3,4-c] pyrroles - Google Patents

Synthèse de pyrrolo [3,4-c] pyrroles Download PDF

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WO2024112764A1
WO2024112764A1 PCT/US2023/080702 US2023080702W WO2024112764A1 WO 2024112764 A1 WO2024112764 A1 WO 2024112764A1 US 2023080702 W US2023080702 W US 2023080702W WO 2024112764 A1 WO2024112764 A1 WO 2024112764A1
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compound
formula
iii
scheme
alkyl
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Inventor
George P. Luke
Sonia Rodriguez
Stephane G. Ouellet
Gilles Gorins
Khalid DIKER
Aurélie BEAUDENON
Jonathan COUSIN
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Novo Nordisk Health Care AG
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Novo Nordisk Health Care AG
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Priority to EP23829208.0A priority Critical patent/EP4622958A1/fr
Priority to CN202380080050.2A priority patent/CN120225503A/zh
Priority to JP2025529303A priority patent/JP2025536754A/ja
Publication of WO2024112764A1 publication Critical patent/WO2024112764A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This disclosure relates to novel synthetic methods of making pyrrolo[3,4-c]pyrroles, derivatives thereof, and intermediates thereto.
  • the disclosure further relates to synthetic processes for preparing bioactive compounds using pyrrolo[3,4-c]pyrroles, derivatives thereof, and intermediates thereto.
  • Pyrrolo[3,4-c]pyrroles are useful as bioactive compounds, e.g., as dual inhibitors of autotaxin and carbonic anhydrase (WO 2017/050791, WO 2017/050792), inhibitors of stearoyl- CoA desaturase (WO 2008/135141, WO 2010/028761), agonists of kappa opioid receptors (WO 2016/181408), inhibitors of dipeptidyl dipeptidase-IV (WO 2014/061031), and Pyruvate Kinase R activating compounds (WO 2018/175474).
  • the present disclosure provides a novel process for preparing a compound according to formula (III-Y) which is useful as a key intermediate for synthesis of pyrrolo[3,4-c]pyrroles, and in particular, for making pyrrolo[3,4-c]pyrroles substituted with different groups on each nitrogen: (III-Y) or a salt thereof, where: R12 is -CR2R3-(C6-C10 aryl), where the C6-C10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C 1 -C 6 alkyl; and R4 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or
  • Intermediate compounds of formula (III-Y) can be used for preparing bioactive compounds, such as PKR Activating Compounds.
  • PKR Activating Compounds can increase the activity of wild-type and mutant PKR enzymes.
  • the present disclosure relates to a process for preparing a compound of formula (III-Y).
  • the process includes a further step of transforming the compound of formula (III-Y) into a compound of formula (III-Z) by reacting with R1-Cl, wherein R1 is -C(O) C 1 -C 6 alkoxy: [0007]
  • the process further includes transforming the compound of formula (III-Z) into a compound of formula (V-Z) by reacting the compound of formula (III-Z) with a sulfonamide: (V-Z) [0008]
  • the present disclosure relates to key intermediate in the synthesis of pyrrolo[3,4-c]pyrroles, wherein said intermediate is the compound of formula (III-Y) or a salt thereof.
  • the present disclosure relates to key intermediate in the synthesis of pyrrolo[3,4-c]pyrroles, wherein said intermediate is the compound of formula (III-Z) or a salt thereof.
  • the present disclosure relates to key intermediate in the synthesis of pyrrolo[3,4-c]pyrroles, wherein said intermediate is the compound of formula (V-Z) or a salt thereof.
  • the present disclosure relates to the use of intermediate compounds of formula (III-Y), (III-Z) or (V-Z) useful for the synthesis of a compound of formula (I), (S)-1- (5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one also known as etavopivat: or for the synthesis of a compound of formula (II), (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2- sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one: (II).
  • C 1 -C 6 alkyl refers to a saturated, branched or straight chain hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • Examples of C 1 -C 6 alkyl include but are not limited to methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, 2-pentyl, 3-pentyl, isoamyl, 2-methylbutyl, neopentyl, 3-methylbutyl, tert-amyl, 1- hexanol, 2-hexanol, 3-hexanol, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2- methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-
  • C 6 -C 10 aryl refers to a cyclic aromatic group comprising from 6-10 carbon atoms. Such aryl group may be substituted or unsubstituted. Examples of C 6 - C10 aryl include but are not limited to phenyl, naphthyl and the like.
  • halo refers to fluoro, chloro, bromo and iodo.
  • C 1 -C 6 haloalkyl refers to a C 1 -C 6 alkyl group as defined herein comprising at least one halo group as defined herein.
  • C 1 -C 6 haloalkyl examples include but are not limited to trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl etc.
  • C 1 -C 6 alkoxy refers to the group -OC 1 -C 6 alkyl. Examples of C 1 -C 6 alkoxy include but are not limited to methoxy, ethoxy, 1-propoxy, iso-propoxy, n- butoxy, tert-butoxy etc.
  • C 1 -C 6 haloalkoxy refers to a C 1 -C 6 alkoxy as defined herein comprising at least one halo group as defined herein.
  • Specific examples of C 1 -C 6 haloalkoxy include but are not limited to trifluoromethoxy, difluoromethoxy, pentafluoroethyl, trichloromethyl etc.
  • 6-10 membered heteroaryl refers to a 6-10 membered cyclic aromatic ring system having ring carbon atoms and 1-3 heteroatoms selected from the group consisting of O, N or S.
  • Such 6-10 membered heteroaryl may be substituted or unsubstituted.
  • Examples of 6-10 membered heteroaryl include but are not limited to 2-pyridyl, 3- pyridyl, 4-pyridyl, 5-benzofuranyl, 6-benzofuranyl, 6-benzooxazol, 6-benzothiazolyl.
  • the present disclosure sets forth synthetic methods, intermediates, and reaction parameters for the efficient preparation of pyrrolo[3,4-c]pyrroles.
  • the present disclosure also encompasses the recognition that intermediate compounds of formula (III-Y), (III-Z) and (III): (i) can be synthesized efficiently from commercially available starting materials; (ii) can be purified without chromatography; and (iii) can be used to synthesize pyrrolo[3,4-c]pyrroles with differentially substituted nitrogen atoms. [0020] Intermediate compounds of formula (III-Y), (III-Z) and (III) can be used for preparing bioactive compounds, such as PKR (Pyruvate Kinase R) Activating Compounds. Such PKR Activating Compounds can increase the activity of wild-type and mutant PKR enzymes.
  • PKR Pyruvate Kinase R
  • the PKR Activating Compound prepared using an intermediate compound of formula (III-Y), (III-Z) or (III) is a compound of formula (I): which can also be referred to as (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)- 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one or etavopivat.
  • the compound of formula (I) is a selective, orally bioavailable PKR Activating Compound that decreases 2,3-DPG (diphosphoglyceric acid), increases ATP, and has anti- sickling effects on red blood cells (RBCs) in disease models with a wide therapeutic margin relative to preclinical toxicity.
  • the compound of formula (I) is a potent activator of PKR and a multi-modal metabolic modulator of RBCs. Activation of PKR simultaneously reduces 2,3-DPG concentrations, which increases hemoglobin-oxygen affinity and decreases sickling, while also increasing intracellular ATP, which improves RBC health and reduces hemolysis, or RBC death.
  • the compound of formula (I) is an allosteric activator of recombinant wild type (WT) PKR and a mutant enzyme, PKR R510Q which is one of the most prevalent PKR mutations in North America. PKR exists in both a dimeric and tetrameric state, but functions most efficiently as a tetramer. PKR is the isoform of pyruvate kinase expressed in RBCs, and is the rate limiting enzyme in the glycolytic pathway. The compound of formula (I) stabilizes the tetrameric form of PKR, thereby lowering the Michaelis-Menten constant (Km) for its substrate, phosphoenolpyruvate (P).
  • Km Michaelis-Menten constant
  • the PKR Activating Compound prepared using an intermediate compound of formula (III-Y), (III-Z) or (III) is a compound of formula (II): which can also be referred to as (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one.
  • Intermediate Compounds of the Disclosure and Methods for Preparing the Same [0025] In one aspect, the present disclosure relates to a process for preparing a compound of formula (III-Y) according to Scheme A1.
  • the compound of formula (III-Y) may further be used for efficient synthesis of pyrrolo[3,4-c]pyrroles.
  • the reaction according to Scheme A1 comprises reacting an azomethine precursor of formula (III-W) with an electron-poor alkyne of formula (III-X) in the presence of an acid: Scheme A1 where R12 is -CR2R3-(C6-C10 aryl), where the C6-C10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C 1 -C 6 alkyl; and R4 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO 2 R7, wherein each R7 is independently selected from
  • R12 of the azomethine precursor of formula (III-W) of is -CH 2 -Ph (benzyl) or 4-methoxybenzyl. In one embodiment, R12 of formula (III-W) is benzyl.
  • the suitable silyl group R9 of (III-W) is selected from the group consisting of TMS, DMPS, TES, TBS or DMIPS. In one embodiment, the suitable silyl group R9 is TMS.
  • R10 of formula (III-W) is a C 1 -C 6 alkyl or a straight chain C 1 -C 6 alkyl.
  • R10 is selected from the group consisting of methyl, ethyl, 1- propyl, 1-butyl. In some embodiments, R10 is methyl.
  • R5 and R6 of the electron poor alkyne of formula (III-X) are each independently selected from chloro, bromo, iodo or -OSO 2 R7. In one embodiment, R5 and R6 are each chloro. In one embodiment, R5 and R6 are each bromo.
  • the reaction according to Scheme A1 is performed in the presence of an acid.
  • the acid is selected from the group consisting of TFA, TMSOTf, TMSI, TMSOTf in combination with CsF, or TMSI in combination with any one of CsF, LiF, ZnCl2 or a combination thereof.
  • the acid is TFA.
  • the acid is present in a substoichiometric amount or catalytic amount of about 0.01-0.2, such as e.g.0.03-0.07 equivalents or about 0.05 equivalents.
  • the reaction of Scheme A1 is performed in a non-polar solvent, e.g. selected from the group consisting of toluene, DCM or a mixture thereof.
  • the solvent is toluene.
  • the reaction according to Scheme A1 is performed in a non-polar solvent selected from DCM, toluene or a mixture thereof using about 0.01-0.2 equivalents of an acid selected from the group consisting of TFA, TMSOTf, TMSI, TMSOTf in combination with CsF, or TMSI in combination with any one of CsF, LiF, ZnCl 2 or a combination thereof, about 1 equivalent of the compound of formula (III-W) and 1.1 to 3 equivalents of the compound of formula (III-X).
  • the reaction of Scheme A1 is performed using a compound of formula (III-W1) according to Scheme A1’ and results in preparation of a compound of formula (III-Y1), wherein R5, R6, R9, R10 are defined as above: Scheme A1’ (III-W1) (III-X) (III-Y1) [0032]
  • the process according to Scheme A1 is a process according to Scheme A wherein the compound of formula (III-Y) is a compound of formula (III-B) which can be prepared, for example, via the process depicted in Scheme A and described more fully in Examples 1 and 2.
