Synthesis of pyrrolo[3,4-c]pyrrole

Abstract

Novel synthetic methods for making pyrrolo[3,4-c]pyrroles, their derivatives, and intermediates thereof are provided, as are methods for using pyrrolo[3,4-c]pyrroles in methods for preparing biologically active compounds, such as PKR-activating compounds.

Description

[Technical Field]

[0001] The present disclosure relates to novel synthetic methods for making pyrrolo[3,4-c]pyrroles, their derivatives, and intermediates thereof. The present disclosure further relates to synthetic methods for preparing biologically active compounds using pyrrolo[3,4-c]pyrroles, their derivatives, and intermediates thereof. [Background technology]

[0002] Pyrrolo[3,4-c]pyrroles are useful as biologically active compounds, for example, 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). Current methods for synthesizing pyrrolo[3,4-c]pyrroles utilize mono- and / or bis-protected pyrrolo[3,4-c]pyrroles, such as N-Boc-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole. [ka]

[0003] However, the synthesis of monoprotected pyrrolo[3,4-c]pyrrole presents several challenges, including difficulty in large-scale production, poor atom economy, generation of large amounts of bromine, and low yields (Heterocycles 1995, 41, 1291; WO 2016 / 046837). Therefore, improved methods for synthesizing pyrrolo[3,4-c]pyrrole are needed. Summary of the Invention [Means for solving the problem]

[0004] In a first aspect, the present disclosure provides a novel method for preparing a compound according to formula (III-Y) or a salt thereof, which is useful as a key intermediate for the synthesis of pyrrolo[3,4-c]pyrroles, in particular for making pyrrolo[3,4-c]pyrroles substituted on each nitrogen with different groups: [ka] (In the formula: R12 is -CR2R3-(C6-C 10 aryl) and C6-C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C1-C6 alkyl; R4 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R5 and R6 are each independently halo, e.g., chloro, bromo, iodo, or -OSO2R7, and each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, C6-C 10 The aryl is optionally substituted with 1 to 3 R8; Each R8 is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0005] The intermediate compounds of formula (III-Y) can be used to prepare biologically active compounds, such as PKR activating compounds, which can increase the activity of wild-type and mutant PKR enzymes.

[0006] In some embodiments, the present disclosure relates to methods for preparing compounds of formula (III-Y).

[0007] In some embodiments, the method includes the further step of converting the compound of formula (III-Y) to a compound of formula (III-Z) by reacting with R1-Cl, where R1 is —C(O)C1-C6 alkoxy. [ka]

[0008] In some embodiments, the method further comprises converting the compound of formula (III-Z) to a compound of formula (VZ) by reacting the compound of formula (III-Z) with a sulfonamide. [ka]

[0009] In a second aspect, the present disclosure relates to a key intermediate in the synthesis of pyrrolo[3,4-c]pyrrole, the intermediate being a compound of formula (III-Y) or a salt thereof:

[0010] In a third aspect, the present disclosure relates to a key intermediate in the synthesis of pyrrolo[3,4-c]pyrrole, the intermediate being a compound of formula (III-Z) or a salt thereof:

[0011] In a fourth aspect, the present disclosure relates to a key intermediate in the synthesis of pyrrolo[3,4-c]pyrrole, the intermediate being a compound of formula (VZ) or a salt thereof:

[0012] In a fifth aspect, the present disclosure provides 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 ethabopibat: [ka] or in 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: [ka] The present invention relates to the use of intermediate compounds of formula (III-Y), (III-Z) or (VZ) useful in the synthesis of DETAILED DESCRIPTION OF THE INVENTION

[0013] The term "C1-C6 alkyl," as used herein, refers to a saturated, branched or straight chain hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of C1-C6 alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, isobutyl, 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-3-pentyl, 3-methyl-3-pentyl, 2,2-dimethyl-1-butanyl, 2,3-dimethyl-1-butyl, and 3,3-dimethyl-1-butyl.

[0014] "C6-C 10 The term "aryl," as used herein, refers to a cyclic aromatic group containing 6 to 10 carbon atoms. Such aryl groups may be substituted or unsubstituted. C6-C 10 Examples of aryl include, but are not limited to, phenyl and naphthyl.

[0015] The term "halo," as used herein, refers to fluoro, chloro, bromo, and iodo.

[0016] The term "C1-C6 haloalkyl," as used herein, refers to a C1-C6 alkyl group, as defined herein, containing at least one halo group, as defined herein. Specific examples of C1-C6 haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0017] The term "C1-C6 alkoxy" as used herein refers to an -O-C1-C6 alkyl group. Examples of C1-C6 alkoxy include, but are not limited to, methoxy, ethoxy, 1-propoxy, isopropoxy, n-butoxy, tert-butoxy, and the like.

[0018] The term "C-C haloalkoxy," as used herein, refers to a C-C alkoxy, as defined herein, containing at least one halo group, as defined herein. Specific examples of C-C haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethyl, trichloromethyl, and the like.

[0019] The term "6- to 10-membered heteroaryl," as used herein, refers to a 6- to 10-membered cyclic aromatic ring system having ring carbon atoms and 1 to 3 heteroatoms selected from the group consisting of O, N, or S. Such 6- to 10-membered heteroaryls may be substituted or unsubstituted. Examples of 6- to 10-membered heteroaryls include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-benzofuranyl, 6-benzofuranyl, 6-benzoxazole, and 6-benzothiazolyl.

[0020] In one aspect, the present disclosure describes synthetic methods, intermediates, and reaction parameters for the efficient preparation of pyrrolo[3,4-c]pyrroles. The present disclosure also provides methods for preparing intermediate compounds of formula (III-Y), (III-Z), and (III): This also encompasses the discovery that (i) it can be efficiently synthesized from commercially available starting materials, (ii) it can be purified without chromatography, and (iii) it can be used to synthesize pyrrolo[3,4-c]pyrroles with differentially substituted nitrogen atoms.

[0021] The intermediate compounds of formula (III-Y), (III-Z) and (III) can be used to prepare biologically active compounds, such as PKR (pyruvate kinase R) activating compounds, which can increase the activity of wild-type and mutant PKR enzymes.

[0022] In some embodiments, the PKR activating compound prepared using the intermediate compound of formula (III-Y), (III-Z) or (III) is a compound of formula (I): [ka] which may also be called (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 ethabopivat.

[0023] The compound of formula (I) is a selective, orally bioavailable PKR activator that reduces 2,3-DPG (diphosphoglycerate), increases ATP, and has anti-sickling effects on red blood cells (RBCs) in disease models with a wide therapeutic margin compared to preclinical toxicity. The compound of formula (I) is a potent activator of PKR and a versatile regulator of RBC metabolism. PKR activation simultaneously reduces 2,3-DPG levels, which increases hemoglobin-oxygen affinity and reduces sickling, while also increasing intracellular ATP, improving RBC health and reducing hemolysis or RBC death.

[0024] The compound of formula (I) is an allosteric activator of recombinant wild-type (WT) PKR, the mutant enzyme PKR R510Q, one of the most common PKR mutations in North America. PKR exists in both dimeric and tetrameric states, but functions most efficiently as a tetramer. PKR is an 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).

[0025] In some embodiments, the PKR activating compound prepared using the intermediate compound of formula (III-Y), (III-Z) or (III) is a compound of formula (II): [ka] which may 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.

[0026] Intermediate compounds of the present disclosure and methods for their preparation In one aspect, the present disclosure relates to a method for preparing a compound of formula (III-Y) according to Scheme A1. The compound of formula (III-Y) can be further used for the efficient synthesis of pyrrolo[3,4-c]pyrrole. The reaction according to Scheme A1 comprises reacting an azomethine precursor of formula (III-W) with an electron-deficient alkyne of formula (III-X) in the presence of an acid. [ka] During the ceremony, R12 is -CR2R3-(C6-C 10 aryl) and C6-C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C1-C6 alkyl; R4 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R5 and R6 are each independently halo, e.g., chloro, bromo, iodo, or -OSO2R7, and each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, C6-C 10 The aryl is optionally substituted with 1 to 3 R8; each R is independently halo, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); R10 is C1-C6 alkyl.

[0027] In some embodiments, R12 of the azomethine precursor of Formula (III-W) is —CH2-Ph(benzyl) or 4-methoxybenzyl. In one embodiment, R12 of Formula (III-W) is benzyl. In some embodiments, a suitable silyl group R9 of (III-W) is selected from the group consisting of TMS, DMPS, TES, TBS, or DMIPS. In one embodiment, a suitable silyl group R9 is TMS. In some embodiments, R10 of Formula (III-W) is C1-C6 alkyl or linear C1-C6 alkyl. In one embodiment, R10 is selected from the group consisting of methyl, ethyl, 1-propyl, and 1-butyl. In some embodiments, R10 is methyl.

[0028] In some embodiments, R5 and R6 of the electron-deficient alkyne of Formula (III-X) are each independently selected from chloro, bromo, iodo, or -OSO2R7. In one embodiment, R5 and R6 are each chloro. In one embodiment, R5 and R6 are each bromo.

[0029] In some embodiments, the reaction according to Scheme A1 is carried out in the presence of an acid. In some embodiments, 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, ZnCl, or combinations thereof. In one embodiment, the acid is TFA. In some embodiments, the acid is present in a substoichiometric or catalytic amount, such as about 0.01 to 0.2, e.g., 0.03 to 0.07 equivalents or about 0.05 equivalents.

[0030] In some embodiments, the reaction of Scheme A1 is carried out in a non-polar solvent, for example, selected from the group consisting of toluene, DCM, or a mixture thereof. In one embodiment, the solvent is toluene. In some embodiments, about 1 equivalent of a compound of Formula (III-W) is reacted with about 1.1 to 3 equivalents, for example, 1.5 to 2 equivalents, of a compound of Formula (III-X).

[0031] In one embodiment, the reaction according to Scheme A1 is carried out using about 0.01 to 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, or combinations thereof, about 1 equivalent of the compound of Formula (III-W), and 1.1 to 3 equivalents of the compound of Formula (III-X) in a non-polar solvent selected from DCM, toluene, or a mixture thereof.

[0032] In some embodiments, the reaction of Scheme A1 is carried out using a compound of formula (III-W1) according to Scheme A1', resulting in the preparation of a compound of formula (III-Y1) (wherein R5, R6, R9, and R10 are defined above). [ka]

[0033] In certain embodiments, the method according to Scheme A1 is a method 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 method shown in Scheme A and more fully described in Examples 1 and 2. [ka]

[0034] In some embodiments, step 1 A employs an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-deficient alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 equivalent or 0.05 equivalent) of a suitable acid (e.g., trifluoroacetic acid (TFA)) in a suitable solvent (e.g., toluene or dichloromethane (DCM)). In some embodiments, step 1 A employs an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-deficient alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 equivalent or 0.05 equivalent) of trimethylsilyl trifluoromethanesulfonate (i.e., MeSiOTf) in a suitable solvent (e.g., toluene or DCM). In some embodiments, step 1 Aemploys an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-deficient alkyne (e.g., dichlorobutyne, III-C) in the presence of substoichiometric amounts (e.g., 0.1 equivalent or 0.05 equivalent) of trimethylsilyl trifluoromethanesulfonate (i.e., MeSiOTf) and CsF in a suitable solvent (e.g., toluene or DCM). In some embodiments, step 1 A employs an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-deficient alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 equivalent or 0.05 equivalent) of trimethylsilyl iodide (i.e., MeSiI) in a suitable solvent (e.g., toluene or DCM). In some embodiments, step 1 A employs an azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and an electron-deficient alkyne (e.g., dichlorobutyne, III-C) in the presence of a substoichiometric amount (e.g., 0.1 equivalent or 0.05 equivalent) of trimethylsilyl iodide (i.e., MeSiI) and an additive selected from CsF, LiF, ZnCl, and combinations thereof in a suitable solvent (e.g., toluene or DCM). One skilled in the art would be able to identify a suitable acid and a suitable solvent without undue experimentation.

[0035] While not wishing to be bound by any particular theory, it is believed that the selection of an electron-deficient alkyne is useful for avoiding by-products and reducing the number of steps in the method. In some aspects of the present disclosure, the stoichiometric ratio between the azomethine precursor and the electron-deficient alkyne is selected to avoid by-products and facilitate purification. In some embodiments, 1.0 equivalent of the azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and 2.0 equivalents of the electron-deficient alkyne (e.g., dichlorobutyne, III-C) are used. In other embodiments, 1.0 equivalent of the azomethine precursor (e.g., N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, III-D) and 1.5 equivalents of the electron-deficient alkyne (e.g., dichlorobutyne, III-C) are used.

[0036] In some embodiments, the process for making a compound of Formula (III-Y), (III-Y1), or (III-B) can involve isolating the product as a salt. In some embodiments, the process for making a compound of Formula (III-Y), (III-Y1), or (III-B) can involve carrying the product forward to further reaction steps without prior purification.

[0037] In some embodiments, the method further requires converting the compound of formula (III-Y) to a compound of formula (III-Z), for example, by contacting the compound of formula (III-Y) with R1-Cl according to Scheme A2. [ka] wherein R1 is C1-C6 alkoxycarbonyl (e.g., tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C6-C 10 Aryloxy (e.g., phenoxycarbonyl), C1-C6 alkylcarbonyl (e.g., acetyl), haloalkylcarbonyl (e.g., trifluoroacetyl), and -SO2-(C6-C 10In one embodiment, R1 is selected from the group consisting of -C(O)(C1-C6 alkoxy). In one embodiment, R1 is -C(O)(C1-C6 alkoxy), wherein the C1-C6 alkoxy is a straight chain C1-C6 alkoxy selected from methoxy, ethoxy, 1-propoxy, 1-butoxy, 1-pentoxy, or 1-hexoxy. In one embodiment, R1 is -C(O)OCH3.

[0038] In some embodiments, a method comprising Schemes 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. [ka]

[0039] In some embodiments, the method of Scheme A2 can be represented by Scheme A2': [ka] A method according to, or 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'. [ka]

[0040] In certain embodiments, the method according to Scheme B1 or B2 is the method shown in Scheme B, by which compounds of formula (III-A), for example, as more fully described in Examples 1 and 2, can be prepared. [ka]

[0041] In some embodiments, step 1 B is step 1 AThis is substantially the same as that described above with respect to

[0042] In some embodiments, step 2 B is completed by contacting the compound of formula (III-B) with methyl chloroformate in the presence of a suitable solvent (e.g., toluene or DCM). Without wishing to be bound by any particular theory, it is believed that the selection of methyl carbamate (instead of, e.g., benzyl or phenyl carbamate) as the protecting group facilitates purification and improves the stability of intermediate compound (III-A), and simplifies subsequent deprotection of intermediate (VA) (e.g., removal of methyl carbamate to provide the free secondary amine).

[0043] In some embodiments, step 1 B and 2 B In some embodiments, step 1 is carried out in the same reaction vessel. B and 2 B is performed without any intervening isolation or purification steps. B and 2 B are carried out sequentially in separate vessels. B and 2 B are carried out sequentially in separate vessels without any intervening isolation or purification steps. B and 2 B are carried out sequentially in separate vessels, and step 1 B is carried out in a first vessel, and step 1 B The product of step 2 is transferred to a second vessel containing a C1-C6 alkyl chloroformate. B Complete the following.

[0044] Specific examples and more detailed experimental conditions for the preparation of compounds of formula (III-A) and (III-B) are provided in Examples 1 and 2 below.

[0045] In another aspect, the present disclosure relates to a method for preparing a compound of Formula (III-Z), as shown in Scheme C below, wherein R1 is —C(O)(C1-C6 alkoxy). [ka] During the ceremony: R5 and R 6は、 Each independently, halo or -OSO2R7, Each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, and the C6-C 10 The aryl is optionally substituted with 1 to 3 R8; Each R8 is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0046] In some embodiments, R5 and R6 are each halo. In some embodiments, 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, R5 and R6 are each -OSO2R7. In some embodiments, R7 is C1-C6 alkyl. In some embodiments, R7 is methyl. In some embodiments, R7 is a C6-C8 alkyl group substituted with one R8. 10In some embodiments, R is aryl. In some embodiments, R is C-C alkyl. In some embodiments, R is methyl. In some embodiments, R is phenyl substituted with one methyl. In some embodiments, 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-yn-1,4-diylbis(methanesulfonate). In some embodiments, the compound of Formula (III-X) is but-2-yn-1,4-diylbis(4-methylbenzenesulfonate).

[0047] In some embodiments, step 1 C is essentially step 1 A Complete as described above for

[0048] In some embodiments, step 2 C is completed by contacting the compound of formula (III-Y1) with ClC(O)(C1-C6 alkoxy) (i.e., C1-C6 alkyl chloroformate) in the presence of a suitable solvent (e.g., toluene or DCM).

[0049] In some embodiments, the method for preparing a compound of formula (III-Z) where R1 is —C(O)(C1-C6 alkoxy) comprises converting 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)) into a compound of formula (III-Z) (e.g., compound (III)) (i.e., step 2 CIn some embodiments, the step of converting a compound of Formula (III-Y1) to a compound of Formula (III-Z) comprises contacting the compound of Formula (III-Y1) with ClC(O)(C-C alkoxy) (i.e., C-C alkyl chloroformate). In some embodiments, R1 is —C(O)OCH3. In some embodiments, 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). For example, in some embodiments where R1 is —C(O)OCH3 and / or the compound of Formula (III-Z) is compound (III-A), the step of converting a compound of Formula (III-Y1) to a compound of Formula (III-Z) comprises contacting the compound of Formula (III-Y1) with methyl chloroformate.

[0050] In some embodiments, the method for preparing a compound of formula (III-Z), wherein R1 is —C(O)(C1-C6 alkoxy), comprises contacting dichlorobutyne (III-C, (III-X) (wherein each R5, R6 is chloro)) with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (III-D) to obtain a compound of formula (III-Y1), wherein R5, R6 are each chloro (i.e., (III-B)) (i.e., Step 1 C In some embodiments, contacting the compound of Formula (III-C) with the compound of Formula (III-D) is carried out in the presence of an acid. In some embodiments, the acid is TFA. In some embodiments, contacting the compound of Formula (III-C) with the compound of Formula (III-D) is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is toluene.

[0051] In some embodiments, step 1 C and 2 C In some embodiments, step 1 C and 2 Cis performed without any intervening isolation or purification steps. C and 2 C are carried out sequentially in separate vessels. C and 2 C are carried out sequentially in separate vessels without any intervening isolation or purification steps. C and 2 C are carried out sequentially in separate vessels, and step 1 C is carried out in a first vessel, and step 1 C The product of step 2 is transferred to a second vessel containing a C1-C6 alkyl chloroformate. C Complete the following.

[0052] In some embodiments, the method further comprises converting the compound of Formula (III-Z) to a compound of Formula (VZ) 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. [ka] , In the formula, R11 is C6-C 10 aryl or 6-10 membered heteroaryl containing 1-3 O, N, or S; C6-C 10 The aryl and 6- to 10-membered heteroaryl are each optionally substituted with one or more substituents selected from R and -OR, each R independently being -C-C alkyl optionally substituted with one or more substituents selected from the group consisting of -H, oxo, -F, -Cl, -Br, -I, -CN, and -NO, or two R on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring; R1 is C1-C6 alkoxycarbonyl (e.g., tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C6-C 10Aryloxy (e.g., phenoxycarbonyl), C1-C6 alkylcarbonyl (e.g., acetyl), haloalkylcarbonyl (e.g., trifluoroacetyl), and -SO2-(C6-C 10 aryl) (e.g., tosyl); R5 and R6 are each independently halo, e.g., chloro, bromo, iodo, or -OSO2R7, where each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, C6-C 10 The aryl is optionally substituted with 1 to 3 R8, each R8 independently being halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0053] In some embodiments, R is a 6- to 10-membered heteroaryl as defined above, such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, where R is a C-C alkoxycarbonyl and R and R are each halo. In one embodiment, R is a 6- to 10-membered heteroaryl as defined above, such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, where R is a C-C alkoxycarbonyl and R and R are each chloro.

[0054] In some embodiments, step 1 A3 The reaction according to Scheme A3 is carried out in the presence of a base such as KCO or CsCO. In one embodiment, the base is KCO. In some embodiments, the reaction according to Scheme A3 is carried out in a suitable solvent selected from the group consisting of DMSO, toluene, or a mixture thereof.

[0055] In some embodiments, the method according to Scheme A3 can be carried out by Scheme A3': [ka] A process for preparing a compound of formula (V) according to Compounds of formula (III-Z), for example (III): [ka] 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV): [ka] to obtain a compound of Formula (V), wherein R is a protecting group. In some embodiments, R is a protecting group, and the protecting group is -C(O)(C-C alkyl), -C(O)(C-C haloalkyl), -C(O)(C-C alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or -S(O)(tolyl). In some embodiments, R is -C(O)(C-C alkoxy). In some embodiments, R is -C(O)OCH.

[0056] In some embodiments, the step of contacting the compound of Formula (III) with the compound of Formula (IV) is carried out in the presence of a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3. In some embodiments, the compound of Formula (V) is formed in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a combination of DMSO and toluene.

[0057] In some embodiments, the compound of formula (III) is Compound of formula (III-A): [ka] which may also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate.

[0058] In some embodiments, the compound of formula (V) is Compounds of formula (VA): [ka] 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.

[0059] In some embodiments, the present disclosure relates to an intermediate compound of formula (III): [ka] (In the formula: R1 is H, -CR2R3-(C6-C 10 aryl), or a protecting group, and C6-C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C1-C6 alkyl; R4 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy).

[0060] The compound of formula (III) is useful for preparing biologically active compounds, such as PKR-activating compounds. In some embodiments, the compound of formula (III) is used in a method for preparing a compound of formula (I). In other embodiments, the compound of formula (III) is used in a method for preparing a compound of formula (II).

