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WO2025228547A1 - Procédés de préparation de composés de phénéthylamine - Google Patents

Procédés de préparation de composés de phénéthylamine

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Publication number
WO2025228547A1
WO2025228547A1 PCT/EP2024/067458 EP2024067458W WO2025228547A1 WO 2025228547 A1 WO2025228547 A1 WO 2025228547A1 EP 2024067458 W EP2024067458 W EP 2024067458W WO 2025228547 A1 WO2025228547 A1 WO 2025228547A1
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WIPO (PCT)
Prior art keywords
deuterium
optionally substituted
alkyl optionally
compound
formula
Prior art date
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Application number
PCT/EP2024/067458
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English (en)
Inventor
Manjeet Kumar
Pravin THOMBRE
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Cybin IRL Ltd
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Cybin IRL Ltd
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Publication of WO2025228547A1 publication Critical patent/WO2025228547A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide

Definitions

  • 5-HT2RS serotonin 5-HT2 receptors
  • 5-HT2A 5-HT2A
  • 5-HT2B 5-HT2C
  • LSD lysergic acid diethylamide
  • DOB 2,5-dimethoxy-4-bromoamphetamine
  • Classic serotonergic psychedelics and entactogens have been actively investigated by the research and medical community to alleviate a multitude of central nervous system (CNS) disorders (Reiff, C.
  • CNS central nervous system
  • PTSD post-traumatic stress disorder
  • MDD major depressive disorder
  • TRD treatment-resistant depression
  • OCD obsessive-compulsive disorder
  • ANS autonomic nervous system
  • pulmonary disorders e.g., asthma and chronic obstructive pulmonary disorder (COPD)
  • cardiovascular disorders e.g., atherosclerosis
  • the present disclosure provides, inter alia, a process for preparing a compound of
  • This process is an efficient and cost-effective method for preparing compounds that act as serotonin 5-HT2 receptor agonists.
  • the present disclosure provides a scalable process for preparing compounds that can be used in the treatment of diseases associated with an 5-HT2 receptor, such as post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), obsessive-compulsive disorder (OCD), social anxiety disorder, substance use disorders, including but not limited to alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, anorexia nervosa, bulimia nervosa, Alzheimer’s disease, pain, and cluster headache and migraine, and others such as those associated with reduced neuroplasticity and/or neuroinflammation.
  • diseases associated with an 5-HT2 receptor such as post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), obsessive-compulsive disorder (OCD), social anxiety disorder, substance use disorders, including but not limited
  • C n-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C , C1-6 and the like.
  • alkyl refers to a straight- or branched-chain alkyl group having the indicated number of carbon atoms in the chain.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, and isohexyl.
  • C1-C3 alkyl as used herein refers to a straight- or branched-chain alkyl group having from 1 to 3 carbon atoms in the chain.
  • Ci-Ce alkyl refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain.
  • aryl means an aromatic carbocyclic system containing 1 , 2 or 3 rings, wherein such rings may be fused, wherein fused is defined above. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated.
  • aryl includes, but is not limited to, phenyl, naphthyl, indanyl, and 1 ,2,3,4-tetrahydronaphthalenyl.
  • aryl groups have 6 carbon atoms.
  • the aryl group has six to ten carbon atoms.
  • the aryl group is phenyl.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.
  • C n-m cycloalkyl refers to a cycloalkyl that has n to m ring member carbon atoms.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C3-7).
  • the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (/.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Preparation of compounds involves the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. Adjustments to the protecting groups and formation and cleavage methods described herein may be adjusted as necessary in light of the various substituents.
  • protecting group refers to a molecular framework that is introduced onto a specific functional group in a poly-functional molecule to block its reactivity under reaction conditions needed to make modifications elsewhere in the molecule.
  • the protecting group is benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), phthalimide, dichlorophthalimide, tetrachlorophthalimide, 4-nitrophthalimide, 2,3- diphenylmaleimide, succinimide, 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4- trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc), t-butoxycarbonyl (Boc), 1- adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohe
  • the protecting group is methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), allyl, t-butyldimethylsilyl (TBDMS), or pivoyl (Piv).
  • MOM methoxymethyl
  • MEM 2-methoxyethoxymethyl
  • TDMS t-butyldimethylsilyl
  • Piv pivoyl
  • a protecting group such as one of those listed above is introduced onto a nitrogen functional group of the molecule, it may be referred to as a “nitrogen protecting group.”
