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WO2025232874A1 - Procédé de fabrication d'un inhibiteur de ménine-mll - Google Patents

Procédé de fabrication d'un inhibiteur de ménine-mll

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Publication number
WO2025232874A1
WO2025232874A1 PCT/CN2025/093750 CN2025093750W WO2025232874A1 WO 2025232874 A1 WO2025232874 A1 WO 2025232874A1 CN 2025093750 W CN2025093750 W CN 2025093750W WO 2025232874 A1 WO2025232874 A1 WO 2025232874A1
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WIPO (PCT)
Prior art keywords
compound
optionally
solvent
acid
base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/093750
Other languages
English (en)
Inventor
Roger Paul Bakale
Dipanjan Sengupta
Xiufeng Sun
Jianbing Zhang
Xiaohu Deng
Kewen CAI
Lei Guo
Chuanbing LI
Linrong ZHU
Animesh HALDAR
Venkata Raghavendra Rao KOVVURI
Santhosh Reddy NAINI
Upendra PAPPULA
Subho Roy
Chris H. Senanayake
Gopal SIRASANI
Ajay YADAW
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kura Oncology Inc
Original Assignee
Kura Oncology Inc
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Application filed by Kura Oncology Inc filed Critical Kura Oncology Inc
Publication of WO2025232874A1 publication Critical patent/WO2025232874A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to methods of making (S) -4-methyl-5- ( (4- ( (2- (methylamino) -6- (2, 2, 2-trifluoroethyl) thieno [2, 3-d] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) -1- (2- (4- (methylsulfonyl) piperazin-1-yl) propyl) -1H-indole-2-carbonitrile (Compound A) and pharmaceutically acceptable salts thereof, and to compounds used as intermediate compounds in the synthetic process.
  • Compound A or (S) -4-methyl-5- ( (4- ( (2- (methylamino) -6- (2, 2, 2-trifluoroethyl) thieno [2, 3-d] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) -1- (2- (4- (methylsulfonyl) piperazin-1-yl) propyl) -1H-indole-2-carbonitrile, can be represented by the following structure: is a potent inhibitor of the menin-KMT2A (MLL) interaction and is described in PCT Publ. No. WO2017/161028 as Compound No. 151. Compound A is also described as KO-539 or ziftomenib.
  • MLL menin-KMT2A
  • Compound A inhibits the survival, growth, and proliferation of certain kinds of leukemia cells as demonstrated in preclinical models (Burrows, F. et al., Mol. Cancer Ther. 2018, 17 (1_Supplement) , Abstract LB-A27 (available at https: //aacrjournals. org/mct/article/17/1_Supplement/LB-A27/238485/Abstract-LB-A27-A-novel-small-molecule-menin-MLL) .
  • Compound A is under clinical investigation as a potential treatment for relapsed or refractory acute myeloid leukemia (ClinicalTrials. gov Identifier NCT04067336) .
  • the process also provides racemic products, rather than one stereoisomer, as in Compound A; to obtain a chiral product from the above sequence would require a chiral resolution with loss of half the throughput or use of racemization-prone and expensive methyl (S) -2-bromopropionate as a starting material.
  • Alkylation of 5-formyl-4-methyl-1H-indole-2-carbonitrile with the mesylate reagent 2-4 is low yielding (53%over two steps) , likely due to the production of mixtures of regioisomers and stereoisomers.
  • Introduction of a formyl group to the indole portion prior to the alkylation step can produce mixtures of formyl-substituted and other products.
  • described herein is a process for the preparation of Compound A or a pharmaceutically acceptable salt thereof: comprising reacting Compound 10 or a salt thereof: with Compound 16 or a salt thereof: in the presence of a reducing agent to form Compound A or a pharmaceutically acceptable salt thereof.
  • described herein is a process for the preparation of Compound 15-Boc: comprising reacting Compound 14-Boc: with methylamine to form Compound 15-Boc.
  • described herein is a compound selected from: and salts thereof.
  • composition comprising a mixture of Compound A and at least one compound selected from Compound A (i) , A (ii) , A (iii) , A (iv) , A (v) , A (vi) , A(vii) , A (viii) , A (ix) , and A (x) .
  • a pharmaceutical composition comprising Compound A prepared according to the methods provided, optionally wherein the pharmaceutical composition comprises a mixture of Compound A and at least one compound selected from Compound A (i) , A (ii) , A (iii) , A (iv) , A (v) , A (vi) , A (vii) , A (viii) , A (ix) , and A (x) .
  • “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1%around a given value. In some embodiments regarding temperatures, “about” means ⁇ 5°C. For example, “about 50 °C” means from 45 °C to 55 °C. In some embodiments regarding temperatures, “about” means ⁇ 3 °C. For example, “about 50 °C” means from 47 °C to 53 °C.
  • C x -C y refers to the range of carbon atoms in a given moiety, and includes, for example, C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 2 -C 4 , or C 1 -C 6 .
  • a group designated as “C 2 -C 8 ” indicates that there are two to eight carbon atoms in the moiety, i.e., groups containing 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, or 8 carbon atoms.
  • C 2 -C 8 carboxylic acid indicates that there are two to eight carbon atoms in the carboxylic acid moiety.
  • a C 2 carboxylic acid is acetic acid
  • a C 3 carboxylic acid includes propionic acid
  • a C 4 carboxylic acid includes butyric acid and isobutyric acid.
  • “Pharmaceutically acceptable, ” as used herein, refers to a formulation, composition, form of a compound, such as a salt form, ingredient, or material, such as a carrier or diluent, which does not substantially abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • %w/w refers to the HPLC area %of one component of a mixture relative to the desired product.
  • an impurity is present at about 0.05%w/w in a sample of a desired material
  • the area %of the HPLC peak for the impurity is about 0.05%the area %of the HPLC peak for the desired material.
  • w/w in the context of synthetic procedures refers to the mass of a reagent used relative to the mass of the starting material.
  • each reactant may be used in free acid or free base form, or in a salt form, if applicable to the particular structure.
  • Each product may be obtained in free acid or free base form, or in a salt form, if applicable to the particular structure.
  • salt forms of intermediate compounds and reagents may be pharmaceutically acceptable salt forms, this is not required, and salts of intermediates can be any suitable salt form known to one in the art.
  • a process for preparing Compound A, or a pharmaceutically acceptable salt thereof comprising reacting Compound 10 with Compound 16 in the presence of a reducing agent to form Compound A or a pharmaceutically acceptable salt thereof.
  • the reacting is by a reductive amination reaction, as shown in Scheme A.
  • the reacting of Compound 10 and Compound 16 is performed in a suitable solvent in the presence of a reducing agent.
  • Compound 10 is used as a reactant in free base or salt form.
  • Compound 16 is the free base of Compound 16.
  • Compound 16 is a salt of Compound 16.
  • Compound 16 is a pharmaceutically acceptable salt of Compound 16.
  • Compound 16 is a hydrochloride salt of Compound 16.
  • Compound 16 is Compound 16 hydrochloride (16-HCl) .
  • Compound 16 is Compound 16 dihydrochloride (16-2HCl) , which can be a solid.
  • the stoichiometry of Compound 16 dihydrochloride is characterized by titration.
  • Compound A is prepared in pharmaceutically acceptable salt form.
  • the reacting is performed in suitable solvent.
  • the solvent is an aprotic solvent.
  • the solvent is a polar solvent.
  • the solvent is a polar, aprotic solvent.
