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WO2024259085A2 - Procédés de synthèse d'inhibiteurs du facteur d du complément et intermédiaires de ceux-ci - Google Patents

Procédés de synthèse d'inhibiteurs du facteur d du complément et intermédiaires de ceux-ci Download PDF

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Publication number
WO2024259085A2
WO2024259085A2 PCT/US2024/033785 US2024033785W WO2024259085A2 WO 2024259085 A2 WO2024259085 A2 WO 2024259085A2 US 2024033785 W US2024033785 W US 2024033785W WO 2024259085 A2 WO2024259085 A2 WO 2024259085A2
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compound
formula
optionally substituted
alxn
protecting
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WO2024259085A3 (fr
Inventor
Akihiro Hashimoto
Virendra Kumar Tiwari
Raja Sekarreddy ANNAPUREDDY
Antonio Christian Ferretti
Ravi Kumar ONGOLU
Bo QU
Chris Hugh Senanayake
Gopal SIRASANI
Ravindranadh Venkata Somu
Suresh TIPPARAJU
Chao Wang
Nageswara Rao KALIKINIDI
Madhusudhan GADI
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Alexion Pharmaceuticals Inc
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Alexion Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the complement system is a part of the innate immune system which does not adapt to changes over the course of the host’s life, but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens. This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction. Over thirty proteins and protein fragments make up the complement system.
  • Complement Factor D plays an early and central role in activation of the alternative pathway of the complement cascade. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of a thioester bond within the C3 protein to produce C3(H2O), which associates with Factor B to form the C3(H 2 O)B complex.
  • Complement Factor D acts to cleave Factor B within the C3(H 2 O)B complex to form Ba and Bb.
  • the Bb fragment remains associated with C3(H 2 O) to form the alternative pathway C3 convertase C3(H2O)Bb.
  • C3b generated by any of the C3 convertases also associates with Factor B to form C3bB, which Factor D cleaves to generate the later stage alternative pathway C3 convertase C3bBb.
  • This latter form of the alternative pathway C3 convertase may provide important downstream amplification within all three of the defined complement pathways, leading ultimately to the recruitment and assembly of additional factors in the complement cascade pathway, including the cleavage of C5 to C5a and C5b.
  • C5b acts in the assembly of factors C6, C7, C8, and C9 into the membrane attack complex, which can destroy pathogenic cells by lysing the cell.
  • the dysfunction of or excessive activation of complement has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.
  • activation of the alternative pathway of the complement cascade contributes to the production of C3a and C5a, both potent anaphylatoxins, which also have roles in a number of inflammatory disorders. Therefore, in some instances, it is desirable to decrease the response of the complement pathway, including the alternative complement pathway.
  • C3G is a recently defined entity comprised of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) which encompasses a population of chronic kidney diseases wherein elevated activity of the alternative complement pathway and terminal complement pathway results in glomerular deposits made solely of complement C3 and no immunoglobulin (Ig).
  • DDD dense deposit disease
  • C3GN C3 glomerulonephritis
  • Immune-complex membranoproliferative glomerulonephritis is a renal disease which shares many clinical, pathologic, genetic and laboratory features with C3G, and therefore can be considered a sister disease of C3G.
  • an underlying disease or disorder most commonly infections, autoimmune diseases, or monoclonal gammopathies—are identified to which the renal disease is secondary.
  • Patients with idiopathic IC-MPGN can have low C3 and normal ALXN.
  • DOCKET ALXN-0761-WO-PCT C4 levels similar to those observed in C3G, as well as many of the same genetic or acquired factors that are associated with abnormal alternative pathway activity.
  • aHUS hemolytic uremic syndrome
  • HUS hemolytic uremic syndrome
  • NMO neuromyelitis optica
  • MG myasthenia gravis
  • MG myasthenia gravis
  • MG myasthenia gravis
  • MG myasthenia gravis
  • fatty liver nonalcoholic steatohepatitis
  • NASH nonalcoholic steatohepatitis
  • liver inflammation cirrhosis
  • liver failure cirrhosis
  • dermatomyositis cirrhosis
  • amyotrophic lateral sclerosis Factor D is an attractive target for inhibition or regulation of the complement cascade due to its early and essential role in the alternative complement pathway, and for its potential role in signal amplification within the classical and lectin complement pathways.
  • Factor D effectively interrupts the pathway and attenuates the formation of the membrane attack complex.
  • small molecule Factor D inhibitors have been developed and investigated for potential therapeutic uses. Examples of these Factor D inhibiting compounds methods of preparing them are described in, e.g., PCT Publications Nos. WO2015/130838, WO2017/035353, WO2017/035409, WO2018/160889, WO2020/041301, and WO2021/168320. New methods for the synthesis of small molecule Factor D inhibitors and intermediates thereof are desirable. Summary The present disclosure generally relates to an improved method of preparing compounds useful for treating disorders mediated by complement factor D and intermediates thereof.