[0061] In some embodiments, R1 is H. In some embodiments, R1 is a protecting group. In some embodiments, R1 is -CR2R3-(C6-C 10aryl). R1 ​​is -CR2R3-(C6-C 10 In some embodiments, R and R are each H. -CR2R3-(C6-C 10 aryl), in some embodiments, R2 is C1-C6 alkyl and R3 is H. -CR2R3-(C6-C 10 In some embodiments, R2 is methyl and R3 is H. R1 is -CR2R3-(C6-C 10 In some embodiments, C-C 10 The aryl is unsubstituted. -CR2R3-(C6-C 10 In some embodiments, C-C 10 The alkyl is substituted with one C1-C6 alkoxy. When R1 is -CR2R3-(C6-C 10 In some embodiments, C-C 10 The aryl is substituted with one methoxy. R1 is -CR2R3-(C6-C 10 In some embodiments, C-C 10 Aryl is phenyl. R1 is -CR2R3-(C6-C 10 In some embodiments, C-C 10 Aryl is 4-methoxyphenyl. In some embodiments, R1 is benzyl (i.e., -Bn, which may also be represented as -CH2-Ph). In some embodiments, R1 is 4-methoxybenzyl.

[0062] The term "protecting group," when used with respect to R, refers to any group that is removable under conditions that do not adversely affect the remainder of the molecule, while preventing the amine group of a compound of formula (III) from participating in or affecting reactions with other portions of the molecule (e.g., reaction with either or both of the chloromethyl groups of the compound). Examples of amine protecting groups that may be suitable for the disclosed methods include alkoxycarbonyl (such as tert-butoxycarbonyl, or BOC, and methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C-C 10 Examples of suitable amine protecting groups include aryloxycarbonyl (e.g., phenoxycarbonyl), C1-C6 alkylcarbonyl (e.g., acetyl), haloalkylcarbonyl (e.g., trifluoroacetyl), and tosyl. Those skilled in the art will appreciate that other compounds of formula (III) in which other amine protecting groups are used are considered to be within the scope of the compounds of formula (III).

[0063] In some embodiments, R1 is a protecting group and the protecting group is -C(O)(C-C alkyl), -C(O)(C-C haloalkyl), -C(O)(C-C alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or -S(O)2(tolyl). In some embodiments, R1 is a protecting group and the protecting group is -C(O)(C-C alkoxy). In some embodiments, R1 is a protecting group and the protecting group is -C(O)OCH3.

[0064] In some embodiments, the present disclosure provides a compound of formula (III), wherein the compound is: (i) methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate, or (ii) The compound is 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole.

[0065] In some embodiments, the compound of formula (III) is Compound of formula (III-A): [ka] which may also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate.

[0066] In some embodiments, the compound of formula (III) has the formula Compound (III-B): [ka] which may also be called 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole.

[0067] In some embodiments, the present disclosure provides an intermediate compound of formula (V): [ka] wherein R1 is a protecting group.

[0068] In some embodiments, R is —C(O)(C-C alkyl), —C(O)(C-C haloalkyl), In some embodiments, R is -C(O)(C-Calkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or -S(O)(tolyl). In some embodiments, R is -C(O)OCH.

[0069] In some embodiments, the compound of formula (V) is Compounds of formula (VA): [ka]

[0070] (VA) 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.

[0071] In some embodiments, the present disclosure provides a compound of formula (VA): [ka]

[0072] (VA) wherein the compound is The present invention relates to a compound prepared by a method comprising 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. In some embodiments, the base is CsCO or KCO. In some embodiments, the base is CsCO. In some embodiments, the base is KCO. In some embodiments, the compound of Formula (VA) is formed in the presence of a suitable solvent. In some embodiments, the suitable solvent is dimethyl sulfoxide (DMSO), toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a combination of DMSO and toluene.

[0073] In another aspect, the present disclosure provides an intermediate compound of formula (IV): [ka] which may also be referred to as 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide.

[0074] In another aspect, the present disclosure relates to methods for preparing compounds of formula (IV), as shown in Scheme D and more fully described in Example 3. In some embodiments, compounds of formula (IV) are obtained via the method shown in Scheme D and more fully described in Example 3. [ka]

[0075] In some embodiments, the method for preparing a compound of formula (IV) comprises converting a compound of formula (IV-D) to a compound of formula (IV-C) (i.e., step 1 D In some embodiments, step 1 D comprises contacting a compound of formula (IV-D) with 1,2-dibromoethane to obtain a compound of formula (IV-C). D is carried out in the presence of a base. D It will be appreciated that there are many bases that would be compatible with the method of step 1. For example, in some embodiments, the base is potassium carbonate. D is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is water, ethanol (EtOH), or a combination thereof. In some embodiments, the suitable solvent is a mixture of EtOH and water. In some embodiments, the suitable solvent is a mixture of EtOH and water in a ratio of about 80:20 to 98:2, e.g., about 85:15 or about 95:5.

[0076] In some embodiments, the method for preparing a compound of formula (IV) comprises converting a compound of formula (IV-C) to a compound of formula (IV-B) (i.e., step 2 D In some embodiments, step 2 D involves contacting a compound of formula (IV-C) with a brominating reagent. DIt will be appreciated that there are many brominating reagents that would be compatible with the method of step 2. For example, in some embodiments, the brominating reagent is N-bromosuccinimide (NBS). In some embodiments, step 2 D is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is ethyl acetate (EtOAc), N,N-dimethylformamide (DMF), or a combination thereof.

[0077] In some embodiments, the method for preparing a compound of formula (IV) comprises converting a compound of formula (IV-B) to a compound of formula (IV-A) (i.e., step 3). D In some embodiments, step 3 D is a method for treating a compound of formula (IV-B) with a Grignard reagent, C 1- In some embodiments, step 3 comprises contacting the C6 alkyl lithium with sulfuryl chloride. D comprises contacting the compound of formula (IV-B) with isopropylmagnesium chloride, butyllithium, and sulfuryl chloride. In some embodiments, step 3 D comprises first contacting a compound of formula (IV-B) with a Grignard reagent to obtain a first metallated intermediate compound, contacting the first metallated intermediate compound with a C-C alkyllithium (e.g., butyllithium, n-butyllithium, or hexyllithium) to obtain a second metallated intermediate compound, and subsequently contacting the second metallated intermediate compound with sulfuryl chloride to obtain a compound of formula (IV-A). In some embodiments, step 3 Dcomprises first contacting a compound of Formula (IV-B) with isopropylmagnesium chloride to obtain a first metallated intermediate compound, subsequently contacting the first metallated intermediate compound with butyllithium to obtain a second metallated intermediate compound, and subsequently contacting the second metallated intermediate compound with sulfuryl chloride to obtain a compound of Formula (IV-A). In some embodiments, the butyllithium is selected from n-butyllithium, sec-butyllithium, and tert-butyllithium. In some embodiments, the butyllithium is n-butyllithium. In some embodiments, the butyllithium is sec-butyllithium. In some embodiments, the butyllithium is tert-butyllithium. In some embodiments, step 3 D is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is tetrahydrofuran (THF).

[0078] In some embodiments, the method for preparing a compound of formula (IV) comprises converting a compound of formula (IV-A) to a compound of formula (IV) (i.e., step 4 D In some embodiments, step 4 D comprises contacting a compound of formula (IV-A) with ammonia to obtain a compound of formula (IV). In some embodiments, step 4 D is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is methanol (MeOH).

[0079] In another aspect, the present disclosure relates to methods for preparing compounds of formula (IV), as shown in Scheme E and more fully described in Example 4. In some embodiments, compounds of formula (IV) are obtained via the method shown in Scheme E and more fully described in Example 4. [ka]

[0080] In some embodiments, the method for preparing a compound of formula (IV) comprises converting a compound of formula (IV-F) to a compound of formula (IV-E) (i.e., step 1 E In some embodiments, step 1 E includes contacting a compound of formula (IV-F) with bromine, a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), and sulfamic acid. In some embodiments, step 1 E comprises first contacting a compound of formula (IV-F) with a first portion of bromine, followed by contacting the compound of formula (IV-F) with hydrochloric acid, followed by 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. In some embodiments, step 1 E comprises first contacting a compound of formula (IV-F) with a first portion of bromine, followed by contacting the compound of formula (IV-F) with hydrobromic acid, followed by 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. In some embodiments, step 1 E comprises first contacting a compound of formula (IV-F) with a first portion of bromine to obtain a first intermediate compound, then contacting the first intermediate compound with hydrochloric acid to obtain a second intermediate compound, then contacting the second intermediate compound with a second portion of bromine to obtain a third intermediate compound, and finally contacting the third intermediate compound with sulfamic acid to obtain a compound of formula (IV-E). E comprises first contacting a compound of formula (IV-F) with a first portion of bromine to obtain a first intermediate compound, then contacting the first intermediate compound with hydrobromic acid to obtain a second intermediate compound, then contacting the second intermediate compound with a second portion of bromine to obtain a third intermediate compound, and finally contacting the third intermediate compound with sulfamic acid to obtain a compound of formula (IV-E). E is carried out in a suitable solvent. In some embodiments, the suitable solvent is water.

[0081] In some embodiments, the method for preparing a compound of formula (IV) comprises converting a compound of formula (IV-E) to a compound of formula (IV-B) (i.e., step 2 E In some embodiments, step 2 E comprises contacting a compound of formula (IV-E) with 1,2-dibromoethane to obtain a compound of formula (IV-B). E is carried out in the presence of a base. E It will be appreciated that there are many bases that would be compatible with the method of step 2. For example, in some embodiments, the base is potassium carbonate. E is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is water, EtOH, or a combination thereof. In some embodiments, the suitable solvent is a combination of water and EtOH. In some embodiments, the suitable solvent is a combination of water and EtOH in a ratio of about 1 to about 1.

[0082] In some embodiments, the method for preparing a compound of formula (IV) comprises converting a compound of formula (IV-B) to a compound of formula (IV-A) (i.e., step 3). E In some embodiments, step 3 E is a method for treating a compound of formula (IV-B) with a Grignard reagent, C 1- In some embodiments, step 3 comprises contacting the C6 alkyl lithium with sulfuryl chloride. E comprises contacting the compound of formula (IV-B) with isopropylmagnesium chloride, butyllithium, and sulfuryl chloride. Ecomprises first contacting a compound of formula (IV-B) with a Grignard reagent (e.g., isopropylmagnesium chloride) to obtain a first metallated intermediate compound, contacting the first metallated intermediate compound with a C1-C6 alkyllithium (e.g., butyllithium, n-butyllithium, or hexyllithium) to obtain a second metallated intermediate compound, and subsequently contacting the second metallated intermediate compound with sulfuryl chloride to obtain a compound of formula (IV-A). In some embodiments, step 3 E comprises first contacting a compound of Formula (IV-B) with isopropylmagnesium chloride to obtain a first metallated intermediate compound, subsequently contacting the first metallated intermediate compound with butyllithium to obtain a second metallated intermediate compound, and subsequently contacting the second metallated intermediate compound with sulfuryl chloride to obtain a compound of Formula (IV-A). In some embodiments, the butyllithium is selected from n-butyllithium, sec-butyllithium, and tert-butyllithium. In some embodiments, the butyllithium is n-butyllithium. In some embodiments, the butyllithium is sec-butyllithium. In some embodiments, the butyllithium is tert-butyllithium. In some embodiments, step 3 E is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is THF.

[0083] In some embodiments, the method for preparing a compound of formula (IV) comprises converting a compound of formula (IV-A) to a compound of formula (IV) (i.e., step 4 E In some embodiments, step 4 E comprises contacting a compound of formula (IV-A) with ammonia to obtain a compound of formula (IV). In some embodiments, step 4 E is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is MeOH.

[0084] In another aspect, the present disclosure provides an intermediate compound of formula (VII): [ka] (S)-Tropic acid may be prepared as described below, or alternatively from racemic tropic acid by optical resolution via diastereomeric salt formation with, for example, (1R,2S)-2-amino-1,2-diphenylethanol ((1R,2S)-ADPE) using EtOH, isopropanol (IPA), or mixtures of EtOH / water or IPA / water, as described, for example, in Tetrahedron 70 (2014) 7923-7928.

[0085] In another aspect, the present disclosure relates to methods for preparing intermediate compounds of formula (VII), as shown in Scheme F and more fully described in Example 5. In some embodiments, compounds of formula (VII) are obtained via the method shown in Scheme F and more fully described in Example 5. [ka]

[0086] In some embodiments, the method for preparing a compound of formula (VII) comprises converting a compound of formula (VII-C) to a compound of formula (VII-B) (i.e., step 1 F In some embodiments, step 1 F comprises contacting a compound of formula (VII-C) with methyl formate to obtain a compound of formula (VII-B). F is carried out in the presence of a base. F It will be appreciated that there are many bases that would be compatible with the method of step 1. In some embodiments, 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 Fis carried out in the presence of a suitable solvent. In some embodiments, 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.

[0087] In some embodiments, the method for preparing a compound of formula (VII) comprises converting a compound of formula (VII-B) to a compound of formula (VII-A) (i.e., step 2 F In some embodiments, step 2 F Step 2 involves contacting the compound of formula (VII-B) with a reducing agent. F comprises contacting a compound of Formula (VII-B) with a reducing agent in the presence of an enzyme. In some embodiments, the reducing agent is an enzyme. In some embodiments, the reducing agent is NADPH. In some embodiments, the enzyme is carbonyl reductase (CRED). In some embodiments, the enzyme is an engineered form of CRED. In some embodiments, step 2 F is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is a phosphate buffer, toluene, MTBE, or a combination thereof. In some embodiments, the suitable solvent is a phosphate buffer. In some embodiments, the suitable solvent is a combination of a phosphate buffer and toluene. In some embodiments, the suitable solvent is a combination of a phosphate buffer and MTBE. In some embodiments, the phosphate buffer has a pH of about 6.5 to 7. In some embodiments, the phosphate buffer comprises one or more additional reagents and enzyme cofactors. In some embodiments, the one or more additional reagents and enzyme cofactors comprise thiamine·HCl, L-lysine, GDP, NADP, or a combination thereof. In some embodiments, the one or more additional reagents and enzyme cofactors comprise each of thiamine·HCl, L-lysine, GDP, and NADP. In some embodiments, step 2 FIn some embodiments, step 2 comprises isolating or purifying the (S)-methyl tropate. F The method includes isolating or purifying (S)-methyl tropate from a mixture of (R)-methyl tropate and (S)-methyl tropate. The isolation or purification step can be carried out via any method commonly known to those of skill in the art. For example, in some embodiments, the isolation or purification step includes a chromatographic step (e.g., chiral resolution via HPLC, UPLC, or SFC). In other embodiments, the isolation or purification step includes a recrystallization step. In some embodiments, 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 skill in the art.

[0088] In some embodiments, the method for preparing a compound of formula (VII) comprises converting a compound of formula (VII-A) to a compound of formula (VII) (i.e., step 3). F In some embodiments, step 3 F comprises contacting the compound of formula (VII-A) with a base or an enzyme. F involves contacting the compound of formula (VII-A) with a base. Those skilled in the art will recognize that many bases can be used in step 3. F It will be appreciated that the method is compatible with the method of step 3. In some embodiments, the base is sodium hydroxide (i.e., NaOH). F is carried out in the presence of an enzyme. F is carried out in the presence of a lipase. F In some embodiments, step 3 is carried out in the presence of Candida Antarctica lipase B (CALB). Fis carried out 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.

[0089] In yet another aspect, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein R1 is a protecting group.

[0090] In some embodiments, the composition comprising a compound of Formula (III) comprises a compound of Formula (IV): [ka] or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the composition comprising a compound of Formula (III) further comprises a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3.

[0092] In some embodiments, the composition comprising a compound of Formula (III) comprises a compound of Formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein R1 is a protecting group.

[0093] In some embodiments of a composition comprising a compound of Formula (III), an R group present on the compound of Formula (III) and / or the compound of Formula (V) is -C(O)(C-C alkyl), -C(O)(C-C haloalkyl), -C(O)(C-C alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or -S(O)(tolyl). In some embodiments, R is C(O)(C-C alkoxy). In some embodiments, R is -C(O)OCH.

[0094] In some embodiments of the composition comprising a compound of Formula (III), the compound of Formula (III) is a compound of Formula (III-A): [ka] which may also be referred to as methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate.

[0095] In some embodiments of the composition comprising a compound of Formula (III), the compound of Formula (V) is a compound of Formula (VA): [ka] 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.

[0096] Method for preparing PKR-activating compounds In another aspect, the present disclosure provides a compound of formula (I), which is (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 ethabopibat: [ka] relates to a method for preparing as shown in Scheme G and more fully described in Examples 6-12. [ka]

[0097] In some embodiments, the method for preparing a compound of formula (I) comprises contacting a compound of formula (III) with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV) to obtain a compound of formula (V), and converting the compound of formula (V) to a compound of formula (I) (i.e., step 1). G , followed by step 2 G and 3 G ) wherein R1 is a protecting group. In some embodiments, step 1 G is carried out in the presence of a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3. In some embodiments, step 1 G is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a mixture of DMSO and toluene.

[0098] In some embodiments, R is -C(O)(C-C alkyl), -C(O)(C-C haloalkyl), -C(O)(C-C alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or -S(O)(tolyl). In some embodiments, R is C(O)(C-C alkoxy). In some embodiments, R is -C(O)OCH.

[0099] In some embodiments, the compound of Formula (III) is obtained by the method shown 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), which is obtained by the method shown in Scheme B and more fully described in Examples 1 and 2.

[0100] In some embodiments, compounds of formula (IV) are obtained by the methods shown in one of Schemes D or E and more fully described in Examples 3 and 4, respectively.

[0101] In some embodiments, the compound of formula (V) is obtained by the above-described method for preparing a compound of formula (V). In some embodiments, the compound of formula (V) is a compound of formula (VA).

[0102] In some embodiments, the method for preparing a compound of Formula (I) comprises converting a compound of Formula (V) to a compound of Formula (VI) (i.e., Step 2 G In some embodiments, step 2 G comprises deprotecting a compound of formula (V) to obtain a compound of formula (VI). In some embodiments, deprotecting a compound of formula (V) to obtain a compound of formula (VI) comprises contacting a compound of formula (V) with an acid. Those skilled in the art will recognize that step 2 G It will be appreciated that there are many acids that will be compatible with the method of step 2. In some embodiments, the acid comprises HBr and acetic acid. In other embodiments, the acid comprises dibutylsulfane and methanesulfonic acid (MSA). In other embodiments, the acid comprises dibutylsulfane, TFA, and MSA. In some embodiments, the acid of step 2 G further comprises neutralizing the acid with a suitable base. In some embodiments, the suitable base is ammonium hydroxide. In some embodiments, step 2 Gfurther comprises 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 carried out neat, without the presence of an additional solvent (e.g., dibutylsulfane and MSA are present in an amount sufficient to solubilize the compound of formula (VI)). G It will be appreciated that the reaction may be carried out in the presence of a suitable solvent or co-solvent.

[0103] In some embodiments, the method for preparing a compound of formula (I) comprises contacting (VI) with (S)-tropic acid (VII) to obtain a compound of formula (I) (i.e., step 3). G In some embodiments, step 3 G comprises coupling a compound of formula (VI) with (S)-tropic acid (VII) to obtain a compound of formula (I). In some embodiments, step 3 G is carried out in the presence of a coupling reagent. In some embodiments, the coupling reagent is a carbodiimide coupling reagent. In some embodiments, step 3 G Step 3 is carried out in the presence of a coupling reagent and an additive. G is carried out in the presence of a carbodiimide coupling reagent and an additive. GIt will be appreciated that there are many coupling reagents (e.g., carbodiimide coupling reagents such as EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide), or HATU (azabenzotriazole tetramethyluronium hexafluorophosphate) and additives (e.g., ethyl (hydroxyamino)cyanoacetate (OxymaPure®), 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or 2-hydroxypyridine N-oxide (HOPO) and the like) that will be compatible with the method of step 3. In some embodiments, for example, the coupling reagent includes EDC. In some embodiments, the coupling reagent includes propylphosphonic anhydride (T3P®). In some embodiments, the coupling reagent includes T3P® and EDC. In some embodiments, the coupling reagent includes step 3. G is carried out in the presence of EDC and an additive, the additive being OxymaPure®. In some embodiments, step 3 G is carried out in the presence of EDC and an additive, and the additive is HOPO. In some embodiments, step 3 G is carried out in the presence of T3P® and EDC and an additive, the additive being OxymaPure®. In some embodiments, step 3 G is carried out in the presence of T3P® and EDC and an additive, the additive being HOPO. In some embodiments, step 3 G is carried out in the presence of T3P® and an additive, the additive being OxymaPure®. In some embodiments, step 3 G is carried out in the presence of T3P® and an additive, the additive being HOPO. In some embodiments, step 3 Gis carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, N,N-dimethylacetamide (DMAc), EtOH, DCM, 2-methyltetrahydrofuran (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 a combination of DMAc and EtOH. In some embodiments, the suitable solvent is 2-MeTHF. In some embodiments, 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.

[0104] In yet another aspect, the present disclosure provides a compound of formula (II) which is (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: [ka] is shown in Scheme H and more fully described in Example 13. [ka]

[0105] In some embodiments, the method for preparing a compound of formula (II) comprises contacting a compound of formula (III) with pyridine-2-sulfonamide (VIII-A) to obtain a compound of formula (VIII) and converting the compound of formula (VIII) to a compound of formula (II) (i.e., step 1). H , followed by step 2 H and 3 H) wherein R1 is a protecting group. In some embodiments, step 1 H is carried out in the presence of a base. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is K2CO3. In some embodiments, step 1 H is carried out in the presence of a suitable solvent. In some embodiments, the suitable solvent is DMSO, toluene, or a combination thereof. In some embodiments, the suitable solvent is DMSO. In some embodiments, the suitable solvent is a mixture of DMSO and toluene.