  • the solvent is dichloromethane (DCM) , tetrahydrofuran (THF) , 2-methytetrahydrofuran (Me-THF) , acetonitrile (ACN) , 1, 2-dichloroethane (DCE) , dichlorobenzene, cyclopentyl methyl ether (CPME) , methyl tert-butyl ether (MTBE) , ethyl acetate, isopropyl acetate, or a mixture thereof.
  • the solvent is DCM, DCE, or dichlorobenzene.
  • the solvent is DCM.
  • the reducing agent comprises a boron hydride.
  • the reducing agent comprises NaBH 4 , sodium tri (C 2 -C 8 alkyl carboxy) borohydride (NaBH (OC (O) C 2-8 alkyl) 3 ) , sodium triacetoxyborohydride (NaBH (OAc) 3 ) , or sodium cyanoborohydride (NaCNBH 3 ) .
  • the reducing agent comprises NaBH 4 .
  • the reducing agent comprises NaBH 4 and a C 2 -C 8 alkyl carboxylic acid.
  • the C 2 -C 8 alkyl carboxylic acid is acetic acid, propionic acid, butyric acid, isobutyric acid, pentanoic acid, 3-methylbutanoic acid, 2-methylbutanoic acid, valproic acid, or hexanoic acid.
  • the C 2 -C 8 alkyl carboxylic acid is isobutyric acid.
  • the NaBH 4 and the C 2 -C 8 alkyl carboxylic acid are mixed to form a reducing agent mixture prior to mixing with Compound 10 and Compound 16.
  • the reducing agent mixture is combined with Compound 10 and Compound 16, optionally a mixture of Compound 10 and Compound 16.
  • the mixture of Compound 10 and Compound 16 comprises a base, that is used, for example, to free base the starting material (s) .
  • the base is an organic base.
  • the organic base is triethylamine (TEA) , N, N-diisopropylethylamine (DIPEA) , 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) , pyridine, or N-methylmorpholine.
  • the organic base is TEA.
  • the reacting comprises: (a) mixing NaBH 4 and a C 2 -C 8 alkyl carboxylic acid, such as isobutyric acid, to form a reducing agent mixture; (b) mixing Compound 10, Compound 16, and optionally a base to form a reagent mixture; and (c) mixing the reducing agent mixture and the reagent mixture.
  • a reducing agent mixture such as isobutyric acid
  • a base such as isobutyric acid
  • a base such as isobutyric acid
  • isolation of Compound A, or a pharmaceutically acceptable salt thereof comprises dispersing the crude product of the reaction of Compound 10 and Compound 16 in EtOH to provide Compound 16 as a suspended solid in the EtOH, optionally dilution the suspension with IPA, removing a portion of the EtOH by concentrating, and collecting the remaining solid by filtration from the EtOH/IPA mixture.
  • a molar excess of Compound 16 is used (relative to Compound 10) , such as about 1.02 to 1.2 equivalents, or about 1.05 equivalents.
  • about 1 to 6 equivalents or 1, 2, 3, 4, 5, or 6 equivalents (relative to Compound 10) of the reducing agent are used in the reductive amination.
  • about 2 to 4 equivalents of the reducing agent are used in the reductive amination.
  • about 3 equivalents of the reducing agent are used in the reductive amination.
  • about 1 to 12 equivalents or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 equivalents, or about 9.5 equivalents (relative to Compound 10) of the C 2 -C 8 alkyl carboxylic acid are used in the reductive amination.
  • about 2 to 4 equivalents of the C 2 -C 8 alkyl carboxylic acid are used in the reductive amination.
  • about 3 equivalents of the C 2 -C 8 alkyl carboxylic acid are used in the reductive amination.
  • about 8 to 11 equivalents of the C 2 -C 8 alkyl carboxylic acid are used in the reductive amination.
  • about 9 to 10 equivalents of the C 2 -C 8 alkyl carboxylic acid are used in the reductive amination. In some embodiments, about 9.5 equivalents of the C 2 -C 8 alkyl carboxylic acid are used in the reductive amination. In some embodiments, the molar ratio of the C 2 -C 8 alkyl carboxylic acid to the reducing agent used is at least 3: 1, or is about 3: 1, or is about 9.5: 3. In some embodiments, the C 2 -C 8 alkyl carboxylic acid is isobutyric acid. In some embodiments, such as where Compound 10 and Compound 16 are both used in free base form, no added base is used.
  • At least 1 or 2 equivalents of base, respectively, are added to free base the starting material (s) .
  • the base is TEA.
  • one or more of the following are used: (a) about 2 to 4, or about 3, equivalents of NaBH 4 , (b) about 2 to 4, or about 3 equivalents, or about 8 to 10, or about 9.5 equivalents of isobutyric acid, (c) about 1.05 equivalents of Compound 16-2HCl, (d) 1.0 equivalent of Compound 10, and (e) about 4 to 8, or about 6 equivalents of TEA.
  • the solvent is held at a temperature of about 15 °C to about 60 °C, or at a temperature of about 20 °C to about 30 °C. In some embodiments, the solvent is held at a temperature of about 25 °C. In some embodiment “about 25 °C” means 25 ⁇ 5 °C. In some embodiments, the solvent is held at a temperature of 20 to 30 °C.
  • the reacting of Compound 10 and Compound 16 is performed until the remaining Compound 10 is at level of no more than 1%relative to Compound A, as measured by HPLC.
  • Compound A is obtained as a mixture with one or more of Compounds A (i) , A (ii) , A (iii) , A (iv) , A (v) , A (vi) , A (vii) , A (viii) , A (ix) , and A (x) .
  • Compound A is obtained as a mixture with one or more of Compounds A (i) , A (ii) , A (iii) , A (iv) , A (v) , A (vi) , A (vii) , A (viii) , A (ix) , A (xi) , A (xii) , A (xiii) , A (xiv) , A (xv) , A (xvi) , A (xvii) , and A (xviii) .
  • Compound A is a mixture with Compounds A (i) , A (ii) , A (vi) , A (v) , A (viii) , and A (ix) .
  • Compound A is a mixture with at least one of Compounds A (ii) , A (v) , A (ix) , A (xi) , A (xv) , and A (xvii) .
  • Compound A is a mixture with Compound A (ii) .
  • Compound A is a mixture with Compound A (v) .
  • Compound A is a mixture with Compound A (ix) .
  • Compound A is a mixture with Compound A (xi) . In some embodiments, Compound A is a mixture with Compound A (xv) . In some embodiments, Compound A is a mixture with Compound A (xvii) .
  • Compound A (i) is present at about 0.05 to about 0.3%w/w. In some embodiments, Compound A (i) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (i) is present at not more than about 0.15%w/w. In some embodiments, Compound A (i) is present and is present at not more than about 0.15%w/w.
  • Compound A (ii) is present at about 0.05 to about 0.25%w/w. In some embodiments, Compound A (ii) is present at about 0.05 to about 0.2%w/w. In some embodiments, Compound A (ii) is present at not more than about 0.25%w/w. In some embodiments, Compound A (ii) is present and is present at not more than about 0.25%w/w.
  • Compound A (iii) is present at not more than about 0.15%w/w. In some embodiments, Compound A (iii) is present and is present at not more than about 0.15%w/w. In some embodiments, Compound A (iii) is present at not more than about 0.05%w/w. In some embodiments, Compound A (iii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (iii) is present at about 0.05 to about 0.15%w/w.