  • the protecting group is phthalimide.
  • protecting group reagent refers to a reactant that installs a protecting group on another reactant in a process.
  • Protecting group reagents include reactants that protect a free nitrogen atom or free oxygen atom.
  • Examples of protecting group reagents include but are not limited to phthalic anhydride, dichlorophthalic anhydride, tetrachlorophthalic anhydride, 4-nitrophthalic anhydride, 2,3-diphenylmaleic anhydride, succinic anhydride, MOMCI, MEMCI, Boc 2 O, TrtCI, SEMCI, BnCI, PivCI, TBDPSCI, TIPSCI, TMSCI, and BzCI.
  • Mono- or bisesters e.g., mono-methyl or bis-methyl esters
  • mono-methyl or bis-methyl esters of any of the anhydrides may also be used as the protecting group reagent.
  • alkylating reagent refers to chemical species that alkylates a reactant.
  • a “trifluoromethylating reagent” is an alkylating agent that donates a -CF3 moiety to the reactant.
  • oxidizing reagent refers to a substance in a redox chemical reaction that gains or accepts an electron from a reducing agent.
  • An oxidizing reagent is a chemical species that undergoes a chemical reaction in which it gains one or more electrons.
  • reducing reagent refers to a chemical species that donates an electron to an electron recipient in a redox reaction.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted.
  • the present disclosure also includes salt forms of the compounds described herein.
  • salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference in its entirety.
  • the acid used to form the salt (or salt form) may be a monoacid, a diacid, a triacid, a tetraacid, or may contain a higher number of acid groups.
  • the acid groups may be, e.g., a carboxylic acid, a sulfonic acid, a phosphonic acid, or other acidic moieties containing at least one replaceable hydrogen atom.
  • acids which may be used to form the salts (or salt forms) disclosed herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5- disulfonic acid,
  • Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas.
  • solvent refers to any solvent that contains one or more carbon-hydrogen bonds.
  • organic solvents include hexane, heptane, tetrahydrofuran, dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, propylene glycol methyl ether, /V,/V-dimethylformamide, /V,/V-dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, and the like.
  • protic solvent refers to any solvent that contains a labile hydrogen atom.
  • the labile hydrogen atom is bound to an oxygen (as in a hydroxyl group), a nitrogen (as in an amino group), or a sulfur (as in a thiol group).
  • Suitable protic solvents can include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1 -propanol, 2-propanol, 2-methoxyethanol, 1 -butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, propylene glycol methyl ether, 2- ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • aprotic solvent refers to any solvent that does not contain a labile hydrogen atom.
  • Suitable aprotic solvents can include, by way of example and without limitation, tetrahydrofuran (THF), /V,/V-dimethylformamide (DMF), /V,/V-dimethylacetamide (DMA), 1 ,3- dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPLI), 1 ,3-dimethyl-2-imidazolidinone (DMI), /V-methylpyrrolidinone (NMP), formamide, /V-methylacetamide, /V-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane,
  • reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures).
  • reactions of the processes described herein can be carried out in air or under an inert atmosphere.
  • reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan.
  • preparation of compounds can involve the addition of acids or bases to effect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.
  • Example acids can be inorganic or organic acids.
  • Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid.
  • Organic acids include formic acid, acetic acid, propionic acid, butanoic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid.
  • base refers to any species that contains a filled orbital containing an electron pair which is not involved in bonding.
  • Example bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, pyridine, imidazole, triethylamine, triethylamine, N,N- diisopropylethylamine (DIPEA), sodium ethoxide, potassium ethoxide, and the like.
  • Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate.
  • Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and metal dialkylamides include sodium, lithium, and potassium salts of methyl, ethyl, n-propyl, i-propyl, n- butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.
  • isolation and purification operations such as concentration, filtration, extraction, solidphase extraction, recrystallization, chromatography, and the like may be used, to isolate the desired products.
  • the present disclosure provides, inter alia, processes for preparing a compound of Formula I, which is useful for the treatment of CNS disorders.