  • Step 1 A uses an azomethine precursor (e.g., N- (methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-poor alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 eq or 0.05 eq) of a suitable acid (e.g., trifluoroacetic acid (TFA)) in a suitable solvent (e.g., toluene or dichloromethane (DCM)).
  • a suitable acid e.g., trifluoroacetic acid (TFA)
  • TFA trifluoroacetic acid
  • DCM dichloromethane
  • Step 1 A uses an azomethine precursor (e.g., N- (methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-poor alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 eq or 0.05 eq) of trimethylsilyl trifluoromethanesulfonate (i.e. Me 3 SiOTf) in a suitable solvent (e.g., toluene or DCM).
  • a substoichiometric amount e.g., 0.1 eq or 0.05 eq
  • a suitable solvent e.g., toluene or DCM
  • Step 1 A uses an azomethine precursor (e.g., N-(methoxymethyl)- N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-poor alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 eq or 0.05 eq) of trimethylsilyl trifluoromethanesulfonate (i.e. Me 3 SiOTf) and CsF in a suitable solvent (e.g., toluene or DCM).
  • a substoichiometric amount e.g., 0.1 eq or 0.05 eq
  • trimethylsilyl trifluoromethanesulfonate i.e. Me 3 SiOTf
  • CsF a suitable solvent
  • Step 1 A uses an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-poor alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 eq or 0.05 eq) of trimethylsilyl iodide (i.e. Me 3 SiI) in a suitable solvent (e.g., toluene or DCM).
  • a substoichiometric amount e.g., 0.1 eq or 0.05 eq
  • trimethylsilyl iodide i.e. Me 3 SiI
  • Step 1 A uses an azomethine precursor (e.g., N-(methoxymethyl)-N- (trimethylsilylmethyl)benzylamine, III-D) and an electron-poor alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 eq or 0.05 eq) of trimethylsilyl iodide (i.e. Me3SiI) and an additive selected from CsF, LiF, ZnCl2, and combinations thereof, in a suitable solvent (e.g., toluene or DCM).
  • a substoichiometric amount e.g., 0.1 eq or 0.05 eq
  • a substoichiometric amount e.g., 0.1 eq or 0.05 eq
  • trimethylsilyl iodide i.e. Me3SiI
  • the choice of electron-poor alkyne is useful for avoiding side products and to reduce the number of steps in the process.
  • the stoichiometric ratio between the azomethine precursor and the electron-poor alkyne is selected in order to avoid side products and to facilitate purification.
  • 1.0 eq of azomethine precursor e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D
  • 2.0 eq of electron- poor alkyne e.g., dichlorobutyne, III-C
  • 1.0 eq of azomethine precursor e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D
  • 1.5 eq of electron-poor alkyne e.g., dichlorobutyne, III-C
  • the process for making the compound of formula (III-Y), (III- Y1) or (III-B) may involve isolating the product as a salt. In some embodiments, the process for making the compound of formula (III-Y), (III-Y1) or (III-B) may involve carrying over the product to a further reaction step without prior purification. [0036] In some embodiments, the process further involves a step of transforming the compound of formula (III-Y) into a compound of formula (III-Z) e.g.
  • R1 is selected from the group consisting of C 1 -C 6 alkoxycarbonyl (e.g. tert- butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e. Cbz), C 6 -C 10 aryloxy (e.g. phenoxycarbonyl), C 1 -C 6 alkylcarbonyl (e.g. acetyl), haloalkylcarbonyl (e.g.
  • R1 is -C(O)(C 1 -C 6 alkoxy). In one embodiment, R1 is -C(O)(C 1 -C 6 alkoxy) wherein C 1 -C 6 alkoxy is straight chain C 1 -C 6 alkoxy selected from the methoxy, ethoxy, 1-propoxy, 1-butoxy, 1-pentoxy or 1-hexoxy. In one embodiment, R1 is -C(O)OCH3.
  • the process including Scheme A1 and A2 together is represented by Scheme B1, wherein R9, R10, R12, R5, R6 and R1 are defined as above for Schemes A1 and A2: Scheme B1
  • the process of Scheme A2 is according to Scheme A2’: Scheme A2’ or the process including Schemes A1’ and A2’ together is represented by Scheme B2 wherein R9, R10, R5, R6 and R1 are as defined above for Schemes A1’ and A2’: Scheme B2
  • the process according to Scheme B1 or B2 is the process depicted in Scheme B wherein the compound of formula (III-A) can be prepared, for example as described more fully in Examples 1 and 2.
  • Step 1 B is substantially the same as described above with respect to Step 1 A .
  • Step 2 B is completed by contacting a compound of formula (III-B) with methyl chloroformate in the presence of a suitable solvent (e.g. toluene or DCM).
  • a suitable solvent e.g. toluene or DCM.
  • Steps 1 B and 2 B are performed in the same reaction vessel. In some embodiments, Steps 1 B and 2 B are performed without any intervening isolation or purification steps. In other embodiments, Steps 1 B and 2 B are performed sequentially in distinct vessels. In other embodiments, Steps 1 B and 2 B are performed sequentially in distinct vessels without any intervening isolation or purification steps. In other embodiments, Steps 1 B and 2 B are performed sequentially in distinct vessels, where the Step 1 B is performed in a first vessel and the product of Step 1 B is transferred to a second vessel containing a C 1 -C 6 alkyl chloroformate to complete Step 2 B .
  • R 5 and R 6 are each, independently, halo or –OSO 2 R 7 ; each R 7 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or C6-C10 aryl, where the C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R 8 is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.
  • R5 and R6 are each halo.
  • R5 and R6 are each chloro. In some embodiments, R5 and R6 are each bromo. In some embodiments, R5 and R6 are each iodo. In some embodiments, R 5 and R 6 are each –OSO 2 R 7 . In some embodiments, R 7 is C 1 -C 6 alkyl. In some embodiments, R7 is methyl. In some embodiments, R7 is C6-C10 aryl substituted with one R8. In some embodiments, R8 is C 1 -C 6 alkyl. In some embodiments, R8 is methyl. In some embodiments, R 7 is phenyl substituted with one methyl.
  • the compound of formula (III-X) is 1,4-dichloro-2-butyne. In some embodiments, the compound of formula (III-X) is 1,4-dibromo-2-butyne. In some embodiments, the compound of formula (III-X) is 1,4-diiodo-2-butyne. In some embodiments, the compound of formula (III-X) is but-2-yne-1,4-diyl bis(methanesulfonate). In some embodiments, the compound of formula (III- X) is but-2-yne-1,4-diyl bis(4-methylbenzenesulfonate).
  • Step 1 C is completed substantially as described above with respect to Step 1 A .
  • Step 2 C is completed by contacting a compound of formula (III-Y1) with ClC(O)(C 1 -C 6 alkoxy) (i.e. a C 1 -C 6 alkyl chloroformate) in the presence of a suitable solvent (e.g. toluene or DCM).
  • a suitable solvent e.g. toluene or DCM
  • a process for preparing a compound of formula (III-Z), wherein R 1 is –C(O)(C 1 -C 6 alkoxy) includes a step of transforming 1-benzyl-3,4- bis(substituted)-2,5-dihydro-1H-pyrrole (III-Y1) (e.g.1-benzyl-3,4-bis(chloromethyl-2,5- dihydro-1H-pyrrole (III-B)) to the compound of formula (III-Z) (i.e. Step 2 C ) (e.g. compound (III)).
  • the step of transforming the compound of formula (III-Y1) to the compound of formula (III-Z) includes contacting the compound of formula (III-Y1) with ClC(O)(C 1 -C 6 alkoxy) (i.e. a C 1 -C 6 alkyl chloroformate).
  • R1 is – C(O)OCH3.
  • the compound of formula (III-Z) is methyl 3,4- bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (i.e. compound III-A, R1 is methoxycarbonyl and R5, R6 are each chloro).
  • the step of transforming the compound of formula (III-Y1) to the compound of formula (III-Z) includes contacting the compound of formula (III-Y1) with methyl chloroformate.
  • a process for preparing a compound of formula (III-Z), wherein R 1 is –C(O)(C 1 -C 6 alkoxy) includes a step of contacting dichlorobutyne (III-C, (III-X) where each R5, R6 are chloro) with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (III-D) to afford the compound of formula (III-Y1) wherein R5, R6 are each chloro (i.e. (III-B)) (i.e. Step 1 C ).
  • contacting a compound of formula (III-C) with a compound of formula (III-D) is performed in the presence of an acid.
  • the acid is TFA.
  • contacting a compound of formula (III-C) with a compound of formula (III-D) is performed in the presence of a suitable solvent.
  • the suitable solvent is toluene.
  • Steps 1 C and 2 C are performed in the same vessel. In some embodiments, Steps 1 C and 2 C are performed without any intervening isolation or purification steps. In other embodiments, Steps 1 C and 2 C are performed sequentially in distinct vessels. In other embodiments, Steps 1 C and 2 C are performed sequentially in distinct vessels without any intervening isolation or purification steps.
  • Steps 1 C and 2 C are performed sequentially in distinct vessels, where the Step 1 C is performed in a first vessel and the product of Step 1 C is transferred to a second vessel containing a C 1 -C 6 alkyl chloroformate to complete Step 2 C .
  • the process further involves a step of transforming the compound of formula (III-Z) into a compound of formula (V-Z) by reacting the compound of formula (III-Z) with a compound of formula (IV-Y) in the presence of a base according to Scheme A3: Scheme A3 , wherein R11 is C6-C10 aryl or 6-10 membered heteroaryl comprising 1-3 O, N, S, wherein C6-C10 aryl and 6-10 membered heteroaryl are each optionally substituted with one or more substituents selected from R13 and -OR13; each R13 is independently -H, -C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, -F, -Cl, -Br, -I, -CN, - NO 2 ; or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl
  • benzyloxycarbonyl i.e. Cbz
  • C6-C10 aryloxy e.g. phenoxycarbonyl
  • C 1 -C 6 alkylcarbonyl e.g. acetyl
  • haloalkylcarbonyl e.g. trifluoroacetyl
  • -SO2-(C6-C10 aryl) e.g.
  • R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO2R7, wherein each R7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or C6-C10 aryl, where C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.
  • halo such as chloro, bromo, iodo, or -OSO2R7
  • each R7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1
  • R11 is a 6-10 membered heteroaryl as defined above such as e.g.2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-ylm, R1 is C 1 -C 6 alkoxycarbonyl, and R5, R6 are each halo.
  • R11 is a 6-10 membered heteroaryl as defined above such as e.g.2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-7-yl; R1 is C 1 -C 6 alkoxycarbonyl, and R5, R6 are each chloro.