[0106] In some embodiments, R is -C(O)(C-C alkyl), -C(O)(C-C haloalkyl), -C(O)(C-C alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or -S(O)(tolyl). In some embodiments, R is C(O)(C-C alkoxy). In some embodiments, R is -C(O)OCH.

[0107] In some embodiments, the compound of Formula (III) is obtained by the method shown 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), which is obtained by the method shown in Scheme B and more fully described in Examples 1 and 2.

[0108] In some embodiments, the method for preparing a compound of Formula (II) comprises converting a compound of Formula (VIII) to a compound of Formula (IX) (i.e., Step 2 H In some embodiments, step 2 Hcomprises deprotecting a compound of formula (VIII) to obtain a compound of formula (IX). In some embodiments, deprotecting a compound of formula (VIII) to obtain a compound of formula (IX) comprises contacting a compound of formula (VIII) with an acid. Those skilled in the art will recognize that step 2 H It will be appreciated that there are many acids that would be compatible with the method of step 2. In some embodiments, the acid includes HBr and acetic acid. In other embodiments, the acid includes dibutylsulfane, TFA, and MSA. In other embodiments, the acid includes dibutylsulfane and MSA. In some embodiments, step 2 H further comprises neutralizing the acid with a suitable base. In some embodiments, the suitable base is ammonium hydroxide. In some embodiments, deprotecting the compound of Formula (VIII) to obtain a compound of Formula (IX) comprises contacting the compound of Formula (VIII) with a strong base. In some embodiments, the strong base is potassium hydroxide. In some embodiments, step 2 H further comprises contacting the compound of formula (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to form a complex of compounds (IX) and (XI). H is carried out neat, without the presence of an additional solvent (e.g., dibutylsulfane and MSA are present in an amount sufficient to solubilize the compound of formula (VI)). H It will be appreciated that step 2 may be carried out in the presence of a suitable solvent or co-solvent. For example, in some embodiments, step 2 H is carried out in the presence of water.

[0109] In some embodiments, the method for preparing a compound of formula (II) comprises contacting (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to obtain a compound of formula (II) (i.e., step 3). H In some embodiments, step 3 Hcomprises coupling a compound of formula (IX) with (R)-2-hydroxy-2-phenylacetic acid (XI) to obtain a compound of formula (II). In some embodiments, step 3 H is carried out in the presence of a coupling reagent. In some embodiments, the coupling reagent is a carbodiimide coupling reagent. In some embodiments, step 3 H Step 3 is carried out in the presence of a coupling reagent and an additive. H is carried out in the presence of a carbodiimide coupling reagent and an additive. H Many coupling reagents (e.g., carbodiimide coupling reagents such as EDC, or HATU, or T3P) would be compatible with this method. (登録商標) etc.) and additives (e.g., OxymaPure (登録商標) It will be appreciated that coupling reagents include ethyl (hydroxyamino)cyanoacetate, HOBt, HOSu, or HOPO. In some embodiments, for example, the coupling reagent includes EDC. In some embodiments, the coupling reagent includes T3P®. In some embodiments, the coupling reagent includes T3P (登録商標) and EDC. In some embodiments, step 3 G is carried out in the presence of EDC and an additive, the additive being OxymaPure®. In some embodiments, step 3 G is carried out in the presence of EDC and an additive, and the additive is HOPO. In some embodiments, step 3 G is carried out in the presence of T3P® and an additive, the additive being OxymaPure®. In some embodiments, step 3 Gis carried out 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. In some embodiments, the coupling reagent includes HOBt and EDC. In some embodiments, the coupling reagent includes HOPO and EDC. In some embodiments, step 3 H is carried out in the presence of a suitable solvent. In some embodiments, 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. In some embodiments, 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.

[0110] List of Embodiments The present invention is further illustrated by the following non-limiting embodiments.

[0111] 1. A compound of formula (III): [ka] or a salt thereof, wherein: R1 is H, -CR2R3-(C6-C 10 aryl), or a protecting group, and C6-C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C1-C6 alkyl; R4 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy).

[0112] 2. R1 is -CR2R3-(C6-C 10 aryl).

[0113] 3. The compound of embodiment 1 or 2, wherein R2 and R3 are each H.

[0114] 4. The compound of embodiment 1, wherein R1 is a protecting group.

[0115] 5. R1 is —C(O)(C1-C6 alkyl), -C(O)(C1-C6 haloalkyl), -C(O)(C1-C6 alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or The compound of embodiment 1 or 4, wherein the compound is -S(O)2 (tolyl).

[0116] 6. The compound of any one of embodiments 1, 4, or 5, wherein R1 is -C(O)(C1-C6 alkoxy).

[0117] 7. The compound is [ka] The compound of any one of embodiments 1 or 4-6, which is methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate, or a salt thereof.

[0118] 8. The compound is [ka] The compound of any one of embodiments 1 to 3, which is 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole, or a salt thereof.

[0119] 9. Compounds of formula (III): [ka] wherein R1 is —C(O)(C1-C6 alkoxy), comprising step (i): Compound of formula (III-B): [ka] to a compound of formula (III).

[0120] 10. Converting a compound of formula (III-B) to a compound of formula (III) 10. The method of embodiment 9, comprising contacting with ClC(O)(C1-C6 alkoxy).

[0121] 11. The method of embodiment 9, wherein R1 is —C(O)OCH3.

[0122] 12. The method of embodiment 11, wherein converting the compound of formula (III-B) to the compound of formula (I) comprises contacting the compound of formula (III-B) with methyl chloroformate.

[0123] 13. The compound of formula (III-B) is: (ii) contacting a compound of formula (III-X) with a compound of formula (III-D): [ka] [ka]

[0124] The method according to any one of embodiments 9 to 12, obtained by step (ii) comprising obtaining a compound of formula (III-B), wherein: R5 and R6 are each independently halo or -OSO2R7; Each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 Aryl, C6-C 10 The aryl is optionally substituted with 1 to 3 R8; Each R8 is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy).

[0125] 14. The method of embodiment 13, wherein R5 and R6 are each halo.

[0126] 15. The method of embodiment 14, wherein R5 and R6 are each chloro, i.e., the compound of formula (III-C).

[0127] 16. The method of any one of embodiments 13-15, wherein contacting the compound of formula (III-C) or (III-X) with the compound of formula (III-D) is carried out in the presence of an acid.

[0128] 17. The method of embodiment 16, wherein the acid is trifluoroacetic acid.

[0129] 18. The method of any one of embodiments 13-15, wherein contacting the compound of formula (III-C) or (III-X) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl trifluoromethanesulfonate.

[0130] 19. The method of any one of embodiments 13-15, wherein contacting the compound of Formula (III-C) or (III-X) with the compound of Formula (III-D) is carried out in the presence of trimethylsilyl trifluoromethanesulfonate and CsF.

[0131] 20. The method of any one of embodiments 13-15, wherein contacting the compound of formula (III-C) or (III-X) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl iodide.

[0132] 21. The method of any one of embodiments 13-15, wherein contacting the compound of Formula (III-C) or (III-X) with the compound of Formula (III-D) is carried out in the presence of trimethylsilyl iodide and an additive selected from CsF, LiF, ZnCl2, and combinations thereof.

[0133] 22. Compound of formula (III-A): [ka] And essentially, (i) A compound of formula (III-C): [ka] and a compound of formula (III-D): [ka] in the presence of an acid to obtain a compound of formula (III-B): [ka] (ii) contacting a compound of formula (III-B) with methyl chloroformate to obtain a compound of formula (III-A).

[0134] 23. The compound of embodiment 22, wherein the acid is trifluoroacetic acid.

[0135] 24. Compound of formula (IV): [ka] Or its salt.

[0136] 25. Compound of formula (IV): [ka] A process for preparing a compound of formula (IV-A): [ka] with ammonia to obtain a compound of formula (IV).

[0137] 26. The compound of formula (IV-A) Compound of formula (IV-B): [ka] to a compound of formula (IV-A).

[0138] 27. The method of embodiment 26, wherein converting 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, a C1-C6 alkyllithium, and sulfuryl chloride.

[0139] 28. Converting a compound of formula (IV-B) to a compound of formula (IV-A) contacting the compound of formula (IV-B) with a Grignard reagent to obtain a first metallated intermediate compound (IV-B1); contacting the first metalated intermediate compound (IV-B1) with a C1-C6 alkyllithium (e.g., butyllithium, n-butyllithium, or hexyllithium) to form a second metalated intermediate compound obtaining (IV-B2); 28. The method of embodiment 26 or 27, comprising contacting the second metallated intermediate compound (IV-B2) with sulfuryl chloride to obtain the compound of formula (IV-A).

[0140] 29. The method of embodiment 27 or 28, wherein the Grignard reagent is isopropylmagnesium chloride.

[0141] 30. The method of any one of embodiments 27-29, wherein the C1-C6 alkyl lithium is butyl lithium, for example, n-butyl lithium.

[0142] 31. The compound of formula (IV-B) is a compound of formula (IV-C): [ka] to a compound of formula (IV-B).

[0143] 32. The method of embodiment 31, wherein converting the compound of formula (IV-C) to the compound of formula (IV-B) comprises contacting the compound of formula (IV-C) with a brominating reagent.

[0144] 33. The method of embodiment 32, wherein the brominating reagent is N-bromosuccinimide.

[0145] 34. The compound of formula (IV-C) is a compound of formula (IV-D): [ka] with 1,2-dibromoethane to obtain a compound of formula (IV-C).

[0146] 35. The method of embodiment 34, wherein contacting the compound of formula (IV-D) with 1,2-dibromoethane is carried out in the presence of a first base.

[0147] 36. The method of embodiment 35, wherein the first base is K2CO3.

[0148] 37. The compound of formula (IV-B) is a compound of formula (IV-E):

[0149] [ka] with 1,2-dibromoethane to obtain a compound of formula (IV-B).

[0150] 38. Compound of formula (IV-E) 38. The method of embodiment 37, wherein the contacting with 1,2-dibromoethane is carried out in the presence of a first base.

[0151] 39. The method of embodiment 38, wherein the first base is K2CO3.

[0152] 40. The compound of formula (IV-E) is a compound of formula (IV-F): [ka] to a compound of formula (IV-E).

[0153] 41. The method of embodiment 40, wherein converting the compound of formula (IV-F) to the compound of formula (IV-E) comprises contacting the compound of formula (IV-F) with bromine, hydrohalic acid, and sulfamic acid.

[0154] 42. Converting a compound of formula (IV-F) to a compound of formula (IV-E) contacting the compound of formula (IV-F) with a first portion of bromine to obtain a first intermediate compound (IV-F1); contacting the first intermediate compound (IV-F1) with hydrohalic acid to obtain a second intermediate compound (IV-F2); contacting the second intermediate compound (IV-F2) with a second portion of bromine to obtain a third intermediate compound (IV-F3); and contacting the third intermediate compound (IV-F3) with sulfamic acid to obtain the compound of formula (IV-E).

[0155] 43. The method of embodiment 41 or 42, wherein the hydrohalic acid is hydrochloric acid.

[0156] 44. The method of embodiment 41 or 42, wherein the hydrohalic acid is hydrobromic acid.

[0157] 45. Compound of formula (IV): [ka] And essentially, (i) A compound of formula (IV-D): [ka] with 1,2-dibromoethane in the presence of a base to obtain a compound of formula (IV-C): [ka] (ii) contacting the compound of formula (IV-C) with a brominating reagent to obtain a compound of formula (IV-B): [ka] (iii) reacting a compound of formula (IV-B) with a Grignard reagent, and contacting the compound of formula (IV-A) with a C1-C6 alkyllithium and sulfuryl chloride to obtain a compound of formula (IV-A): [ka] (iv) contacting a compound of formula (IV-A) with ammonia to obtain a compound of formula (IV).

[0158] 46. ​​Step (iii) is contacting the compound of formula (IV-B) with a Grignard reagent to obtain a first metallated intermediate compound (IV-B1); contacting the first metalated intermediate compound (IV-B1) with a C1-C6 alkyllithium (e.g., butyllithium, n-butyllithium, or hexyllithium) to form a second metalated intermediate compound obtaining (IV-B2); The compound of embodiment 45, further comprising contacting the second metallated intermediate compound (IV-B2) with sulfuryl chloride to obtain the compound of formula (IV-A).

[0159] 47. The compound of embodiment 45 or 46, wherein the base is K2CO3.

[0160] 48. The brominating reagent is The compound of any one of embodiments 45-47, which is N-bromosuccinimide.

[0161] 49. The compound of any one of embodiments 45-48, wherein the Grignard reagent is isopropylmagnesium chloride.

[0162] 50. The compound of any one of embodiments 45-49, wherein the C1-C6 alkyllithium is butyllithium, for example, n-butyllithium.

[0163] 51. Compound of formula (IV): [ka] And essentially, (i) A compound of formula (IV-F): [ka] with bromine, a hydrohalic acid, and a sulfamic acid to obtain a compound of formula (IV-E): [ka] (ii) contacting the compound of formula (IV-E) with 1,2-dibromoethane in the presence of a base to obtain a compound of formula (IV-B): [ka] (iii) contacting the compound of formula (IV-B) with a Grignard reagent, a C1-C6 alkyllithium, and sulfuryl chloride to obtain a compound of formula (IV-A); [ka] (iv) contacting a compound of formula (IV-A) with ammonia to obtain a compound of formula (IV).

[0164] 52. Step (i) is contacting the compound of formula (IV-F) with a first portion of bromine to obtain a first intermediate compound (IV-F1); contacting the first intermediate compound (IV-F1) with hydrohalic acid to obtain a second intermediate compound (IV-F2); contacting the second intermediate compound (IV-F2) with a second portion of bromine to obtain a third intermediate compound (IV-F3); 52. The compound of embodiment 51, further comprising contacting the third intermediate compound (IV-F3) with sulfamic acid to obtain a compound of formula (IV-E).

[0165] 53. Step (iii) is contacting the compound of formula (IV-B) with a Grignard reagent to obtain a first metallated intermediate compound (IV-B1); contacting the first metalated intermediate compound (IV-B1) with a C1-C6 alkyllithium (e.g., butyllithium, n-butyllithium, or hexyllithium) to form a second metalated intermediate compound obtaining (IV-B2); 53. The compound of embodiment 51 or 52, further comprising contacting the second metallated intermediate compound (IV-B2) with sulfuryl chloride to obtain the compound of formula (IV-A).

[0166] 54. The compound of any one of embodiments 51-53, wherein the hydrohalic acid is hydrochloric acid.

[0167] 55. The compound of any one of embodiments 51 or 53, wherein the hydrohalic acid is hydrobromic acid.

[0168] 56. The compound of any one of embodiments 51-55, wherein the base is K2CO3.

[0169] 57. The compound of any one of embodiments 51-56, wherein the Grignard reagent is isopropylmagnesium chloride.

[0170] 58. The compound of any one of embodiments 51-57, wherein the C1-C6 alkyllithium is butyllithium, for example, n-butyllithium.

[0171] 59. A compound of formula (V): [ka] 1. A process for preparing a compound of formula (III): [ka] with a compound of formula (IV): [ka] to obtain a compound of formula (V). (wherein R1 is a protecting group).

[0172] 60. The method of embodiment 59, wherein contacting the compound of formula (III) with the compound of formula (IV) is carried out in the presence of a base.

[0173] 61. The method of embodiment 60, wherein the base is Cs2CO3 or K2CO3.

[0174] 62. R1 is -C(O)(C1-C6 alkyl), -C(O)(C1-C6 haloalkyl), -C(O)(C1-C6 alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or 62. The method of any one of embodiments 59-61, wherein -S(O)2 (tolyl).

[0175] 63. The method of any one of embodiments 59-62, wherein R1 is —C(O)(C1-C6 alkoxy).

[0176] 64. The method of any one of embodiments 59-63, wherein R1 is —C(O)OCH3.

[0177] 65. A compound of formula (VA): [ka] Or its salt.

[0178] 66. A compound of formula (VA): [ka] or a salt thereof, wherein methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate: [ka] to 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide: [ka] in the presence of a base.

[0179] 67. The compound of embodiment 66, wherein the base is Cs2CO3 or K2CO3.

[0180] 68. Compounds of formula (I): [ka] 1. A process for preparing a compound of formula (III): [ka] with a compound of formula (IV): [ka] to produce a compound of formula (V): [ka] and converting the compound of formula (V) to a compound of formula (I). (wherein R1 is a protecting group).

[0181] 69. The method of embodiment 68, wherein contacting the compound of formula (III) with the compound of formula (IV) is carried out in the presence of a first base.

[0182] 70. The method of embodiment 69, wherein the first base is Cs2CO3 or K2CO3.

[0183] 71. Converting a compound of formula (V) to a compound of formula (I) Deprotecting the compound of formula (V) to give a compound of formula (VI): [ka] 71. The method of any one of embodiments 68-70, comprising obtaining α-aminopropyl methylcellulose, or a salt thereof.

[0184] 72. The method of embodiment 71, wherein deprotecting the compound of formula (V) to obtain the compound of formula (VI) comprises contacting the compound of formula (V) with a first acid.

[0185] 73. the first acid comprises HBr and acetic acid; or the first acid comprises dibutylsulfane, trifluoroacetic acid, and methanesulfonic acid; or 73. The method of embodiment 72, wherein the first acid comprises dibutylsulfane and methanesulfonic acid.

[0186] 74. Converting a compound of formula (V) to a compound of formula (I) Reacting a compound of formula (VI) with a compound of formula (VII): [ka] to obtain the compound of formula (I).

[0187] 75. The method of embodiment 74, wherein coupling the compound of formula (VI) with the compound of formula (VII) is carried out in the presence of a coupling reagent.

[0188] 76. The method of embodiment 74 or 75, wherein the coupling reagent comprises EDC.

[0189] 77. The method of embodiment 75 or 76, wherein coupling the compound of formula (VI) with the compound of formula (VII) is further carried out in the presence of an additive.

[0190] 78. The method of embodiment 77, wherein the additive is ethyl (hydroxyimino)cyanoacetate or 2-hydroxypyridine-N-oxide.

[0191] 79. R1 is -C(O)(C1-C6 alkyl), -C(O)(C1-C6 haloalkyl), -C(O)(C1-C6 alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or The method of any one of embodiments 68-78, wherein -S(O)2 (tolyl).

[0192] 80. The method of any one of embodiments 68-79, wherein R1 is —C(O)(C1-C6 alkoxy).

[0193] 81. The method of any one of embodiments 68-80, wherein R1 is —C(O)OCH3.

[0194] 82. R1 is —C(O)(C1-C6 alkoxy) and the compound of formula (III) is prepared by step (i): (i) A compound of formula (III-B): [ka] to a compound of formula (III).

[0195] 83. Converting a compound of formula (III-B) into a compound of formula (III) is carried out by converting a compound of formula (III-B) into a compound of formula (III). 83. The method of embodiment 82, comprising contacting with ClC(O)(C1-C6 alkoxy).

[0196] 84. The method of embodiment 82, wherein R1 is —C(O)OCH3.

[0197] 85. The method of embodiment 84, wherein converting the compound of formula (III-B) to the compound of formula (I) comprises contacting the compound of formula (III-B) with methyl chloroformate.

[0198] 86. A compound of formula (III-B) is prepared by the process (ii): (ii) contacting a compound of formula (III-C) with a compound of formula (III-D): [ka] [ka]

[0199] The method according to any one of embodiments 82 to 85, obtained by obtaining a compound of formula (III-B), wherein: R5 and R6 are each independently halo or -OSO2R7; Each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 Aryl, C6-C 10 The aryl is optionally substituted with 1 to 3 R8; Each R8 is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy).

[0200] 87. The method of embodiment 86, wherein R5 and R6 are each halo.

[0201] 88. The method of embodiment 87, wherein R5 and R6 are each chloro.

[0202] 89. The method of any one of embodiments 86-88, wherein contacting the compound of Formula (III-C) with the compound of Formula (III-D) is carried out in the presence of a second acid.

[0203] 90. The method of embodiment 89, wherein the second acid is trifluoroacetic acid.

[0204] 91. The method of any one of embodiments 86-88, wherein contacting the compound of Formula (III-C) with the compound of Formula (III-D) is carried out in the presence of trimethylsilyl trifluoromethanesulfonate.

[0205] 92. The method of any one of embodiments 86-88, wherein contacting the compound of Formula (III-C) with the compound of Formula (III-D) is carried out in the presence of trimethylsilyl trifluoromethanesulfonate and CsF.

[0206] 93. The method of any one of embodiments 86-88, wherein contacting the compound of Formula (III-C) with the compound of Formula (III-D) is carried out in the presence of trimethylsilyl iodide.

[0207] 94. The method of any one of embodiments 86-88, wherein contacting the compound of formula (III-C) with the compound of formula (III-D) is carried out in the presence of trimethylsilyl iodide and an additive selected from CsF, LiF, ZnCl2, and combinations thereof.

[0208] 95. The compound of formula (IV) is a compound of formula (IV-A): [ka] with ammonia to obtain a compound of formula (IV).

[0209] 96. A compound of formula (IV-A): Compound of formula (IV-B): [ka] to a compound of formula (IV-A).

[0210] 97. The method of embodiment 96, wherein converting 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, a C1-C6 alkyllithium, and sulfuryl chloride.

[0211] 98. Converting a compound of formula (IV-B) into a compound of formula (IV-A) contacting the compound of formula (IV-B) with a Grignard reagent to obtain a first metallated intermediate compound (IV-B1); contacting the first metalated intermediate compound (IV-B1) with a C1-C6 alkyllithium (e.g., butyllithium, n-butyllithium, or hexyllithium) to form a second metalated intermediate compound obtaining (IV-B2); 98. The method of embodiment 96 or 97, comprising contacting the second metallated intermediate compound (IV-B2) with sulfuryl chloride to obtain the compound of formula (IV-A).