  • X is S, S(O), or S(O) 2 ;
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; comprising the steps of f) reacting a compound of Formula VII: wherein
  • PG is a nitrogen protecting group
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; with a trifluoromethylating reagent to form a compound of Formula VIII: wherein
  • PG is a nitrogen protecting group
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; g) optionally treating the compound of Formula VIII with an oxidizing reagent to form a compound of Formula VIII*: wherein
  • PG is a nitrogen protecting group
  • Y is S(O) or S(O) 2 ;
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; and h) treating the compound of Formula VIII or VIII* under deprotecting conditions to form the compound of Formula I.
  • the process further comprises the step of e) treating a compound of Formula VI: wherein
  • PG is a nitrogen protecting group
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; with a reducing reagent to form the compound of Formula VII.
  • the process further comprises the step of d) reacting a compound of Formula V: wherein
  • PG is a nitrogen protecting group
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; with chlorosulfonic acid to form the compound of Formula VI.
  • the process further comprises the step of c) reacting a compound of Formula IV: wherein
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; with a protecting group reagent to form the compound of Formula V.
  • the process further comprises the step of b) treating a compound of Formula III: wherein
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; with a reducing reagent to form the compound of Formula IV.
  • the process further comprises the step of a) reacting a compound of Formula II: wherein
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; with a compound of Formula Ila: R 1 -NC>2, wherein R 1 in Formula Ila is C1-7 alkyl optionally substituted with deuterium; to form the compound of Formula III.
  • the process further comprises the step of reacting a compound that is 2,5-dihydroxybenzaldehyde: with R 2 X and R 3 X; wherein
  • R 2 and R 3 are each independently C1-6 alkyl optionally substituted with deuterium; and each X is independently a leaving group such as halo (e.g., I, Br, Cl), a sulfonate (e.g., triflate, tosylate, mesylate, etc.), dinitrogen (-N2 + ), and the like; to form a compound of Formula II.
  • halo e.g., I, Br, Cl
  • a sulfonate e.g., triflate, tosylate, mesylate, etc.
  • dinitrogen -N2 +
  • the process comprises preparing a compound of Formula I: or a pharmaceutically acceptable salt thereof; wherein
  • X is S, S(O), or S(O) 2 ;
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; comprising the steps of a) reacting a compound of Formula II: wherein
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; with a compound of Formula Ila: R 1 -NC>2, wherein R 1 in Formula Ila is C1-7 alkyl optionally substituted with deuterium; to form a compound of Formula III: wherein
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; b) treating the compound of Formula III with a reducing reagent to form a compound of Formula IV: wherein
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; c) reacting the compound of Formula IV with a protecting group reagent to form a compound of Formula V: wherein PG is a nitrogen protecting group;
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; d) reacting the compound of Formula V with chlorosulfonic acid to form a compound of Formula VI: wherein
  • PG is a nitrogen protecting group
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; e) treating the compound of Formula VI with a reducing reagent to form a compound of Formula VII: wherein
  • PG is a nitrogen protecting group
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; f) reacting the compound of Formula VII with a trifluoromethylating reagent to form a compound of Formula VIII: wherein
  • PG is a nitrogen protecting group
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; g) optionally treating the compound of Formula VIII with an oxidizing reagent to form a compound of Formula VIII*: wherein
  • PG is a nitrogen protecting group
  • Y is S(O) or S(O) 2 ;
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium; and h) treating the compound of Formula VIII or VIII* under deprotecting conditions to form the compound of Formula I.
  • the process further comprises reacting the compound of Formula I with an alkylating reagent to form a compound of Formula IX: or a pharmaceutically acceptable salt thereof;
  • X is S, S(O), or S(O) 2 ;
  • R 1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;
  • R 2 is C1-6 alkyl optionally substituted with deuterium
  • R 3 is C1-6 alkyl optionally substituted with deuterium
  • R 4 is C1-6 alkyl optionally substituted with C3-6 cycloalkyl or aryl.
  • the alkylating reagent for preparing the compound of Formula IX is selected from the group consisting of benzyl halide (e.g., benzyl bromide, benzyliodide, etc.), benzaldehyde, cyclopropylmethylhalide (e.g., cyclopropylmethyl bromide, cyclopropylmethyl chloride, etc.), cyclopropanecarboxaldehyde, aldehydes such as formaldehyde and acetaldehyde, and alkyl halide (e.g., methyl iodide, methyl bromide, ethyl bromide, and the like).
  • benzyl halide e.g., benzyl bromide, benzyliodide, etc.