  • the present disclosure provides a method of preparing a compound of Formula (VI).
  • the method includes providing a compound of Formula (V): , in which P 1 and P 2 are as defined herein, of Formula (VI) from the compound of Formula (V). Forming the compound contacting the compound of Formula (V) with a Co(II) catalyst in the presence of Zn and CH 2 Br 2 .
  • methods of preparing compounds of Formula (XI): from the compound of Formula (VI) methods disclosed herein. To facilitate the of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the disclosure.
  • salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable acid. Methods for preparation of the appropriate salts are well-established in the art. ALXN.
  • acyl refers to a monovalent radical having the structure –COR, where R is alkyl, alkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. Acyl can be optionally substituted as defined for each R group.
  • alkyl refers to a branched or straight-chain monovalent saturated aliphatic radical containing only C and H when unsubstituted. The monovalency of an alkyl group does not include the optional substituents on the alkyl group.
  • alkyl group may contain, e.g., 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ).
  • Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl.
  • alkenyl group may contain, e.g., 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4).
  • Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1- butenyl, 2-butenyl, 3-butenyl, and the like.
  • alkenyloxy refers to a monovalent radical having the structure -O- alkenyl, in which “alkenyl” is as defined herein. Examples include, but are not limited to ethenyloxy, propenyloxy, and the like.
  • alkoxy refers to a monovalent radical having the structure -O-alkyl, in which “alkyl” is as defined herein. Examples include, but are not limited to methoxy, ethoxy, and n-butoxy, i-butoxy, t-butoxy, and the like.
  • alkynyl refers to a branched or straight-chain monovalent unsaturated aliphatic radical containing at least one carbon-carbon triple bond and only C and H when unsubstituted. Monovalency of an alkynyl group does not include the optional substituents on the alkynyl group. For example, if an alkynyl group is attached to a compound, monovalency of the alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkynyl group.
  • An aryl group may have, e.g., six to sixteen carbons (e.g., C 6 -C 16 aryl, C 6 -C 14 aryl, C 6 -C 13 aryl, or C 6 -C 10 aryl).
  • ALXN. DOCKET ALXN-0761-WO-PCT
  • arylalkyl refers to a monovalent radical having the structure –R’R”, where R’ is alkylene, and R” is aryl.
  • Arylalkyl can be optionally substituted in the same manner as defined for each R’ and R” group.
  • carbocyclyl represents a monovalent, saturated or unsaturated non- aromatic cyclic group containing only C and H when unsubstituted.
  • a carbocyclyl e.g., a cycloalkyl or a cycloalkenyl
  • Carbocyclyl also includes bicyclic and polycyclic (e.g., tricyclic and tetracyclic) fused ring structures.
  • cycloalkyl refers to a saturated carbocyclyl. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • cycloalkyl also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1]heptyl and adamantyl.
  • cycloalkyl also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spirocyclic compounds.
  • cyano refers to a monovalent radical having the structure -CN.
  • cycloalkenyl represents a monovalent, unsaturated carbocyclyl group that includes at least one carbon-carbon double bond, no carbon-carbon triple bond, only C and H when unsubstituted, and is not fully aromatic.
  • a cycloalkenyl may have, e.g., four to fourteen carbons (e.g., a C 4 -C 7 , C 4 -C 8 , C 4 -C 9 , C 4 -C 10 , C 4 -C 11 , C 4 -C 12 , C 4 -C 13 , or C 4 -C 14 cycloalkenyl).
  • cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • cycloalkenyl also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.2]oct-2-ene.
  • cycloalkenyl also includes fused ring bicyclic and multicyclic systems containing one or more double bonds, e.g., fluorene.
  • halo refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
  • heteroarylalkyl represents a monovalent radical of structure –R’R”, where R’ is alkylene, and R” is heteroaryl. Heteroarylalkyl can be optionally substituted in the same manner as defined for each R’ and R” group.
  • Exemplary 5-membered groups include, for example, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted ALXN.
  • Exemplary 6-membered heterocyclyl groups include, but are not limited to, optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, and optionally substituted tetrahydropyran.
  • Exemplary 7-membered heterocyclyl groups include, but are not limited to, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, and optionally substituted 1,4- thiazepine.
  • Exemplary 8- to 10-membered bicyclic groups include, but are not limited to, optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted thiazolo[5,4-b]pyridinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl.
  • carboxyl-protecting group refers to any group capable of protecting the oxygen atom of the -OH functionality of a carboxyl group from participating in one or more undesirable reactions during chemical synthesis.
  • a carboxyl-protecting group is installed by reacting a molecule including an unprotected carboxyl group with a carboxyl-protecting reagent, which can be removed by a carboxyl-protecting-group-removing agent.