  • Compound A (iv) is present at about 0.05 to about 0.3%w/w. In some embodiments, Compound A (iv) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (iv) is present at not more than aboaut 0.15%w/w. In some embodiments, Compound A (iv) is present and is present at not more than about 0.15%w/w.
  • Compound A (v) is present at about 0.05 to about 0.25%w/w. In some embodiments, Compound A (v) is present at about 0.05 to about 0.2%w/w. In some embodiments, Compound A (v) is present at not more than about 0.25%w/w. In some embodiments, Compound A (v) is present and is present at not more than about 0.25%w/w.
  • Compound A (vi) is present at not more than about 0.15%w/w. In some embodiments, Compound A (vi) is present at not more than about 0.05%w/w. In some embodiments, Compound A (vi) is present at about 0.01 to about 0.15%w/w or at about 0.01 to about 0.05%w/w. In some embodiments, Compound A (vi) is present and is present at not more than about 0.15%w/w.
  • Compound A (vii) is present at not more than about 0.15%w/w. In some embodiments, Compound A (vii) is present at not more than about 0.05%w/w. In some embodiments, Compound A (vii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (viii) is present and is present at not more than about 0.15%w/w.
  • Compound A (viii) is present at about 0.05 to about 0.3%w/w. In some embodiments, Compound A (viii) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (viii) is present at not more than about 0.4%w/w. In some embodiments, Compound A (viii) is present at about 0.05 to about 0.4%w/w. In some embodiments, Compound A (viii) is present and is present at not more than about 0.4%w/w.
  • Compound A (ix) is present at about 0.05 to about 0.25%w/w. In some embodiments, Compound A (ix) is present at about 0.05 to about 0.1%w/w. In some embodiments, Compound A (ix) is present at not more than about 0.25%w/w. In some embodiments, Compound A (ix) is present and is present at not more than about 0.25%w/w.
  • Compound A (x) is present at less than about 0.15%w/w. In some embodiments, Compound A (x) is present at less than about 0.05%w/w. In some embodiments, Compound A (x) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w.
  • Compound A (xi) is present at not more than about 0.4%w/w. In some embodiments, Compound A (xi) is present and is present at not more than about 0.4%w/w. In some embodiments, Compound A (xi) is present at not more than about 0.25%w/w. In some embodiments, Compound A (xi) is present and is present at not more than about 0.25%w/w. In some embodiments, Compound A (xi) is present at about 0.05 to about 0.25%w/w.
  • Compound A (xii) is present at about 0.05 to about 0.4%w/w. In some embodiments, Compound A (xii) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (xii) is present at not more than about 0.4%w/w.
  • Compound A (xiii) is present at about 0.05 to about 0.4%w/w. In some embodiments, Compound A (xiii) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (xiii) is present at not more than about 0.4%w/w.
  • Compound A (xiv) is present at not more than about 0.15%w/w. In some embodiments, Compound A (xiv) is present at not more than about 0.05%w/w. In some embodiments, Compound A (xiv) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (xiv) is present and is present at not more than about 0.15%w/w.
  • Compound A (xv) is present at not more than about 0.5%w/w. In some embodiments, Compound A (xv) is present and is present at not more than about 0.5%w/w. In some embodiments, Compound A (xv) is present at about 0.05 to about 0.5%w/w.
  • Compound A (xvi) is present at not more than about 0.15%w/w. In some embodiments, Compound A (xvi) is present at not more than about 0.05%w/w. In some embodiments, Compound A (xvi) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (xvi) is present and is present at not more than about 0.15%w/w.
  • Compound A (xvii) is present at not more than about 0.25%w/w. In some embodiments, Compound A (xviii) is present and is present at not more than about 0.25%w/w. In some embodiments, Compound A (xvii) is present at about 0.05 to about 0.25%w/w.
  • Compound A (xviii) is present at not more than about 0.15%w/w. In some embodiments, Compound A (xviii) is present at not more than about 0.05%w/w. In some embodiments, Compound A (xviii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (xviii) is present and is present at not more than about 0.15%w/w. Preparation of Compound 10
  • Compound 2 is prepared from Compound 1 as shown in Scheme B-1, Step 1.
  • the process for preparing Compound 2 comprises condensing Compound 1 with an oxalic acid equivalent, such as diethyl oxalate or dimethyl oxalate, in the presence of a base, such as a sodium or potassium alkoxide, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, or sodium hydride, optionally in the presence of a de-frothing agent, such as a C 4 -C 8 alkanol, such as tert-amyl alcohol, n-amyl alcohol, or isobutyl alcohol, optionally in the presence of an additional solvent, such as THF, N, N-dimethylformamide (DMF) , or a mixture thereof, preferably a mixture of THF and DMF, optionally at a ratio of 3: 1 to 5: 1, or
  • a base such as a
  • Compound 1 is combined with a mixture of the base in the suitable solvent at a reduced temperature.
  • the reduced temperature is between about 0 °C to about 15 °C. In some embodiments, the reduced temperature is between about 0 °C to about 5 °C.
  • Compound 1a may be isolated and/or purified or may be carried forward in situ without isolation or purification.
  • the reaction time is reduced, the yield is increased, or the purity of the product is increased, or a combination thereof, when the reaction is performed where the solvent is a mixture of THF and DMF as compared to THF in the absence of DMF.
  • Compound 1a (in the prior reaction mixture, or isolated and optionally purified) is treated with a suitable nitro group reducing agent, such as Na 2 S 2 O 4 in a suitable solvent such as ethanol, or H 2 and Pd/C, optionally wherein the reducing step is initiated at a reduced temperature, to effect a reductive cyclization to form Compound 1b:
  • the reducing agent is Na 2 S 2 O 4 , optionally where the solvent is ethanol or an ethanol/water mixture, optionally wherein the reduced temperature is between about 0 °C to about 15 °C. In some embodiments, the reduced temperature is between about 0 °C to about 5 °C.
  • Compound 1b can be isolated and purified or used in situ in the next step.
  • the process for preparing Compound 2 comprises hydrolysis of the ester of Compound 1b to form Compound 2.
  • hydrolysis is performed in the presence of a suitable base, such as NaOH, in a suitable solvent such as an alcohol (e.g., EtOH) , water, or a mixture thereof, optionally at a reduced temperature, to form Compound 2.
  • a suitable base such as NaOH
  • a suitable solvent such as an alcohol (e.g., EtOH)
  • EtOH e.g., EtOH
  • the reduced temperature is between about 0 °C to about 15 °C.
  • the reduced temperature is between about 0 °C to about 10 °C.
  • the NaOH is a solid or a powder.
  • the NaOH is an aqueous solution.
  • the reaction mixture is acidified, for example, with a mineral acid, such as aqueous HCl, and Compound 2 is precipitation and isolated by filtration.
  • a mineral acid such as aqueous HCl
  • Compound 1a can be reacted to form Compound 2 directly under Zn/acetic acid conditions.
  • the process for preparing Compound 3 comprises converting Compound 2 to Compound 3, as shown in Scheme B-1.
  • the process comprises condensing Compound 2 with an ammonia equivalent, such as NH 3 , optionally by amide coupling under conditions known to one in the art, such as DCC, EDC, or PyBop, or via the corresponding acyl chloride, e.g., by treating Compound 2 with oxalyl chloride or thionyl chloride, preferably oxalyl chloride, in the presence of DMF, in a suitable solvent such as DCM, optionally at a temperature from about 40 °C to about 55 °C, or from about 45 °C to about 50 °C, followed by treatment of the resulting acid chloride reaction mixture in situ with an ammonia equivalent, such as ammonia or aqueous ammonia.