  • benzaldehyde e.g., benzaldehyde
  • cyclopropylmethylhalide e.g.,
  • the compound of Formula Ila is nitromethane or nitroethane. In still another embodiment, the compound of Formula Ila is nitromethane. In another embodiment, the compound of Formula Ila is nitroethane.
  • the reacting of the compound of Formula II with the compound of Formula Ila in step a) involves using an organic amine in the presence of an acid.
  • the organic amine is selected from the group consisting of ammonium acetate, n- butylamine, and ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • the organic amine is n-butylamine.
  • the acid is hydrochloric acid or acetic acid.
  • the acid is acetic acid.
  • step a) is run at reflux temperature.
  • the reducing reagent in step b) is selected from the group consisting of LiAIF , LiBF , NaBF , H 2 Pd/C, PPha, sodium amalgam, sodium hydride, Na(OAc) 3 BH, NaBHsCN, and BH3-THF.
  • the reducing reagent in step b) is LiAIFU.
  • the treating the compound of Formula III with the reducing reagent in step b) involves dissolving the reactants in an organic solvent.
  • the organic solvent is an aprotic solvent.
  • the solvent is a polar solvent.
  • the solvent is selected from the group consisting of tetrahydrofuran (THF), acetonitrile, water, and toluene.
  • THF tetrahydrofuran
  • the protecting group reagent in step c) is phthalic anhydride or succinic anhydride. In another embodiment, the protecting group reagent in step c) is phthalic anhydride. In yet another embodiment, the protecting group reagent in step c) is succinic anhydride. In another embodiment, the protecting group reagent in step c) is benzyl bromide. In another embodiment, the protecting group reagent in step c) is acetyl chloride or acetic anhydride.
  • the reacting of the compound of Formula IV with the protecting group reagent in step c) involves dissolving the compound of Formula IV and the protecting group reagent in a solvent and refluxing.
  • the solvent is an aprotic solvent.
  • the solvent is a nonpolar solvent.
  • the solvent is toluene.
  • the reflux temperature is between 120 °C to 130 °C.
  • the reacting of the compound of Formula V with chlorosulfonic acid in step d) involves diluting the reaction mixture with an organic solvent.
  • the organic solvent is dichloromethane.
  • the reacting of the compound of Formula V with chlorosulfonic acid in step d) involves using at least 2 equivalents of chlorosulfonic acid, at least 4 equivalents of chlorosulfonic acid, at least 6 equivalents of chlorosulfonic acid, at least 8 equivalents of chlorosulfonic acid.
  • the reducing reagent in step e) is selected from the group consisting of LiAIFL, NaBF , H2 Pd/C, PPha, sodium amalgam, sodium hydride, NaBHsCN, and BH3-THF.
  • the reducing reagent in step e) is PPha.
  • the treating of the compound of Formula VI with the reducing reagent in step e) involves dissolving the reactants in an organic solvent.
  • the organic solvent is an aprotic solvent.
  • the solvent is a polar solvent.
  • the solvent is selected from the group consisting of toluene, THF, and ethyl acetate. In an embodiment, the solvent is toluene.
  • the trifluoromethylating reagent in step f) is a compound of Formula X:
  • the compound of Formula X is also known as trifluoromethyl thianthrenium triflate or 5- (trifluoromethyl)-5H-thianthren-5-ium trifluoromethanesulfonate.
  • Other trifluoromethylating reagents include but are not limited to, trifluoromethyl thianthrenium tetrafluoroborate, sodium trifluoromethanesulfinic acid (Langlois reagent), diaryl(trifluoromethyl) sulfonium salt (Ar2S + CF3SbFe”), 5-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate, 5-(trifluoromethyl)dibenzothiophenium tetrafluoroborate, hypervalent iodine(lll)-CF3 reagents or Togni reagents such as 3,3-dimethyl-1-(trifluoromethyl)-1 ,2- benziodoxole, or other salts
  • the reacting of the compound of Formula VII with the trifluoromethylating reagent in step f) involves reacting the compound of Formula VII with the compound of Formula X (or other trifluoromethylating reagent such as trifluoromethyl thianthrenium tetrafluoroborate, sodium trifluoromethanesulfinic acid, etc.) in the presence of a base and a solvent.
  • trifluoromethylating reagent such as trifluoromethyl thianthrenium tetrafluoroborate, sodium trifluoromethanesulfinic acid, etc.