  • carboxyl-protecting groups include, but are not limited to alkyl (e.g., methyl, ethyl, or tert-butyl), benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4- dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, pentamethylbenzyl, benzydryl, 3,4-methylenedioxybenzyl, 4,4-dimethoxytrityl, 4,4′,4′′-trimethoxytrityl, 2- phenylpropyl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, ⁇ -(trimethylsilyl)ethyl, ⁇ -(di(n- butyl)methylsilyl)ethyl, p-toluenesulf
  • N-protecting group refers to a group protecting a nitrogen atom in a molecule from participating in one or more undesirable reactions during chemical synthesis.
  • An N- protecting group is installed by reacting the molecule including a nitrogen atom with an N-protecting reagent and can be removed using an N-protecting-group-removing agent.
  • N-protecting groups, their corresponding N-protecting reagents, and N-protecting-group-removing agents are disclosed in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006.
  • N-protecting groups include acyl (e.g., formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ - chlorobutyryl, benzoyl, 4-chlorobenzoyl, and 4-bromobenzoyl); sulfonyl-containing groups (e.g., benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl); carbamate forming groups (e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxy
  • DOCKET ALXN-0761-WO-PCT 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, ⁇ , ⁇ -dimethyl- 3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthio
  • N-protecting groups include acetyl, benzoyl, phenylsulfonyl, p- toluenesulfonyl, p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
  • thioalkyl refers to a monovalent radical having the structure -S-alkyl, in which “alkyl” is as defined herein.
  • optionally substituted X is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional.
  • optionally substituted refers to having 0, 1, or more substituents (e.g., 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0 or 1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents).
  • Alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl groups may be substituted with one or more of carbocyclyl, cycloalkyl; cycloalkenyl; aryl; heterocyclyl; heteroaryl; halo; OH; cyano; alkoxy; alkenyloxy; thioalkyl; NO2; N3; NRR ′ ; wherein each of R and R ′ is, independently, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl; SO2R, wherein R is H, alkyl or aryl; SO 2 NRR ′ , wherein each of R and R ′ is, independently, H, alkyl, or aryl; or NRSO 2 R, wherein each of R and R ′
  • Aryl, carbocyclyl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclyl groups may also be substituted with alkyl, alkenyl, or alkynyl.
  • Alkyl, alkoxy, carbocyclyl, cycloalkyl, cycloalkenyl, and unsaturated heterocyclyl groups may also be substituted with oxo.
  • a substituent is further substituted as described herein.
  • a C 6 aryl group i.e., phenyl, may be substituted with an alkyl group, which may be further substituted with a heterocyclyl group.
  • FIG.1 is a schematic of a continuous flow setup used for the synthesis of Compound 2d described in Example 3.
  • the present disclosure provides methods for the synthesis of small molecule complement factor D inhibitors and intermediates thereof.
  • the complement factor D inhibitors are compounds of Formula (XIII): ALXN.
  • DOCKET ALXN-0761-WO-PCT or pharmaceutically acceptable salts R 6 , X 1 -X 5 , m, and B are as defined herein.
  • Exemplary compounds of Formula (XIII) are described in, e.g., PCT Publications Nos.
  • the methods herein relate to the preparation of a compound of Formula (VI): , in which P 1 is H or an N-protecting group and P 2 is H or a carboxyl-protecting group (e.g., an alkyl group such as providing a compound of Formula (V): , in which P 1 is H or an N-protecting group protecting group (e.g., an alkyl group such as methyl); and forming the the compound of Formula (V) via a cyclopropanation reaction performed with a Co(II) catalyst in the presence of Zn and CH 2 Br 2 .
  • a carboxyl-protecting group e.g., an alkyl group such as providing a compound of Formula (V): , in which P 1 is H or an N-protecting group protecting group (e.g., an alkyl group such as methyl)
  • a Co(II) catalyst in the presence of Zn and CH 2 Br 2 .
  • the Zn is present in amount of 2-10 equivalents (e.g., 3-8 equiv, 4-6 equiv, 3 equiv, 4 equiv, 5 equiv, 6 equiv, 7 equiv, 8 equiv, 9 equiv, or 10 equiv) relative to the compound of Formula (V). In some embodiments, the Zn is present in amount of 5 equiv relative to the compound of Formula (V). In some embodiments, the Zn is sequentially added in more than one portion.
  • the Zn is sequentially added in two portions (e.g., a first portion of 3 equiv relative to the compound of Formula (V), then a second portion of 2 equiv relative to the compound of Formula (V)).
  • the ZnCl2 is present in an amount of 2-10 equivalents (e.g., 3-8 equiv, 4-6 equiv, 3 equiv, 4 equiv, 5 equiv, 6 equiv, 7 equiv, 8 equiv, 9 equiv, or 10 equiv) relative to the compound of Formula (V).