  • the reaction according to Step 1 A3 is performed in the presence on a base such as K 2 CO 3 or Cs 2 CO 3 .
  • the base is K 2 CO 3 .
  • the reaction according to Scheme A3 is performed in a suitable solvent selected from the group consisting of DMSO, toluene or a mixture thereof.
  • the process according to scheme A3 relates to a process for preparing a compound of formula (V) according to scheme A3’: Scheme A3’ that includes the step of: contacting a compound of formula (III-Z) e.g. (III): with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV): to afford the compound of formula (V), wherein R 1 is a protecting group.
  • R1 is a protecting group, wherein the protecting group is –C(O)(C 1 -C 6 alkyl), –C(O)(C 1 -C 6 haloalkyl), –C(O)(C 1 -C 6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)2(tolyl).
  • R 1 is –C(O)(C 1 -C 6 alkoxy).
  • R 1 is –C(O)OCH 3 .
  • the step of contacting a compound of formula (III) with a compound of formula (IV) is performed in the presence of a base.
  • the base is Cs2CO3 or K2CO3.
  • the base is Cs2CO3.
  • the base is K 2 CO 3 .
  • the compound of formula (V) is formed in the presence of a suitable solvent.
  • the suitable solvent is DMSO, toluene, or a combination thereof.
  • the suitable solvent is DMSO.
  • the suitable solvent is a combination of DMSO and toluene.
  • the compound of formula (III) is a compound of formula (III-A): which can also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1- carboxylate.
  • the compound of formula (V) is a compound of formula (V-A): which can also be referred to as methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7- yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
  • the present disclosure relates to an intermediate compound of formula (III): where: R1 is H, –CR2R3-(C6-C10 aryl), or a protecting group, where the C6-C10 aryl is optionally substituted with 1 to 3 R4; R 2 and R 3 are each independently H or C 1 -C 6 alkyl; and R 4 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.
  • Compounds of formula (III) are useful for preparing bioactive compounds, for example, PKR Activating Compounds.
  • a compound of formula (III) is used in a process for preparing a compound of formula (I). In other embodiments, a compound of formula (III) is used in a process for preparing a compound of formula (II).
  • R1 is H. In some embodiments, R1 is a protecting group. In some embodiments, R 1 is –CR 2 R 3 -(C 6 -C 10 aryl). In some embodiments where R 1 is –CR2R3-(C6-C10 aryl), R2 and R3 are each H. In some embodiments where R1 is –CR2R3-(C6-C10 aryl), R2 is C 1 -C 6 alkyl and R3 is H.
  • R1 is –CR 2 R 3 -(C 6 -C 10 aryl)
  • R 2 is methyl and R 3 is H.
  • R 1 is –CR 2 R 3 -(C 6 -C 10 aryl)
  • the C 6 -C 10 aryl is unsubstituted.
  • the C6-C10 alkyl is substituted with one C 1 -C 6 alkoxy.
  • the C 6 -C 10 aryl is substituted with one methoxy.
  • R 1 is –CR 2 R 3 -(C 6 -C 10 aryl)
  • the C 6 -C 10 aryl is phenyl.
  • the C6-C10 aryl is 4-methoxyphenyl.
  • R1 is benzyl (i.e. –Bn, which may also be shown as –CH2-Ph).
  • R 1 is 4-methoxybenzyl.
  • protecting group refers to any group capable of preventing the amine group of the compound of formula (III) from participating in or affecting reactions on other parts of the molecule (e.g. reactions with either or both of the chloromethyl groups of the compound), while being removable under conditions that do not adversely affect the rest of the molecule.
  • amine protecting groups that may be suitable for the disclosed process include alkoxycarbonyl (such as tert-butoxycarbonyl, or BOC, and methoxycarbonyl), benzyloxycarbonyl (i.e. Cbz), C 6 -C 10 aryloxycarbonyl (e.g.
  • R1 is a protecting group, wherein the protecting group is –C(O)(C 1 -C 6 alkyl), –C(O)(C 1 -C 6 haloalkyl), –C(O)(C 1 -C 6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O) 2 (tolyl).
  • R 1 is a protecting group, wherein the protecting group is –C(O)(C 1 -C 6 alkoxy).
  • R 1 is a protecting group, wherein the protecting group is –C(O)OCH3.
  • the present disclosure relates to a compound of formula (III), wherein the compound is: (i) methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate; or (ii) 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole.
  • the compound of formula (III) is a compound of formula (III-A): which may also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1- carboxylate.
  • the compound of formula (III) is a compound of formula (III-B): which may also be referred to as 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole.
  • the present disclosure relates to an intermediate compound of formula (V): wherein R 1 is a protecting group.
  • R1 is –C(O)(C 1 -C 6 alkyl), –C(O)(C 1 -C 6 haloalkyl), –C(O)(C 1 -C 6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)2(tolyl).
  • R 1 is –C(O)OCH 3 .
  • the compound of formula (V) is a compound of formula (V-A): which may also be referred to as methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7- yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
  • the present disclosure relates to a compound of formula (V- A): wherein the compound is prepared by a process that includes the step of: contacting methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV) in the presence of a base.
  • the base is Cs2CO3 or K2CO3.
  • the base is Cs2CO3.
  • the base is K2CO3.
  • the compound of formula (V- A) is formed in the presence of a suitable solvent.
  • the suitable solvent is dimethyl sulfoxide (DMSO), toluene, or a combination thereof.
  • the suitable solvent is DMSO.
  • the suitable solvent is a combination of DMSO and toluene.
  • the present disclosure relates to an intermediate compound of formula (IV): which may also be referred to as 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide.
  • the present disclosure relates to a process for preparing a compound of formula (IV), as depicted in Scheme D and described more fully in Example 3.
  • a compound of formula (IV) is obtained via the process depicted in Scheme D and described more fully in Example 3.
  • the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-D) to a compound of formula (IV-C) (i.e. Step 1 D ).
  • Step 1 D includes contacting a compound of formula (IV-D) with 1,2-dibromoethane to afford the compound of formula (IV-C).
  • Step 1 D is performed in the presence of a base.
  • a base is potassium carbonate.
  • Step 1 D is performed in the presence of a suitable solvent.
  • the suitable solvent is water, ethanol (EtOH), or a combination thereof.
  • the suitable solvent is a mixture of EtOH and water.
  • the suitable solvent is a mixture of EtOH and water in a ratio of about 80:20 to 98:2, such as about 85:15 or about 95:5.
  • the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-C) to the compound of formula (IV-B) (i.e. Step 2 D ).
  • Step 2 D includes contacting the compound of formula (IV-C) with a brominating reagent.
  • a brominating reagent is N-bromosuccinimide (NBS).
  • Step 2 D is performed in the presence of a suitable solvent.
  • the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-B) to the compound of formula (IV-A) (i.e. Step 3 D ).
  • Step 3 D includes contacting the compound of formula (IV-B) with a Grignard reagent, a C 1- C 6 alkyl lithium, and sulfuryl chloride.
  • Step 3 D includes contacting the compound of formula (IV-B) with isopropyl magnesium chloride, butyl lithium, and sulfuryl chloride.
  • Step 3 D includes first contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound, contacting the first metalated intermediate compound with C 1 -C 6 alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated intermediate compound, and subsequently contacting the second metalated intermediate compound with sulfuryl chloride to afford the compound of formula (IV-A).
  • C 1 -C 6 alkyl lithium e.g. butyl lithium, n-butyl lithium or hexyl lithium
  • Step 3 D includes first contacting the compound of formula (IV-B) with isopropyl magnesium chloride to afford a first metalated intermediate compound, subsequently contacting the first metalated intermediate compound with butyl lithium to afford a second metalated intermediate compound, and then subsequently contacting the second metalated intermediate compound with sulfuryl chloride to afford the compound of formula (IV-A).
  • the butyl lithium is selected from n-butyl lithium, sec-butyl lithium, and tert- butyl lithium.
  • the butyl lithium is n-butyl lithium.
  • the butyl lithium is sec-butyl lithium.
  • the butyl lithium is tert-butyl lithium.
  • Step 3 D is performed in the presence of a suitable solvent.
  • the suitable solvent is tetrahydrofuran (THF).
  • the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-A) to the compound of formula (IV) (i.e. Step 4 D ).
  • Step 4 D includes contacting a compound of formula (IV-A) with ammonia to obtain the compound of formula (IV).
  • Step 4 D is performed in the presence of a suitable solvent.
  • the suitable solvent is methanol (MeOH).
  • the present disclosure relates to a process for preparing a compound of formula (IV), as depicted in Scheme E and described more fully in Example 4.
  • a compound of formula (IV) is obtained via the process depicted in Scheme E and described more fully in Example 4.
  • the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-F) to the compound of formula (IV-E) (i.e. Step 1 E ).
  • Step 1 E includes contacting the compound of formula (IV-F) with bromine, hydrohalic acid (e.g. hydrochloric acid or hydrobromic acid), and sulfamic acid.
  • Step 1 E includes first contacting the compound of formula (IV-F) with a first portion of bromine, subsequently contacting the compound of formula (IV-F) with hydrochloric acid, subsequently contacting the compound of formula (IV-F) with a second portion of bromine, and finally contacting the compound of formula (IV-F) with sulfamic acid.
  • Step 1 E includes first contacting the compound of formula (IV-F) with a first portion of bromine, subsequently contacting the compound of formula (IV-F) with hydrobromic acid, subsequently contacting the compound of formula (IV-F) with a second portion of bromine, and finally contacting the compound of formula (IV-F) with sulfamic acid.
  • Step 1 E includes first contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound, subsequently contacting the first intermediate compound with hydrochloric acid to afford a second intermediate compound, subsequently contacting the second intermediate compound with a second portion of bromine to afford a third intermediate compound, and finally contacting the third intermediate compound with sulfamic acid to afford the compound of formula (IV-E).
  • Step 1 E includes first contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound, subsequently contacting the first intermediate compound with hydrobromic acid to afford a second intermediate compound, subsequently contacting the second intermediate compound with a second portion of bromine to afford a third intermediate compound, and finally contacting the third intermediate compound with sulfamic acid to afford the compound of formula (IV-E).
  • Step 1 E is performed in a suitable solvent.
  • the suitable solvent is water.
  • the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-E) to the compound of formula (IV-B) (i.e.
  • Step 2 E includes contacting a compound of formula (IV-E) with 1,2-dibromoethane to afford the compound of formula (IV-B).
  • Step 2 E is performed in the presence of a base.
  • the base is potassium carbonate.
  • Step 2 E is performed in the presence of a suitable solvent.
  • the suitable solvent is water, EtOH, or a combination thereof.
  • the suitable solvent is a combination of water and EtOH.
  • the suitable solvent is a combination of water and EtOH in a ratio of about 1 to about 1.
  • the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-B) to the compound of formula (IV-A) (i.e. Step 3 E ).