  • the solvent is an aprotic solvent. In yet another embodiment, the solvent is a polar solvent. In still another embodiment, the solvent is selected from the group consisting of acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, and pyridine. In an embodiment, the solvent is dimethylformamide. In another embodiment, the solvent is acetonitrile.
  • the base is selected from triethylamine, pyridine, 4- dimethylaminopyridine, imidazole, and potassium persulfate.
  • the base is triethylamine.
  • the oxidizing reagent in step g) is selected from the group consisting of mCPBA, potassium permanganate, pyridinium chlorochromate (PCC), ceric ammonium nitrate (CAN), hydrogen peroxide, potassium nitrate, pyridinium dichromate (PDC), Dess-Martin periodinane, diethyl azodicarboxylate (DEAD), 2,3-dichloro-5,6- Dicyanobenzoquinone (DDQ), diisopropyl azodicarboxylate (DIAD), NMO, osmium tetroxide, and TEMPO.
  • the oxidizing reagent in step g) is mCPBA.
  • the molar equivalence of the oxidizing reagent in step g) relative to the compound of Formula VIII is adjusted for monooxidation for sulfoxide formation (X or Y is S(O)) or bisoxidation for sulfone formation (X or Y is S(O)2).
  • monooxidation may be carried out through the use of about one molar equivalent (e.g., about 1.0 to about 1.5 molar equivalence) of oxidizing agent (e.g., mCPBA), whereas bisoxidation may be produced through the use of superstiochiometric (e.g., about 2.0+ molar equivalence) of oxidizing agent.
  • oxidizing agent e.g., mCPBA
  • superstiochiometric e.g., about 2.0+ molar equivalence
  • the deprotecting conditions in step h) comprise aqueous alkylamine such as methylamine, butylamine, etc. In another embodiment, the deprotecting conditions in step h) comprise methylamine.
  • Other deprotecting conditions in step h) comprise the use of one or more of the following: hydrazine, arylhydrazine (e.g., phenylhydrazine), alkylhydrazine (e.g., methylhydrazine), strong bases such as sodium sulfide, a reducing reagent (e.g., sodium borohydride), enzyme reagents such as phthalyl amidase, polyamines (e.g., N,N- dimethyl-1,3-propanediamine, N-methyl-1,3-propanediamine, ethylenediamine, polymer bound ethylenediamine), hydroxylamine, hydrazine acetate, and the like.
  • the process comprises forming a pharmaceutically acceptable salt of the compound of Formula I.
  • the salt formation step may involve contacting the compound of Formula I as a free base with an acid.
  • a stoichiometric (or superstoichiometric) quantity of the acid is contacted with the free base compound of Formula I.
  • a sub-stoichiometric (e.g., 0.5 molar equivalents) quantity of the acid is contacted with the free base compound of Formula I.
  • the use of sub-stoichiometric quantities of the acid may be desirable when, for example, the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt.
  • the contacting may optionally be performed in a solubilizing solvent (i.e. , a solvent that is capable of dissolving the salt form thus obtained), a non-limiting example of which is 1,4-dioxane.
  • a solubilizing solvent i.e. , a solvent that is capable of dissolving the salt form thus obtained
  • the salt formation step may optionally involve removing the solubilizing solvent after salt formation is deemed complete, and optionally replacing with a non-solubilizing solvent (i.e., a solvent which is not capable of dissolving the salt form), a non-limiting example of which is ethyl acetate.
  • the contacting may optionally be performed in a non-solubilizing solvent whereby the salt form is precipitated out of solution upon formation.
  • the salt formation step may comprise isolating the salt form.
  • Isolation of the salt may be performed by various well-known isolation techniques, such as filtration, decantation, and the like.
  • the isolating step is performed by filtration.
  • the salt is isolated in crystalline form.
  • the salt is isolated in amorphous form.
  • additional crystallization and/or recrystallization steps may also optionally be performed, if desired, for example to increase purity, crystallinity, etc.
  • the salt formation step is performed during workup of the deprotecting conditions from the step h).
  • the pharmaceutically acceptable salt of the compound of Formula I is a hydrochloride (HCI) salt.
  • X is S. In still another embodiment, X is S(O). In an embodiment, X is S(O)2.
  • Y is S(O). In yet another embodiment, Y is S(O)2.