  • the ZnCl 2 is present in amount of 5 equiv relative to the compound of Formula (V).
  • the CH2Br2 is present in an amount of 1-10 (e.g., 2-9 equiv, 3-7 equiv, 4-6 equiv, 2 equiv, 3 equiv, 4 equiv, 5 equiv, 6 equiv, 7 equiv, 8 equiv, 9 equiv, or 10 equiv) relative to the compound of Formula (V).
  • the CH 2 Br 2 is present in an amount of 4 equiv relative ALXN. DOCKET ALXN-0761-WO-PCT to the compound of Formula (V).
  • the CH 2 Br 2 is sequentially added in more than one portion.
  • the CH 2 Br 2 is sequentially added in three portions (e.g., a first portion of 1.5 equiv relative to the compound of Formula (V), a second portion of 1 equiv relative to the compound of Formula (V), then a third portion of 1.5 equiv relative to the compound of Formula (V)).
  • Embodiments of the method disclosed herein unexpectedly provides the compound of Formula (VI) with high stereoselectivity ( ⁇ 97:3), which is carried over in, e.g., subsequent reactions in the multi- step synthesis of the compounds of Formula (XI).
  • the compound of Formula (VI), prior to the present disclosure, was typically prepared using a procedure reported in US Publication No.2011/0274648 A1, which provides a ⁇ 1:3 diastereomeric mixture of the compound of Formula (VI) and its diastereomer.
  • Other published procedures used silyl protective groups (Bioorg. Med. Chem., 21 (2013) 5725-5737), which render the product difficult to purify, compared to the reaction disclosed herein.
  • Another published procedure relies on LiHMDS and methyl iodide for methyl insertion into the compound of Formula (I), which results in a mixture of mono- and di- methylated compounds in addition to unreacted starting material, thus requiring additional chromatographic separation.
  • the Co(II) catalyst is Co(II) complex containing a pyridine(diimine) (PDI) ligand.
  • the Co(II) complex is of structure: , wherein each X is independently Cl, C1-C6 alkyl; each R is independently H or C 1 -C 6 alkyl; and R” is H, halo, C 1 - or C 6 -C 10 aryl.
  • the Co(II) complex may be of structure: , in which each X is independently Br, C 1 -C 6 alkyl.
  • the Co(II) catalyst is (i.e., as opposed to being assembled in situ).
  • each X is independently Cl and Br.
  • each X is independently Cl or I.
  • each X is independently Br or I.
  • each X is Cl.
  • each X is Br.
  • each X is I.
  • each R is independently ethyl, n-propyl, isopropyl, or tert-butyl. In some embodiments, each R is ethyl.
  • each R is n-propyl. In some embodiments, each R is isopropyl. In some embodiments, each R is tert-butyl.
  • ALXN. DOCKET ALXN-0761-WO-PCT Compounds of Formula (V) In some embodiments, the compound of Formula (V): (V), in which P 1 and P 2 are as defined above, a compound of Formula (IV): (IV), in which P 1 is an N-protecting group t- and P 2 is a carboxyl-protecting group (e.g., an alkyl group such as methyl), to a reaction).
  • the dehydration reaction is typically performed under the presence of a strong acid, such as sulfuric acid, phosphoric acid, or from the hydrolysis of trifluoroacetic anhydride).
  • the dehydration may also be performed in refluxing methylene chloride in the presence of catalytic p-toluenesulfonic acid (TsOH).
  • TsOH catalytic p-toluenesulfonic acid
  • the compound of Formula (V) is prepared by reacting the compound of Formula (IV) with trifluoroacetic anhydride, e.g., in the presence of 2,6-lutidine.
  • the compound of Formula (IV): (IV), in which P 1 and P 2 are as defined above, is prepared by reducing a compound of Formula (III): , in which P 1 is an N-protecting group P 2 is a carboxyl-protecting group (e.g., an alkyl group such as methyl).
  • the compound of Formula (IV) may be reduced using a reducing agent such as lithium triethylborohydride borohydride.
  • the compound of Formula (IV) is reduced Compounds of Formula (III)
  • the compound of Formula (III): (III), in which P 1 and P 2 are as defined above, is prepared by subjecting a compound of Formula (II): ALXN.
  • the compound of Formula (II): (II), in which P 1 and P 2 are as defined above, is prepared by reacting a compound of Formula (I): , in which P 1 is an N-protecting group (e.g., and P 2 is a carboxyl-protecting group (e.g., an alkyl group such as methyl), with butoxy bis(dimethylamino)methane; see, e.g., Rosso, Synlett.2006; 5: 0809-0810).
  • P 1 is an N-protecting group
  • P 2 is a carboxyl-protecting group (e.g., an alkyl group such as methyl)
  • butoxy bis(dimethylamino)methane see, e.g., Rosso, Synlett.2006; 5: 0809-0810).