  • Compound 3 is isolated by precipitation and filtration.
  • the process for preparing Compound 4 comprises converting Compound 3 to Compound 4, as shown in Scheme B-1.
  • the process comprises treating Compound 3 with a suitable dehydrating agent, such as POCl 3 , P 2 O 5 , thionyl chloride, or oxalyl chloride, preferably POCl 3 , in a non-polar solvent such as toluene, to form Compound 4.
  • a suitable dehydrating agent such as POCl 3 , P 2 O 5 , thionyl chloride, or oxalyl chloride, preferably POCl 3
  • a non-polar solvent such as toluene
  • a process for preparing Compound 5, wherein X is -Cl (Compound 5-Cl) , -Br (Compound 5-Br) , or -I (Compound 5-I) comprises reacting Compound 4 with a halogenating agent to provide Compound 5 as shown in Step 4a in Scheme B-1.
  • X is -Br.
  • X is -I.
  • the halogenation agent comprises an N-halosuccinimide, such as N-iodosuccinimide or N-bromosuccinimide, Br 2 , or I 2 , optionally in the presence of an activating agent.
  • the activating agent is a Lewis acid. In some embodiments, the activating agent is trifluoroacetic acid, acetic acid, H 2 SO 4 , H 2 SO 4 /HIO 3 , methanesulfonic acid, trifluoromethanesulfonic acid (TfOH) , silver trifluoromethanesulfonate (AgOTf) , silver bis (trifluoromethylsulfonyl) azanide (AgN (Tf) 2 ) , AlCl 3 , In (OTf) 3 , trimethylsilyl trifluoromethanesulfonate (TMSOTf) , BF 3 ⁇ H 2 O, or BF 3 ⁇ OEt 2 , or a combination thereof.
  • TfOH trifluoromethanesulfonic acid
  • AgOTf silver trifluoromethanesulfonate
  • AgN (Tf) 2 silver bis (trifluoromethylsulfonyl) azan
  • the reaction is performed in the presence of a phase transfer catalyst, such as tetrabutylammonium iodide (Bu 4 NI) .
  • a phase transfer catalyst such as tetrabutylammonium iodide (Bu 4 NI) .
  • the activating agent is TFA or acetic acid.
  • the activating agent is acetic acid.
  • the halogenation agent is N-iodosuccinimide and the activating agent is BF 3 ⁇ OEt 2 , and the reaction is optionally performed in DCM.
  • the halogenating agent is N-iodosuccinimide and the activating agent is TMSOTf, and the reaction is optionally performed in ACN.
  • the N-halosuccinimide is N-iodosuccinimide and X is -I.
  • the reaction is done in a solvent such as DCM or ACN.
  • halogenation occurs at the desired 5-position and also at the 3-position of the indole to provide a di-iodo product, which can be converted to Compound 5 by treatment with a trialkylamine such as Et 3 N in a solvent such as ACN.
  • a process for preparing Compound 6 comprises formylating Compound 5, wherein X is -Cl, -Br, or -I, to form Compound 6 (Step 4.5a) .
  • X is -Br (Compound 5-Br) .
  • X is -I (Compound 5-I) .
  • the formylating comprises reacting Compound 5 with a CO source, such as CO or formic acid, in the presence of a transition metal catalyst, optionally in the presence of a ligand, for example in a suitable solvent, optionally in the presence of a base, to form Compound 6.
  • the transition metal catalyst comprises Pd, Ni, or Rh. In some embodiments, the transition metal catalyst comprises Pd. In some embodiments, the transition metal catalyst comprises Pd (0) . In some embodiments, the transition metal catalyst comprises Pd (II) , and the reaction optionally comprises mixing the transition metal catalyst with a reducing agent, such as Et 3 SiH (e.g., to form Pd (0) in situ) . In some embodiments, the transition metal catalyst is Pd (OAc) 2 . In some embodiments, the formylating is done with a palladium catalyst in the presence of a ligand. In some embodiments, the ligand is a phosphine ligand.
  • the ligand is an aliphatic phosphine ligand, such as trimethylphosphine, tricyclohexylphosphine (P (Cy) 3 ) , tricyclohexylphosphine tetrafluoroborate (P (Cy) 3 ⁇ HBF 4 ) , tri-tert-butyl-phosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, tri-n-octylphosphine, or the like.
  • aliphatic phosphine ligand such as trimethylphosphine, tricyclohexylphosphine (P (Cy) 3 ) , tricyclohexylphosphine tetrafluoroborate (P (Cy) 3 ⁇ HBF 4 ) , tri-tert-butyl-phosphine, tri-tert-butylphos
  • the ligand is an aromatic phosphine, such as XPhos, SPhos, JohnPhos, Amphos, triphenylphosphine (TPP) , methyldiphenylphosphine, or the like.
  • the ligand is a bis-phosphine ligand, such as diphenyl phosphinomethane (dppm) , diphenyl phosphinoethane (dppe) , 1, 1’-bis (diphenylphosphino) ferrocene (dppf) , or the like.
  • the ligand is P (Cy) 3 .
  • the ligand is tricyclohexylphosphine tetrafluoroborate.
  • the CO source is CO or formic acid.
  • the CO source is CO.
  • the base is Na 2 CO 3 .
  • the CO source is CO
  • the transition metal catalyst is Pd (OAc) 2
  • the ligand is tricyclohexylphosphine tetrafluoroborate
  • the reducing agent is Et 3 SiH
  • the optional base is Na 2 CO 3 .
  • the formylating is performed at an elevated temperature. In some embodiments, the elevated temperature is between about 60 °C and about 80 °C.
  • the elevated temperature is between about 65 °C and about 70 °C.
  • the solvent comprises DMF, DMA, THF, 2-MeTHF, ACN, or a mixture thereof.
  • the solvent comprises DMF and water.
  • the water is present in a catalytic amount. In some embodiments, about 1 molar equivalent of water is used.
  • the reaction time is reduced, the yield is increased, or the purity of the product is increased, or a combination thereof, when the reaction is performed in the presence of water.
  • a process for preparing Compound 6 comprises formylating Compound 4 to provide Compound 6 (Step 4b) .
  • the formylating comprises reacting Compound 4 with a formylation reagent in a suitable solvent.
  • the formylation reagent comprises dichloromethyl methyl ether and an acid, hexamethylenetetramine (HMTA) and TFA, DMF and POCl 3 , DMF and (COCl) 2 , DMF and cyanuric chloride, or ethyl formate and an acid.
  • the formylation reagent comprises dichloromethyl methyl ether and an acid, such as a Lewis acid, optionally selected from TiCl 4 , TiCl 2 (O-iPr) 2 , Ti (O-iPr) 4 , AlCl 3 , BF 3 ⁇ OEt 2 , TMSOTf, In (OTf) 3 , TfOH, HClO 4 , H 2 SO 4 , TFA, AgOTf, Tf 2 Sn, or ZnCl 2 .
  • the formylation reagent is dichloromethyl methyl ether and TiCl 4 .
  • the formylation reagent comprises HMTA and TFA.