  • R 1 is H. In yet another embodiment, R 1 is D. In still another embodiment, R 1 is methyl.
  • R 2 is methyl. In another embodiment, R 2 is CD3. In yet another embodiment, R 3 is methyl. In still another embodiment, R 3 is CD3. In an embodiment, R 2 is methyl and R 3 is methyl. In another embodiment, R 2 is CD3 and R 3 is CD3. In yet another embodiment, R 4 is methyl. In still another embodiment, R 4 is ethyl. In an embodiment, R 4 is -CH2-cyclopropyl. In another embodiment, R 4 is -CH2-phenyl.
  • PG is phthalimide. In still another embodiment, PG is succinimide.
  • X is S, S(O), or S(O) 2 ;
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; comprising the steps of f) reacting a compound of Formula VII’: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; with a compound of Formula X: to form a compound of Formula VIII’: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; g) optionally treating the compound of Formula VIII’ with mCPBA to form a compound of Formula VIII*’: wherein
  • Y is S(O) or S(O) 2 ;
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; and h) treating the compound of Formula VIII’ or VIII*’ under deprotecting conditions to form the compound of Formula I.
  • the process further comprises the step of e) treating a compound of Formula VI’: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; with triphenylphosphine to form the compound of Formula VII’.
  • the process further comprises the step of d) reacting a compound of Formula V’: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; with chlorosulfonic acid to form the compound of Formula VI’.
  • the process further comprises the step of c) reacting a compound of Formula IV: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; with phthalic anhydride to form the compound of Formula V’.
  • the process further comprises the step of b) treating a compound of Formula III: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; with lithium aluminum hydride to form the compound of Formula IV.
  • the process further comprises the step of a) reacting a compound of Formula II: wherein
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; with a compound of Formula Ila: R 1 -NC>2, wherein R 1 is C1-4 alkyl optionally substituted with deuterium; to form the compound of Formula III.
  • the process further comprises the step of reacting a compound that is 2,5-dihydroxybenzaldehyde: with R 2 X and R 3 X; wherein
  • R 2 and R 3 are each independently C1-6 alkyl optionally substituted with deuterium; and each X is independently halo; to form a compound of Formula II.
  • the process comprises preparing a compound of Formula I: or a pharmaceutically acceptable salt thereof; wherein
  • X is S, S(O), or S(O) 2 ;
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; comprising the steps of a) reacting a compound of Formula II: wherein
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; with a compound of Formula Ila: R 1 -NO 2 , wherein R 1 is C1-4 alkyl optionally substituted with deuterium; to form a compound of Formula III: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; b) treating the compound of Formula III with lithium aluminum hydride to form a compound of Formula IV: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; c) reacting the compound of Formula IV with phthalic anhydride to form a compound of Formula wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; d) reacting the compound of Formula V’ with chlorosulfonic acid to form a compound of Formula VI’: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; e) treating the compound of Formula VI’ with triphenylphosphine to form a compound of Formula VII’: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; f) reacting the compound of Formula VII’ with a compound of Formula X: to form a compound of Formula VIII’: wherein
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; g) optionally treating the compound of Formula VIII’ with an oxidizing reagent to form a compound of Formula VIII*’: wherein
  • Y is S(O) or S(O) 2 ;
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium; and h) treating the compound of Formula VIII’ or VIII*’ with aqueous methylamine to form the compound of Formula I.
  • the process further comprises reacting the compound of Formula I with an alkylating reagent to form a compound of Formula IX: or a pharmaceutically acceptable salt thereof;
  • X is S, S(O), or S(O) 2 ;
  • R 1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;
  • R 2 is C1-3 alkyl optionally substituted with deuterium
  • R 3 is C1-3 alkyl optionally substituted with deuterium
  • R 4 is C1-3 alkyl, C1-3 alkyl-(C3-6 cycloalkyl), or C1-3 alkyl-(phenyl).
  • the compound of Formula I is selected from the group consisting of or a pharmaceutically acceptable salt thereof.
  • the compound of Formula IX is selected from the group consisting of
  • the compound of Formula I is isolated in high yield. In some embodiments, the compound of Formula I is isolated in at least about 85% yield. In some embodiments, the compound of Formula I is isolated in at least about 90% yield.