  • Step 3 E includes contacting the compound of formula (IV-B) with a Grignard reagent, a C 1- C 6 alkyl lithium, and sulfuryl chloride.
  • Step 3 E includes contacting the compound of formula (IV-B) with isopropyl magnesium chloride, butyl lithium, and sulfuryl chloride.
  • Step 3 E includes first contacting the compound of formula (IV-B) with a Grignard reagent (e.g.
  • Step 3 E includes first contacting the compound of formula (IV-B) with isopropyl magnesium chloride to afford a first metalated intermediate compound, subsequently contacting the first metalated intermediate compound with butyl lithium to afford a second metalated intermediate compound, and then subsequently contacting the second metalated intermediate compound with sulfuryl chloride to afford the compound of formula (IV-A).
  • the butyl lithium is selected from n-butyl lithium, sec-butyl lithium, and tert-butyl lithium.
  • the butyl lithium is n- butyl lithium.
  • the butyl lithium is sec-butyl lithium.
  • the butyl lithium is tert-butyl lithium.
  • Step 3 E is performed in the presence of a suitable solvent.
  • the suitable solvent is THF.
  • the process for preparing a compound of formula (IV) includes the step of transforming a compound of formula (IV-A) to the compound of formula (IV) (i.e. Step 4 E ).
  • Step 4 E includes contacting a compound of formula (IV-A) with ammonia to obtain the compound of formula (IV).
  • Step 4 E is performed in the presence of a suitable solvent.
  • the suitable solvent is MeOH.
  • the present disclosure relates to an intermediate compound of formula (VII): which may also be referred to as (S)-tropic acid.
  • (S)-Tropic acid may be prepared as described below or alternatively from racemic tropic acid by optical resolution via diastereomeric salt formation with e.g. (1R,2S)-2-amino-1,2-diphenylethanol ((1R,2S)-ADPE) using e.g. EtOH, isopropanol (IPA) or a mixture of EtOH/water or IPA/water such as described in Tetrahedron 70 (2014) 7923-7928.
  • the present disclosure relates to a process for preparing an intermediate compound of formula (VII), as depicted in Scheme F and described more fully in Example 5.
  • a compound of formula (VII) is obtained via the process depicted in Scheme F and described more fully in Example 5.
  • the process for preparing a compound of formula (VII) includes the step of transforming a compound of formula (VII-C) to a compound of formula (VII-B) (i.e. Step 1 F ).
  • Step 1 F includes contacting the compound of formula (VII-C) with methyl formate to afford the compound of formula (VII-B).
  • Step 1 F is performed in the presence of a base.
  • a base One of ordinary skill in the art will appreciate that there are many bases that would be compatible with the process of Step 1 F .
  • the base is sodium tert-butoxide or sodium methoxide. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is sodium methoxide. In some embodiments, Step 1 F is performed in the presence of a suitable solvent.
  • the suitable solvent is toluene, THF, or methyl tert-butyl ether (MTBE). In some embodiments, the suitable solvent is toluene. In some embodiments, the suitable solvent is THF. In some embodiments, the suitable solvent is MTBE.
  • the process for preparing a compound of formula (VII) includes the step of transforming a compound of formula (VII-B) to a compound of formula (VII-A) (i.e. Step 2 F ).
  • Step 2 F includes contacting the compound of formula (VII-B) with a reducing agent.
  • Step 2 F includes contacting the compound of formula (VII-B) with a reducing agent in the presence of an enzyme.
  • the reducing agent is an enzyme.
  • the reducing agent is NADPH.
  • the enzyme is carbonyl reductase (CRED).
  • the enzyme is an engineered form of CRED.
  • Step 2 F is performed in the presence of a suitable solvent.
  • the suitable solvent is phosphate buffer, toluene, MTBE or a combination thereof.
  • the suitable solvent is phosphate buffer.
  • the suitable solvent is a combination of phosphate buffer and toluene.
  • the suitable solvent is a combination of phosphate buffer and MTBE.
  • the phosphate buffer has a pH of about 6.5-7.
  • the phosphate buffer includes one or more additional reagents and enzyme cofactors.
  • Step 2 F includes the step of isolating or purifying (S)-methyl tropate. In some embodiments, Step 2 F includes the step of isolating or purifying (S)-methyl tropate from a mixture of (R)-methyl tropate and (S)-methyl tropate. The isolation or purification step can be performed via any methods commonly known to those of ordinary skill in the art.
  • the isolation or purification step includes a chromatography step (e.g. chiral resolution via HPLC, UPLC, or SFC).
  • the isolation or purification step includes a recrystallization step.
  • the isolation or purification step can include derivatizing the mixture of (R)- tropic acid and (S)- tropic acid to form a mixture of diastereomers, and then isolating the derivatized diastereomers via any method commonly known to those of ordinary skill in the art.
  • the process for preparing a compound of formula (VII) includes the step of transforming a compound of formula (VII-A) to the compound of formula (VII) (i.e. Step 3 F ).
  • Step 3 F includes contacting the compound of formula (VII-A) with a base or an enzyme.
  • Step 3 F includes contacting the compound of formula (VII-A) with a base.
  • the base is sodium hydroxide (i.e. NaOH).
  • Step 3 F is performed in the presence of an enzyme.
  • Step 3 F is performed in the presence of a lipase. In some embodiments, Step 3 F is performed in the presence of Candida antarctica lipase B (CALB). In some embodiments, Step 3 F is performed in the presence of a suitable solvent. In some embodiments, the suitable solvent is toluene or MTBE. In some embodiments, the suitable solvent is toluene. In some embodiments, the suitable solvent is MTBE. [0085] in yet another aspect, the present disclosure relates to a composition including a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein R1 is a protecting group.
  • the composition including a compound of formula (III) further includes a compound of formula (IV): or a pharmaceutically acceptable salt thereof.
  • the composition including a compound of formula (III) further includes a base.
  • the base is Cs 2 CO 3 or K 2 CO 3 .
  • the base is Cs2CO3.
  • the base is K2CO3.
  • the composition including a compound of formula (III) further includes a compound of formula (V): or a pharmaceutically acceptable salt thereof, wherein R 1 is a protecting group.
  • the R1 group present on the compound of formula (III) and/or the compound of formula (V) is –C(O)(C 1 -C 6 alkyl), –C(O)(C 1 -C 6 haloalkyl), –C(O)(C 1 -C 6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O) 2 (tolyl).
  • R 1 is –C(O)(C 1 -C 6 alkoxy).
  • R1 is –C(O)OCH3.
  • the compound of formula (III) is a compound of formula (III-A): which can also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1- carboxylate.
  • the compound of formula (V) is a compound of formula (V-A): which can also be referred to as methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7- yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
  • the present disclosure relates to a process for preparing a compound of formula (I), (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one also known as etavopivat: as depicted in Scheme G and described more fully in Examples 6 to 12.
  • the process for preparing a compound of formula (I) includes the step of contacting a compound of formula (III) with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine- 7-sulfonamide (IV) to afford a compound of formula (V); and transforming the compound of formula (V) to the compound of formula (I), wherein R1 is a protecting group (i.e. Step 1 G , followed by Steps 2 G and 3 G ).
  • Step 1 G is performed in the presence of a base.
  • the base is Cs 2 CO 3 or K 2 CO 3 .
  • the base is Cs2CO3.
  • the base is K2CO3.
  • Step 1 G is performed in the presence of a suitable solvent.
  • the suitable solvent is DMSO, toluene, or a combination thereof.
  • the suitable solvent is DMSO.
  • the suitable solvent is a mixture of DMSO and toluene.
  • R1 is –C(O)(C 1 -C 6 alkyl), –C(O)(C 1 -C 6 haloalkyl), –C(O)(C 1 -C 6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O) 2 (tolyl).
  • R 1 is –C(O)(C 1 -C 6 alkoxy).
  • R 1 is –C(O)OCH 3 .
  • the compound of formula (III) is obtained by the process depicted in Scheme C.
  • the compound of formula (III) is a compound of formula (III-A). In some embodiments, the compound of formula (III) is a compound of formula (III-A), wherein the compound of formula (III-A) is obtained by the process depicted in Scheme B and described more fully in Examples 1 and 2. [0096] In some embodiments, the compound of formula (IV) is obtained by the process depicted in one of Schemes D or E and described more fully in Examples 3 and 4, respectively. [0097] In some embodiments, the compound of formula (V) is obtained by the process described above for preparing a compound of formula (V). In some embodiments, the compound of formula (V) is a compound of formula (V-A).
  • the process for preparing a compound of formula (I) includes the step of transforming the compound of formula (V) to a compound of formula (VI) (i.e. Step 2 G ).
  • Step 2 G includes deprotecting the compound of formula (V) to afford a compound of formula (VI).
  • deprotecting the compound of formula (V) to afford the compound of formula (VI) comprises contacting the compound of formula (V) with an acid.
  • the acid includes HBr and acetic acid.
  • the acid includes dibutylsulfane and methanesulfonic acid (MSA). In other embodiments, the acid includes dibutylsulfane, TFA and MSA. In some embodiments, Step 2 G further includes the step of neutralizing the acid with a suitable base. In some embodiments, the suitable base is ammonium hydroxide. In some embodiments, Step 2 G further includes contacting the compound of formula (VI) with (S)-tropic acid (VII) to form a complex of compounds (VI) and (VII). In some embodiments, Step 2 G is performed neat, without the presence of an additional solvent (e.g. the dibutylsulfane and MSA are present in sufficient quantities to solubilize the compound of formula (VI)).
  • an additional solvent e.g. the dibutylsulfane and MSA are present in sufficient quantities to solubilize the compound of formula (VI)).
  • the process for preparing a compound of formula (I) includes the step of contacting (VI) with (S)-tropic acid (VII) to afford the compound of formula (I) (i.e. Step 3 G ).
  • Step 3 G includes coupling the compound of formula (VI) with (S)-tropic acid (VII) to afford the compound of formula (I).
  • Step 3 G is performed in the presence of a coupling reagent.
  • the coupling reagent is a carbodiimide coupling reagent.
  • Step 3 G is performed in the presence of a coupling reagent and an additive.
  • Step 3 G is performed in the presence of a carbodiimide coupling reagent and an additive.
  • a coupling reagent e.g. carbodiimide coupling reagents, such as EDC (N-(3- dimethylaminopropyl)-N’-etylcarbodiimide), or HATU (hexafluorophosphate azabenzotriazole tetramethyl uronium), etc.
  • additives e.g.
  • the coupling reagent includes EDC.
  • the coupling reagent includes propylphosphonic anhydride (T3P ® ).
  • the coupling reagent includes T3P ® and EDC.
  • Step 3 G is performed in the presence of EDC and an additive, where the additive is OxymaPure ® .