  • the formylation reagent comprises DMF and POCl 3 . In some embodiments, the formylation reagent comprises DMF and (COCl) 2 . In some embodiments, the formylation reagent comprises DMF and cyanuric chloride. In some embodiments, the formylation reagent comprises ethyl formate and an acid, optionally wherein the acid is TFA. In some embodiments, the dichloromethyl methyl ether is added to a mixture of Compound 4 and the acid in a solvent at a reduced temperature. In some embodiments, the reduced temperature is from about 0 °C to about 10 °C. In some embodiments, the reduced temperature is from about 0 °C and about 5 °C.
  • the solvent is a polar, aprotic solvent, such as 1, 2-dichlorobenzene, DCM, DCE, nitrobenzene, or chlorobenzene.
  • the solvent is 1, 2-dichlorobenzene.
  • the solvent is DCM.
  • a process for preparing Compound 10 comprises coupling Compound 6 and Compound 7, where R is -OH (Compound 7-OH) , -Br (Compound 7-Br) , -Cl (Compound 7-Cl) , -I (Compound 7-I) , or sulfonate, such as mesylate, tosylate, brosylate, nosylate, fluorosulfate, triflate (Compound 7-OTf) , or nonaflate, as shown in Scheme B-2, Step 5a.
  • the coupling is a nucleophilic substitution reaction.
  • the coupling comprises reacting Compound 6 and Compound 7, where R is -OH (Compound 7-OH) , -Br (Compound 7-Br) , -Cl (Compound 7-Cl) , -I (Compound 7-I) , or sulfonate, such as mesylate (Compound 7-OMs) , tosylate (Compound 7-OTs) , brosylate, nosylate, fluorosulfate, triflate (Compound 7-OTf) , or nonaflate, to provide Compound 10.
  • R is -OH (Compound 7-OH) , -Br (Compound 7-Br) , -Cl (Compound 7-Cl) , -I (Compound 7-I) , or sulfonate, such as mesylate (Compound 7-OMs) , tosylate (Compound 7-OTs) , brosylate, nosylate, fluorosulf
  • R is -Br (Compound 7-Br) , -Cl (Compound 7-Cl) , -I (Compound 7-I) , or sulfonate, such as mesylate (Compound 7-OMs) , tosylate (Compound 7-OTs) , brosylate, nosylate, fluorosulfate, triflate (Compound 7-OTf) , or nonaflate
  • the reacting is in the presence of a base.
  • the coupling solvent is a polar aprotic solvent.
  • the solvent is DMF, dimethyl acetamide (DMA) , N-methyl-2-pyrrolidone (NMP) , ACN, THF, Me-THF, dioxane, DME, or dimethylsulfoxide (DMSO) , or a mixture thereof.
  • the solvent is DMF.
  • the base is Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , DBU, DIPEA, TEA, or pyridine.
  • the base is Cs 2 CO 3 .
  • the sulfonate is a triflate group.
  • R in Compound 7 is -OH, and the coupling is a Mitsunobu-type alkylation reaction.
  • the coupling of Compound 6 and Compound 7 is performed in the presence of a phosphine, such as triphenylphosphine, tri-tert-butylphosphine, tri-n-butylphosphine, or tri-n-octylphosphine, and an azodicarboxylate, such as diisopropyl azodicarboxylate (DIAD) , diethyl azodicarboxylate (DEAD) , 1, 1’ - (azodicarbonyl) dipiperidine, or azodicarboxylic dimorpholide, or in the presence of a phosphorane, in a suitable solvent, to yield Compound 10.
  • a phosphine such as triphenylphosphine, tri-tert-butylphosphine, tri-n-butylphosphine,
  • the phosphine is triphenyphosphine.
  • the azodicarboxylate is DIAD.
  • the phosphorane is cyanomethylenetributylphosphorane or cyanomethylenetrimethylphosphorane.
  • the reagents, such as the azadicarboxylate and the starting material are mixed at a reduced temperature.
  • the reduced temperature is from about -10 °C to about 10 °C, or from about -5 °C to about 0 °C. In some embodiments, the reduced temperature is from about 0 °C to about 5 °C.
  • the solvent is THF, Me-THF, DCM, ACN, DCE, dioxane, or DME, or a mixture thereof. In some embodiments, the solvent is THF. This route removes one step relative to the activation/displacement route. In some embodiments, this procedure improves the yield of the desired regioisomer of the alkylated product.
  • the reactant is Compound 7, where R is mesylate (Compound 7-OMs) .
  • the process comprises preparing Compound 7-OMs by reacting Compound 7, where R is -OH (Compound 7-OH) , with a mesylating reagent (e.g., methanesulfonic anhydride, methanesulfonyl chloride, and the like) , in the presence of a base (e.g., DIPEA, TEA, pyridine) and in a solvent (e.g., DCM, THF) .
  • a base e.g., DIPEA, TEA, pyridine
  • a solvent e.g., DCM, THF
  • the reactant is Compound 7, where R is triflate (Compound 7-OTf) .
  • the process comprises preparing Compound 7-OTf by reacting Compound 7, where R is -OH (Compound 7-OH) , with a triflating reagent (e.g., trifluoromethanesulfonic anhydride, N-phenyl triflimide, trifluoroacetyl triflate, and the like) in the presence of a base (e.g., DIPEA, TEA, pyridine) and in a solvent (e.g., DCM, THF) .
  • a base e.g., DIPEA, TEA, pyridine
  • a solvent e.g., DCM, THF
  • the reactant is Compound 7, where R is -Br, -Cl, or -I.
  • the process comprises preparing Compound 7, where R is -Br, -Cl, or -I, from Compound 7-OH by reacting with a halogenating agent such as thionyl chloride, thionyl bromide, or HI.
  • Compound 10 is obtained as-is and/or is used in the next reaction step as a mixture with one or more of Compound 10 (i) , 10 (ii) , 10 (iii) , 10 (iv) , 10 (v) , 10 (vi) , 10 (vii) , 10 (viii) , or 10 (ix) :
  • Compound 10 is obtained as-is and/or is used in the next reaction step as a mixture with one or more of Compound 10 (i) , 10 (iii) , 10 (iv) , (v) , and (ix) .
  • Compound 10 (i) is present at about 0.05 to about 0.1%w/w.
  • Compound 10 (i) is present at about 0.05 to about 0.2%w/w. In some embodiments, Compound 10 (ii) is present at less than 0.2%w/w. In some embodiments, Compound 10 (ii) is present at less than about 0.05%w/w. In some embodiments, Compound 10 (ii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.2%w/w. In some embodiments, Compound 10 (iii) is present at about 0.05 to about 0.6%w/w. In some embodiments, Compound 10 (iii) is present at about 0.05 to about 0.4%w/w.
  • Compound 10 (iv) is present at about 0.05 to about 0.4%w/w. In some embodiments, Compound 10 (iv) is present at about 0.05 to about 0.2%w/w. In some embodiments, Compound 10 (v) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound 10 (v) is present at about 0.05 to about 0.2%w/w. In some embodiments, Compound 10 (vi) is present at less than about 0.15%w/w. In some embodiments, Compound 10 (vi) is present at less than about 0.05%w/w. In some embodiments, Compound 10 (vi) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w.