  • the carboxyl-protecting group is alkyl (e.g., methyl)
  • the carboxyl-protecting-group-removing agent is a base (e.g., NaOH, LiOH, or KOH).
  • carboxyl-protecting reagents and reaction conditions required to install and remove carboxyl- protecting groups are well known in the art (see, e.g., Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, the carboxyl-protecting-group- removing agent is NaOH. In some is added in an amount sufficient to achieve a pH of > 11. ALXN.
  • the compound of formula (VI’) is purified by first reacting it with an organic amine to form an organoammonium salt of the compound of formula (I) (e.g., in an organic solvent such as THF or toluene), then reacting the organoammonium salt of the compound of formula (I) with an acid to reform the compound of formula (I).
  • organic amines include, but are not limited to, benzylamine and chiral amines such as (R)- ⁇ -methylbenzylamine.
  • the organic amine is benzylamine, which forms a benzylammonium salt of the compound of formula (I).
  • the organic amine is (R)- ⁇ -methylbenzylamine, which forms a (R)- ⁇ -methylbenzylammonium salt of the compound of Formula (I).
  • the compound of Formula (VI’) can then be coupled to a compound of Formula (VII): (VII), or a salt thereof, in which R 1 is H or optionally substituted C 1 -C 6 alkyl; each of R 2 and R 3 is independently H or methyl; m is 0, 1, or 2; and B is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C3-C10 carbocyclyl, C6-C14 aryl, optionally substituted 5- to 10- membered heterocyclyl, or optionally heteroaryl; in an amidation reaction to form a compound of Formula (VIII): (VIII), in which P 1 is an N-protecting group (e.g., tert-butoxycarbonyl), and all other variables are as defined for
  • a compound of Formula (VI’) in which P 1 is H may first be reacted with an N- protecting reagent (e.g., d-tert-butyl to the compound of Formula (VII) or salt thereof to form a compound of removal of P 1 that is an N-protecting group in the compound of Formula removing agent provides a compound of Formula (IX): (IX), or a salt thereof, in which all variables are as defined for Formula (VIII).
  • N- protecting reagent e.g., d-tert-butyl to the compound of Formula (VII) or salt thereof to form a compound of removal of P 1 that is an N-protecting group in the compound of Formula removing agent provides a compound of Formula (IX): (IX), or a salt thereof, in which all variables are as defined for Formula (VIII).
  • N-protecting reagents and reaction conditions required to install and remove N-protecting groups are well known in the art (see, e.g., Wuts, Green
  • the N- butyl dicarbonate (Boc 2 O), and the reaction is performed in an organic the presence of a base (e.g., 4- dimethylaminipyridine), and the N- (Boc).
  • a base e.g., 4- dimethylaminipyridine
  • the N-protecting group is Boc
  • the N-protecting group includes treating the compound of Formula (VIII) in an organic solvent with an acid as the N-protecting-group-removing agent.
  • the N-protecting-group-removing agent is hydrogen chloride (4 N HCl in dioxane)
  • the reaction is performed in, e.g., dioxane
  • the deprotection reaction forms a hydrochloride salt of the compound of Formula (IX).
  • the acid is hydrogen bromide (e.g., 33% HBr solution in acetic acid), the reaction is performed in, e.g., ethyl acetate, and the deprotection reaction forms a ALXN.
  • the acid is trifluoroacetic acid, the reaction is performed in, e.g., dichloromethane, and the deprotection reaction forms a trifluoroacetic acid salt of the compound of Formula (IX).
  • Suitable coupling reagents include, but are not limited to n-propanephosphonic acid anhydride (T3P) and (2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU).
  • T3P n-propanephosphonic acid anhydride
  • HBTU 2,3,3-tetramethyluronium hexafluorophosphate
  • Exemplary compounds of Formulas (VIII) and (IX) and methods of preparing such compounds are described in, e.g., U.S. Patents Nos. PCT Publications Nos. WO2015/130838, WO2017/035353, WO2017/035409, WO2018/160889, WO2020/041301, and WO2021/168320, the entire contents of which are incorporated herein by reference.
  • the compound of Formula (IX): (IX), or the salt thereof is coupled to a compound of Formula (X): , in which: R 4 is H; halo; OH; NH2; cyano; C1-C6 alkyl; optionally substituted C2-C6 alkenyl; optionally substituted 3- to 8- -C(O)NRaRa’, in which each of Ra and Ra ’ is, independently, H, optionally substituted substituted C 2 -C 6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally -C(O)Rb; -OC(O)Rb; or -C(O)ORb; in which Rb, in each instance, substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally each of R 5 and R 6 is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
  • DOCKET ALXN-0761-WO-PCT substituted C 4 -C 10 aryl, optionally substituted 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally substituted 4- to 10-membered saturated or unsaturated non-aromatic heterocyclyl containing 1-4 heteroatoms selected from N, O, and S; to form a compound of Formula (XI): or a pharmaceutically acceptable salt are as defined for Formulas (IX) and (X).