  • Step 3 G is performed in the presence of EDC and an additive, where the additive is HOPO. In some embodiments, Step 3 G is performed in the presence of T3P ® and EDC and an additive, where the additive is OxymaPure ® . In some embodiments, Step 3 G is performed in the presence of T3P ® and EDC and an additive, where the additive is HOPO. In some embodiments, Step 3 G is performed in the presence of T3P ® and an additive, where the additive is OxymaPure ® . In some embodiments, Step 3 G is performed in the presence of T3P ® and an additive, where the additive is HOPO. In some embodiments, Step 3 G is performed in the presence of a suitable solvent.
  • the suitable solvent is DMSO, N,N-dimethylacetamide (DMAc), EtOH, DCM, 2- methyl tetrahydrofuran (2-MeTHF) or a combination thereof.
  • the suitable solvent is DMSO.
  • the suitable solvent is DMAc.
  • the suitable solvent is EtOH.
  • the suitable solvent is DCM.
  • the suitable solvent is a combination of DMAc and EtOH.
  • the suitable solvent is 2-MeTHF.
  • the suitable solvent is a combination of 2-MeTHF and DMAc.
  • the suitable solvent is a combination of 2-MeTHF and EtOH.
  • the suitable solvent is a combination of EtOH, DMAc and 2- MeTHF.
  • the present disclosure relates to a process for preparing a compound of formula (II), (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)- 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one: as depicted in Scheme H and described more fully in Example 13.
  • the process for preparing a compound of formula (II) includes the step of contacting a compound of formula (III) with pyridine-2-sulfonamide (VIII-A) to afford a compound of formula (VIII); and transforming the compound of formula (VIII) to the compound of formula (II), wherein R1 is a protecting group (i.e. Step 1 H , followed by Steps 2 H and 3 H ).
  • Step 1 H is performed in the presence of a base.
  • the base is Cs 2 CO 3 or K 2 CO 3 .
  • the base is Cs 2 CO 3 .
  • the base is K2CO3.
  • Step 1 H is performed in the presence of a suitable solvent.
  • the suitable solvent is DMSO, toluene, or a combination thereof.
  • the suitable solvent is DMSO.
  • the suitable solvent is a mixture of DMSO and toluene.
  • R1 is –C(O)(C 1 -C 6 alkyl), –C(O)(C 1 -C 6 haloalkyl), –C(O)(C 1 -C 6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O) 2 (tolyl).
  • R 1 is –C(O)(C 1 -C 6 alkoxy). In some embodiments, R 1 is –C(O)OCH 3 .
  • the compound of formula (III) is obtained by the process depicted in Scheme C. In some embodiments, the compound of formula (III) is a compound of formula (III-A). In some embodiments, the compound of formula (III) is a compound of formula (III-A), wherein the compound of formula (III-A) is obtained by the process depicted in Scheme B and described more fully in Examples 1 and 2.
  • the process for preparing a compound of formula (II) includes the step of transforming the compound of formula (VIII) to a compound of formula (IX) (i.e. Step 2 H ).
  • Step 2 H includes deprotecting the compound of formula (VIII) to afford a compound of formula (IX).
  • deprotecting the compound of formula (VIII) to afford the compound of formula (IX) comprises contacting the compound of formula (VIII) with an acid.
  • the acid includes HBr and acetic acid.
  • the acid includes dibutylsulfane, TFA and MSA. In other embodiments, the acid includes dibutylsulfane and MSA.
  • Step 2 H further includes the step of neutralizing the acid with a suitable base.
  • the suitable base is ammonium hydroxide.
  • deprotecting the compound of formula (VIII) to afford the compound of formula (IX) includes contacting the compound of formula (VIII) with a strong base. In some embodiments, the strong base is potassium hydroxide.
  • Step 2 H further includes contacting the compound of formula (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to form a complex of compounds (IX) and (XI).
  • Step 2 H is performed neat, without the presence of an additional solvent (e.g. the dibutylsulfane and MSA are present in sufficient quantities to solubilize the compound of formula (VI)).
  • Step 2 H could be run in the presence of a suitable solvent or co-solvent.
  • Step 2 H is performed in the presence of water.
  • the process for preparing a compound of formula (II) includes the step of contacting (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to afford the compound of formula (II) (i.e. Step 3 H ).
  • Step 3 H includes coupling the compound of formula (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to afford the compound of formula (II).
  • Step 3 H is performed in the presence of a coupling reagent.
  • the coupling reagent is a carbodiimide coupling reagent.
  • Step 3 H is performed in the presence of a coupling reagent and an additive.
  • Step 3 H is performed in the presence of a carbodiimide coupling reagent and an additive.
  • a carbodiimide coupling reagent e.g. carbodiimide coupling reagents, such as EDC, or HATU, or T3P ® etc.
  • additives e.g. OxymaPure ® (ethyl (hydroxyamino)cyanoacetate), HOBt, HOSu, or HOPO, etc.
  • the coupling reagent includes EDC.
  • the coupling reagent includes T3P ® .
  • the coupling reagent includes T3P ® and EDC. In some embodiments, Step 3 G is performed in the presence of EDC and an additive, where the additive is OxymaPure ® . In some embodiments, Step 3 G is performed in the presence of EDC and an additive, where the additive is HOPO. In some embodiments, Step 3 G is performed in the presence of T3P ® and an additive, where the additive is OxymaPure ® . In some embodiments, Step 3 G is performed in the presence of T3P ® and EDC and an additive, where the additive is OxymaPure ® . In some embodiments, the coupling reagent includes OxymaPure ® and EDC•HCl.
  • the coupling reagent includes HOBt and EDC. In some embodiments, the coupling reagent includes HOPO and EDC. In some embodiments, Step 3 H is performed in the presence of a suitable solvent.
  • the suitable solvent is DMSO, DMAc, EtOH, DCM, 2-MeTHF or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is DMAc. In some embodiments, the suitable solvent is EtOH. In some embodiments, the suitable solvent is DCM. In some embodiments, the suitable solvent is 2-MeTHF. In some embodiments, the suitable solvent is a combination of DMAc and EtOH.
  • the suitable solvent is a combination of 2-MeTHF and DMAc. In some embodiments, the suitable solvent is a combination of 2-MeTHF and EtOH. In some embodiments, the suitable solvent is a combination of EtOH, DMAc and 2-MeTHF. In some embodiments, the suitable solvent is DMSO. List of embodiments [0106] The invention is further described by the following non-limiting embodiments: 1.
  • R 1 is –CR 2 R 3 -(C 6 -C 10 aryl).
  • R 2 and R 3 are each H.
  • R1 is a protecting group.
  • R 1 is –C(O)(C 1 -C 6 alkyl), –C(O)(C 1 -C 6 haloalkyl), –C(O)(C 1 -C 6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O)2(tolyl).
  • R1 is –C(O)(C 1 -C 6 alkoxy). 7.
  • step (ii) comprising: (ii) contacting a compound of formula (III-X) with a compound of formula (III-D): to afford the compound of formula (III-B), wherein: R5 and R6 are each, independently, halo or –OSO2R7 each R 7 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or C6-C10 aryl, where the C6-C10 aryl is optionally substituted with 1 to 3 R8; and each R8 is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.
  • transforming the compound of formula (IV-B) to the compound of formula (IV-A) comprises contacting the compound of formula (IV-B) with a Grignard reagent, C 1 -C 6 alkyl lithium, and sulfuryl chloride.
  • transforming the compound of formula (IV-B) to the compound of formula (IV-A) comprises the steps of: contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound (IV-B1); contacting the first metalated intermediate (IV-B1) compound with C 1 -C 6 alkyl lithium (e.g.
  • transforming a compound of formula (IV- F) to the compound of formula (IV-E) comprises the steps of: contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound (IV-F 1 ); contacting the first intermediate compound (IV-F1) with a hydrohalic acid to afford a second intermediate compound (IV-F 2 ); contacting the second intermediate compound (IV-F 2 ) with a second portion of bromine to afford a third intermediate compound (IV-F3); and contacting the third intermediate compound (IV-F3) with sulfamic acid to afford the compound of formula (IV-E).
  • the hydrohalic acid is hydrochloric acid.
  • step (iii) further comprises the steps of: contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound (IV-B1); contacting the first metalated intermediate (IV-B 1 ) compound with C 1 -C 6 alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated intermediate compound (IV-B 2 ); and contacting the second metalated intermediate compound (IV-B2) with sulfuryl chloride to afford the compound of formula (IV-A).
  • step (iii) further comprises the steps of: contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound (IV-B1); contacting the first metalated intermediate (IV-B 1 ) compound with C 1 -C 6 alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated intermediate compound
  • a compound of formula (IV) prepared by a process consisting essentially of the steps of: (i) contacting a compound of formula (IV-F): with bromine, a hydrohalic acid, and sulfamic acid to afford a compound of formula (IV-E): (ii) contacting the compound of formula (IV-E) with 1,2-dibromoethane in the presence of a base to afford a compound of formula (IV-B): (iii) contacting the compound of formula (IV-B) with a Grignard reagent, C 1 -C 6 alkyl lithium, and sulfuryl chloride to afford a compound of formula (IV-A): (iv) contacting the compound of formula (IV-A) with ammonia to obtain the compound of formula (IV).
  • step (i) further comprises the steps of: contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound (IV-F 1 ); contacting the first intermediate compound (IV-F 1 ) with a hydrohalic acid to afford a second intermediate compound (IV-F2); contacting the second intermediate compound (IV-F 2 ) with a second portion of bromine to afford a third intermediate compound (IV-F 3 ); and contacting the third intermediate compound (IV-F3) with sulfamic acid to afford the compound of formula (IV-E). 53.
  • step (iii) further comprises the steps of: contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound (IV-B 1 ); contacting the first metalated intermediate (IV-B 1 ) compound with C 1 -C 6 alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated intermediate compound (IV-B 2 ); and contacting the second metalated intermediate compound (IV-B2) with sulfuryl chloride to afford the compound of formula (IV-A).
  • step (iii) further comprises the steps of: contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound (IV-B 1 ); contacting the first metalated intermediate (IV-B 1 ) compound with C 1 -C 6 alkyl lithium (e.g. butyl lithium, n-butyl lithium or hexyl lithium) to afford a second metalated
  • the compound of embodiment 66, wherein the base is Cs 2 CO 3 or K 2 CO 3 . 68.
  • 69. The process of embodiment 68, wherein contacting a compound of formula (III) with a compound of formula (IV) is performed in the presence of a first base.
  • the first base is Cs 2 CO 3 or K 2 CO 3 . 71.
  • transforming the compound of formula (IV-B) to the compound of formula (IV-A) comprises contacting the compound of formula (IV-B) with a Grignard reagent, C 1 -C 6 alkyl lithium, and sulfuryl chloride.
  • transforming the compound of formula (IV-B) to the compound of formula (IV-A) comprises the steps of: contacting the compound of formula (IV-B) with a Grignard reagent to afford a first metalated intermediate compound (IV-B1); contacting the first metalated intermediate (IV-B1) compound with C 1 -C 6 alkyl lithium (e.g.