  • Compound 10 (vii) is present at less than about 0.15%w/w. In some embodiments, Compound 10 (vii) is present at less than about 0.05%w/w. In some embodiments, Compound 10 (vii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound 10 (viii) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound 10 (viii) is present at about 0.05 to about 0.1%w/w. In some embodiments, Compound 10 (ix) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound 10 (ix) is present at about 0.05 to about 0.3%w/w. Scheme B-3
  • a process for preparing Compound 10 or Compound 8 comprises coupling Compound 4 with Compound 7, where R is -OH, Br, Cl, I, or s sulfonate, such as mesylate, tosylate, brosylate, nosylate, fluorosulfate, triflate, or nonaflate, to provide Compound 8 (Step 4c) .
  • the coupling comprises reacting Compound 4 and Compound 7, where R is -Br (Compound 7-Br) , -Cl (Compound 7-Cl) , -I (Compound 7-I) , or sulfonate, such as mesylate (Compound 7-OMs) , tosylate (Compound 7-OTs) , brosylate, nosylate, fluorosulfate, triflate (Compound 7-OTf) , or nonaflate, in the presence of a base and in a suitable solvent to provide Compound 8.
  • the sulfonate is a triflate group.
  • the coupling solvent is a polar aprotic solvent.
  • the solvent is DMF, dimethyl acetamide (DMA) , N-methyl-2-pyrrolidone (NMP) , ACN, THF, Me-THF, dioxane, DME, or dimethylsulfoxide (DMSO) , or a mixture thereof.
  • the solvent is DMF.
  • the base is Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , DBU, DIPEA, TEA, or pyridine. In some embodiments, the base is Cs 2 CO 3 .
  • R in Compound 7 is -OH.
  • the coupling comprises an in situ activation of the -OH group into a suitable leaving group, for example, a Mitsunobu-type alkylation reaction.
  • the coupling comprises mixing Compound 4 and Compound 7 in the presence of a phosphine, such as triphenylphosphine, tri-tert-butylphosphine, tri-n-butylphosphine, or tri-n-octylphosphine, and an azodicarboxylate or a phosphorane, in a suitable solvent, to yield Compound 8.
  • a phosphine such as triphenylphosphine, tri-tert-butylphosphine, tri-n-butylphosphine, or tri-n-octylphosphine, and an azodicarboxylate or a phosphorane
  • the azodicarboxylate is diisopropyl azodicarboxylate (DIAD) , diethyl azodicarboxylate (DEAD) , 1, 1’- (azodicarbonyl) dipiperidine, or azodicarboxylic dimorpholide.
  • the azodicarboxylate is DIAD.
  • the phosphorane is cyanomethylenetributylphosphorane or cyanomethylenetrimethylphosphorane.
  • the reagents are mixed at a reduced temperature. In some embodiments, the reduced temperature is from about -10 °C to about 10 °C.
  • the reduced temperature is from about about –5 °C to about 0 °C, or about 0 °C to about 5 °C.
  • the solvent is THF, Me-THF, DCM, ACN, DCE, dioxane, or DME, or a mixture thereof.
  • the solvent is THF. This route removes one reaction step relative to the activation/displacement route. In addition, a reduction in the relative amounts of regioisomeric side-products, such as Compound 8-X, was achieved with this procedure.
  • a process of preparing Compound 10 comprises reacting Compound 8 to provide Compound 9 (where X is -Cl, -Br, or -I) , as shown in Scheme B-3, Step 4.5b.
  • reacting comprises reacting Compound 8 in the presence of a halogenating reagent to give Compound 9.
  • X is -Br.
  • X is -I.
  • the halogenating reagent comprises an N-halosuccinimide, such as N-iodosuccinimide or N-bromosuccinimide, Br 2 , or I 2 , optionally in the presence of an activating agent.
  • the activating agent is a Lewis acid. In some embodiments, the activating agent is trifluoroacetic acid, acetic acid, H 2 SO 4 , H 2 SO 4 /HIO 3 , methanesulfonic acid, TfOH, AgOTf, AgN (Tf) 2 , AlCl 3 , In (OTf) 3 , TMSOTf, BF 3 ⁇ H 2 O, or BF 3 ⁇ OEt 2 , or a combination thereof. In some embodiments, the reaction is performed in the presence of a phase transfer catalyst, such as tetrabutylammonium iodide. In some embodiments, the activating agent is TFA or acetic acid.
  • the activating agent is acetic acid.
  • the acetic acid also serves as solvent.
  • the halogenating is done with NIS (1.2 to 2.5 equiv., or 1.2 to 1.7 equiv., or 1.5 equiv. ) , a phase transfer catalyst such as Bu 4 NI, in AcOH, optionally at a temperature of about 25 to 60 °C, or about 50 to 60 °C.
  • the N-halosuccinimide is N-iodosuccinimide and X is -I.
  • X is -I in Compound 9 (Compound 9-I, ) .
  • a process of preparing Compound 10 comprises formylating Compound 9, wherein X is -Cl, -Br, or -I, to provide Compound 10, as shown in Scheme B-3, Step 5c.
  • X is -Br (Compound 9-Br) .
  • X is I (Compound 9-I) .
  • the formylating comprises reacting Compound 9 with a CO source, such as CO or formic acid, in the presence of a transition metal catalyst, for example in a suitable solvent, to yield Compound 10.
  • the transition metal catalyst comprises Pd, Ni, or Rh.
  • the transition metal catalyst comprises Pd.
  • the transition metal catalyst comprises Pd (0) .
  • the transition metal catalyst comprises Pd (II)
  • the reaction optionally comprises mixing the transition metal catalyst with a reducing agent, such as Et 3 SiH (e.g., to form Pd (0) in situ) .
  • the transition metal catalyst is Pd (OAc) 2 .
  • the transition metal catalyst is mixed with a ligand and/or the reducing agent.
  • the ligand is a phosphine ligand.
  • the ligand is an aliphatic phosphine ligand, such as trimethyl phosphine, P (Cy) 3 , P (Cy) 3 ⁇ HBF 4 , tri-tert-butyl-phosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, tri-n-octylphosphine, or the like.
  • the ligand is an aromatic phosphine, such as XPhos, SPhos, JohnPhos, Amphos, TPP, methyldiphenylphosphine, or the like.
  • the ligand is a bis-phosphine ligand, such as diphenylphosphinomethane (dppm) , diphenyl phosphinoethane (dppe) , 1, 1’ -bis (diphenylphosphino) ferrocene (dppf) , or the like.
  • the ligand is P (Cy) 3 .
  • the ligand is P (Cy) 3 ⁇ HBF 4 .
  • the CO source is CO or formic acid. In some embodiments, the CO source is CO.
  • the CO source is formic acid
  • the reaction is performed in the presence of Pd (OAc) 2 , a tertiary amine base such as DABCO, and a carbodiimide such as DCC, in polyethylene glycol.
  • the formylating is performed at an elevated temperature.
  • the elevated temperature is between about 60 °C and about 80 °C.
  • the elevated temperature is between about 65 °C and about 70 °C.
  • the solvent comprises DMF, DMA, 2-MeTHF, ACN, or a mixture thereof.
  • the solvent comprises DMF and water.
  • the water is a catalytic amount.
  • the reaction time is reduced, the yield is increased, or the purity of the product is increased, or a combination thereof, when the reaction is performed in the presence of water..
  • a process for preparing Compound 10 comprises formylating Compound 8 (optionally as a mixture with Compound 8-X, at ⁇ 5%or about 2-4% (a/a) ) to provide Compound 10 (Scheme B-3, Step 5b) .
  • the formylating comprises reacting Compound 8 with a formylation reagent in a suitable solvent.