  • the salt of the compound of Formula (IX) and a compound of in the presence of 1- [bis(dimethylamino)methylene]-1H- 3-oxide hexafluorophosphate and N,N- diisopropylethylamine is included in the presence of 1- [bis(dimethylamino)methylene]-1H- 3-oxide hexafluorophosphate and N,N- diisopropylethylamine.
  • the reaction is performed with a trifluoroacetic acid salt of the compound of Formula (IX) with a compound of Formula (X) in dimethylformamide in the presence of N,N-diisopropylethylamine and 1-[bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1H-benzotriazole-1-yl)-1,1,3,3- tetramethylaminium tetrafluoroborate.
  • R 1 is H. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), R 1 is CH3.
  • m is 0. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), m is 0. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), m is 1. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), m is 2. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), each of R 2 and R 3 is H.
  • R 2 is H and R 3 is CH3.
  • R 3 is CH3.
  • B is optionally substituted 5- to 10-membered heteroaryl.
  • B is optionally substituted 6-membered heteroaryl, e.g., optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl.
  • B is optionally substituted pyridyl, e.g., , , , , , F 3 C N , ,
  • B is optionally substituted pyridazinyl, .
  • B or ALXN.
  • B is bicyclic 9- or 10-membered .
  • B is optionally substituted C 6 -C 14 aryl, e.g., optionally substituted phenyl, , , ALXN.
  • DOCKET ALXN-0761-WO-PCT In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted 5- to 9-membered unsaturated , .
  • X 1 is C(CH 3 ).
  • X 1 is CH.
  • X 2 is CRd.
  • X 2 is C(C 1 -C 6 alkyl). In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X 2 is C(CH 3 ). In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X 2 is CH. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X 5 is CR d .
  • X 5 is CH.
  • X 3 is CRf and X 4 is N.
  • X 3 is CRf and X 4 is CH.
  • X 4 is CR f and X c is N.
  • X 4 is CRf and X 3 is CH.
  • Rf is optionally substituted 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.
  • Rf is , ALXN. DOCKET ALXN-0761-WO-PCT , ), Rf is e.g., , or , Rf is from N, O, and S.
  • Rf is optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted thiazolo[5,4-b]pyridinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, 1H-thieno[3,2- c]pyrazolyl, imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl, e.g., , , ALXN.
  • DOCKET ALXN-0761-WO-PCT is is or may to atom to through a carbon ring atom contained , ALXN. DOCKET ALXN-0761-WO-PCT .
  • Rf may be a nitrogen atom contained therein . is optionally substituted 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and . an 4 d (XI)), R is - C(O)Rb.
  • R 4 is , R 4 is - (XI)), , .
  • R 4 is - (XI)), R 4 is -C(O)OCH3. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is -C(O)OH. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R 4 is optionally substituted C1-C6 alkyl. In some embodiments of any of the aspects described herein (e.g., ALXN. DOCKET ALXN-0761-WO-PCT Formulas . In some embodiments of any of the aspects described herein (e.g., Formulas .
  • R 4 is .
  • R 4 is cyano.
  • R 4 is halo, e.g., Br.
  • R 5 is H.
  • R 6 is H.
  • the compound of Formula (XI) is: , or a pharmaceutically acceptable salt In some embodiments, the is: , or a pharmaceutically acceptable salt In some embodiments, the is: , ALXN. DOCKET ALXN-0761-WO-PCT or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (XI) is: , or a pharmaceutically acceptable salt In some embodiments, the compound of Formula (XI) is: , or a pharmaceutically acceptable salt In some embodiments, the compound of Formula (XI) is: , or a pharmaceutically acceptable salt In some embodiments, the , or a pharmaceutically acceptable salt The examples described herein serve to illustrate the present disclosure, and the disclosure is not limited to the examples given. ALXN.
  • Step 2 Synthesis of 1-(tert-butyl) 2-methyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (2c) (E)-4- Pd/C then After was concentrated under reduced pressure at 45 oC to afford a light-brown thick oil. Cyclohexane (40 mL) was added to the oil, and it was allowed to stir at -5 oC for 30-50 min. The obtained solids were filtrated at -5 ALXN. DOCKET ALXN-0761-WO-PCT oC.
  • Step 3 Synthesis of 1-(tert-butyl) 2-methyl (2S)-5-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (2d) 1,2- under in °C. mixture at -75 °C, and reaction mixture was gradually warmed to room temperature. The organic layer was separated, and aqueous layer was further extracted with toluene (180 mL). The combined organic phase was used directly in the next step.
  • Step 4 Synthesis of 1-(tert-butyl) 2-methyl (S)-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2e) mmol, 14 h. and layer was washed by 1M HCl (360 mL).