  • transforming a compound of formula (IV-F) to the compound of formula (IV-E) comprises the steps of: contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound (IV-F1); contacting the first intermediate compound (IV-F1) with a hydrohalic acid to afford a second intermediate compound (IV-F 2 ); contacting the second intermediate compound (IV-F2) with a second portion of bromine to afford a third intermediate compound (IV-F3); and contacting the third intermediate compound (IV-F 3 ) with sulfamic acid to afford the compound of formula (IV-E).
  • contacting the compound of formula (IV-F) with a first portion of bromine to afford a first intermediate compound (IV-F1)
  • contacting the first intermediate compound (IV-F1) with a hydrohalic acid to afford a second intermediate compound (IV-F 2 )
  • contacting the second intermediate compound (IV-F2) with a second portion of bromine to afford a third intermediate compound (IV-
  • transforming the compound of formula (VII-A) to the compound of formula (VII) comprises contacting the compound of formula (VII-A) with an enzyme. 119.
  • the process of embodiment 118, wherein the enzyme is a lipase. 120.
  • the process of embodiment 119, wherein the lipase is CALB. 121.
  • the process of any one of embodiments 115 to 120, wherein the compound of formula (VII-A) is obtained by transforming a compound of formula (VII-B): to the compound of formula (VII-A). 122.
  • transforming the compound of formula (VII-B) to the compound of formula (VII-A) comprises contacting the compound of formula (VII-B) with a reducing agent.
  • a reducing agent in the presence of an enzyme.
  • the enzyme is carbonyl reductase (CRED).
  • CRED carbonyl reductase
  • 133. The composition of any one of embodiments 128 to 132, wherein R 1 is –C(O)(C 1 -C 6 alkyl), –C(O)(C 1 -C 6 haloalkyl), –C(O)(C 1 -C 6 alkoxy), –C(O)(benzyloxy), –C(O)(phenoxy), or –S(O) 2 (tolyl).
  • R 1 is –C(O)(C 1 -C 6 alkoxy). 135.
  • R9 is trimethylsilyl (TMS).
  • R10 is straight chain C 1 -C 6 alkyl selected from the group consisting of methyl, ethyl, 1-propyl, 1-butyl, 1-pentyl or 1-hexyl.
  • R10 is C 1 -C 4 alkyl selected from the group consisting of methyl, ethyl, 1-propyl or 1-butyl.
  • R10 is methyl.
  • R5 and R6 are each halo. 10. The process according to any of the preceding embodiments, wherein R5 and R6 are each selected from chloro, bromo, or iodo. 11. The process according to any of the preceding embodiments wherein R5 and R6 are each chloro. 12. The process according to any of the preceding embodiment, wherein the compound of formula (III-Y) or (III-Y1) is carried over to a further reaction step without prior purification. 13. The process according to any one of embodiments 1-11 wherein the compound of formula (III-Y) or (III-Y1) is isolated as a salt. 14.
  • Step2 A2 is performed by contacting a compound according to formula (III-Y) or (III-Y1) with R1-Cl.
  • Step 2 A2 is performed by contacting the compound of formula (III-Y) or (III-Y1) with ClC(O)(C 1 -C 6 alkoxy).
  • Step 2 A2 is performed by contacting the compound of formula (III-Y) or (III-Y1) with methyl chloroformate.
  • Step 2 A2 is performed in a second nonpolar solvent. 35.
  • step 2 A2 is performed by adding the reaction mixture from step 1 A1 or step 1 A1’ comprising the compound of formula (III-Y) or (III-Y1) to a mixture of R1-Cl in n-heptane at a temperature of -20 o C to -5 o C while maintaining the temperature during the addition.
  • step 1 A1 is ClC(O)(C 1 -C 6 alkoxy), e.g. methyl chloroformate.
  • step 2 A2 is performed by adding R1-Cl to the reaction mixture from step 1 A1 or step 1 A1’ comprising the compound of formula (III-Y) or (III-Y1) at a temperature of -10 o C to 0 o C while maintaining the temperature during the addition.
  • step 2 A2 is performed by adding R1-Cl to the reaction mixture from step 1 A1 or step 1 A1’ comprising the compound of formula (III-Y) or (III-Y1) at a temperature of -10 o C to 0 o C while maintaining the temperature during the addition.
  • step 1 A2 is performed by adding R1-Cl to the reaction mixture from step 1 A1 or step 1 A1’ comprising the compound of formula (III-Y) or (III-Y1) at a temperature of -10 o C to 0 o C while maintaining the temperature during the addition.
  • step 3 A2 is performed by adding R1-Cl to the reaction mixture from step 1 A1 or step 1 A1’ comprising the compound of formula (III-Y) or (
  • R11 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl.
  • R11 is 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-7-yl.
  • the base is selected from the group selected from the group consisting of Cs 2 CO 3 and K 2 CO 3 .
  • the base is K 2 CO 3 .
  • a process for preparing a compound of formula (V-Z) comprising the steps of: a. reacting an azomethine precursor of formula (III-W) with an electron-poor alkyne of formula (III-X) according to Scheme A1, wherein the reaction is performed in the presence of an acid and in a first non-polar solvent: Scheme A1 , wherein R12 is -CR2R3-(C 6 -C 10 aryl), where the C 6 -C 10 aryl is optionally substituted with 1 to 3 R4; wherein R2 and R3 are each independently H or C 1 -C 6 alkyl; and R4 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and R5 and R6 are each, independently, halo, such as chloro, bromo, iodo, or -OSO2R7, wherein each
  • Scheme A2 III-Y (III-Z)
  • R1 is selected from the group consisting of C 1 -C 6 alkoxycarbonyl (e.g. tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e. Cbz), C6-C10 aryloxy (e.g. phenoxycarbonyl), C 1 -C 6 alkylcarbonyl (e.g. acetyl), haloalkylcarbonyl (e.g.
  • Scheme G2 e. performing a coupling reaction of the compound of formula (VI) and a compound of formula (VII) according to Scheme G3 or performing a coupling reaction from the salt of formula (VI) ⁇ (VII) according to Scheme G3’ using a coupling reagent and an additive in a second suitable solvent to afford the compound of formula (I): Scheme G3 Scheme G3’ 83.
  • the process according to embodiment 82, wherein the compound of formula (III-D) in step a. is the rate limiting reagent.
  • 84 The process according to any one of embodiments 82-83, wherein about 1.5-2.0 equivalents of the compound of formula (III-C) is reacted with about 1 equivalent of the compound of formula (III-D) in step a.
  • step a the compound of formula (III-C) is mixed with the first non-polar solvent and cooled to about -5 to 5 o C and the first acid added followed by addition of the compound of formula (III-D) in the first non-polar solvent while maintaining the temperature.
  • step a the compound of formula (III-C) is mixed with the first non-polar solvent and cooled to about -5 to 5 o C and the first acid added followed by addition of the compound of formula (III-D) in the first non-polar solvent while maintaining the temperature.
  • 86 The process according to any one of embodiments 82-85, wherein the first acid is TFA.
  • 87 The process according to any one of embodiments 82-86, wherein the first acid is TFA and about 0.05 equivalents are used.
  • 88 The process according to any one of embodiments 82-87, wherein the first non-polar solvent is toluene. 89.
  • step c. the suitable solvent in step c. is a mixture of DMSO and toluene.
  • the suitable solvent in step c. is a mixture of DMSO and toluene.
  • step c. the compound of formula (IV)
  • the first base and the suitable solvent are mixed and heated to about 100 o C prior to addition of the compound of formula (III) in the suitable solvent.
  • step c. the compound of formula (IV), K 2 CO 3 and DMSO are mixed and heated to about 100 o C prior to addition of the compound of formula (III) in toluene. 101.
  • step c. the compound of formula (III) is the compound of formula (III-A).
  • suitable solvent in step c. is DMSO, toluene or a mixture thereof.
  • step d. the compound of formula V is a compound of formula (V-A).
  • step d. the second acid is a mixture of Bu 2 S and MSA.
  • the mixture of the compound of formula (V) and the second acid is heated to about 70 o C. 106.
  • the second base is aqueous NH 4 OH. 107.
  • step e. the coupling reagent selected from the group consisting of EDC, DCC, propylphosphonic anhydride (T3P ® ), and HATU. 110.
  • step e. the coupling reagent is EDC ⁇ HCl.
  • step e. the additive is selected from the group consisting of ethyl (hydroxyamino)cyanoacetate (OxymaPure ® ), HOBt, HOSu, HOPO. 112.
  • step e. the additive is ethyl (hydroxyamino)cyanoacetate (OxymaPure ® ) or HOPO.
  • step e. the coupling reagent is EDC ⁇ HCl and the additive is ethyl (hydroxyamino)cyanoacetate (OxymaPure ® ).
  • step e. the coupling reagent is EDC ⁇ HCl and the additive is HOPO.
  • the second suitable solvent is selected from the group of DMAc, 2-MeTHF, EtOH or a combination thereof.
  • 116. The process according to any one of embodiments 82-115, wherein in step e. the second suitable solvent is a combination of DMAc and EtOH.
  • 117. The process according to any one of embodiments 82-116, wherein in step e. the second suitable solvent is a combination of DMAc, EtOH and 2-MeTHF.
  • a process for preparing a compound according to formula (II): comprising the steps of: a.
  • the compound of formula (III-C) is mixed with the first non-polar solvent and cooled to about -5 to 5 o C and the first acid added followed by addition of the compound of formula (III-D) in the first non-polar solvent while maintaining the temperature.
  • 124. The process according to any one of embodiments 120-123, wherein the first acid is TFA.
  • 125. The process according to any one of embodiments 120-124, wherein the first acid is TFA and about 0.05 equivalents are used.
  • 126. The process according to any one of embodiments 120-125, wherein the first non-polar solvent is toluene.
  • the process according to any one of embodiments 120-126, wherein the reaction mixture from step a. is used without further purification in the next step b. 128.
  • step c. the compound of formula (VIII-A)
  • the first base and the suitable solvent are mixed and heated to about 80-100 o C prior to addition of the compound of formula (III) in the suitable solvent.
  • step c. the compound of formula (VIII-A)
  • K2CO3 and DMSO are mixed and heated to about 80-100 o C prior to addition of the compound of formula (III) in DMSO.
  • step c. the compound of formula (III) is the compound of formula (III-A).
  • step d. the suitable solvent in step c. is DMSO. 141.
  • step d. the compound of formula (VIII) is a compound of formula (VIII-B): . 142.
  • the fourth base is KOH. 143.
  • the fourth base is KOH and the reaction is performed in MeOH. 144.
  • step d. is performed by heating e.g.
  • step d. the third acid is selected from the group consisting of a mixture of HBr/AcOH, a mixture of Bu2S/MSA and a mixture of Bu2S, TFA and MSA. 147.
  • the third acid is a mixture of HBr and AcOH.
  • the dihydrobromide salt of compound (IX) is formed.