[0212] 99. The method of embodiment 97 or 98, wherein the Grignard reagent is isopropylmagnesium chloride.

[0213] 100. The method of any one of embodiments 97-99, wherein the C1-C6 alkyl lithium is butyl lithium, for example, n-butyl lithium.

[0214] 101. The compound of formula (IV-B) is a compound of formula (IV-C): [ka] to a compound of formula (IV-B).

[0215] 102. The method of embodiment 101, wherein converting the compound of formula (IV-C) to the compound of formula (IV-C) comprises contacting the compound of formula (IV-C) with a brominating reagent.

[0216] 103. The method of embodiment 102, wherein the brominating reagent is N-bromosuccinimide.

[0217] 104. The compound of formula (IV-C) is a compound of formula (IV-D): [ka] with 1,2-dibromoethane to obtain a compound of formula (IV-C).

[0218] 105. The method of embodiment 104, wherein contacting the compound of formula (IV-D) with 1,2-dibromoethane is carried out in the presence of a second base.

[0219] 106. The method of embodiment 105, wherein the second base is K2CO3.

[0220] 107. The compound of formula (IV-B) is a compound of formula (IV-E): [ka] with 1,2-dibromoethane to obtain a compound of formula (IV-B).

[0221] 108. Compound of formula (IV-E) 108. The method of embodiment 107, wherein the contacting with 1,2-dibromoethane is carried out in the presence of a second base.

[0222] 109. The method of embodiment 108, wherein the second base is K2CO3.

[0223] 110. The compound of formula (IV-E) is a compound of formula (IV-F): [ka] to a compound of formula (IV-E).

[0224] 111. The method of embodiment 110, wherein converting the compound of formula (IV-F) to the compound of formula (IV-E) comprises contacting the compound of formula (IV-F) with bromine, hydrohalic acid, and sulfamic acid.

[0225] 112. Converting a compound of formula (IV-F) into a compound of formula (IV-E) contacting the compound of formula (IV-F) with a first portion of bromine to obtain a first intermediate compound (IV-F1); contacting the first intermediate compound (IV-F1) with hydrohalic acid to obtain a second intermediate compound (IV-F2); contacting the second intermediate compound (IV-F2) with a second portion of bromine to obtain a third intermediate compound (IV-F3); 112. The method of embodiment 110 or 111, comprising contacting the third intermediate compound (IV-F3) with sulfamic acid to obtain the compound of formula (IV-E).

[0226] 113. The method of embodiment 111 or 112, wherein the hydrohalic acid is hydrochloric acid.

[0227] 114. The method of embodiment 111 or 112, wherein the hydrohalic acid is hydrobromic acid.

[0228] 115. The compound of formula (VII) is a compound of formula (VII-A): [ka] to a compound of formula (VII).

[0229] 116. The method of embodiment 115, wherein converting the compound of formula (VII-A) to a compound of formula (VII) comprises contacting the compound of formula (VII-A) with a third base.

[0230] 117. The method of embodiment 116, wherein the third base is NaOH.

[0231] 118. The method of embodiment 115, wherein converting the compound of formula (VII-A) to the compound of formula (VII) comprises contacting the compound of formula (VII-A) with an enzyme.

[0232] 119. The method of embodiment 118, wherein the enzyme is a lipase.

[0233] 120. The method of embodiment 119, wherein the lipase is CALB.

[0234] 121. A compound of formula (VII-A) is a compound of formula (VII-B): [ka] to a compound of formula (VII-A).

[0235] 122. The method of embodiment 121, wherein converting 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.

[0236] 123. The method of embodiment 122, wherein the compound of formula (VII-B) is contacted with a reducing agent in the presence of an enzyme.

[0237] 124. The method of embodiment 123, wherein the enzyme is carbonyl reductase (CRED).

[0238] 125. The compound of formula (VII-B) is a compound of formula (VII-C): [ka] with methyl formate to obtain a compound of formula (VII-B).

[0239] 126. The method of embodiment 125, wherein contacting the compound of formula (VII-C) with methyl formate is carried out in the presence of a fourth base.

[0240] 127. The method of embodiment 126, wherein the fourth base is sodium tert-butoxide or sodium methoxide.

[0241] 128. A compound of formula (III):

[0242] [ka] (wherein R1 is a protecting group), or a salt thereof.

[0243] 129. Compound of formula (IV): [ka] 129. The composition of embodiment 128, further comprising:

[0244] 130. The composition of embodiment 128 or 129, further comprising a base.

[0245] 131. The composition of embodiment 130, wherein the base is Cs2CO3 or K2CO3.

[0246] 132. A compound of formula (V): [ka] 132. The composition of any one of embodiments 128-131, further comprising:

[0247] 133. R1 is -C(O)(C1-C6 alkyl), -C(O)(C1-C6 haloalkyl), -C(O)(C1-C6 alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or The composition of any one of embodiments 128-132, wherein —S(O)2 (tolyl).

[0248] 134. The composition of any one of embodiments 128-133, wherein R1 is —C(O)(C1-C6 alkoxy).

[0249] 135. A compound of formula (III): [ka] The composition of any one of embodiments 128-134, which is methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate.

[0250] 136. A compound of formula (V): [ka] The composition of any one of embodiments 132-135, which is 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.

[0251] List of additional specific embodiments: The following are alternative non-limiting embodiments of the present invention.

[0252] 1. Compounds according to formula (III-Y): [ka] azomethine precursor according to formula (III-W) in step 1 of Scheme A1 A1 with an electron-deficient alkyne according to formula (III-X) according to A1 is carried out in the presence of an acid: [ka]

[0253] (Wherein, R12 is —CR2R3—(C6-C 10 aryl) and C6-C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C1-C6 alkyl; R4 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R5 and R6 are each independently halo, e.g., chloro, bromo, iodo, or -OSO2R7, and each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, C6-C 10 The aryl is optionally substituted with 1 to 3 R8; each R is independently halo, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); R10 is C1-C6 alkyl).

[0254] 2. The method of embodiment 1, wherein R12 is -CH2Ph ​​(benzyl) or 4-methoxybenzyl.

[0255] 3. The method of embodiment 1 or 2, wherein R12 is benzyl.

[0256] 4. The azomethine precursor according to formula (III-W1) is reacted with the azomethine precursor according to step 1 of Scheme A1′. A1’ with an electron-deficient alkyne according to formula (III-X) according to A1’ 4. The method of any one of embodiments 1 to 3, wherein: [ka]

[0257] wherein R and R are each independently halo, e.g., chloro, bromo, iodo, or -OSOR; and each R is independently C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, or C-C 10 aryl, C6-C 10 the aryl is optionally substituted with 1 to 3 R, each R independently being halo, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); R10 is C1-C6 alkyl).

[0258] 5. The method of any one of embodiments 1 to 4, wherein R9 is trimethylsilyl (TMS).

[0259] 6. The method of any one of embodiments 1 to 5, wherein R10 is a linear C1-C6 alkyl selected from the group consisting of methyl, ethyl, 1-propyl, 1-butyl, 1-pentyl, or 1-hexyl.

[0260] 7. The method of any one of embodiments 1 to 6, wherein R10 is a C1-C4 alkyl selected from the group consisting of methyl, ethyl, 1-propyl, or 1-butyl.

[0261] 8. The method of any one of embodiments 1 to 7, wherein R10 is methyl.

[0262] 9. The method of any one of embodiments 1 to 8, wherein R5 and R6 are each halo.

[0263] 10. The method of any one of embodiments 1 to 9, wherein R5 and R6 are each selected from chloro, bromo, or iodo.

[0264] 11. The method of any one of embodiments 1 to 10, wherein R5 and R6 are each chloro.

[0265] 12. The method of any one of embodiments 1 to 11, wherein the compound of formula (III-Y) or (III-Y1) is carried forward to further reaction steps without prior purification.

[0266] 13. The method of any one of embodiments 1-11, wherein the compound of formula (III-Y) or (III-Y1) is isolated as a salt.

[0267] 14. The method of any one of embodiments 1 to 13, wherein about 1 equivalent of a compound of formula (III-W) or (III-W1) is reacted with about 1.1 to 3 equivalents of a compound of formula (III-X).

[0268] 15. The method of embodiment 14, wherein about 1 equivalent of a compound of formula (III-W) or (III-W1) is reacted with about 1.5 to 2 equivalents of a compound of formula (III-X).

[0269] 16. The method of embodiment 14 or 15, wherein about 1 equivalent of a compound of formula (III-W) or (III-W1) is reacted with about 1.5 equivalents or about 2 equivalents of a compound of formula (III-X).

[0270] 17. The method of any one of embodiments 1 to 16, wherein the acid is present in a sub-stoichiometric amount of about 0.01 to 0.2 equivalents.

[0271] 18. The method of any one of embodiments 1 to 17, wherein the acid is present in a sub-stoichiometric amount of about 0.03 to 0.07 equivalents, for example, about 0.05 equivalents.

[0272] 19. The method of any one of embodiments 1-18, wherein 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 combinations thereof.

[0273] 20. The method of any one of embodiments 1 to 19, wherein the acid is TFA.

[0274] 21. The method of any one of embodiments 1 to 20, wherein the reaction of the compound of formula (III-W) or (III-W1) with the compound of formula (III-X) is carried out in a non-polar solvent, for example, selected from the group consisting of toluene, DCM, or a mixture thereof.

[0275] 22. The method of embodiment 21, wherein the non-polar solvent is toluene.

[0276] 23. A compound of formula (III-X) is dissolved in a non-polar solvent, such as toluene, and the mixture is heated to about -10 ° C~10 ° 23. The method of embodiment 21 or 22, wherein the reaction mixture is cooled to a temperature of C, followed by addition of an acid, such as TFA.

[0277] 24. A compound of formula (III-X) is dissolved in a non-polar solvent, such as toluene, and the mixture is heated to about -5 ° The mixture is cooled to a temperature of ~5°C, followed by the addition of TFA. 、 24. The method according to any one of embodiments 21 to 23.

[0278] 25. The method of embodiment 23 or 24, wherein the compound of formula (III-W) or (III-W1) is subsequently added.

[0279] 26. The compound of formula (III-W) or (III-W1) is then added, and the temperature is maintained at about -10 ° C~20 °26. The method of any one of embodiments 23 to 25, wherein the cell is maintained in C.

[0280] 27. Converting a compound of formula (III-Y) or (III-Y1) to a compound of formula (III-Z) according to Scheme A2, Step 2 A2 27. The method of any one of embodiments 1 to 26, further comprising: [ka]

[0281] (wherein R1 is C1-C6 alkoxycarbonyl (e.g., tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C6-C 10 Aryloxy (e.g., phenoxycarbonyl), C1-C6 alkylcarbonyl (e.g., acetyl), haloalkylcarbonyl (e.g., trifluoroacetyl), and -SO2-(C6-C 10 aryl) (e.g., tosyl).

[0282] 28. The method of embodiment 27, wherein the compound of formula (III-Y) is a compound of formula (III-Y1).

[0283] 29. The method of embodiment 27 or 28, wherein R1 is -C(O)(C1-C6 alkoxy).

[0284] 30. The method of any one of embodiments 27-29, wherein R1 is —C(O)OCH3.

[0285] 31. Process 2 A2 The method of any one of embodiments 27-30, wherein is carried out by contacting a compound according to formula (III-Y) or (III-Y1) with R1-Cl.

[0286] 32.Process 2 A2The method of any one of embodiments 27-31, wherein is carried out by contacting a compound of formula (III-Y) or (III-Y1) with ClC(O)(C1-C6 alkoxy).

[0287] 33. Process 2 A2 The method of any one of embodiments 27-32, wherein is carried out by contacting the compound of formula (III-Y) or (III-Y1) with methyl chloroformate.

[0288] 34. Process 2 A2 34. The method of any one of embodiments 27-33, wherein is carried out in a second non-polar solvent.

[0289] 35. The method of embodiment 34, wherein the second non-polar solvent is selected from the group consisting of toluene, DCM, n-heptane, or a combination thereof.

[0290] 36. The method of embodiment 34 or 35, wherein the second nonpolar solvent is toluene, n-heptane, or a combination of toluene and n-heptane.

[0291] 37. Process 2 A2 comprises a compound of formula (III-Y) or (III-Y1), A1 or Step 1 A1’ The reaction mixture from was heated to -20 ° C~-5 ° 37. The method of any one of embodiments 27-36, wherein the method is carried out by adding to a mixture of R1-Cl in n-heptane at a temperature of C.

[0292] 38. The method of embodiment 37, wherein R1-Cl is ClC(O)(C1-C6 alkoxy), for example, methyl chloroformate.

[0293] 39. Process 2 A2 While R1-Cl was added, the temperature was maintained at -10 ° C~0 °Step 1, comprising a compound of formula (III-Y) or (III-Y1) at a temperature of C A1 or Step 1 A1’ 39. The method of any one of embodiments 27-38, wherein the method is carried out by adding to the reaction mixture from

[0294] 40. The method of any one of embodiments 37-39, wherein R1-Cl is ClC(O)(C1-C6 alkoxy), for example, methyl chloroformate.

[0295] 41. The method of any of the preceding embodiments, wherein the compound of formula (III-W) is a compound of formula (III-D). [ka] 42. The method of any one of embodiments 1-41, wherein the compound of formula (III-X) is a compound of formula (III-C). [ka] 43. The method of any one of embodiments 1-42, wherein the compound of formula (III-Y) or (III-Y1) is a compound of formula (III-B). [ka] 44. The method of any one of embodiments 1-43, wherein the compound of formula (III-Z) is a compound of formula (III-A). [ka] 45. Step 3: Reacting a compound of formula (III-Z) with a compound of formula (IV-Y) to obtain a compound of formula (VZ) according to Scheme A3 A3 45. The method according to any one of embodiments 27 to 44, further comprising: [ka]

[0296] (Wherein R11 is C6-C10 aryl, and a 6- to 10-membered heteroaryl containing 1 to 3 O, N, or S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and -OR13, and each R13 is independently -C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of -H, oxo, -F, -Cl, -Br, -I, -CN, and -NO2, or two R13 on adjacent atoms form a heterocycloalkyl ring together with the atoms to which they are attached), and the reaction is carried out in the presence of a base.

[0297] 46. ​​The method of embodiment 45, wherein R11 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, and 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl.

[0298] 47. The method of any one of embodiments 45-46, wherein R11 is 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl.

[0299] 48. The method of any one of embodiments 45-47, wherein the base is selected from the group selected from the group consisting of Cs2CO3 and K2CO3.

[0300] 49. The derivative according to any one of embodiments 45-48, wherein the X base is K2CO3.

[0301] 50. The method of any one of embodiments 45-49, wherein the reaction according to Scheme A3 is carried out in a suitable solvent selected from the group consisting of DMSO, toluene, or a mixture thereof.

[0302] 51. About 1 equivalent of a compound according to formula (IV-Y) and about 1 to 2 equivalents of a base are mixed in DMSO, and about 75 to 110 °The method of any one of embodiments 45-50, wherein the reaction mixture is heated to a temperature of C, followed by addition of about 1 equivalent of a compound according to Formula (III-Z) in toluene, DMSO, or a mixture thereof.

[0303] 52. A mixture of a compound of formula (IV-Y) and a base in DMSO is heated to about 85-100°C. ° 52. The method of embodiment 51, wherein the heating is performed to a temperature of C.

[0304] 53. A mixture of a compound of formula (IV-Y) and a base in DMSO is heated to about 100 ° 53. The method of embodiment 51 or 52, wherein the heating is performed to a temperature of C.

[0305] 54. The method of any one of embodiments 45-53, wherein the compound of formula (III-Z) is in toluene.

[0306] 55. The method of any one of embodiments 45-53, wherein the compound of formula (III-Z) is in DMSO.

[0307] 56. The method of any one of embodiments 45-55, wherein the compound of formula (IV-Y) is a compound of formula (IV) or a compound of formula (VIII-A).

[0308] [ka] [ka] 57. A process for preparing a compound of formula (VZ), comprising: a. Reacting an azomethine precursor of Formula (III-W) with an electron-deficient alkyne of Formula (III-X) according to Scheme A1, wherein the reaction is carried out in a first non-polar solvent in the presence of an acid:

[0309] [ka] (In the formula, R12 is -CR2R3-(C6-C 10 aryl) and C6-C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C1-C6 alkyl; R4 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R5 and R6 are each independently halo, e.g., chloro, bromo, iodo, or -OSO2R7, and each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, C6-C 10 The aryl is optionally substituted with 1 to 3 R8; each R is independently halo, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy; R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); R10 is C1-C6 alkyl; b. Converting the compound of formula (III-Y) to a compound of formula (III-Z) by reacting with R1-Cl in a second non-polar solvent according to Scheme A2: [ka]

[0310] (In the formula, R1 is C1-C6 alkoxycarbonyl (e.g., tert-butoxycarbonyl or methoxycarbonyl), benzyloxycarbonyl (i.e., Cbz), C6-C 10Aryloxy (e.g., phenoxycarbonyl), C1-C6 alkylcarbonyl (e.g., acetyl), haloalkylcarbonyl (e.g., trifluoroacetyl), and -SO2-(C6-C 10 aryl) (e.g., tosyl) and c. Reacting a compound of formula (III-Z) with a compound of formula (IV-Y) in the presence of a base in a suitable solvent to form compound (VZ) according to Scheme A3: [ka] (In the formula, R11 is C6-C 10 aryl, and a 6- to 10-membered heteroaryl containing 1 to 3 O, N, or S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and -OR13, and each R13 is independently -C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of -H, oxo, -F, -Cl, -Br, -I, -CN, and -NO2, or two R13 on adjacent atoms form a heterocycloalkyl ring together with the atoms to which they are attached.

[0311] 58. The method of embodiment 57, wherein R12 is benzyl.

[0312] 59. The method of embodiment 57 or 58, wherein R10 is methyl.

[0313] 60. The method of any one of embodiments 57-59, wherein R9 is trimethylsilyl.

[0314] 61. The method of any one of embodiments 57-60, wherein R5 and R6 are each chloro.

[0315] 62. The method of any one of embodiments 57-61, wherein the first polar solvent is selected from DCM, toluene, or a mixture thereof.

[0316] 63. The method of any one of embodiments 57-62, wherein the acid is TFA.

[0317] 64. The method of any one of embodiments 57-63, wherein R1-Cl is ClC(O)(C1-C6 alkoxy).

[0318] 65. The method of any one of embodiments 57-64, wherein R1-Cl is methyl chloroformate.

[0319] 66. The method of any one of embodiments 57-65, wherein the second non-polar solvent is n-heptane, DCM, toluene, or a mixture thereof.

[0320] 67. The method of any one of embodiments 57-66, wherein the compound of formula (IV-Y) is a compound of formula (IV) or (VIII-A). [ka] [ka] 68. The method of any one of embodiments 57-67, wherein the suitable solvent is selected from the group consisting of DMSO, toluene, or a mixture thereof.

[0321] 69. A peptide described in any of embodiments 57-68, wherein the base is K2CO3.

[0322] 70. A compound of formula (III-Y) or a salt thereof: [ka] (Wherein, R12 is —CR2R3—(C6-C 10 aryl) and C6-C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C1-C6 alkyl; R4 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R5 and R6 are each independently halo, e.g., chloro, bromo, iodo, or -OSO2R7, and each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C6-C 10 aryl, C6-C 10 The aryl is optionally substituted with 1 to 3 R8; Each R8 is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0323] 71. The compound according to embodiment 70, wherein the compound is a compound of formula (III-Y2) or a salt thereof: [ka] (Wherein, R12 is —CR2R3—(C6-C 10 aryl) and C6-C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C1-C6 alkyl; R4 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy).

[0324] 72. R12 is benzyl, i.e., a compound of formula (III-B): [ka] The compound of embodiment 70 or 71, which is (1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate).

[0325] 73. A compound of formula (III) or a salt thereof: [ka] (Wherein, R1 is —C(O)(C1-C6 alkyl), —C(O)(C 1‐ -C(O)(C-C haloalkyl), -C(O)(C-C alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or -S(O)2(tolyl)).

[0326] 74. The compound according to embodiment 73, wherein R1 is —C(O)(C1-C6 alkoxy).

[0327] 75. The compound is a compound of formula (III-A): [ka] 75. The compound of embodiment 73 or 74, which is (methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate), or a salt thereof.

[0328] 76. Compound of formula (VZ): [ka] wherein R1 is —C(O)(C1-C6 alkyl), —C(O)(C1-C6 haloalkyl), —C(O)(C1-C6 alkoxy), —C(O)(benzyloxy), —C(O)(phenoxy), or —S(O)2(tolyl); R11 is C6-C 10 aryl, and 6-10 membered heteroaryl containing 1-3 O, N, or S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and -OR13, and each R13 is independently -C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of -H, oxo, -F, -Cl, -Br, -I, -CN, and -NO2, or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring).

[0329] 77. The compound according to embodiment 076, wherein the compound is a compound of formula (V): [ka] (wherein R1 is —C(O)(C1-C6 alkyl)).

[0330] 78. The compound of embodiment 76 or 77, wherein the compound is a compound of formula (VA). [ka] 79. The compound according to embodiment 076, wherein the compound is of formula (VIII): [ka] (wherein R1 is —C(O)(C1-C6 alkyl)).

[0331] 80. The compound of any one of embodiments 76 or 790, wherein the compound is a compound of formula (VIII-B). [ka] 81. Use of a compound according to any one of embodiments 70-80 for preparing a compound according to formula (I) or (II).