  • the compound of Formula I is isolated with high purity. In some embodiments, the compound of Formula I is isolated with at least about 90% purity. In some embodiments, the compound of Formula I is isolated with at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% purity. In some embodiments, the compound of Formula I is isolated with at least about 95% purity. In some embodiments, the compound of Formula I is isolated with at least about 99% purity.
  • the compound of Formula IX is isolated in high yield. In some embodiments, the compound of Formula IX is isolated in at least about 85% yield. In some embodiments, the compound of Formula IX is isolated in at least about 90% yield.
  • the compound of Formula IX is isolated with high purity. In some embodiments, the compound of Formula IX is isolated with at least about 90% purity. In some embodiments, the compound of Formula IX is isolated with at least about 95%, at least about
  • the compound of Formula IX is isolated with at least about 95% purity. In some embodiments, the compound of Formula IX is isolated with at least about 99% purity.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
  • Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas.
  • Suitable solvents can include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1 ,1,1- trichloroethane, 1 ,1,2-trichloroethane, 1 ,1 -dichloroethane, 2-chloropropane, a,a,a- trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4- trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof and the like.
  • halogenated solvents such as carbon tetrachloride, bro
  • Suitable ether solvents include: dimethoxymethane, tetra hydrofuran, 1,3-dioxane, 1 ,4- dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, mixtures thereof and the like.
  • Suitable protic solvents can include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1- propanol, 2-propanol, 2-methoxyethanol, 1 -butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • Suitable aprotic solvents can include, by way of example and without limitation, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3- dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPLI), 1,3-dimethyl-2-imidazolidinone (DMI), N methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.
  • THF
  • Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.
  • Supercritical carbon dioxide and ionic liquids can also be used as solvents.
  • reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures).
  • reactions of the processes described herein can be carried out in air or under an inert atmosphere.
  • reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan.
  • preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.
  • Example acids can be inorganic or organic acids.
  • Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid.
  • Organic acids include formic acid, acetic acid, propionic acid, butanoic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid.
  • Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate.
  • Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.
  • the usual isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, chromatography, and the like may be used, to isolate the desired products.
  • triphenylphosphine was added in the reaction during isolation (as a stabilizing agent).
  • trifluoromethylation of lnt-3* was attempted using different trifluoromethylating agents. All the reagents tried gave ⁇ 10% desired product. None of the reagents resulted in >10% desired product formation. Therefore, this process is not suitable for process scale.
  • Step-b various reducing reagents were screened, e.g., Ni/Pd/Rh hydrogenations, metal hydride reagents, such as LiAIFL, NaBH4, UBH4, and NiCl2/NaBH4. Reduction using lithium aluminum hydride gave maximum conversion to Int-IV.
  • the crude material was subjected to the next step without any purification.
  • N-protecting groups were explored in view of their compatibility with downstream chemistry.
  • N-Acetylation, N-Cbz protection, and N-phthalimide protection were considered as a priority screening to understand the complete route feasibility: a) N-Cbz protection was successful on small scale, but this intermediate did not result in desired thiol scaffold when subjected to optimized reduction conditions (described in route-1). b) N-phthalimide protection resulted in good conversion and isolated as solid material. This intermediate worked well in downstream chemistry (discussed below). c) N-acetyl protection also resulted in desired product on small scale. Later, this intermediate was subjected to the trifluoromethylation step, which gave the desired product but in lower yields. Also, the material obtained was gummy mass, which requires column purification. Further, deprotection trials also resulted in lower yields.
  • N-phthalimide protection resulted in maximum conversion and was easier to isolate as a solid compound, thus it was optimized and scaled-up to gram scale.
  • phthalimido-protected intermediate-Va was subjected to chlorosulfonation conditions (step d) followed by triphenylphosphine mediated reduction (step e) using the earlier optimized process (Scheme 1).
  • the crude material Vila was purified through column chromatography to remove triphenylphosphine related byproducts. This key scaffold was subjected to extensive screening using different trifluoromethylating agents detailed below.
  • Entry-9 was considered for scale-up batches.
  • Step-2 Synthesis of 2,5-dimethoxybenzenethiol (lnt-3*): Summary of Feasibility and Optimization Experiments: The synthesis of lnt-3* was explored using different reducing reagents and reaction conditions like Zn/HCI, Zn/AcOH, triphenylphosphine, lithium aluminium hydride. In all conditions, lnt-3* was formed, but a dimer of lnt-3* was also observed. The Zn/HCI, triphenylphosphine reaction condition gave major lnt-3*, later scaled-up in multiple batches.