  • the degassed solution of CH2Br2 (1/3 portion of total volume) in THF was added dropwise over 30 min to the reaction mixture, and it was allowed to stir at RT for 1h.
  • the internal temperature was gradually increased to 41 oC and decreased to 22 oC within an hour.
  • a second portion of Zn (1.63 g. 24.87 mmol, 2.0 eq) was added to the reaction mixture and the reaction mixture was allowed to stir for 10- 20 min, then a second portion of CH 2 Br 2 (1/3 portion of total solution) was added dropwise for 10 min, after which the reaction mixture was allowed to stir for 1h.
  • the remaining third portion of Zn (1.63 g. 24.87 mmol) was added to the reaction mixture, and it was allowed to stir for 10 min.
  • Procedure B To a clean and dry 1L three-neck round-bottom with a magnetic stirrer was charged with a first portion of Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%), THF (20 mL), ZnCl2 (0.56 g, 4.14 mmol) and the first portion of Zn dust ((1.08 g, 16.58 mmol; directly used from commercially available bottle). The reaction mixture was allowed to stir until a dark purple color appeared.
  • the internal reaction temperature gradually increased to 28.3 oC.
  • the second portion of Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%) and Zn ALXN.
  • DOCKET ALXN-0761-WO-PCT (1.08 g, 16.58 mmol) were added to the reaction mixture and allowed to stir for 10 min.
  • the second portion of CH 2 Br 2 (1/3 of the total solution) was added dropwise over 10 min, and the reaction mixture was allowed to stir 1 h.
  • the third portion of Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%) and 2.0 equiv. of Zn (1.08 g, 16.58 mmol) were added to the mixture and allowed to stir for 10 min.
  • Step 6 Synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2g)
  • Procedure A To mmol) in 3:1 mixture of EtOH/H2O (37 mL) LiOH 6-8 h. After completion of reaction, the reaction layer was further washed with 7.4 mL of EtOAc. The aqueous layer was collected, and its pH was adjusted to between 1-2 by adding aqueous 2M HCl solution. The solution was extracted with EtOAc (18.5 mL), and the combined organic layer was washed with 10% NaCl solution (7.4 mL).
  • Co(PDI)X2 complexes can be prepared based on the following procedure.
  • Step 1. Synthesis of PDI Ligand charged 2,6- 2.2 eq) to reaction ALXN. DOCKET ALXN-0761-WO-PCT mixture at rt. After the addition of p-TsOH (500 mg), the solution was refluxed and distilled for 6 h. Upon cooling to room temperature, 1M NaOH (2V) was added, and the reaction mixture was filtered through funnel and the product was diluted with ethanol and refluxed for 0.5 h.
  • Co( t Bu-PDI)Br2 Complex THF (4 v) was charged in a 5 L reactor followed by the addition of PDI ligand (200 g, 469.9 mmol,1.0 equiv) under the nitrogen flow, subsequently, additional THF (11 v) was charged in the reactor and allowed to stir for 10-30 min and gives the homogeneous solution.
  • CoBr2 (102.8 g, 469.9 mmol, 1.0 equiv) was charged in the reaction under nitrogen flow followed by the addition of THF (5 v). The reaction mass was allowed to stir for 60-72 h at room temperature under nitrogen flow. After 60-72 h, the reaction mixture was filtered and dried 8-12 h under vacuum at room temperature and was used without further purification.
  • Example 3 Improved Synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxylic acid Step 1,2- 2a (2.5 v, 625 . the reaction mass was heated at 75 ⁇ 3 °C over 6-8 h. Upon completion of the reaction, the reaction mass was cooled to -5 ⁇ 3 °C. was washed with cold cyclohexane (2.5 v).
  • Step 2 Synthesis of 1-(tert-butyl) 2-methyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (2c)
  • Compound 2b (40 g, 298.34 mmol, 1.0 equiv) was charged into a reactor, followed by IPA (4-7 v, 160-280 mL) and 10%w/w of 10% Pd/C (50% wet) (0.5 w/w Pd content).
  • the reactor was equipped with overhead, sealed and placed in polyblock at 1500 rpm for 12-18 h. After completion of the reaction, mass was passed through celite (2-4 w/w) bed.
  • Step 3 Synthesis of 1-(tert-butyl) 2-methyl (2S)-5-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (2d) Continuous Flow Protocol
  • a continuous flow setup providing a throughput of 148 g/h based on 1/4” OD PFA tubular reactor (170 mL) (FIG.1) was used.
  • Feed 1 Carboy charged with Compound 2c (411.5 g, 1612.80 mmol, 1.0 equiv) and toluene (3320 mL, 8 v) under N2 atmosphere.
  • Feed 2 Super Hydride (1 M in THF, 2096.9 mL, 1.3 way valve was used to switch empty.