[0332] 82. A compound according to formula (I): [ka] 1. A method for preparing a. Step 1 of Scheme B1' B1’ reacting a compound of formula (III-D) with a compound of formula (III-C) in the presence of a first acid in a first non-polar solvent according to the formula: [ka]

[0333] b. Step 2 of Scheme B1' B1’converting the compound of formula (III-B) to a compound of formula (III) by reacting with R1-Cl, where R1 is —C(O)C1-C6 alkoxy (e.g., methoxycarbonyl), in a second non-polar solvent according to c. reacting a compound of formula (III) (wherein R is C-C alkoxycarbonyl (e.g., methoxycarbonyl)) with a compound of formula (IV) in the presence of a first base in a suitable solvent to form compound (V) according to Scheme G1: [ka] d. deprotecting the compound of formula (V) (wherein R1 is C1-C6 alkoxycarbonyl (e.g., methoxycarbonyl)) with a second acid, followed by neutralization with a second base to obtain a compound of formula (VI), or forming a salt of the compounds of formula (VI) and (VII) by addition of compound (VII); [ka]

[0334] e. carrying out a coupling reaction of a compound of formula (VI) with a compound of formula (VII) according to Scheme G3, or carrying out a coupling reaction from a salt of formula (VI)-(VII) according to Scheme G3', using a coupling reagent and an additive in a second suitable solvent to obtain a compound of formula (I). [ka] or [ka] 83. The method of embodiment 82, wherein the compound of formula (III-D) in step a is the rate-limiting reagent.

[0335] 84. The method of embodiment 82 or 83, wherein about 1.5 to 2.0 equivalents of a compound of formula (III-C) are reacted with about 1 equivalent of a compound of formula (III-D) in step a.

[0336] 85. In step a, the compound of formula (III-C) is mixed with a first non-polar solvent and the resulting mixture is dissolved in about -5 to 5 ° C, and a first acid is added, followed by the addition of a compound of Formula (III-D) in a first non-polar solvent while maintaining the temperature.

[0337] 86. The method of any one of embodiments 82-85, wherein the first acid is TFA.

[0338] 87. The method of any one of embodiments 82-86, wherein the first acid is TFA and about 0.05 equivalents are used.

[0339] 88. The method of any one of embodiments 82-87, wherein the first nonpolar solvent is toluene.

[0340] 89. The method of any one of embodiments 82-88, wherein the reaction mixture from step a is used in the subsequent step b without further purification.

[0341] 90. The method of any one of embodiments 82-89, wherein the second nonpolar solvent is toluene or a mixture of toluene and n-heptane.

[0342] 91. The method of any one of embodiments 82-90, wherein R1-Cl is mixed with n-heptane before adding the reaction mixture from step a, which contains the compound of formula (III-B).

[0343] 92. Step b is performed at about -15°C to about -5 ° 92. The method of any one of embodiments 82-91, wherein the method is carried out at a temperature of C.

[0344] 93. R1-Cl is about -15 ° C~approx.-5 ° 93. The method of any one of embodiments 82-92, wherein the reaction mixture from step a is added at a temperature of C.

[0345] 94. The method of any one of embodiments 82-93, wherein R1-Cl is methyl chloroformate.

[0346] 95. The method of any one of embodiments 82-94, wherein in step c, the first base is K2CO3.

[0347] 96. The method of any one of embodiments 82-95, wherein in step c, about 1.1 equivalents of the first base are used.

[0348] 97. The method of any one of embodiments 82-96, wherein the suitable solvent in step c is DMSO, toluene, or a mixture thereof.

[0349] 98. The method of any one of embodiments 82-97, wherein the suitable solvent in step c is a mixture of DMSO and toluene.

[0350] 99. In step c, the compound of formula (IV), the first base and a suitable solvent are mixed and heated for about 100 minutes before adding the compound of formula (III) in the suitable solvent. ° 99. The method of any one of embodiments 82-98, wherein the heating is performed at RT.

[0351] 100. In step c, the compound of formula (IV), K2CO3 and DMSO are mixed and heated to about 100°C before adding the compound of formula (III) in toluene. ° 99. The method of any one of embodiments 82-99, wherein the heating is performed at RT.

[0352] 101. The method of any one of embodiments 82 to 100, wherein in step c, the compound of formula (III) is a compound of formula (III-A).

[0353] 102. The method of any one of embodiments 82-101, wherein the suitable solvent in step c is DMSO, toluene, or a mixture thereof.

[0354] 103. The method of any one of embodiments 82-102, wherein in step d, the compound of formula V is a compound of formula (VA).

[0355] 104. The method of any one of embodiments 82-103, wherein in step d, the second acid is a mixture of Bu2S and MSA.

[0356] 105. In step d, the mixture of the compound of formula (V) and the second acid is heated to about 70 ° 105. The method of any one of embodiments 82-104, wherein the heating is performed at RT.

[0357] 106. The method of any one of embodiments 82-105, wherein in step d, the second base is aqueous NH4OH.

[0358] 107. The method of any one of embodiments 82-106, wherein in step d, when a salt of a compound of formula (VI) and (VII) is formed, about 1 equivalent of (VI) and about 1 equivalent of (VII) are mixed in DCM or MeCN.

[0359] 108. The method of any one of embodiments 82 to 107, wherein in step e, the reaction is carried out using a salt of (VI)·(VII) according to Scheme G3′.

[0360] 109. The method of any one of embodiments 82 to 108, wherein in step e, the coupling reagent is selected from the group consisting of EDC, DCC, propylphosphonic anhydride (T3P®), and HATU.

[0361] 110. The method of any one of embodiments 82-109, wherein in step e, the coupling reagent is EDC·HCl.

[0362] 111. The method of any one of embodiments 82 to 110, wherein in step e, the additive is selected from the group consisting of ethyl (hydroxyamino)cyanoacetate (OxymaPure®), HOBt, HOSu, and HOPO.

[0363] 112. The method of any one of embodiments 82 to 111, wherein in step e, the additive is ethyl (hydroxyamino)cyanoacetate (OxymaPure®) or HOPO.

[0364] 113. The method of any one of embodiments 82-112, wherein in step e, the coupling reagent is EDC·HCl and the additive is ethyl (hydroxyamino)cyanoacetate (OxymaPure®).

[0365] 114. The method of any one of embodiments 82-112, wherein in step e, the coupling reagent is EDC·HCl and the additive is HOPO.

[0366] 115. The method of any one of embodiments 82-114, wherein in step e, the second suitable solvent is selected from the group of DMAc, 2-MeTHF, EtOH, or a combination thereof.

[0367] 116. The method of any one of embodiments 82-115, wherein in step e, the second suitable solvent is a combination of DMAc and EtOH.

[0368] 117. The method of any one of embodiments 82-116, wherein in step e, the second suitable solvent is a combination of DMAc, EtOH, and 2-MeTHF.

[0369] 118. A compound of formula (VI)·(VII). [ka] 119. Use of the compound according to embodiment 118 for the preparation of ethabopibat (I).

[0370] 120. A compound according to formula (II): [ka] 1. A method for preparing a. Step 1 of Scheme B1' B1’ reacting a compound of formula (III-D) with a compound of formula (III-C) in a first non-polar solvent in the presence of a first acid according to: [ka]

[0371] b. Step 2 of Scheme B1' B1’ converting the compound of formula (III-B) to a compound of formula (III) by reacting with R1-Cl, where R1 is —C(O)C1-C6 alkoxy (e.g., methoxycarbonyl), in a second non-polar solvent according to c. reacting a compound of formula (III) (wherein R is C-C alkoxycarbonyl (e.g., methoxycarbonyl)) with a compound of formula (VIII-A) in the presence of a first base in a suitable solvent to form a compound of formula (VIII) according to Scheme H1: [ka] d. deprotecting the compound of formula (VIII) (wherein R1 is C1-C6 alkoxycarbonyl (e.g., methoxycarbonyl)) with a fourth base or a third acid to obtain a compound of formula (IX) or a salt thereof; [ka] e. carrying out a coupling reaction between the compound of formula (IX) or a salt thereof and the compound of formula (XI) using a coupling reagent and an additive in a third suitable solvent according to Scheme G4 to obtain the compound of formula (II). [ka]

[0372] 121. The method of embodiment 120, wherein the compound of formula (III-D) in step a. is the rate-limiting reagent.

[0373] 122. The method of embodiment 120 or 121, wherein about 1.5 to 2.0 equivalents of a compound of formula (III-C) are reacted with about 1 equivalent of a compound of formula (III-D) in step a.

[0374] 123. In step a, the compound of formula (III-C) is mixed with a first non-polar solvent and the first non-polar solvent is added to the mixture at a concentration of about -5 to 5 ° C, and a first acid is added, followed by the addition of a compound of Formula (III-D) in a first non-polar solvent while maintaining the temperature.

[0375] 124. The method of any one of embodiments 120-123, wherein the first acid is TFA.

[0376] 125. The method of any one of embodiments 120-124, wherein the first acid is TFA and about 0.05 equivalents are used.

[0377] 126. The method of any one of embodiments 120-125, wherein the first nonpolar solvent is toluene.

[0378] 127. The method of any one of embodiments 120-126, wherein the reaction mixture from step a is used in the subsequent step b without further purification.

[0379] 128. The method of any one of embodiments 120-127, wherein the second nonpolar solvent is toluene or a mixture of toluene and n-heptane.

[0380] 129. The method of any one of embodiments 120-128, wherein R1-Cl is mixed with n-heptane before adding the reaction mixture from step a, which contains the compound of formula (III-B).

[0381] 130. Step b is performed at about -15°C to about -5 ° 130. The method of any one of embodiments 120-129, wherein the method is carried out at a temperature of C.

[0382] 131. R1-Cl is about -15 ° C~approx.-5 ° 131. The method of any one of embodiments 120-130, wherein the reaction mixture from step a is added at a temperature of C.

[0383] 132. The method of any one of embodiments 120-131, wherein R1-Cl is methyl chloroformate.

[0384] 133. The method of any one of embodiments 120-132, wherein in step c, the first base is K2CO3.

[0385] 134. The method of any one of embodiments 120-133, wherein in step c, about 1.1 equivalents of the first base are used.

[0386] 135. The method of any one of embodiments 120-134, wherein the suitable solvent in step c is DMSO, toluene, or a mixture thereof.

[0387] 136. The method of any one of embodiments 120-135, wherein the suitable solvent in step c is DMSO.

[0388] 137. In step c, the compound of formula (VIII-A), the first base and a suitable solvent are mixed and heated for about 80 to 100 minutes before adding the compound of formula (III) in the suitable solvent. ° 137. The method of any one of embodiments 120-136, wherein the heating is performed at RT.

[0389] 138. In step c, the compound of formula (VIII-A), K2CO3 and DMSO are mixed and cooled to about 80-100°C before adding the compound of formula (III) in DMSO. ° 138. The method of any one of embodiments 120-137, wherein the heating is performed at RT.

[0390] 139. The method of any one of embodiments 120-138, wherein in step c, the compound of formula (III) is a compound of formula (III-A).

[0391] 140. The method of any one of embodiments 120-139, wherein the suitable solvent in step c is DMSO.

[0392] 141. The method of any one of embodiments 120-140, wherein in step d, the compound of formula (VIII) is a compound of formula (VIII-B). [ka] . 142. The method of any one of embodiments 120-141, wherein in step d, the fourth base is KOH.

[0393] 143. The method of embodiment 142, wherein the fourth base is KOH and the reaction is carried out in MeOH.

[0394] 144. The method of embodiment 142 or 143, wherein about 3 M KOH in MeOH is used.

[0395] 145. The method of any one of embodiments 142-144, wherein step d is carried out by heating, for example, by heating to reflux.

[0396] 146. The method of any one of embodiments 120-141, wherein in 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.

[0397] 147. The method of embodiment 146, wherein the third acid is a mixture of HBr and AcOH.

[0398] 148. The method of embodiment 147, wherein the dihydrobromide salt of compound (IX) is formed.

[0399] 149. The method of embodiment 148, wherein the dihydrobromide (X) is neutralized with a base such as NH4OH or NaOH to form a compound of formula (IX).

[0400] 150. The method of any one of embodiments 120 to 149, wherein in step e, the coupling reagent is selected from the group consisting of EDC, DCC, propylphosphonic anhydride (T3P®), and HATU.

[0401] 151. The method of any one of embodiments 120-150, wherein in step e, the coupling reagent is EDC or EDC·HCl.

[0402] 152. The method of any one of embodiments 120 to 151, wherein in step e, the additive is selected from the group consisting of ethyl (hydroxyamino)cyanoacetate (OxymaPure®), HOBt, HOSu, and HOPO.

[0403] 153. The method of any one of embodiments 120-152, wherein in step e, the additive is HOBt.

[0404] 154. The method of any one of embodiments 120-153, wherein in step e, the coupling reagent is EDC and the additive is HOBt.

[0405] 155. The method of any one of embodiments 120-154, wherein in step e, the third suitable solvent is DMSO. [Example]

[0406] The compounds described in this application are prepared using the methods of the present invention, as detailed below. The following illustrates embodiments of the claimed methods. Those skilled in the art will understand that other embodiments encompassed by the claimed methods can be practiced using the following examples with some modifications within the skill of those skilled in the art. Intermediate compounds and any final products were analyzed using conventional analytical techniques.

[0407] List of abbreviations: 1 H NMR proton nuclear magnetic resonance 2,3-DPG 2,3-diphosphoglyceric acid 2-MeTHF 2-methyltetrahydrofuran Bn Benzyl CALB / Cal B Candida Antarctica Lipase B CDCl3 deuterated chloroform CRED carbonyl reductase d chemical shift DCC Dicyclohexylcarbodiimide DCM dichloromethane DMAc N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d6 Deuterated dimethyl sulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Eq equivalent EtOAc ethyl acetate EtOH ethanol GC Gas Chromatography GDH glucose dehydrogenase h time HATU Hexafluorophosphate Azabenzotriazole Tetramethyluronium HOBt Hydroxybenzotriazole HOPO 2-Hydroxypyridine N-oxide HOSu N-hydroxysuccinimide HPLC High Performance Liquid Chromatography HCl Hydrochloric acid IPA Isopropyl Alcohol iPr Isopropyl iPrAc Isopropyl acetate KF Karl Fischer LCMS Liquid Chromatography / Mass Spectrometry LOD Loss on drying Me methyl MeCN acetonitrile MeOH Methanol MHz Megahertz Min MSA methanesulfonic acid MTBE Methyl tert-butyl ether NADP Nicotinamide adenine dinucleotide phosphate NBS N-Bromosuccinimide n-BuLi n-butyllithium NLT or higher NMH or less NMMNTB N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine PKR Pyruvate kinase R ppm parts per million QNMR Quantitative NMR RBC red blood cells rt room temperature SFC Supercritical Fluid Chromatography T3P® Propylphosphonic Anhydride TfO triflate, trifluoromethanesulfonate TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl UPLC Ultra High Performance Liquid Chromatography UPLCMS Ultra High Performance Liquid Chromatography Mass Spectrometry vol volume Example 1 Synthesis of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) and 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B) [ka]

[0408] Synthesis 1: 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B) The first reactor was charged with 1,4-dichloro-2-butyne (1.163 kg, 1.5 equiv.) and toluene (2.84 L, 1.9 vol.) under a nitrogen atmosphere, and the mixture was cooled to a temperature of -5°C to 5°C. TFA (0.036 kg, 0.05 equiv.) was added to the reactor while maintaining a temperature of -5°C to 5°C. The charge line was rinsed with toluene (0.075 L, 0.05 vol.), and the rinse was added to the reactor. N-(methoxymethyl)-N-(trimethyl-silylmethyl)benzylamine (NMMNTB) (1.496 kg, 1.0 equiv., 1.0 vol.; limiting reagent) was added to the reactor in several portions over 1 to 2 hours while maintaining a temperature of -5°C to 10°C. The charge line was rinsed with toluene (0.075 L, 0.05 vol.), and the rinse was added to the reactor. The reaction mixture was then stirred at -7°C to 10°C for approximately 1 hour. A 2 mL aliquot of the reaction mixture was removed and quenched with 4 mL of saturated, ice-cold aqueous sodium bicarbonate. 1 H NMR evaluation confirmed the completion of step 1 and the formation of 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole, intermediate compound (III-B).

[0409] 1 H NMR (CDCl3, 300MHz) δ(ppm): 7.34-7.14 (m, 5H), 4.27 (s, 4H), 3.80 (s, 2H), 3.59 (s, 4H) ppm.

[0410] Step 2: Methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) The second reactor was charged with n-heptane (1.35 L, 0.9 vol) followed by methyl chloroformate (0.834 kg, 1.4 eq). The charge line was rinsed with n-heptane (0.15 L, 0.1 vol), and the wash was added to the second reactor. The second reactor was then cooled to a temperature of -15°C to -10°C, and the contents of the first reactor were charged to the second reactor over 1 to 2 hours while maintaining a temperature of -15°C to -10°C. The charge 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 minutes at a temperature of -15°C to -5°C. The progress of the reaction was monitored by HPLC analysis, and stirring was continued until the reaction was complete.

[0411] The second reactor was then charged with deionized water (3.0 L, 2 vol), while maintaining the temperature of the reaction mixture at <20°C during the addition. The reaction mixture was stirred overnight at 10°C. The second reactor was then charged with n-heptane (13.5 L, 9.0 vol) over at least 1 hour, resulting in precipitation of the product. The reaction mixture was cooled to -5°C to 2°C over at least 1 hour and then stirred for at least 1 hour while maintaining a temperature of -5°C to 2°C. The reaction mixture was then filtered to obtain the solid product, which was then rinsed with deionized water (6 x 3.9 L, 6 x 2.6 vol), stirring for at least 15 minutes between each wash. The filter cake was then rinsed with n-heptane (2 x 3.9 L, 2 x 2.6 vol), stirring for at least 15 minutes between each wash. The filter cake was then dried under vacuum at 40 °C to give methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A, 1.3 kg, 70% yield) as a white to pale pink / beige solid with a purity of >95% as assessed by HPLC.

[0412] 1H NMR (CDCl3, 300MHz) δ (ppm): 4.38 (m, 2H), 4.35 (m, 2H), 4.19 (s, 4H), 3.75 (s, 3H) ppm.

[0413] Example 2 Alternative synthesis of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) and 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B) Step 1: 1-Benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B) [ka]

[0414] 1,4-Dichlorobut-2-yne (556 mL, 2.0 equiv.) and toluene (1.35 L, 2 vol.) were charged to a 4 L reactor under a stream of nitrogen, and the solution was cooled to 0 °C. TFA (10.9 mL, 0.05 equiv.) was added at -2 °C, and the mixture was stirred for 18 min. NMMNTB (750.0 g, 675.0 g pure, 1.0 equiv.) was then charged to the reactor over 2 hours and 39 minutes at -3°C. At the end of the addition, an exothermic reaction was observed to a maximum temperature of 14°C. The mixture was stirred while cooling at -5 to 0°C. After 1 hour and 20 minutes 1 Monitoring the conversion by H NMR showed 91.3% conversion to 1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole (III-B). The product was carried on to the next step without further purification.

[0415] 1 H NMR (CDCl3, 300MHz) δ(ppm): 7.34-7.14 (m, 5H), 4.27 (s, 4H), 3.80 (s, 2H), 3.59 (s, 4H) ppm.

[0416] Step 2: Methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A) [ka]

[0417] The product mixture from the first step was cooled to -8°C and methyl chloroformate (208 mL, 1.4 equiv.) was added over 36 minutes. The reactor reached a maximum temperature of -3°C during the addition. The contacting was continued at a temperature of -5°C. After 40 minutes, HPLC and 1 Monitoring the product conversion by 1 H NMR showed 100% conversion to give methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A).

[0418] The reaction mixture was transferred to a 15 L reactor (cooled to -5 °C) for workup. n-Heptane (675 mL, 1 vol) was added, followed by deionized water (1.35 L, 2 vol). An exothermic reaction up to 10 °C was observed, and the mixture was warmed to 15–20 °C to promote phase separation. After decantation, three layers were observed: an upper organic layer (turbid, yellowish), a middle aqueous layer (turbid, white), and a bottom organic layer (dense, oily, orange). The bottom and middle layers were discarded, and the top layer was washed first with deionized water (675 mL, 1 vol), then with saturated aqueous sodium bicarbonate (675 mL, 1 vol), and finally with brine (675 mL, 1 vol). After sequentially discarding the aqueous layers, the organic layer was cooled to 5 °C and stored in the reactor overnight without stirring. No change in appearance was observed.

[0419] The reactor contents were drained into a clean drum (Note: Treatment of the solution with anhydrous sodium sulfate can be included at this stage to ensure no aqueous layer is carried over in the isolation step), and the reactor was washed with deionized water (2 L) followed by acetone (1 L) and dried under vacuum.

[0420] The resulting solution was filtered through glass fiber and then charged to a clean 15 L reactor. n-Heptane (6.1 L, 9 vol) was added over 8 min at 18–20 °C, and then the mixture was cooled to −20 °C over 1 h 45 min. After stirring at −20 °C for 1 h 50 min, the resulting white suspension was filtered, washed with ice-cold n-heptane (2 × 1 L, 2 × 1.5 vol), and dried under vacuum at 40 °C overnight to give 361.8 g of product (57% yield, QNMR = 103%).

[0421] The crude solid product (50.1 g) and toluene (100 mL, 2 vol) were charged into a 1 L reactor flushed with nitrogen, and the mixture was warmed to 25-30 °C to give a brown solution. Then, n-heptane (50 mL, 1 vol) and deionized water (100 mL, 2 vol) were added, and the mixture was stirred at approximately 25 °C for 9 min.