  • Step-3 Synthesis of (2, 5-dimethoxyphenyl) (tri fluoromethyl) sulfane (lnt-4*):
  • Step-b Synthesis of (2-(2,5-dimethoxyphenyl) ethan-1 -amine (lnt-3):
  • N-phthalimide protection works well on trial scale. Initially, the intermediate was purified by silica gel column purification, but a later crystallization method in isopropanol was developed. The optimized conditions were used in scale up batches.
  • Step-d Synthesis of 4-(2-(1 ,3-dioxoisoindolin-2-yl) ethyl)-2,5-dimethoxybenzenesulfonyl chloride (lnt-5a): Summary of Feasibility Experiments:
  • Step-f Synthesis of2-(2,5-dimethoxy-4-((trifluoromethyl)thio) phenethyl) isoindoline-1, 3- dione(lnt-7a):
  • Step-c to e N-CBz strategy: Summary of Feasibility Experiments: lnt-5B was confirmed by LCMS analysis, but the subsequent step-e did not result in desired product formation. Polar spots observed seem to indicate Cbz-protection may not be stable under reaction conditions. Step-c to h: N-acylation strategy:
  • N-acylation strategy was demonstrated until the pentultimate step, but all intermediates obtained were sticky material and hard to isolate. The process required significant optimization before scale-up.
  • Step-a Synthesis of (E)-1 ,4-dimethoxy-2-(2-nitrovinyl) benzene (lnt-2): Raw Material Table:
  • Step-b Synthesis of (2-(2,5-dimethoxyphenyl) ethan-1-amine (lnt-3): Raw Material Table:
  • Reaction mass was diluted with DCM (20V) and quenched in sodium sulfate decahydrate (10 w/w of LAH) slowly at rt and stirred for 1 hr.
  • the reaction mixture was filtered over Buckner funnel, and the filtrate was collected and concentrated under vacuum below 45 °C to afford crude lnt-3.
  • reaction mass was stirred at 120-130 °C for 16-18 h.
  • the progress of the reaction was monitored by TLC.
  • reaction mass was diluted with DCM (10 V) and the reaction mass was quenched in ice water.
  • the DCM layer was dried over sodium sulfate and concentrated under vacuum below 50 °C to get crude lnt-5a.
  • Step-h Synthesis of 2-(2,5-dimethoxy-4-((trifluoromethyl)thio)phenyl)ethan- 1-amine hydrochloride (Compound 1):
  • reaction mass was extracted in DCM (2X 20V). The combined DCM layer was concentrated under vacuum below 45 °C. Then HCI in 1 ,4 Dioxane (10V) was added and the reaction mass stirred for 12h. The reaction mass was concentrated under vacuum below 45 °C. Ethyl acetate (15V) was added to the residue and stirred for 2.0 h. The product was filtered and washed with ethyl acetate (3X 5 V) to get off white solid of lnt-6 (HCI salt). Then the solid was dried under vacuum below 45 °C to get Compound 1 (HCI Salt).
  • Step-1 Synthesis of 5-(trifluoromethyl)-5H-thianthren-5-ium trifluoromethanesulfonate (Reagent- X):
  • Reaction mixture was added in NaHCOs solution (10V) and the compound extracted in DCM (2X10V). Combined DCM layers were concentrated to obtain crude Reagent-X, which was washed with MTBE (4X2V) and the solid was dried under vacuum at 50 °C to get crude Reagent-X.
  • the phthalimido-protected intermediate was subjected to chlorosulfonation using chlorosulfonic acid.
  • the reaction and isolation conditions were optimized for gram scale synthesis.
  • the crude was used in the next step without further purification.
  • the chlorosulfonic intermediate was then subjected to different reduction conditions to get the thiol intermediate, out of which triphenylphosphine gave best results.
  • the intermediates were purified by column, which can be eliminated by using triphenylphosphine removing agents.
  • the thiol intermediate was further converted to a thiotrifluoromethoxy ether intermediate for which various reagents and conditions were tried.

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Abstract

La présente invention concerne des procédés rentables, efficaces et évolutifs pour la préparation de composés de phénéthylamine.
PCT/EP2024/067458 2024-05-01 2024-06-21 Procédés de préparation de composés de phénéthylamine Pending WO2025228547A1 (fr)

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