  • Methanol for quenching was mL pre-cooling loops.
  • ALXN. DOCKET ALXN-0761-WO-PCT Batch Protocol In a four neck 5 L RB connected to an overhead stirrer, Compound 2c (238.52 g, 1.0 equiv) was charged and dissolved in toluene (10 v) under nitrogen.
  • reaction solution was cooled to -78 °C and a 1.0 M solution of super-hydride (834.34 mL, 0.9 equiv) in THF was added slowly using a a peristaltic pump (4 mL/min). The mixture was stirred for 2 h at around -75 °C to -70 °C. The progress was monitored by 1 H NMR analysis. Based on the conversion of Compound 2c, another 0.16 equiv of super- hydride was charged slowly using a peristaltic pump (4 mL/min), and reaction was stirred for 30 min at around -75 °C to -70 °C. The progress was monitored by 1 H NMR.
  • Step 4 Synthesis of 1-(tert-butyl) 2-methyl (S)-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2e)
  • Compound 2d 240.4 g, 927.1 mmol, 1.0 equiv) in 10 v toluene (2.4 L) was charged to 5 L reactor with the help of a wide funnel under nitrogen flow.
  • the reaction temperature was cooled to 0 °C.2,6- Lutidine (280.7 mL, 2410.4 mmol, 2.6 equiv) was added under nitrogen flow.
  • Trifluoroacetic anhydride (TFAA) (167.5 funnel (connected with a long tube while maintaining the the reaction mass was was monitored by 1 H NMR to 22 ⁇ 5 °C.
  • the pale-yellow liquid was dried under vacuum for the next 8-10 h.
  • Step 5 Synthesis of 2-(tert-butyl) 3-methyl (1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3- dicarboxylate (2f) Co( t Bu-PDI) Br2 (40.06 of THF also and subsequently, activated Zn (48.78, 745.99 mmol, 3.0 equiv) dust was charged into the reactor and rinsed the reactor with 3 v of THF. Then, the reaction mass in the reactor was deep subsurface purged with N 2 using long tubing for 10-15 minutes and it was allowed to stir for next 20-50 min. A deep purple color appeared.
  • the progress of the reaction was monitored again by 1 H NMR at the 6 th hour of the reaction, and the conversion was at 97A%.
  • the reaction mass was passed through MTBE wetted sloka floc (4 w/w) bed, and the bed was washed with 6-8 v of MTBE. Filtrate was charged in a 5 L reactor followed by a mixture of 1:1 ratio of 10% NH4Cl (2 v) and 10% NaCl solution (2 v) was also charged into the reactor and stirred the RM for 20-40 min. Phase cut was done to remove the aqueous layer.
  • the reaction mixture was distilled to 2-3 v and the crude RM was used for the next step.
  • Step 5 was tested with Zn activated with 1 N HCl and unactivated Zn, as well as various amounts of ZnCl 2 .
  • the results are shown in Tables 1-3 below.
  • ALXN. DOCKET ALXN-0761-WO-PCT Table 1. Reaction with 1 N HCl Activated Zn with Higher Loading of ZnCl 2 B h i PDIB Z ⁇ Z l HB R i i .0 .5 .5 size is three portions into the reaction mixture.
  • Table 2 Table 2.
  • the reaction mixture after charcoal treatment and azeotropic distillation was kept at 50-55 °C while stirring in a nitrogen atmosphere, into which (R)- ⁇ -methylbenzylamine (0.5 eq.) was dosed in 2 hours.
  • the system was aged for 1 h, and additional (R)- ⁇ -methylbenzylamine (0.5 eq.) was dosed in 2 h.
  • the final mixture was kept stirring at 50-55 °C for 1 hour.
  • the reaction mixture was then cooled to 20 °C with a linear temperature profile over 4 hours, and stirred at 20 °C for NLT 16 h.
  • the (R)- ⁇ -methylbenzylamine salt was dispersed in 10 V isopropyl acetate while stirring at 20-25 °C.4.5 v 2 M HCl (aq.) was dosed to the mixture at 20-25 °C over 15 min. The mixture was then stirred for 10-15 min. The aqueous layer was discharged.3 v of water was charged into the remaining organic layer, and was stirred for 30 min. The aqueous layer was discharged. The organic layer was heated to 55-60 °C while stirring and was distilled to 1.5-2 v under vacuum.3 v isopropyl acetate was charged into the solution, and the solution was distilled to 1.5-2 v under vacuum.

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Abstract

La présente divulgation concerne des procédés de synthèse d'inhibiteurs du facteur D du complément et des intermédiaires de ceux-ci.
PCT/US2024/033785 2023-06-14 2024-06-13 Procédés de synthèse d'inhibiteurs du facteur d du complément et intermédiaires de ceux-ci Pending WO2024259085A2 (fr)

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