[0422] The aqueous layer (pH = 2-3) was decanted and discarded. The organic layer was washed with saturated aqueous sodium bicarbonate (50 mL, 1 vol) and brine (50 mL, 1 vol). The 1 L reactor was washed with water and acetone and dried. The organic layer was then filtered over glass fiber and transferred to a clean 1 L reactor under nitrogen. n-Heptane (450 mL, 9 vol) was added over 2 minutes at 23 °C. Crystallization occurred approximately halfway through the addition; the suspension initially became thick and then more fluid toward the end of the addition.

[0423] The suspension was cooled to approximately -15 °C and stirred at this temperature for 17 min. The solid was filtered, washed with cold n-heptane (2 × 50 mL, 2 × 1 vol) and dried under vacuum at 40 °C. The product was obtained as a fine white solid (III-A, 23.2 g) with an HPLC purity of 99.5%.

[0424] 1 H NMR (CDCl3, 300MHz) δ (ppm): 4.38 (m, 2H), 4.35 (m, 2H), 4.19 (s, 4H), 3.75 (s, 3H) ppm.

[0425] Example 3 Synthesis of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV) Step 1: 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine (IV-C) [ka]

[0426] The reactor was charged with EtOH (9.87 L, 8.5 vol), followed by 2,3-dihydroxypyridine (1.16 kg, 10.45 mol, 1 equiv.), and then deionized water (1.74 L, 1.5 vol.). KCO (3.61 kg, 2.5 equiv.) was then added to the reactor via the manway. 1,2-Dibromoethane (3.93 kg, 2.0 equiv.) was then slowly charged to the reactor. The charge line was rinsed with EtOH (approximately 1 L), and the rinse was added to the reactor. The resulting suspension was heated to 75-85 °C (reflux) and stirred 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.

[0427] The EtOH in the reaction mixture was azeotropically distilled off at a temperature of 80-90°C until a residual volume of 3-4 volumes was reached (approximately 7 volumes). Deionized water (5.81 L, 5 volumes) was charged to the reactor, and distillation resumed until the mass temperature reached 99-100°C. Additional deionized water (2.31 L, 2 volumes) was charged to the reactor, and distillation resumed until the mass temperature reached 99-100°C. The mixture was then cooled to below 30°C. EtOAc (5.81 L, 5 volumes) was charged to the reactor, and the mixture was stirred at a temperature below 30°C for 30 minutes. The stirring was stopped, the layers were allowed to separate for 30 minutes, and the bottom aqueous layer was drained into a clean container. The first upper organic layer was drained into another clean container.

[0428] The aqueous layer was returned to the reactor, which was then charged with EtOAc (5.81 L, 5 volumes), and the resulting mixture was stirred for 30 minutes at a temperature below 30°C. The stirring was stopped, the layers were allowed to separate for 30 minutes, and the bottom aqueous layer was drained into a clean container. The first upper organic layer was then charged to the reactor, followed by brine (approximately 5 volumes, 4.35 L of water, and 1.45 kg of sodium chloride, approximately 25 wt% brine solution). The mixture was then stirred for 30 minutes, at which point the stirring was stopped, the layers were allowed to separate for 30 minutes, and the bottom aqueous layer was drained into a clean container.

[0429] The combined organic extracts remaining in the reactor were then concentrated to approximately 2 volumes by distillation. The mixture was then cooled to 25°C and discharged into a clean container. The reactor was rinsed with additional EtOAc and combined with the concentrated organic extracts. The resulting 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-C) was stored as a concentrated solution in EtOAc and carried on to the next step.

[0430] 1 H NMR(DMSO-d6, 300MHz)δ(ppm):7.73 (dd, J = 4.8, 1.5 Hz, 1H), 7.28 (dd, J = ddd, 7.8, 1.5, 0.6 Hz, 1H), 6.95 (ddd, J = 7.8, 4.8, 0.3 Hz, 1H), 4.40-4.38 (m, 2H), 4.26-4.24 (m, 2H) ppm.

[0431] Step 2: 7-Bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B) [ka]

[0432] The concentrated solution of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-C) (919.1 g pure, 1.0 equiv.) prepared in the first step was charged to a reaction vessel along with DMF (4.5955 L, 5.0 vol.). N-bromosuccinimide (NBS) (1.5506 kg, 1.3 equiv.) was then charged to the reactor via a hopper at 20-30 °C. The resulting mixture was heated to 55-60 °C and stirred at this temperature for 8 h. The mixture was cooled to 25 °C and evaluated by HPLC to confirm complete conversion to the desired product. The mixture was then further cooled to a temperature below 5 °C, and a solution of sodium metabisulfite (1.274 kg, 1.0 equiv.) in deionized water (9.191 L, 10 vol.) was charged to the reactor while maintaining the temperature below 15 °C. The resulting mixture was further cooled to a temperature of 0–5°C and stirred for at least 2 hours. The product precipitated from solution and was isolated by filtration. The filter cake was washed with deionized water (5 × 4.5955 L, 5 × 5 vol) and then dried under vacuum at 55°C for 16 hours to yield 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B, 1.8900 kg, 62% yield) as an off-white to pale yellow powder.

[0433] 1 H NMR (DMSO-d6, 300MHz) δ(ppm): 7.85 (d, J = 2.1Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 4.44-4.41 (m, 2H), 4.29-4.27 (m, 2H) ppm.

[0434] Step 3: 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV) [ka]

[0435] THF (14.051 L, 9 volumes) was charged to the first reactor, and 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 through the manhole. The mixture was stirred at 25 °C for 15 minutes. The mixture was evaluated for water content, and if the water content was determined to be less than 0.1% v / v, it was proceeded to the next step.

[0436] The reaction mixture was then cooled to -25°C to -18°C, and the reactor was charged with isopropylmagnesium chloride in THF (0.8696 kg, 1.17 equiv.) while maintaining a temperature of -25°C to -5°C. The charge line was rinsed with THF (1.5612 L, 1 vol.), and the wash was charged to the reactor. n-Butyllithium (0.7268 kg, 1.57 equiv.) in hexane was then charged to the reactor while maintaining a temperature of -25°C to -5°C. The charge line was rinsed with THF (1.5612 L, 1 vol.), and the wash was charged to the reactor. The mixture was stirred for 15 to 25 minutes at a temperature between -25°C and -5°C.

[0437] Toluene (4.6836 L, 3 vol) was charged to the second reactor, followed by sulfuryl chloride (2.9262 kg, 3 eq.) while maintaining a temperature below 25°C. The charge line was rinsed with toluene (1.5612 L, 1 vol), and the rinse 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 rinse was added to the second reactor. The resulting reaction mixture in the second reactor was stirred for at least 30 minutes while maintaining a temperature between -25°C and 0°C. After 30 minutes, an aliquot of the reaction mixture was removed, quenched with ice water, and analyzed via HPLC to confirm complete conversion to the desired product, intermediate compound 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride (IV-A).

[0438] The second reactor was charged with deionized water (6.2448 L, 4 volumes) while maintaining the temperature below 0°C. The mixture was stirred for 20 minutes at a temperature between -10°C and 0°C. After stirring, the layers were allowed to separate for at least 15 minutes, and the bottom aqueous layer was returned to the first reactor while maintaining the temperature below 0°C. A 20% w / w solution of sodium chloride (1.5612 kg) in deionized water (brine, 6.2448 L, 4 volumes) was prepared in a separate container, and half of it (approximately 2 volumes) was charged to the second reactor while maintaining the temperature below 0°C. The mixture was then stirred for 20 minutes at a temperature below 0°C. After stirring, the layers were allowed to separate for at least 15 minutes, and the bottom aqueous layer was returned to the first reactor while maintaining the temperature below 0°C. The second half of the brine solution (approximately 2 volumes) was charged to the second reactor while maintaining the temperature below 0°C. The mixture was then stirred for 15 minutes at a temperature below 0° C. After stirring, the layers were allowed to separate for at least 15 minutes, and the bottom aqueous layer was returned to the first reactor while maintaining the temperature below 0° C.

[0439] The reactor holding the aqueous wash was charged with DCM (7.0860 L, 5 vol) and stirred for 15 minutes while maintaining the temperature below 5°C. After stirring, the layers were allowed to separate for approximately 60 minutes. The remaining organic layer in the second reactor was cooled to -15°C, and the bottom organic layer from the first reactor was added to the second reactor. The combined organic extracts in the second reactor were cooled to -20°C.

[0440] The ammonium solution in MeOH (0.9846 kg, 8.0 equiv.) was charged to the second reactor over 1 hour while maintaining a temperature below 5°C. The charge line was rinsed with MeOH, and the washings were charged to the second reactor. The reaction mixture was then stirred for 1-3 hours while maintaining a temperature below 0°C. An aliquot of the reaction mixture was removed and evaluated via HPLC to confirm complete conversion to the desired product, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV).

[0441] The reaction mixture was cooled to -10°C and the reactor was charged with deionized water (7.806 L, 5 vol) while maintaining the 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 solid was washed by allowing the reactor wash to percolate through the filter for 15 minutes, stirring the solid, and then filtering again under vacuum. Deionized water (3.122 L, 2 vol) was charged to the reactor and the collected solid was washed by allowing the reactor wash to percolate through the filter for 15 minutes, stirring the solid, and then filtering again under vacuum.

[0442] 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 stirred under reflux for 1-2 hours. After stirring, the slurry was cooled to 15-25°C and further The mixture was stirred for 30 minutes. The solid product was collected by filtration under vacuum, and the reactor was filled with deionized water (3.1 L, 2 volumes). The collected solid was washed by allowing the wash from the reactor to percolate through the filter for 15 minutes, the solid was stirred, and then filtered again under vacuum. An aliquot of the solid product was removed and evaluated by HPLC to confirm the purity of the product.

[0443] DCM (3.750 L, 2.4 vol) was charged to the reactor along with the wet cake collected via filtration in the previous step. MeOH (1.250 L, 0.8 vol) was charged to the reactor, and the mixture was stirred for at least 30 minutes at a temperature of 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 solid was washed by allowing the wash from the reactor to percolate through the filter for 15 minutes, stirring the solid, and then filtering again under vacuum. An aliquot of the solid product was removed and evaluated by HPLC to confirm the purity of the product. The solid was dried under vacuum at 50 °C for 16 hours to yield 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV, 0.94 kg, 60% yield, 99.4% purity by HPLC) as a white to gray / beige powder.

[0444] 1 H NMR(DMSO-d6, 300MHz)δ(ppm):8.15 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.47 (br s, 2H), 4.52-4.50 (m, 2H), 4.35-4.32 (m, 2H) ppm.

[0445] Example 4 Alternative synthesis of 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B) Step 1: 5-Bromopyridine-2,3-diol (IV-E) [ka]

[0446] Furfural (IV-F, 5.8 g, 0.06 mol) in 70 g of water was cooled to 0 °C, and bromine (9.7 g, 0.06 mol) was added dropwise while maintaining the temperature at 0–5 °C. After stirring for 30 min, HBr (concentrated, 3 mL) was added in one portion and stirred for an additional 30 min at 0–5 °C. The resulting solution was then cooled to -10 °C. Bromine (9.7 g, 0.06 mol) was added dropwise to the reaction solution while maintaining the temperature below 0 °C. The reaction solution was stirred at -5 °C for 1 h and then added to a solution of sulfamic acid (6 g, 0.062 mol) in water (23 g) while maintaining the temperature at 45–55 °C. The reaction was stirred at 50–55 °C for 30 min. The reaction mixture was then cooled to 0-10 °C and stirred for an additional 1 h, and finally filtered to collect the desired product as a precipitate. The precipitated product was then dried at 50 °C for 18 h to collect the crude product, 5-bromopyridine-2,3-diol (IV-E), as a gray solid (65% yield).

[0447] 1H NMR (400MHz, DMSO-d6)δ(ppm): 11.84 (brs, 1H), 9.55 (brs, 1H), 7.06 (d, J = 2.4Hz, 1H), 6.78 (d, J = 2.4Hz, 1H).

[0448] Step 2: 7-Bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B) [ka]

[0449] To a solution of 5-bromopyridine-2,3-diol (IV-E, 1.0 equiv.) in EtOH / HO (10 vol / 10 vol), K2CO3 (1.41 equiv.) and BrCH2CH2Br (1.76 equiv.) were added. The mixture was heated to 70-75 °C for 44 h. Additional K2CO3 (0.35 equiv.) and BrCH2CH2Br (0.35 equiv.) were added, and heating was continued for an additional 10 h. The reaction progress was monitored via HPLC to confirm complete consumption of the starting material. The reaction solution was then concentrated to remove EtOH. EtOAc (20 vol.) was added to extract the desired product. The product solution in EtOAc was concentrated. DMF (1.5 vol.) was added, followed by HO (7.5 vol.). The precipitate was filtered and dried to give the desired product, 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (IV-B) (45% yield).

[0450] 1 H NMR (DMSO-d6, 300MHz) δ(ppm): 7.85 (d, J = 2.1Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 4.44-4.41 (m, 2H), 4.29-4.27 (m, 2H) ppm.

[0451] Example 5 Synthesis of (S)-tropic acid (VII) Step 1: Methyl 2-formyl-phenylacetate (VII-B) [ka]

[0452] Sodium methoxide (1.3 equiv.) 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 equiv.) was charged over a period of at least 20 minutes while maintaining a temperature of 15-20°C. Additional MTBE (0.5 vol.) was used to rinse the charge line, and the rinse was added to the reactor. The reactor contents were held and stirred for 30-60 minutes at a temperature of 15-25°C. Methyl formate (1.80 kg, 1.5 equiv.) was then charged to the reactor over a period of at least 1 hour while maintaining a temperature of 15-25°C. Additional MTBE (0.5 vol.) was used to rinse the charge line, and the rinse was added to the reactor. The reactor contents were then heated to a temperature of 15-25°C and stirred for at least 5 hours while maintaining the aforementioned temperature. An aliquot of the reaction mixture was removed and 1 The progress of the reaction was monitored by assessing the methyl phenylacetate content by 1 H NMR.

[0453] The reaction mixture was then cooled to -10°C to 5°C, and water (4 volumes) was charged to the reactor while maintaining the reactor temperature between -10°C and 5°C. The reactor contents were then stirred for at least 15 minutes while maintaining the 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.

[0454] The reactor contents were allowed to settle for at least 15 minutes, and the bottom aqueous layer containing the desired product was drained into a suitable container stored at a temperature between -10°C and 5°C. The upper organic layer was then drained from the reactor. The aqueous layer was returned to the reactor and maintained at a temperature between -10°C and 5°C. MTBE (4 volumes) was charged to the reactor, and the mixture was stirred while maintaining a temperature between -10°C and 5°C. While maintaining a temperature between -10°C and 5°C, a 25% w / w aqueous solution of citric acid (3 volumes) was charged to the reactor, and the resulting mixture was stirred for at least 15 minutes.

[0455] The reaction mixture was allowed to settle for at least 40 minutes and the layers were separated. The top organic layer, containing the desired product, was set aside, and the bottom aqueous layer was returned to the reactor. The pH of the aqueous layer was monitored and adjusted until it was within the range of 4-5. MTBE (1.5 volumes) was charged to the reactor containing the aqueous layer and stirred for at least 10 minutes while maintaining a temperature of 5-20°C. The contents of the reactor were allowed to settle for at least 15 minutes, and the bottom aqueous layer was removed.

[0456] The combined organic layer was charged to a reactor, followed by 20% w / w sodium chloride solution (1.5 volumes). The mixture was then stirred for at least 10 minutes while maintaining a temperature of 5-20°C. The reactor contents were allowed to settle for at least 15 minutes, and then the bottom aqueous layer was removed. The reactor contents were then heated to a temperature of 28-35°C under reduced pressure until the combined organic layer was concentrated to approximately 4.5 volumes.

[0457] The reactor contents were cooled and the final product solution was drained into a clean container and stored at −20 °C to obtain methyl 2-formyl-phenylacetate (VII-B; 3.31 kg active, 93% yield was obtained. The final product solution 1 Assay by 1 H NMR confirmed the identity and purity of the product.

[0458] 1H NMR, enol form (500MHz, CDCl3) δ(ppm): 12.0 (br s, 1H), 7.20-7.40 (m, 5H), 3.78 (s, 3H).

[0459] 1 H NMR, aldehyde hydrate form (500MHz, CDCl3)δ(ppm): 7.90 (s, 1H), 7.20-7.40 (m, 5H), 3.70 (s, 3H).

[0460] 1 H NMR, aldehyde form (500MHz, CDCl3)δ(ppm): 9.83 (s, 1H), 7.20-7.40 (m, 5H), 3.60 (s, 3H).

[0461] Alternative Step 1: Methyl 2-formyl-phenylacetate (VII-B) [ka]

[0462] Sodium methoxide (30 g, 0.56 mol) was added to a 1 L flask equipped with overhead stirring, followed by toluene (415 ml). Methyl phenylacetate (VII-C, 79 ml, 0.56 mol) was added dropwise over 30 minutes, and the mixture was stirred at room temperature for an additional 10 minutes. Methyl formate was added dropwise, adjusting the addition rate to maintain the reaction temperature below 31°C. After all the methyl formate was added, the reaction mixture was stirred at room temperature for 3.5 hours and cooled to 5°C. A 0.4 M solution of citric acid (540 ml, 0.22 mol) was added dropwise with stirring. The layers were separated, and the aqueous layer was extracted with toluene (415 ml). The combined toluene extracts were washed with brine and concentrated in vacuo to give 105.5 g of a colorless liquid that partially solidified on standing. The crude product contained 77% methyl 2-formyl-2-phenylacetate (VII-B, 81.2 g, 82% yield) and 14% methyl phenylacetate.

[0463] 1H NMR, enol form (500MHz, CDCl3) δ(ppm): 12.0 (br s, 1H), 7.20-7.40 (m, 5H), 3.78 (s, 3H).

[0464] 1 H NMR, aldehyde hydrate form (500MHz, CDCl3)δ(ppm): 7.90 (s, 1H), 7.20-7.40 (m, 5H), 3.70 (s, 3H).

[0465] 1 H NMR, aldehyde form (500MHz, CDCl3)δ(ppm): 9.83 (s, 1H), 7.20-7.40 (m, 5H), 3.60 (s, 3H).

[0466] Step 2: Crude (S)-tropic acid (VII) [ka]

[0467] Water (8.75 vol), KH2PO4 (0.178 equiv.), and glucose monohydrate (2.5 equiv.) were charged into a reactor and stirred for at least 5 min at a temperature of 20–28 °C. The pH of the solution was adjusted to 6.75 ± 0.25 using 3 M NaOH, and the temperature of the solution was adjusted to 25–28 °C. CRED-A231M165-GDH-102 lyophilized cell-free extract (0.138 wt%) was charged into the reactor, and the solution was stirred for at least 15 min at a temperature of 25–28 °C. The 2.2–2.6 wt.% enzyme-glucose solution was removed and stored under ambient conditions for later use.

[0468] Next, NADP disodium salt (0.002265 equiv.) and MTBE (7.25 vol.) were charged to the reactor, and the solution was stirred while maintaining a temperature of 25–28 °C. The product solution containing methyl 2-formyl-2-phenylacetate (VII-B) produced in step 1 above was then charged to the reactor at a constant rate over 4.5–5.5 h, maintaining a pH range of 6.75 ± 0.25 using 3 M NaOH and a reaction temperature of 25–28 °C. After complete addition of methyl 2-formyl-2-phenylacetate (VII-B), the previously removed enzyme-glucose solution was added to the reactor all at once. The remaining methyl 2-formyl-2-phenylacetate (VII-B) solution (1.51-1.81 volumes) was then charged to the reactor at a constant rate over 5.5-6.5 hours, maintaining a pH range of 6.75 ± 0.25 and a reaction temperature of 25-28 °C using 3 M NaOH. The reactor contents were stirred for an additional 4 hours at a temperature of 25-28 °C and a pH of 6.75 ± 0.25. Completion of the reaction was assessed by NMR, which confirmed conversion to the desired product, (S)-methyl tropate (VII-A).

[0469] 1 H NMR(500MHz, CDCl3)δ(ppm):7.36-7.26 (m, 5H), 4.08-4.18 (m, 1H), 3.87-3.80 (m, 2H), 3.71 (s, 3H), 2.35 (br s, 1H).

[0470] The reactor contents were concentrated under reduced pressure to a total volume of 10-11.25 volumes, while maintaining a temperature below 40°C. After concentration, the reactor contents were heated to 40-50°C and stirred for 5-15 minutes. Liquid CALB (0.5% by weight) was charged to the reactor in one portion, and the resulting solution was stirred for 24 hours while maintaining a temperature of 40-50°C and a pH of 7.25 ± 0.25. The pH of the reaction mixture was adjusted, as needed, using 3 M aqueous NaOH. The reaction process was evaluated by HPLC, and after the reaction was determined to be complete, the reactor contents were cooled to 10-15°C and stirred for 5-15 minutes.

[0471] The pH of the reactor contents was adjusted to a value of 1.0-1.5 using 25% hydrochloric acid (approximately 1.4 vol) while maintaining a temperature of 10-15 °C. After pH adjustment, the reactor contents were stirred for at least 4 hours while maintaining a temperature of 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, cooled to a temperature of 10-15 °C, and then used to wash the wet filter cake. The wet filter cake yielded crude (S)-tropic acid (VII, 1.51 kg active, 81% yield), which was evaluated for purity (99.32%) and enantiomeric purity (99.3%) by HPLC.

[0472] 1 H NMR (500MHz, MeOD) δ(ppm): 7.25-7.35 (m, 5H), 4.90 (br s, 1H), 4.05-4.15 (m, 1H), 3.69-3.77 (m, 2H).

[0473] 1 H NMR (400MHz, DMSO-d6)δ(ppm): 7.17-7.27 (m, 5H), 6.90 (br s, 2H), 3.82-3.77 (m, J = 1H), 3.42-3.56 (m, 2H).