  • the dihydrobromide (X) is neutralized with base, such as NH4OH or NaOH to form the compound of formula (IX).
  • step e. the coupling reagent selected from the group consisting of EDC, DCC, propylphosphonic anhydride (T3P ® ), and HATU. 151.
  • step e. the coupling reagent is EDC or EDC ⁇ HCl.
  • step e. the additive is selected from the group consisting of ethyl (hydroxyamino)cyanoacetate (OxymaPure ® ), HOBt, HOSu, HOPO. 153.
  • TFA (0.036 kg, 0.05 eq) was added to the reactor while maintaining a temperature of -5°C to 5°C.
  • the loading line was rinsed with toluene (0.075 L, 0.05 vol) and the wash was added to the reactor.
  • N-(methoxymethyl)-N-(trimethyl-silylmethyl) benzylamine (NMMNTB) (1.496 kg, 1.0 eq, 1.0 vol; limiting reagent) was added to the reactor in portions over 1-2 h while maintain a temperature of at -5°C to 10°C.
  • the loading line was rinsed with toluene (0.075 L, 0.05 vol) and the wash was added to the reactor.
  • Step 2 methyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A)
  • III-A methyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate
  • the loading line was rinsed with n-heptane (0.15 L, 0.1 vol) and the wash was added to the second reactor.
  • the reaction mixture was stirred for approximately 40 min at a temperature of -15°C to -5°C. Reaction progress was monitored by HPLC analysis and stirring was continued until reaction completion.
  • the second reactor was then charged with deionized water (3.0 L, 2 vol) while maintaining a reaction mixture temperature of ⁇ 20°C during the addition. The reaction mixture was stirred at 10°C overnight.
  • the second reactor was then charged with n-heptane (13.5 L, 9.0 vol) over a period of at least 1 h, leading to precipitation of the product.
  • the reaction mixture was cooled to -5°C to 2°C over a period of at least 1 h and then stirred for at least 1 h while maintaining a temperature of -5°C to 2°C.
  • the reaction mixture was then filtered to obtain the solid product, which was then rinse-washed with deionized water (6 ⁇ 3.9 L; 6 ⁇ 2.6 vol), with stirring for at least 15 min during each wash.
  • the filter-cake was then rinse-washed with n- heptane (2 ⁇ 3.9 L; 2 ⁇ 2.6 vol), with stirring for at least 15 min during each wash.
  • the loading line was rinsed with EtOH (approximately 1 L) and the wash was added to the reactor.
  • the resulting suspension was heated to 75-85 ⁇ C (reflux) and agitated at this temperature for 12 h.
  • An aliquot of the reaction mixture was removed and analyzed by HPLC to confirm complete formation of the desired product.
  • the EtOH in the reaction mixture was azeotropically distilled off (approximately 7 vol) at temperature 80-90°C until 3-4 vol of residual volume.
  • Deionized water (5.81 L, 5 vol) was charged in to the reactor and distillation was resumed until mass temperature reached 99-100 ⁇ C.
  • Step 2 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B) [0133]
  • the concentrated solution of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-C) (919.1 g pure, 1.0 eq) prepared in the first step was charged into a reaction vessel, along with DMF (4.5955 L, 5.0 vol).
  • N-Bromosuccinimide (NBS) (1.5506 kg, 1.3 eq) was then charged in to the reactor via the hopper at 20-30 ⁇ C.
  • the resulting mixture was heated to 55-60 ⁇ C and agitated at this temperature for 8 h.
  • the mixture was cooled to 25°C and assessed by HPLC to confirm complete conversion to the desired product.
  • the mixture was then further cooled to a temperature ⁇ 5°C and a solution of sodium metabisulfite (1.274 kg, 1.0 eq) in deionized water (9.191 L, 10 vol) was charged in to the reactor while maintaining the temperature at ⁇ 15 ⁇ C.
  • the resulting mixture was further cooled to a temperature of 0-5°C and agitated for at least 2 h.
  • Step 3 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV) [0136] THF (14.051 L, 9 vol) was charged into a first reactor and the 7-bromo-2,3-dihydro- [1,4]dioxino[2,3-b]pyridine (IV-B, 1.8900 kg, 1.5612 kg pure) produced in step 2 was added to the reactor via manhole. The mixture was agitated for 15 min at 25°C. The mixture was assessed for water content and proceeded to the next step upon determination that the water content was ⁇ 0.1% v/v.
  • reaction mixture was then cooled to -25°C to -18°C and the reactor charged with isopropyl magnesium chloride in THF (0.8696 kg, 1.17 eq) while maintaining a temperature between -25°C and -5 ⁇ C.
  • the charge lines were rinsed with THF (1.5612 L, 1 vol) and the wash was charged to reactor.
  • n-Butyl lithium in hexanes (0.7268 kg, 1.57 eq) was then charged to the reactor while maintaining a temperature between -25°C and -5 ⁇ C.
  • the charge lines were rinsed with THF (1.5612 L, 1 vol) and the wash was charged to reactor.
  • the mixture was agitated for 15-25 min at a temperature between -25°C and -5 ⁇ C.
  • Toluene (4.6836 L, 3 vol) was charged to a second reactor, followed by sulfuryl chloride (2.9262 kg, 3 eq) while maintaining a temperature ⁇ 25°C.
  • the charge lines were rinsed with toluene (1.5612 L, 1 vol) and the wash was charged to the second reactor.
  • the reaction mixture from the first reactor was slowly added to the second reactor while maintaining a temperature between -25°C and -5 ⁇ C.
  • the first reactor was rinsed with THF and the wash was added to the second reactor.
  • the resulting reaction mixture in the second reactor was agitated for at least 30 min while maintaining a temperature between -25°C and 0°C.
  • a 20% w/w solution of sodium chloride (1.5612 kg) in deionized water (brine, 6.2448 L, 4 vol) was prepared in a separate container, half of which (ca.2 vol) was charged to the second reactor while maintaining a temperature ⁇ 0°C.
  • the mixture was then agitated for 20 min at a temperature ⁇ 0°C.
  • the layers were allowed to separate for at least 15 min and the bottom aqueous layer was transferred back to the first reactor while maintain a temperature ⁇ 0°C.
  • the second half of the brine solution (ca.2 vol) was charged to the second reactor while maintaining a temperature ⁇ 0°C.
  • the mixture was then agitated for 15 min at a temperature ⁇ 0°C.
  • the layers were allowed to separate for at least 15 min and the bottom aqueous layer was transferred back to the first reactor while maintain a temperature ⁇ 0°C.
  • the reaction mixture was cooled to -10°C and the reactor was charged with deionized water (7.806 L, 5 vol) while maintaining a temperature between -10°C and 0 ⁇ C.
  • the solid product was collected by filtration under vacuum.
  • DCM (7.0860 L, 5 vol) was charged to the reactor and the collected solids were washed by allowing the washings from the reactor to penetrate the filter for 15 min, agitating the solids, and then filtering again under vacuum.
  • Deionized water (3.122 L, 2 vol) was charged to the reactor and the collected solids were washed by allowing the washings from the reactor to penetrate the filter for 15 min, agitating the solids, and then filtering again under vacuum.
  • the wet filter cake was transferred to a clean third reactor, which was then charged with deionized water (15.6 L, 10 vol). The resulting mixture was agitated for 1-2 h at reflux. After agitation, the slurry was cooled to 15-25°C and stirred for an additional 30 min. The solid product was collected by filtration under vacuum and the reactor was charged with deionized water (3.1 L, 2 vol). The collected solids were washed by allowing the washings from the reactor to penetrate the filter for 15 min, agitating the solids, and then filtering again under vacuum. An aliquot of the solid product was removed and assessed by HPLC to confirm product purity.
  • DCM (3.750 L, 2.4 vol) was charged to the reactor, along with the wet cake collected via filtration in the preceding step.
  • MeOH (1.250 L, 0.8 vol) was charged to the reactor and the mixture was agitated for at least 30 min at a temperature between 15-20°C.
  • the solid product was isolated by filtration under vacuum and the reactor was charged with DCM (2.000 L, 1.3 vol). The collected solids were washed by allowing the washings from the reactor to penetrate the filter for 15 min, agitating the solids, and then filtering again under vacuum. An aliquot of the solid product was removed and assessed by HPLC to confirm product purity.
  • Step 2 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B) [0150] To a solution of 5-bromopyridine-2,3-diol (IV-E, 1.0 eq) in EtOH/H2O (10 vol/10 vol) was added K2CO3 (1.41 eq) and BrCH2CH2Br (1.76 eq). The mixture was heated to a temperature of 70-75°C for 44 h. Additional K 2 CO 3 (0.35 eq) and BrCH 2 CH 2 Br (0.35 eq) was added and the heating was continued for 10 additional h. Reaction progress was monitored via HPLC to confirm complete consumption of the starting material.
  • Step 1 Methyl 2-formyl-phenylacetate (VII-B) [0152] Sodium methoxide (1.3 eq) was charged to a clean, dry reactor under nitrogen, followed by MTBE (6 vol). The reactor contents were then heated to a temperature of 15-25°C and methyl phenylacetate (3.0 kg, 1 eq) was charged over at least 20 min while maintaining a temperature between 15-20°C. Additional MTBE (0.5 vol.) was used to rinse the charge lines and the wash was added to the reactor. The reactor contents were held and agitated for 30-60 min at a temperature between 15-25°C.
  • Methyl formate (1.80 kg, 1.5 eq) was then charged to the reactor over at least 1 h while maintaining a temperature between 15-25°C. Additional MTBE (0.5 vol.) was used to rinse the charge lines and the wash was added to the reactor. The reactor contents were then heated to a temperature between 15-25°C and agitated for at least 5 h while maintaining the aforementioned temperature. Reaction progress was monitored by removing an aliquot of the reaction mixture and assessing the methyl phenylacetate content by 1 H NMR. [0153] The reaction mixture was subsequently cooled to -10°C to 5°C and water (4 vol.) was charged to the reactor while maintaining reactor temperature between -10°C and 5°C.
  • the reactor contents were then agitated for at least 15 min while maintaining a temperature between -10°C and 5°C.
  • the pH of the aqueous layer was determined and adjusted with either sodium hydroxide or citric acid until the pH was within the range of 11.5 to 12.5.
  • the reactor contents were allowed to settle for at least 15 min and the bottom aqueous layer, containing the desired product, was discharged into a suitable container at stored at a temperature between -10°C and 5°C.
  • the upper organic layer was subsequently drained from the reactor.
  • the aqueous layer was charged back into the reactor and maintained at a temperature between -10°C and 5°C.
  • MTBE (4 vol.) was charged into the reactor and the mixture agitated while maintaining a temperature between -10°C and 5°C.
  • a 25% w/w aqueous solution of citric acid (3 vol.) was charged to the reactor while maintaining a temperature between -10°C and 5°C and the resulting mixture was agitated for at least 15 min.
  • the reaction mixture was allowed to settle for at least 40 min and the layers separated.