  • the formylation reagent comprises dichloromethyl methyl ether and an acid, HMTA and TFA, DMF and POCl 3 , DMF and (COCl) 2 , DMF and cyanuric chloride, or ethyl formate and an acid.
  • the formylation reagent comprises dichloromethyl methyl ether and an acid, such as a Lewis acid, optionally selected from TiCl 4 , TiCl 2 (O-iPr) 2 , Ti (O-iPr) 4 , AlCl 3 , BF 3 ⁇ OEt 2 , TMSOTf, In (OTf) 3 , TfOH, HClO 4 , H 2 SO 4 , TFA, AgOTf, Tf 2 Sn, or ZnCl 2 .
  • the formulation reagent is dichloromethyl methyl ether and TiCl 4 .
  • the formylation reagent comprises HMTA and TFA.
  • the formylation reagent comprises DMF and POCl 3 . In some embodiments, the formylation reagent comprises DMF and (COCl) 2 . In some embodiments, the formylation reagent comprises DMF and cyanuric chloride. In some embodiments, the formylation reagent comprises ethyl formate and an acid, optionally wherein the acid is TFA. In some embodiments, the dichloromethyl methyl ether is added to a mixture of Compound 8 and the acid at a reduced temperature. In some embodiments, the reduced temperature is from about -5 °C to about 15 °C, or about 0 °C to about 10 °C.
  • the reduced temperature is from about -5 °C to about 0 °C, or about 0 °C to about 5 °C.
  • the solvent is a polar, aprotic solvent, such as 1, 2-dichlorobenzene, DCM, DCE, or chlorobenzene.
  • the solvent is 1, 2-dichlorobenzene.
  • the solvent is DCM.
  • Compound 10 is isolated by precipitation and filtration.
  • Compound 7-OH is prepared as shown in Scheme B-4.
  • Scheme B-4 the process of preparing Compound 7-OH comprises reacting diethanolamine with a mesylating reagent, such as Ms 2 O or MsCl, in the presence of a base such as DIPEA, TEA, or pyridine, in a solvent such as DCM, THF, or DMF, to form Compound 7A.
  • a mesylating reagent such as Ms 2 O or MsCl
  • a base such as DIPEA, TEA, or pyridine
  • a solvent such as DCM, THF, or DMF
  • the process of preparing Compound 7-OH comprises reacting Compound 7A with (2S) -2-aminopropan-1-ol in the presence of a suitable base, such as Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , DBU, DIPEA, TEA, or pyridine, in a polar, aprotic solvent such as ACN, to provide Compound 7-OH.
  • a suitable base such as Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , DBU, DIPEA, TEA, or pyridine
  • a process for preparing Compound 16 comprises chlorinating Compound 11 to provide Compound 12 (Scheme C, Step 6) .
  • the chlorinating is performed in the presence of a chlorination reagent, for example in a suitable solvent, optionally in the presence of a phase transfer catalyst, such as a tetraalkylammonium salt, such as tetraethylammonium chloride or tetrabutylammonium bromide, optionally in the presence of a base.
  • a phase transfer catalyst such as a tetraalkylammonium salt, such as tetraethylammonium chloride or tetrabutylammonium bromide
  • the chlorination reagent comprises POCl 3 , SOCl 2 , PCl 3 , (COCl) 2 , HCl, and the like, preferably POCl 3 , optionally in an amount of about 3 to 4 equivalents.
  • the suitable solvent is non-polar.
  • the suitable solvent is p-xylene, 1, 2-dichlorobenzene, chlorobenzene, or toluene.
  • the suitable solvent is toluene.
  • the base is an organic base. In some embodiments, the base is TEA, N, N-diethylaniline, DIPEA, DBU, pyridine, or NMP.
  • the base is TEA or N, N-diethylaniline. In some embodiments, the base is N,N-diethylaniline. In some embodiments, the phase transfer catalyst is tetraethylammonium chloride. In some embodiments, the reacting is done in the presence of POCl 3 and tetraethylammonium chloride. In some embodiments, the chlorinating is performed at an elevated temperature. In some embodiments, the elevated temperature is from about 60 °C to about 120 °C. In some embodiments, the elevated temperature is from about 70 °C to about 110 °C. In some embodiments, the elevated temperature is from about 100 °C to about 110 °C.
  • Compound 12 is used in the next step without isolation or purification. In some embodiments, where Compound 12 is obtained in solution, e.g., toluene solution, and is used directly in the next step, impurities related to hydrolysis of Compound 12 are reduced. In some embodiments, Compound 16 is obtained as-is and/or used in the next reaction step as a mixture with one or more of Compound 16 (i) , 16 (ii) , 16 (iii) , and 16 (iv) : In some embodiments, Compound 16 is obtained as-is and/or used in the next reaction step as a mixture with Compound 16 (i) , 16 (ii) , 16 (iii) , and 16 (iv) .
  • Compound 16 is obtained as and/or used in the next reaction step as a mixture with Compound 16 (i) at 16 (ii) .
  • Compound 16 (i) is present at about 0.05 to about 0.4%w/w.
  • Compound 16 (i) is present at about 0.05 to about 0.3%w/w.
  • Compound 16 (ii) is present at about 0.05 to about 0.2%w/w.
  • Compound 16 (ii) is present at about 0.05 to about 0.15%w/w.
  • Compound 16 (iii) is present at less than about 0.4%w/w.
  • Compound 16 (iii) is present at less than about 0.05%w/w. In some embodiments, Compound 16 (iii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.4%w/w. In some embodiments, Compound 16 (iv) is present at less than about 0.15%w/w. In some embodiments, Compound 16 (iv) is present at less than about 0.05%w/w. In some embodiments, Compound 16 (iv) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w.
  • a process of preparing Compound 16 comprises reacting Compound 12 with Compound 13, wherein P 1 is an amine protecting group (see, e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley &Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure) , to form Compound 14 (Scheme C, Step 7) .
  • P 1 is an amine protecting group
  • P 1 is tert-butyloxycarbonyl (Boc; Compound 13-Boc) , fluorenylmethyloxycarbonyl (Fmoc) , trifluoroacetyl, phthalimide, benzylideneamine, or trityl.
  • P 1 is Boc.
  • the reacting of Compound 12 and Compound 13 is a nucleophilic aromatic substitution in a suitable solvent.
  • the solvent is an aprotic solvent.
  • the solvent is DMF, DMA, NMP, ACN, dioxane, DME, toluene, THF, or Me-THF, or a mixture thereof.
  • the solvent is toluene, THF, or Me-THF.
  • the reacting of Compound 12 and Compound 13 is in the presence of a base.
  • the base is an organic base.
  • the base is DIPEA, DBU, TEA, pyridine, or NMP.
  • the base is DIPEA.
  • the reacting comprises combining Compound 13 with Compound 12 and the base at a first temperature to form a reaction mixture, and heating the reaction mixture to a second temperature.
  • the first temperature is from about 0 °C to about 40 °C. In some embodiments, the first temperature is from about 0 °C to about 30 °C.
  • the first temperature is from about 15 °C to about 30 °C.
  • the second temperature is from about 50 °C to 100 °C. In some embodiments, the second temperature is from about 65 °C to about 85 °C.
  • P 1 is Boc and Compound 13 is (Compound 13-Boc) .
  • Compound 14 is isolated by precipitation and filtration. In some embodiments, Compound 14 is isolated by crystallization from a mixture of toluene and heptane.