[0474] Alternative Step 2a: (S)-Methyl tropate (VII-A) [ka]

[0475] In a 1 L flask equipped with overhead stirring, glucose monohydrate (57.8 g, 1.3 equiv.), L-lysine hydrochloride (8.2 g, 0.2 equiv.), and thiamine hydrochloride (7.6 g, 0.1 equiv.) were dissolved in 0.1 M potassium phosphate buffer (430 ml). The resulting solution was warmed to 30 °C and the pH was adjusted to 6.5 using aqueous KCO (20% w / w). 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). A solution of methyl 2-formyl-2-phenylacetate (40 g, 1 equiv.) in 40 ml of toluene was added via syringe pump over 10 h, maintaining the reaction temperature at 30 °C and pH 6.5. Five hours after the start of the addition, additional GDH-102 (0.8 g, 2 wt%) and CRED-41 (4 g, 10 wt%) were added.

[0476] After stirring for 16 hours, 100 ml of toluene was added and the reaction mixture was filtered through a layer of celite. The layers were separated and the aqueous phase was extracted with toluene (2 x 75 ml). The organic layers were combined and washed with brine. (1×100 mL) Concentration under reduced pressure gave 45.2 g of crude reaction mixture containing 57% of (S)-methyl tropate (VII-A, ee 87% (S), yield 64%).

[0477] 1 H NMR(500MHz, CDCl3)δ(ppm):7.36-7.26 (m, 5H), 4.08-4.18 (m, 1H), 3.87-3.80 (m, 2H), 3.71 (s, 3H), 2.35 (br s, 1H).

[0478] Alternative step 2b: Crude (S)-tropic acid (VII) [ka]

[0479] A 1 M NaOH solution in 15% aqueous NaCl was prepared in a 1 L flask equipped with overhead stirring (NaOH: 15 g (2 equiv.); NaCl: 58 g, HO: 393 ml). This solution was cooled to −10°C. A solution of crude (S)-methyl tropate (VII-A, 33 g, 1 equiv.) in toluene (200 ml) was added dropwise over 2 hours with vigorous stirring, maintaining the reaction temperature at −10°C. After all the toluene solution had been added, stirring was continued for an additional hour.

[0480] The pH of the reaction mixture was adjusted to 8 by the addition of aqueous hydrochloric acid (28%) while maintaining the temperature below 0°C. MTBE (100 ml) was added with stirring, the phases were allowed to separate, and the organic layer was discarded. The aqueous phase was washed once more with 100 ml of MTBE (discarded organic layer).

[0481] Aqueous sulfuric acid (50%) was added to adjust the pH to 2, followed by extraction with 2-MeTHF (3 x 100 ml). The combined organic layers were concentrated under reduced pressure to give crude (S)-tropic acid (VII, ee 86% (S), 27 g).

[0482] 1 H NMR (500MHz, MeOD) δ(ppm): 7.25-7.35 (m, 5H), 4.90 (br s, 1H), 4.05-4.15 (m, 1H), 3.69-3.77 (m, 2H).

[0483] 1 H NMR (400MHz, DMSO-d6)δ(ppm): 7.17-7.27 (m, 5H), 6.90 (br s, 2H), 3.82-3.77 (m, J = 1H), 3.42-3.56 (m, 2H).

[0484] Step 3: Recrystallization of (S)-tropic acid (VII) Crude (S)-tropic acid (VII, 1 equivalent) prepared in the previous step was charged to a clean reactor. THF (6 volumes, based on the input from step 2) was charged to the reactor. The reactor contents were heated to a temperature of 35-45°C and held for at least 1 hour.

[0485] The reactor contents were then filtered and the filter cake was washed twice with THF (3 volumes). Any undissolved material remaining on the filter was discarded. The filtrate and THF washes were 1 The (S)-tropic acid content in each solution was assessed by 1 H NMR.

[0486] The reactor was conditioned by rinsing with THF. The THF filtrate and washes prepared during the first filtration step were then returned to the reactor, and the mixture was concentrated to approximately 2 volumes by distillation under reduced pressure at a temperature of 35-45 °C.

[0487] After concentration, the reactor contents were heated to a temperature of 35-45°C, and water (4 volumes) was charged to the reactor. The reactor contents were then concentrated to approximately 4 volumes by distillation under reduced pressure at a temperature of 35-45°C. The THF content of the reaction mixture was 1 The 1 H NMR analysis confirmed that the content was 3 to 10%.

[0488] The reactor contents were then heated to a temperature of 35-45°C, and toluene (2 volumes) was added while maintaining the temperature at 35-45°C. The reactor contents were then cooled to a temperature of 0-10°C over at least 5 hours and held at this temperature for at least 15 hours. The reactor contents were then filtered while maintaining a temperature of 0-10°C. The reactor was visually inspected for any remaining solids, and the mother liquor was used to rinse the reactor and collect all remaining solid material.

[0489] The filter cake was then washed with toluene (2 volumes) while maintaining a temperature of 0-10°C. After washing, the filter cake was pulled dry under vacuum for at least 2 hours. The resulting semi-dried filter cake was then evaluated 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 hours. The dried filter cake was evaluated for water and solvent content by KF and GC, respectively. The dried product material was collected to give (S)-tropic acid (VII, 92% yield) with a purity of 99.8% and an enantiopurity of 99.7%.

[0490] 1H NMR (500MHz, MeOD) δ(ppm): 7.25-7.35 (m, 5H), 4.90 (br s, 1H), 4.05-4.15 (m, 1H), 3.69-3.77 (m, 2H).

[0491] 1 H NMR (400MHz, DMSO-d6)δ(ppm): 7.17-7.27 (m, 5H), 6.90 (br s, 2H), 3.82-3.77 (m, J = 1H), 3.42-3.56 (m, 2H).

[0492] Alternative Step 3: Recrystallization of (S)-Tropic Acid (VII) Crude (S)-tropic acid (10 g, ee 86% (S)) was suspended in a 1:4 mixture of n-heptane:iPrAc (50 mL), and the suspension was heated to 60 °C. After stirring at this temperature for 1 h, the mixture was allowed to cool to room temperature and equilibrate with stirring (approximately 20 h). Filtration and washing with 10 mL of cold n-heptane:iPrAc (1:4) gave (S)-tropic acid (7 g, ee 98.3% after drying under vacuum).

[0493] 1 H NMR (500MHz, MeOD) δ(ppm): 7.25-7.35 (m, 5H), 4.90 (br s, 1H), 4.05-4.15 (m, 1H), 3.69-3.77 (m, 2H).

[0494] 1 H NMR (400MHz, DMSO-d6)δ(ppm): 7.17-7.27 (m, 5H), 6.90 (br s, 2H), 3.82-3.77 (m, J = 1H), 3.42-3.56 (m, 2H).

[0495] Example 6 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) [ka]

[0496] Step 1: 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 (VA) A 1 L jacketed reactor was charged with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV, 31.00 g), KCO (21.15 g, 1.1 equiv.), and DMSO (300 mL, 10 vol.). The contents were heated to 100 °C. A solution of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A, 31.91 g, 1.0 equiv.) in toluene (270 mL, 9 vol.) was added slowly over 2.5 h through an in-line filter. The vessel was rinsed with toluene (30 mL, 1 vol.), and the rinse was added to the reactor over 10 min. The reactor contents were stirred at 100 °C for 1 h. A sample of the reaction mixture was taken and monitored by HPLC, which indicated 0.1% III-A remaining.

[0497] The reaction mixture was then cooled to room temperature over 6 hours. Toluene was removed by distillation at a jacket temperature of 60°C. The contents of the reactor were cooled to room temperature. To the resulting thick mixture was added water (300 mL, 10 vol) over 1 hour, maintaining the temperature below 30°C. The mixture was aged for 30 minutes.

[0498] The solid was filtered and washed with water (2 x 300 mL, 10 vol) and MeCN (4 x 150 mL, 5 vol). The solid was then dried on the filter for 16 h to give a white solid (42.219 g, 82.8%) with an HPLC purity of 97.8%.

[0499] The solid (42 g) was added to a 1 L jacketed reactor containing MeCN (420 mL, 10 vol). The mixture was heated to 80° C. and stirred for 1 h. The slurry was cooled to room temperature over 4 h, and then it was stirred overnight. The solid was collected by filtration and washed with MeCN (210 mL, 5 vol). The solid was dried on the filter for 2 h to give a white solid (40.21 g, 95.7% recovery, 78.9% overall yield) with an HPLC purity of 99.4%.

[0500] 1 H NMR(300MHz, CDCl3)δ(ppm):8.30 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 4.54-4.51 (m, 2H), 4.34-4.32 (m, 2H), 4.13-4.07 (m, 8H), 3.72 (s, 3H) ppm.

[0501] 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) 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 (VA, 29.4 g, 80 mmol), BuS A mixture of (88.2 mL, 3 vol) and MSA (58.8 mL, 2 vol) was heated at 70 °C for 19 h. LCMS showed the reaction was complete. The mixture was cooled to 10 °C, diluted with water (240 mL) at <25 °C, and extracted with n-heptane (3 × 120 mL). The aqueous solution was divided equally into two portions.

[0502] Portion 1 was cooled to 10 °C and neutralized with 28–30% NH4OH (120 mL) at <25 °C. The mixture was stirred at room temperature for 1 h and extracted with DCM (3×: 120 mL, 60 mL, and 60 mL). The combined DCM extracts were washed with 1 N NaOH (120 mL) and water (120 mL) and added to another flask charged with (S)-tropic acid (VII, 6.65 g, 40 mmol, 1.0 equiv.) and DCM (80 mL). The mixture was stirred at room temperature over the weekend. The solid was filtered, washed with DCM (30 mL), and dried in a vacuum oven at 40 °C for 6 h. 17.3 g (91.0% yield) of VI·VII was obtained.

[0503] Portion 2 was cooled to 10°C and neutralized with 28-30% NH4OH (120 mL) at <25°C. The mixture was stirred at room temperature for 20 minutes, heated to 70°C, and stirred for 1 hour. The mixture was cooled to 15°C and stirred for 0.5 hours. The solid was collected by filtration and washed with water (30 mL). The free amine was reslurried in water (120 mL) at 70°C for 20 hours, then cooled to 15°C and stirred for 0.5 hours. The solid was collected by filtration, washed with water (60 mL), and dried in a vacuum oven at 45°C for 6 hours. 10.1 g (81.6% yield) 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) was obtained.

[0504] 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine and (S)-tropic acid (VII, 5.7 g, 34.3 mmol, 1.05 equiv.) in MeCN (202 mL) / water (2.0 mL) were stirred at room temperature for 18 h. The solid was collected by filtration, washed with MeCN (60 mL), and dried overnight in a vacuum oven at 40 °C. This method afforded 14.5 g (93.5% yield, 76.2% overall) of VI·VII.

[0505] 1H NMR(300MHz, DMSO-d6)δ(ppm):8.18 (d, J = 3 Hz, 1H), 7.65 (d, J = 3 Hz, 1H), 7.27-7.18 (m, 5H), 7.0-6.2 (br, 3H) 4.53-4.50 (m, 2H), 4.35-4.32 (m, 2H), 4.03 (br s, 4H), 3.90-3.92 (m, 1H), 3.60-3.50 (m, 6H).

[0506] 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) To a 10-dram scintillation vial was added VI·VII (2.500 g), EDC·HCl (1.058 g, 0.525 equiv.), OxymaPure® (0.300 g, 0.2 equiv.), and DMAc (10 mL, 2 vol.). The contents of the vial were stirred at 20 ± 5 °C for 1 h. The remaining VI·VII (2.500 g) and EDC·HCl (1.058 g) were added, and the reaction mixture was allowed to stir for 3 h. An aliquot was sampled and analyzed by LCMS, which indicated that 0% of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI) remained. The reactor was charged with 2-MeTHF (15 mL, 3 vol), and the contents of the vial were passed through a 0.45 μm in-line filter. The vial was rinsed with DMAc (1 mL, 0.2 vol), and this solution was passed through the in-line filter. EtOH (2.5 mL, 0.5 vol) and 2-MeTHF (10 mL, 2 vol) were added to the vial, and the mixture was stirred at room temperature overnight.

[0507] Water (60 mL, 12 vol) was added to the reaction mixture. The slurry was aged at room temperature for 30 minutes, and then the solid was collected by filtration. The solid was washed with water (3 × 20 mL, 4 vol) and EtOH (1 × 20 mL, 4 vol). The solid was dried on the filter for 2 hours to give (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) as a white solid (4.29 g, 89.2% yield) with 98.6% HPLC purity.

[0508] 1 H NMR(400MHz, CDCl3)δ(ppm):8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35-7.23 (m, 5H), 4.51-4.50 (m, 2H), 4.32-4.30 (m, 2H), 4.28-3.93 (m, 8H), 3.78-3.67 (m, 3H), 3.15-3.13 (m, 1H) ppm.

[0509] Example 7 Reslurry 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) Crude (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, 13.7 g) was suspended in EtOH (205.5 mL, 15 vol) and water (13.7 mL, 3 vol). The mixture was heated to reflux for 30 minutes, then cooled to 70°C and aged for 3 hours. The slurry was then cooled to 50°C over 4 hours and stirred for 14 hours. The slurry was then cooled to 20°C over 1 hour and stirred for 1 hour. The solid was collected by filtration and washed with EtOH (41.1 mL, 3 vol). The solid was dried on the filter for 2 hours, then dried under full vacuum with a nitrogen bleed for 20 hours. The isolated white solid weighed 12.561 g (91.7% recovery, 81.6% overall yield) with an HPLC purity of 99.6%.

[0510] 1 H NMR(400MHz, CDCl3)δ(ppm):8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35-7.23 (m, 5H), 4.51-4.50 (m, 2H), 4.32-4.30 (m, 2H), 4.28-3.93 (m, 8H), 3.78-3.67 (m, 3H), 3.15-3.13 (m, 1H) ppm.

[0511] 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 (VA) [ka]

[0512] A 10 L jacketed reactor was charged with 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonamide (IV, 516.5 g), KCO (352 g, 1.1 equiv.), and DMSO (5 L, 10 vol.). The contents were heated to 100 °C. A solution of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A, 531.3 g, 1.0 equiv.) in toluene (3 L, 6 vol.) was added slowly over 2.5 h through an in-line filter. The vessel was rinsed with toluene (0.5 L, 1 vol.), and the rinse was added to the reactor over 10 min. The reactor contents were stirred at 100 °C for 1 h. A sample of the reaction mixture was taken and monitored by HPLC, which indicated 0.2% III-A remaining.

[0513] The reaction mixture was cooled to room temperature over 6 hours. Toluene was removed by distillation at a jacket temperature of 65°C.

[0514] The reactor contents were cooled to room temperature. To the thick mixture was added water (5 L, 10 vol) over 1 hour, maintaining the temperature below 30° C. The mixture was aged for 30 minutes.

[0515] The solid was collected by filtration and washed with water (2 × 5 L, 10 vol) and MeCN (4 × 2.5 L, 5 vol). The solid was dried on the filter for 2 h and then dried under full vacuum at 45 °C for 16 h to give a white solid (702 g, 82.6%) with an HPLC purity of 99.5% and a KF of 0.7%.

[0516] The crude solid (700 g) was added to a cleaned 10 L jacketed reactor and suspended in MeCN (7 L, 10 vol). The slurry was heated to 80 °C and stirred for 1 h. The reactor contents were cooled to 20 °C over 4 h and stirred for 14 h. The solid was collected by filtration and washed with MeCN (3.5 L, 5 vol). The solid was dried on the filter for 2 h and then dried overnight in a vacuum oven at 45 °C. The isolated solid was 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 (VA, 96.3% recovery, 79.5% yield) with an HPLC purity of 99.6% and a KF of 0.5%.

[0517] 1 H NMR(CDCl3, 300MHz):δ(ppm):8.30 (s, 1H), 7.59 (s, 1H), 4.55-4.50 (m, 2H), 4.35-4.30 (m, 2H), 4.15-4.05 (m, 8H), 3.72 (s, 3H).

[0518] 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) [ka]

[0519] 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 (VA, 300.0 g, 0.817 mol, obtained via the method of Example 8), BuS (900 mL, 3 vol), and MSA (600 mL, 2 vol) were charged to a 10 L jacketed reactor. The mixture was heated to 70 °C and stirred for 19 h. LCMS indicated the reaction was complete (VA = 0.6%). The mixture was cooled to below 10 °C, diluted with water (2.4 L) at below 25 °C, and extracted with n-heptane (3 × 1.2 L).

[0520] The aqueous solution was cooled to 10 °C and neutralized with 28–30% NH4OH (2.4 L) at ≤ 25 °C to give 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).

[0521] The mixture was stirred at room temperature for 1 h and extracted with DCM (2.4 L, 1.2 L, and 1.2 L). The combined DCM extracts were washed with 1 N NaOH (2.4 L), water (2.4 L), and added to a separate flask charged with (S)-tropic acid (VII, 135.7 g, 0.817 mol, 1.0 equiv.) and DCM (1.55 L). The mixture was stirred at room temperature (23 °C) for 20 h. The solid was collected by filtration, washed with DCM (600 mL), and dried overnight in a vacuum oven at 40 °C to give 360.2 g of (VI)·(VII) with a purity of 99.76% (92.8% yield). LOD: 0.16%.

[0522] 1H NMR(300MHz, DMSO-d6)δ(ppm):8.18 (d, J = 3 Hz, 1H), 7.65 (d, J = 3 Hz, 1H), 7.27-7.18 (m, 5H), 7.0-6.2 (br, 3H) 4.53-4.50 (m, 2H), 4.35-4.32 (m, 2H), 4.03 (br s, 4H), 3.90-3.92 (m, 1H), 3.60-3.50 (m, 6H).

[0523] Example 10 An 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) [ka]

[0524] 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 (VA, 300.0 g, 0.817 mol, obtained via the method of Example 8), BuS (900 mL, 3 vol), and MSA (600 mL, 2 vol) were charged to a 10 L jacketed reactor. The mixture was heated to 70 °C and stirred for 19 h. LCMS indicated the reaction was complete (VA = 0.5%). The mixture was cooled to below 10 °C and, at or below 25 °C, diluted with water (2.4 L) and extracted with n-heptane (3 × 1.2 L).

[0525] The aqueous solution was cooled to 10°C and neutralized with 28-30% NH4OH (2.4 L) at below 25°C.

[0526] The mixture was stirred at room temperature for 20 minutes, then heated to 70°C and stirred for 1 hour. The mixture was cooled to 12°C and stirred for 0.5 hours. The solid was filtered and washed with water (600 mL). The free amine was then reslurried in water (2.4 L) at 70°C for 18 hours. The mixture was cooled to 12°C and stirred for 0.5 hours. The solid was filtered, washed with water (600 mL), and dried in a vacuum oven at 50°C overnight to give 216.1 g 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, 85.5% yield, LOD, 0.20%).

[0527] A suspension 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 and (S)-tropic acid (121.9 g, 0.734 mol, 1.05 equiv.) in MeCN (4.32 L) / HO (43 mL) was stirred at room temperature (20 °C) for 21 h. The solid was collected by filtration, washed with MeCN (600 mL), and dried overnight in a vacuum oven at 40 °C to give 320.6 g of (VI)·(VII) with a purity of 99.66% (96.5% yield: 82.6% overall). LOD: 0.14%.

[0528] 1 H NMR(300MHz, DMSO-d6)δ(ppm):8.18 (d, J = 3 Hz, 1H), 7.65 (d, J = 3 Hz, 1H), 7.27-7.18 (m, 5H), 7.0-6.2 (br, 3H) 4.53-4.50 (m, 2H), 4.35-4.32 (m, 2H), 4.03 (br s, 4H), 3.90-3.92 (m, 1H), 3.60-3.50 (m, 6H).

[0529] Example 11 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) [ka]

[0530] To a 3 L round-bottom flask was added (VI)·(VII) (175.20 g, obtained from the method of Example 9), EDC·HCl (73.85 g, 0.525 equiv.), OxymaPure (20.99 g, 0.2 equiv.), and DMAc (700 mL, 2 vol.). The contents of the flask were stirred at 20 ± 5 °C for 1 h. The remaining (VI)·(VII) (175.49 g) and EDC·HCl (74.18 g) were added, and the reaction mixture was allowed to stir for 4 h. An aliquot was sampled and analyzed by HPLC, which indicated that 1.8% of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI) remained. The flask was charged with 2-MeTHF (700 mL, 2 vol) and the contents of the flask were passed through a 0.45 μm in-line filter into a 10 L jacketed reactor. The flask was rinsed with DMAc (80 mL, 0.23 vol) and this solution was passed through the in-line filter into the reactor.

[0531] To the reactor was added EtOH (175 mL, 0.5 vol) and 2-MeTHF (1.05 L, 3 vol), and the mixture was stirred at room temperature overnight. An aliquot was sampled and analyzed by HPLC, which showed 0.1% of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI) remaining.

[0532] Water (4.2 L, 12 vol) was added to the reaction mixture. The slurry was aged at room temperature for 30 minutes, after which the solid was collected by filtration. The solid was washed with water (3 × 1.4 L, 4 vol) and EtOH (1 × 1.4 L, 4 vol). The solid was dried on the filter for 2 hours to give crude (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) as a white solid (306.0 g, 90.9% yield) with 98.8% HPLC purity.

[0533] To a cleaned 10 L jacketed reactor was added crude (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) (300 g), EtOH (4.5 L, 15 vol), and water (300 mL, 1 vol). The reactor contents were heated to reflux (approximately 78°C) and stirred for 1 hour. The reactor contents were cooled to 70°C and aged for 3 hours. The reactor contents were cooled to 50°C over 5 hours and aged over the weekend. The reactor contents were cooled to 20°C and stirred for 1 hour before filtration. The filter cake was rinsed with EtOH (900 mL, 3 vol). The solid was dried on the filter for 2 hours and then dried under full vacuum with a nitrogen bleed for 16 hours at 45°C. The isolated solid was 288.7 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, 96.2% recovery, 85.7% overall yield) with an HPLC purity of 99.8%.