  • the top organic layer, containing the desired product, was set aside and the bottom aqueous layer was charged back into the reactor.
  • the pH of the aqueous layer was monitored and adjusted until within a range between 4-5.
  • MTBE (1.5 vol.) was charged into the reactor containing the aqueous layer and agitated for at least 10 min while maintaining a temperature between 5-20°C. The reactor contents were allowed to settle for at least 15 min and the bottom aqueous layer was removed. [0156] The combined organic layers were charged into the reactor, followed by a 20% w/w solution of sodium chloride (1.5 vol). The mixture was then agitated for at least 10 min while maintaining a temperature between 5-20°C. The reactor contents were allowed to settle for at least 15 min and the bottom aqueous layer was then removed. The reactor contents were then heated to a temperature between 28-35°C under reduced pressure until the combined organic layers were concentrated to approximately 4.5 vol.
  • Step 2 Crude (S)-tropic acid (VII) [0167] Water (8.75 vol), KH2PO4 (0.178 eq), and glucose monohydrate (2.5 eq) were charged to a reactor and agitated at a temperature between 20-28°C for at least 5 min. The pH of the solution was adjusted to a value of 6.75 ⁇ 0.25 using 3M NaOH and the temperature of the solution was adjusted to be between 25-28°C. CRED-A231M165-GDH-102 lyophilized cell free extract (0.138 wt%) was charged to the reactor and the solution was agitated for at least 15 min at a temperature between 25-28°C.
  • the pH of the reaction mixture was adjusted as needed using an aqueous solution of 3M NaOH. Reaction process was assessed by HPLC, and after determining the reaction was complete, the reactor contents were cooled to a temperature between 10-15°C and agitated for 5-15 min. [0171] The pH of the reactor contents was adjusted to a value between 1.0-1.5 using 25% hydrochloric acid (approx.1.4 vol) while maintaining a temperature between 10-15°C. Following pH adjustment, the reactor contents were agitated for at least 4 h, while maintaining a temperature between 10-15°C. The reactor contents were filtered to collect the solid product as a filter cake. Water (1.0 vol.) was charged to the reactor and cooled to a temperature between 10- 15°C, and subsequently used to wash the wet filter cake.
  • NADP (0.6 g), GDH-102 (0.8 g, 2 wt%) and CRED-41 (4 g, 10 wt%) were added to the reaction mixture, followed by toluene (40 ml).
  • Step 3 Recrystalization of (S)-tropic acid (VII) [0185] The crude (S)-tropic acid (VII, 1 eq.) prepared in the previous step was charged to a clean reactor. THF (6 vol., based on the Step 2 input) was charged into the reactor. The reactor contents were heated to a temperature between 35-45°C and held for a minimum of at least 1 h.
  • the contents of the reactor were then concentrated to approximately 4 volumes via distillation under reduced pressure at a temperature between 35-45°C.
  • the THF content of the reaction mixture was assessed by 1 H NMR and confirmed to be between 3-10%.
  • the reactor contents were then heated to a temperature between 35-45°C and toluene (2 vol.) was added while maintaining a temperature between 35-45°C.
  • the reactor contents were then cooled to a temperature between 0-10°C over a period of at least 5 h and held at this temperature for at least 15 h.
  • the reactor contents were then filtered, while maintaining a temperature between 0-10°C.
  • the reactor was visually inspected for any residual solid and the mother liquor was used to rinse the reactor and collect any residual solid materials.
  • the filter cake was subsequently washed with toluene (2 vol.) while maintaining a temperature of between 0-10°C. After washing, the filter cake was pull-dried under vacuum for at least 2 h. The resulting semi-dry filter cake was then assessed for purity, enantiopurity, and protein content by HPLC. After HPLC analysis, the filter cake was further dried by heating to a temperature of 35-45°C under reduced pressure for at least 24 h. The dried filter cake was assessed for water and solvent content by KF and GC, respectively. The dry product material was collected to afford (S)-tropic acid (VII, 92% yield) with 99.8% purity and 99.7% enantiopurity.
  • the toluene was removed by distillation with a jacket temperature of 60°C.
  • the contents of the reactor were cooled to rt.
  • water 300 mL, 10 vol
  • the mixture was allowed to age for 30 min. [0200]
  • the solids were filtered and washed with water (2 ⁇ 300 mL, 10 vol) and MeCN (4 ⁇ 150 mL, 5 vol). The solids were then dried on the filter for 16 h, yielding white solids (42.219 g, 82.8%), with an HPLC purity of 97.8%.
  • Step 2 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro- [1,4]dioxino[2,3-b]pyridine (VI) [0204] A mixture of methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)- 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A, 29.4 g, 80 mmol), Bu 2 S (88.2 mL, 3 vol) and MSA (58.8 mL, 2 vol) was heated at 70oC for 19 h.
  • the mixture stirred at rt for 20 min, heated to 70oC, and stirred for 1 h.
  • the mixture was cooled to 15oC, stirred for 0.5 h.
  • the solids were collected by filtration and washed with water (30 mL).
  • the free amine was reslurried in water (120 mL) at 70oC for 20 h then cooled to 15oC and stirred for 0.5 h.
  • the solids were collected by filtration, washed with water (60 mL) and dried in a vacuum oven at 45oC for 6 h.
  • Step 3 (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I) [0210] To a 10 dram scintillation vial was added VI ⁇ VII (2.500 g), EDC•HCl (1.058 g, 0.525 eq), OxymaPure ® (0.300 g, 0.2 eq), and DMAc (10 mL, 2 vol).
  • the mixture was heated to reflux for 30 min before cooling to 70°C, where it aged for 3 h.
  • the slurry was then cooled to 50°C over 4 h, where it stirred for 14 h.
  • the slurry was then cooled to 20°C over 1 h, where it stirred for 1 h.
  • the solids were collected by filtration, and washed with EtOH (41.1 mL, 3 vol). The solids were dried on the filter for 2 h before drying under full vacuum with a nitrogen bleed for 20 h.
  • the isolated white solids were 12.561 g (91.7% recovery, 81.6% overall yield) with an HPLC purity of 99.6%.
  • Example 8 Large Scale Synthesis of methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)- 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A) [0215] To a 10 L jacketed reactor was added 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7- sulfonamide (IV, 516.5 g) and K 2 CO 3 (352 g, 1.1 eq) and DMSO (5 L, 10 vol). The contents were heated to 100°C.
  • the slurry was heated to 80°C, where it was stirred for 1 h.
  • the contents of the reactor were cooled to 20°C over 4 h, where they were stirred for 14 h.
  • the solids were collected by filtration and washed with MeCN (3.5 L, 5 vol). The solids were dried on the filter for 2 h before drying in a vacuum oven overnight at 45°C.
  • the isolated solids were 676 g of methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A, 96.3% recovery, 79.5% overall yield) with an HPLC purity of 99.6% and a KF of 0.5%.
  • Example 9 Large Scale Synthesis of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3- dihydro-[1,4]dioxino[2,3-b]pyridine (VI) [0221] Methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A, 300.0 g, 0.817 mol; obtained via the process of Example 8), Bu 2 S (900 mL, 3 vol) and MSA (600 mL, 2 vol) were charged to a 10 L jacket reactor.
  • Example 10 Alternative Large Scale Synthesis of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI) [0225] Methyl 5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (V-A, 300.0 g, 0.817 mol; obtained via the process of Example 8), Bu2S (900 mL, 3 vol) and MSA (600 mL, 2 vol) were charged to a 10 L jacketed reactor.
  • Bu2S 900 mL, 3 vol
  • MSA 600 mL, 2 vol
  • the contents of the reactor were cooled to 50oC over 5 h, where they aged over the weekend.
  • the contents of the reactor were cooled to 20oC, where they were stirred for 1 h prior to filtration.
  • the filter cake was rinsed with EtOH (900 mL, 3 vol). The solids were dried on the filter for 2 h before drying under full vacuum with a nitrogen bleed at 45oC for 16 h.
  • Example 12 Alternative Large Scale Synthesis of (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7- yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan- 1-one (I) EDC (s) Oxymapure EtOH/DMAc (s) (VI).(VII) [0235] To a 2 L jacketed reactor was added (VI)•(VII) (150.01 g; obtained from the process of Example 10), EDC•HCl (63.49 g, 0.525 eq), OxymaPure ® (17.93 g, 0.2 eq), and DMAc (600 mL, 2 vol).
  • the contents of the reactor were cooled to 50oC over 5 h, where they aged overnight.
  • the contents of the reactor were cooled to 20oC, where they were stirred for 1 h prior to filtration.
  • the filter cake was rinsed with EtOH (750 mL, 3 vol). The solids were dried on the filter for 2 h before drying under full vacuum with a nitrogen bleed at 45oC for 16 h.
  • the isolated solids were 237.75 g of (S)-1-(5- ((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (I, 95.6% recovery, 82.4% overall), with an HPLC purity of 99.7%.
  • Step 2 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX) [0244] Methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate (VIII-B, 15 g, 48.5 mmol) and MeOH (118 mL, 2909 mmol) were charged into a reaction vessel. The suspension was stirred at rt for 5 min and a 3M solution of aqueous potassium hydroxide (64.7 mL, 194 mmol) was charged into the reaction vessel.
  • aqueous potassium hydroxide 64.7 mL, 194 mmol
  • Step 3 (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4- c]pyrrol-2-yl]ethan-1-one (II)
  • 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX, 0.5 g, 1.990 mmol) was charged into a reaction vessel with (R)-2-hydroxy-2-phenylacetic acid (0.318 g, 2.089 mmol) and HOBt (0.096 g, 0.497 mmol).
  • composition disclosed herein may comprise, consist of, or consist essentially of any of the compounds or components disclosed herein.
  • phrases “consist essentially of,” “consists essentially of,” “consisting essentially of,” and the like limit the scope of a claim to the specified materials or steps and those materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • the reagents and conditions described herein are intended to be exemplary and not limiting. As one of skill in the art would appreciate, various analogs may be prepared by modifying the synthetic reactions such as using different starting materials, different reagents, and different reaction conditions (e.g., temperature, solvent, concentration, etc.).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne de nouveaux procédés de synthèse pour la fabrication de pyrrolo [3,4-c] pyrroles, de dérivés de ceux-ci et d'intermédiaires de ceux-ci. L'invention concerne également des procédés utilisant des pyrrolo [3,4-c] pyrroles dans les procédés de préparation de composés bioactifs (par exemple des composés d'activation de PKR).
PCT/US2023/080702 2022-11-21 2023-11-21 Synthèse de pyrrolo [3,4-c] pyrroles Ceased WO2024112764A1 (fr)

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CN202380080050.2A CN120225503A (zh) 2022-11-21 2023-11-21 吡咯并[3,4-c]吡咯的合成
JP2025529303A JP2025536754A (ja) 2022-11-21 2023-11-21 ピロロ［３，４－ｃ］ピロールの合成

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