[0534] 1H NMR(400MHz, CDCl3)δ(ppm):8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35-7.23 (m, 5H), 4.51-4.50 (m, 2H), 4.32-4.30 (m, 2H), 4.28-3.93 (m, 8H), 3.78-3.67 (m, 3H), 3.15-3.13 (m, 1H) ppm.

[0535] Example 12 (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-phenylpropane- Alternative large-scale synthesis of 1-one (I) [ka]

[0536] To a 2 L jacketed reactor was added (VI)·(VII) (150.01 g, obtained from the method of Example 10), EDC·HCl (63.49 g, 0.525 equiv.), OxymaPure® (17.93 g, 0.2 equiv.), and DMAc (600 mL, 2 vol.). The contents of the reactor were stirred at 20±5°C for 1 hour. The remaining (VI)·(VII) (150.11 g) and EDC·HCl (63.85 g) were added, and the reaction mixture was allowed to stir for 3 hours. An aliquot was sampled and analyzed by HPLC, which indicated that 1.0% of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI) remained. The reactor was charged with 2-MeTHF (600 mL, 2 vol) and the contents of the flask were passed through a 0.45 μm in-line filter into the 10 L jacketed reactor. The flask was rinsed with DMAc (60 mL, 0.2 vol) and this solution was passed through the in-line filter into the reactor.

[0537] To the reactor was added EtOH (150 mL, 0.5 vol) and 2-MeTHF (900 mL, 3 vol), and the mixture was stirred at room temperature overnight. An aliquot was sampled and analyzed by HPLC, which showed 0.0% of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (VI) remaining.

[0538] Water (3.6 L, 12 vol) was added to the reaction mixture. The slurry was aged at room temperature for 30 minutes before collecting the solid by filtration. The solid was washed with water (3 × 1.2 L, 4 vol) and EtOH (1 × 1.2 L, 4 vol). The solid was dried on the filter for 2 hours and then dried under full vacuum at 45 °C with a nitrogen bleed to give crude (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) (248.7 g, 86.2% yield) as an off-white solid with 98.8% HPLC purity.

[0539] To a cleaned 10 L jacketed reactor was added crude (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, 248.7 g), EtOH (3.75 L, 15 vol), and water (250 mL, 1 vol). The reactor contents were heated to reflux (approximately 78 °C) and stirred for 1 hour. The reactor contents were cooled to 70 °C and aged for 3 hours. The reactor contents were cooled to 50 °C over 5 hours and aged overnight. The reactor contents were cooled to 20 °C and stirred for 1 hour before filtration. The filter cake was rinsed with EtOH (750 mL, 3 vol). The solid was dried on the filter for 2 hours and then dried under full vacuum with a nitrogen bleed for 16 hours at 45°C. The isolated solid was 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 yield) with an HPLC purity of 99.7%.

[0540] 1 H NMR(400MHz, CDCl3)δ(ppm):8.24 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35-7.23 (m, 5H), 4.51-4.50 (m, 2H), 4.32-4.30 (m, 2H), 4.28-3.93 (m, 8H), 3.78-3.67 (m, 3H), 3.15-3.13 (m, 1H) ppm.

[0541] Example 13 Synthesis of (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) Step 1: Methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (VIII-B) [ka]

[0542] K2CO3 (90 g, 648 mmol) and DMSO (750 mL, 15 vol) were charged to a reaction vessel. A yellow solution of pyridine-2-sulfonamide (VIII-A, 52.6 g, 316 mmol) in DMSO (100 mL, 2 vol) was then charged to the reaction vessel within 5 min. The vessel was then rinsed with DMSO (50 mL, 1 vol), and the solution was charged to the reaction vessel. The reaction mixture was heated to 85-90 °C, at which point a light slurry formed.

[0543] A solution of methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (III-A, 70.8 g, 316 mmol) in DMSO (100 mL, 2 vol) was charged to the reaction vessel, and the temperature was maintained at 85-90 °C. The vessel was rinsed with DMSO (50 mL, 1 vol), and the solution was charged to the reaction vessel. Complete conversion was observed after 1 h 20 min, as assessed by UPLC analysis of the reaction mixture.

[0544] The reaction mixture was cooled to 20-25 °C and quenched with water (500 mL), maintaining the temperature at 20-30 °C. The resulting solution was stirred at 20-25 °C for 3 h and then filtered through a fritted funnel. The filter cake was washed with water (2 × 250 mL, 2 × 5 vol) to remove residual inorganic salts. The solid was dried in vacuo at 40-45 °C for 16 h to afford 53 g of methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (VIII-B, 54.2% yield) with a UPLC-MS purity of >99%.

[0545] 1H NMR(400MHz, DMSO-d6)δ(ppm):8.81-8.70 (m, 1H), 8.18-8.06 (m, 1H), 8.01-7.92 (m, 1H), 7.77-7.65 (m, 1H), 4.23 (br s, 4H), 4.00 (br s, 4H), 3.59 (s, 3H).

[0546] Step 2: 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX) [ka]

[0547] 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 to a reaction vessel. The suspension was stirred at room temperature for 5 minutes, and then 3 M aqueous potassium hydroxide (64.7 mL, 194 mmol) was charged to the reaction vessel.

[0548] The resulting solution was heated to reflux (approximately 75°C) and maintained at that temperature for 23 hours. The solution was then concentrated under reduced pressure and extracted with DCM (4 x 65 mL). The combined extracts were concentrated under reduced pressure, and the resulting light brown solid was slurried with MTBE. The resulting slurry was concentrated under reduced pressure and dried at room temperature to give 6.18 g of 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX, 50.7% yield), which was carried on to the next step without further purification.

[0549] 1H NMR(400MHz, DMSO-d6)δ(ppm):8.78-8.72 (m, 1H), 8.16-8.08 (m, 1H), 7.95 (dt, J = 7.8 Hz), 1H, 7.70 (ddd, J = 7.4, 4.7, 1.2 Hz, 1H), 4.15 (s, 4H), 3.50 (s, 4H), 3.32 (br s, 1H).

[0550] Alternative Step 2a: 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide (X) [ka]

[0551] Methyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (VIII-B, 4.13 g, 13.35 mmol) was charged to a reaction vessel, and HBr in acetic acid (33 wt%, 19.87 mL, 113 mmol) was added. The resulting solution was stirred at 20-25 °C for 5 min. The solution was then heated to 45-50 °C over 30 min and stirred at that temperature for approximately 3 h.

[0552] The solution was cooled to 20-25 °C, and EtOAc (40 mL) was slowly added to the reaction mixture. The resulting solution was stirred at room temperature for 2 h, and then the solid was filtered. The filter cake was washed with additional EtOAc (2 × 10 mL) and rinsed with IPA (2 × 10 mL). The resulting brown solid was dried on the filter under vacuum overnight to give 5.5 g of 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide (X, 100% yield).

[0553] 1H NMR(300MHz, DMSO-d6)δ(ppm):10.15-9.90 (br s, 1H), 8.80-8.70 (m, 1H), 8.16-8.06 (m, 1H), 8.00-7.90 (m, 1H), 7.75-7.20 (m, 1H), 7.25-6.35 (br s, 1H), 4.20 (s, 4H), 3.90 (s, 4H).

[0554] Alternative Step 2b: 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX) [ka]

[0555] 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide (X, 1 g, 2.421 mmol) was charged to a reaction vessel and diluted with water (12.5 mL). DCM (7.5 mL) was added to the reaction vessel, followed by IPA (3 mL). The resulting solution was stirred for 5 minutes, after which the solid was filtered.

[0556] The filtrate was washed with DCM (1 mL) and then rinsed with water (1 mL). The resulting layers were separated, and the aqueous layer was extracted with DCM (5 mL). The aqueous layer was then basified to pH 14 with 2.5 M NaOH (3 mL). The aqueous layer was then extracted with DCM (3 × 5 mL). The organic layers were combined and concentrated under reduced pressure to give 0.58 g of 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX, 95% yield), which was used in the next step without further purification.

[0557] 1H NMR(400MHz, DMSO-d6)δ(ppm):8.78-8.72 (m, 1H), 8.16-8.08 (m, 1H), 7.95 (dt, J = 7.8 Hz), 1H, 7.70 (ddd, J = 7.4, 4.7, 1.2 Hz, 1H), 4.15 (s, 4H), 3.50 (s, 4H), 3.32 (br s, 1H).

[0558] 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) [ka]

[0559] 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (IX, 0.5 g, 1.990 mmol) was charged to a reaction vessel containing (R)-2-hydroxy-2-phenylacetic acid (0.318 g, 2.089 mmol) and HOBt (0.096 g, 0.497 mmol). DMSO (4 mL, 8 vol) was then added to the reaction vessel.

[0560] A dilute suspension of EDC (0.115 g, 2.388 mmol) in degassed DMSO (2 mL, 4 vol) was added to the reaction vessel. The vessel was rinsed with degassed DMSO (1 mL, 2 vol) and added to the reaction vessel. The resulting solution was stirred overnight at 20–25 °C.

[0561] After stirring overnight, analysis by UPLCMS indicated that approximately 50% of the pyrrolidine (IX) had been converted to product. Additional EDC (0.34 g) was charged and the resulting mixture was stirred at room temperature for 2 hours, at which point UPLCMS analysis indicated complete conversion to product.

[0562] Water (35 mL) was slowly added to the reaction mixture over 1 h, and the resulting solution was stirred for 16 h. The resulting solid was filtered through a funnel, and the filter cake was washed with water (2 × 3 mL, 1 × 6 vol) and then rinsed with EtOH (6 mL, 12 vol). The solid was dried under air aspirator vacuum for 30 min and then in a vacuum oven at 40–45 °C for 5 h to give 0.61 g of (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, 80% yield).

[0563] 1 H NMR(400MHz, DMSO-d6)δ(ppm):8.71 (d, J = 4.4 Hz, 1H), 8.12-8.05 (m, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.68 (dd, J = 7.6, 4.4 Hz, 1H), 7.40-7.25 (m, 5H), 5.65 (d, J = 6.2 Hz, 1H), 5.18 (d, J = 6.2 Hz, 1H), 4.30-3.90 (m, 8H).

[0564] All patents and publications cited herein are hereby fully incorporated by reference in their entirety.

[0565] Any composition disclosed herein can comprise, consist of, or consist essentially of any of the compounds or components disclosed herein. In accordance with the present disclosure, the 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 to materials or steps that do not materially affect the basic and novel characteristic(s) of the claim.

[0566] The reagents and conditions described herein are for illustrative purposes only and are not limiting. As will be appreciated by those skilled in the art, various analogs can be prepared by modifying the synthetic reactions, such as by using different starting materials, different reagents, and different reaction conditions (e.g., temperature, solvent, concentration, etc.).

[0567] The present disclosure enables those skilled in the relevant art to make and use the present invention provided herein according to multiple and various embodiments. Various modifications, alterations, substitutions, and improvements of the present disclosure that are easily made by those skilled in the art, including certain alterations, modifications, substitutions, and improvements, are also part of the present disclosure. Therefore, the foregoing description and drawings are intended as examples to illustrate the discoveries provided herein.

[0568] The term "about," as used herein, refers to the recited value within a range of error resulting from the standard deviation found in each testing measurement; if such error cannot be determined, then "about" refers to within 10% of the recited value.

[0569] Unless specified to the contrary, the use of the term "a" is intended to include "at least one" or "one or more." For example, "a compound" is intended to include "at least one compound" or "one or more compounds."

[0570] Any range given in either absolute or approximate terms is intended to encompass both, and any definitions used herein are intended to be illustrative, not limiting. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges subsumed therein, including all fractional and full values.

[0571] Furthermore, the present invention encompasses any and all possible combinations of some or all of the various embodiments described herein. It should also be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its intended advantages. Accordingly, it is intended that such changes and modifications be covered by the appended claims.

Claims

1. Compounds according to formula (III-Y): 【Chemistry 1】 azomethine precursor according to formula (III-W) in step 1 of Scheme A1 A1 with an electron-deficient alkyne according to formula (III-X) according to A1 is carried out in the presence of an acid: 【Chemistry 2】 (Wherein R12 is -CR2R3-(C 6 -C 10 aryl), and C 6 -C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C 1 -C 6 is alkyl, R4 is 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 independently halo, e.g., chloro, bromo, iodo, or -OSO 2 R7, each R7 independently being C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, or C 6 -C 10 aryl, C 6 -C 10 the aryl is optionally substituted with 1 to 3 R8; each R8 independently represents a halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C1-C 6 Alkoxy, or C 1 -C 6 haloalkoxy, R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); R10 is C 1 -C 6 (It is alkyl).

2. Step 1 of Scheme A1' A1’ reacting an azomethine precursor according to formula (III-W1) with an electron-deficient alkyne according to formula (III-X) according to A1’ 10. The method of claim 1, wherein the step is carried out in the presence of an acid. 【Transformation 3】 wherein R5 and R6 are each independently halo, e.g., chloro, bromo, iodo, or -OSO 2 R7, each R7 independently being C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, or C 6 -C 10 aryl, C 6 -C 10 The aryl is optionally substituted with 1 to 3 R8, each R8 being independently halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, or C 1 -C 6 haloalkoxy, R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); R10 is C 1 -C 6 (It is alkyl).

3. 3. The method of claim 1 or 2, wherein R5 and R6 are each chloro.

4. The acid is selected from the group consisting of TFA, TMSOTf, TMSI, TMSOTf in combination with CsF, CsF, LiF, ZnCl 2 4. The method of claim 1, wherein the TMSI is selected from the group consisting of: TMSI in combination with any one of the following:

5. Step 2: Converting the compound of formula (III-Y) to a compound of formula (III-Z) according to Scheme A2 A2 The method of any one of claims 1 to 4, further comprising: 【Chemistry 4】 (Wherein R1 is 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., trifluoroacetyl), and -SO 2 -(C 6 -C 10 aryl) (e.g., tosyl).

6. R1 is -C(O)OCH 3 -C(O)(C 1 -C 6 6. The method of claim 5, wherein the aryl group is alkoxy.

7. Step 3: reacting the compound of formula (III-Z) with a compound of formula (IV-Y) to form a compound of formula (VZ) according to Scheme A3. A3 7. The method of claim 5 or 6, further comprising: 【Transformation 5】 (Wherein R11 is C 6 -C 10 aryl, and a 6- to 10-membered heteroaryl containing 1 to 3 O, N, or S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and -OR13, and each R13 is independently -H or -C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, -F, -Cl, -Br, -I, -CN, and -NO2, or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring, and the reaction is carried out in the presence of a base.

8. 8. The method of claim 7, wherein R11 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, and 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl.

9. A process for preparing a compound of formula (VZ), comprising: a. reacting an azomethine precursor of formula (III-W) with an electron-deficient alkyne of formula (III-X) according to Scheme A1, wherein the reaction is carried out in a first non-polar solvent in the presence of an acid: 【Transformation 6】 (In the formula, R12 is -CR2R3-(C 6 -C 10 aryl), and C 6 -C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C 1 -C 6 is alkyl, R4 is 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 independently halo, e.g., chloro, bromo, iodo, or -OSO 2 R7, each R7 independently being C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, or C 6 -C 10 aryl, C 6 -C 10 the aryl is optionally substituted with 1 to 3 R8; each R8 independently represents a halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, or C 1 -C 6 haloalkoxy, R9 is a suitable silyl protecting group selected from the group consisting of trimethylsilyl (TMS), dimethylphenylsilyl (DMPS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), or dimethylisopropylsilyl (DMIPS); R10 is C 1 -C 6 alkyl) and b. Converting the compound of formula (III-Y) to a compound of formula (III-Z) by reacting with R1-Cl in a second non-polar solvent according to Scheme A2: 【Transformation 7】 (In the formula, R1 is 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., trifluoroacetyl), and -SO 2 -(C 6 -C 10 aryl) (e.g., tosyl) and c. Reacting a compound of formula (III-Z) with a compound of formula (IV-Y) in the presence of a base in a suitable solvent to form a compound (VZ) according to Scheme A3: 【Transformation 8】 (In the formula, R11 is C 6 -C 10 aryl, 6- to 10-membered heteroaryl containing 1 to 3 O, N, or S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and -OR13, and each R13 is independently -H, or oxo, -F, -Cl, -Br, -I, -CN, or -NO 2 -C optionally substituted with one or more substituents selected from the group consisting of 1 -C 6 is alkyl, or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring.

10. A compound of formula (III-Y) or a salt thereof: 【Chemistry 9】 (Wherein R12 is -CR2R3-(C 6 -C 10 aryl), and C 6 -C 10 the aryl is optionally substituted with 1 to 3 R4; R2 and R3 are each independently H or C 1 -C 6 is alkyl, R4 is 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 independently halo, e.g., chloro, bromo, iodo, or -OSO 2 R7, each R7 independently being C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, or C 6 -C 10 aryl, C 6 -C 10 the aryl is optionally substituted with 1 to 3 R8; each R8 independently represents a halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, or C 1 -C 6 haloalkoxy).

11. R12 is benzyl, i.e., the compound of formula (III-B): 【Chemistry 10】 11. The compound of claim 10, which is (1-benzyl-3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate).

12. A compound of formula (III) or a salt thereof: 【Chemistry 11】 (Wherein R1 is —C(O)(C 1 -C 6 alkyl), -C(O)(C 1‐ C 6 haloalkyl), -C(O)(C 1 -C 6 -C(O)(alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or -S(O) 2 (trill).

13. The compound is a compound of formula (III-A): 【Chemistry 12】 13. The compound of claim 12, which is (methyl 3,4-bis(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate), or a salt thereof.

14. Compound of formula (VZ): 【Chemistry 13】 (Wherein R1 is —C(O)(C 1 -C 6 alkyl), -C(O)(C 1 -C 6 haloalkyl), -C(O)(C 1 -C 6 -C(O)(alkoxy), -C(O)(benzyloxy), -C(O)(phenoxy), or -S(O) 2 (trill) R11 is C 6 -C 10 aryl, 6- to 10-membered heteroaryl containing 1 to 3 O, N, or S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents selected from -R13 and -OR13, and each R13 is independently -H, or oxo, -F, -Cl, -Br, -I, -CN, or -NO 2 -C optionally substituted with one or more substituents selected from the group consisting of 1 -C 6 alkyl, or two R13 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring).

15. 15. The compound of claim 14, wherein the compound is a compound of formula (V): 【Chemistry 14】 (Wherein R1 is —C(O)(C 1 -C 6 alkyl).

16. 15. The compound of claim 14, wherein the compound is a compound of formula (VIII): 【Chemistry 15】 (Wherein R1 is —C(O)(C 1 -C 6 alkyl).

17. Use of a compound according to any one of claims 14 to 16 for the preparation of a compound according to formula (I) or (II).

18. Compounds according to formula (I): 【Chemistry 16】 1. A method for preparing a. Step 1 of Scheme B1' B1’ reacting a compound of formula (III-D) with a compound of formula (III-C) in the presence of a first acid in a first non-polar solvent according to the formula: 【Chemistry 17】 b. Step 2 of Scheme B1' B1’ in a second non-polar solvent according to 1 -C 6 converting the compound of formula (III-B) to a compound of formula (III) by reacting with an alkoxy (e.g., methoxycarbonyl); c. According to Scheme G1, a compound of formula (III) 1 -C 6 reacting an alkoxycarbonyl (e.g., methoxycarbonyl) with a compound of formula (IV) in the presence of a first base in a suitable solvent to form compound (V); [Chemistry 18] d. A compound of formula (V) (wherein R1 is C 1 -C 6 deprotecting the alkoxycarbonyl (e.g., methoxycarbonyl) with a second acid followed by neutralization with a second base to obtain a compound of formula (VI) or to form a salt of the compounds of formula (VI) and (VII) by addition of compound (VII); 【Chemistry 19】 e. carrying out a coupling reaction of a compound of formula (VI) with a compound of formula (VII) according to Scheme G3, or carrying out a coupling reaction from a salt of formula (VI)-(VII) according to Scheme G3', using a coupling reagent and an additive in a second suitable solvent to obtain a compound of formula (I). 【Chemistry 20】 or 【Chemistry 21】

19. Compounds of formula (VI) and (VII). 【Chemistry 22】 .

20. 20. Use of the compound according to claim 19 for the preparation of ethabopivat (I).

21. Compounds according to formula (II): 【Chemistry 23】 1. A method for preparing a. Step 1 of Scheme B1' B1’ reacting a compound of formula (III-D) with a compound of formula (III-C) in the presence of a first acid in a first non-polar solvent according to: 【Chemistry 24】 b. Step 2 of Scheme B1' B1’ in a second non-polar solvent according to 1 -C 6 converting the compound of formula (III-B) to a compound of formula (III) by reacting with an alkoxy (e.g., methoxycarbonyl); c. Producing a compound of formula (III) according to Scheme H1, wherein R is C 1 -C 6 reacting an alkoxycarbonyl (e.g., methoxycarbonyl) with a compound of formula (VIII-A) in the presence of a first base in a suitable solvent to form a compound of formula (VIII); 【Chemistry 25】 d. A compound of formula (VIII) (wherein R1 is C 1 -C 6 deprotecting the alkoxycarbonyl (e.g., methoxycarbonyl) with a fourth base or a third acid to obtain a compound of formula (IX) or a salt thereof; 【Chemistry 26】 e. carrying out a coupling reaction between the compound of formula (IX) or a salt thereof and the compound of formula (XI) using a coupling reagent and an additive in a third suitable solvent according to Scheme G4 to obtain the compound of formula (II). 【Chemistry 27】

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