  • a process of preparing Compound 16 comprises reacting Compound 14 with methylamine to form Compound 15, wherein P 1 is an amine protecting group (Scheme C, Step 8) .
  • the methylamine is used in an amount of about 3 to about 7 equivalents.
  • P 1 is Boc, Fmoc, trifluoroacetyl, phthalimide, benzylideneamine, or trityl.
  • P 1 is Boc.
  • the reacting is a nucleophilic aromatic substitution reaction and is performed in a suitable solvent.
  • the suitable solvent is a polar solvent such as methanol (MeOH) , ethanol (EtOH) , isopropyl alcohol (IPA) , n-butanol, amyl alcohol, t-butanol, DMF, DMA, ACN, Me-THF, THF, or NMP, or a mixture thereof.
  • the suitable solvent is an alcohol solvent.
  • the alcohol solvent is MeOH, EtOH, IPA, n-butanol, amyl alcohol, or t-butanol.
  • the suitable solvent is EtOH.
  • the reacting is with methylamine in the presence of a supplemental base.
  • the supplemental base is an organic base.
  • the organic base is DIPEA, DBU, TEA, pyridine, or N-methyl morpholine.
  • the supplemental base is TEA.
  • the supplemental base is DIPEA.
  • the supplemental base is used in an amount of about 1 to about 5 equivalents.
  • the reacting is performed at an elevated temperature.
  • the elevated temperature is from about 50 °C to about 100 °C.
  • the elevated temperature is from about 60 °C to about 80 °C.
  • the elevated temperature is from about 90 °C to about 100 °C.
  • P 1 is Boc and Compound 14 is (Compound 14-Boc) .
  • P 1 is Boc and Compound 15 is (Compound 15-Boc) .
  • Compound 15 is isolated by precipitation and filtration.
  • Compound 15 is isolated by crystallization, optionally using a mixture of EtOH and water.
  • the reacting of Compound 14-Boc with methylamine to form Compound 15-Boc provides a mixture of Compound 15-Boc and
  • a process for preparing Compound 16 comprises deprotecting Compound 15, wherein P 1 is an amine protecting group, to provide Compound 16.
  • P 1 is Boc, Fmoc, trifluoroacetyl, phthalimide, benzylideneamine, or trityl.
  • P 1 is Boc.
  • the deprotecting is performed in a sutiable solvent.
  • the solvent is MeOH, EtOH, IPA, n-butanol, amyl alcohol, THF, Me-THF, DMF, DMA, DCM, DCE, or ACN, or a mixture thereof.
  • the solvent is an alcohol solvent.
  • the solvent is methanol.
  • P 1 is an acid-labile protecting group, such as Boc or trityl, and the deprotecting is in the presence of an acid.
  • the acid is phosphoric acid, methanesulfonic acid, trifluoroacetic acid, H 2 SO 4 , HCl, or toluenesulfonic acid.
  • the acid is aqueous HCl.
  • P 1 is Boc and Compound 15 is Compound 15-Boc.
  • Compound 16 is isolated as an HCl salt (Compound 16-HCl or Compound 16-2HCl) .
  • Compound 16 is isolated as a di-HCl salt (Compound 16-2HCl) .
  • Compound 16, Compound 16-HCl, or Compound 16-2HCl is a solid and is isolated by precipitation and filtration.
  • the methods comprise preparing Compound 11, as outlined in Scheme C-2.
  • Scheme C-2
  • preparation of Compound 11 comprises reacting 2-amino-5- (2, 2, 2-trifluoroethyl) thiophene-3-carboxamide with a CO equivalent, such as CDI, in a suitable solvent.
  • the reacting with the CO equivalent, such as CDI is performed at a temperature of from about 50 to about 85 °C, or from about 70 to about 75 °C.
  • methods described herein comprise reacting 4, 4, 4-trifluorobutanal with 2-cyanoacetamide and sulfur S 8 in the presence of a suitable base such as TEA, to provide 2-amino-5- (2, 2, 2-trifluoroethyl) thiophene-3-carboxamide.
  • the reaction is performed in a polar solvent, such as DMF or Me-THF or a mixture thereof. In some embodiments, the reaction is performed at a temperature from about 0 °C to about 60 °C, or about 25 to about 45 °C. In some embodiments, the product is not isolated but is reacted directly in the next step.
  • a polar solvent such as DMF or Me-THF or a mixture thereof.
  • the reaction is performed at a temperature from about 0 °C to about 60 °C, or about 25 to about 45 °C.
  • the product is not isolated but is reacted directly in the next step.
  • the methods described herein comprise converting 3-chloro-1, 1, 1-trifluoropropane to the corresponding Grignard reagent, for example, in the presence of Mg turnings and catalytic I 2 , or in a polar aprotic solvent such as THF or Me-THF, and reacting the Grignard reagent with DMF to form 4, 4, 4-trifluorobutanal.
  • 2-amino-5- (2, 2, 2-trifluoroethyl) thiophene-3-carboxamide is not isolated but is reacted directly in the next step.
  • 4, 4, 4-trifluorobutanal and 2-amino-5- (2, 2, 2-trifluoroethyl) thiophene-3-carboxamide are not isolated or purified, but are used in solution directly; such that the overall process from 3-chloro-1, 1, 1-trifluoropropane to Compound 11 comprises isolation and purification of Compound 11 only. Purity of Compound A
  • compositions of Compound A, or a pharmaceutically acceptable salt thereof, substantially free of impurities are substantially free of Compound A impurities.
  • the composition comprises one or more Compound A impurities, in a total amount that is less than or equal to about 2%w/w of Compound A impurities.
  • the composition comprises one or more Compound A impurities, in a total amount that is less than about 1%w/w of Compound A impurities.
  • the composition comprises Compound A impurities in a total amount that is less than about 1%w/w, less than about 0.75%w/w, less than about 0.50%w/w, less than about 0.25%w/w, less than about 0.20%w/w, less than about 0.15%w/w, less than about 0.10%w/w, or less than about 0.05%w/w of Compound A impurities (relative to Compound A + Compound A impurities) .
  • the composition comprises at least about 95%w/w, at least about 96%w/w, at least about 97%w/w, at least about 98%w/w, or at least about 99%Compound A.
  • Compound A impurities are undetectable, for example by nuclear magnetic resonance spectrometry, high performance liquid chromatography (HPLC) , or the like.
  • Compound A is a mixture with one or more of Compounds A (i) to A (x) . In some embodiments, Compound A is a mixture with one or more of Compounds A (i) to A (xviii) . In some embodiments, Compound A is a mixture with one, two, three, four, five, or all of Compound A (i) , A (ii) , A (vi) , A (v) , A (viii) , and A (ix) .
  • Compound A is a mixture with one, two, three, four, five, or all of Compound A (ii) , A (v) , A (ix) , A (xi) , A (xv) , and A (xvii) .
  • Compound A (i) is present at about 0.05 to about 0.3%w/w. In some embodiments, Compound A (i) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (i) is present at not more than about 0.15%w/w. In some embodiments, Compound A (i) is present and is present at not more than about 0.15%w/w.
  • Compound A (ii) is present at about 0.05 to about 0.25%w/w. In some embodiments, Compound A (ii) is present at about 0.05 to about 0.2%w/w. In some embodiments, Compound A (ii) is present at not more than about 0.25%w/w. In some embodiments, Compound A (ii) is present and is present at not more than about 0.25%w/w.
  • Compound A (iii) is present at not more than about 0.15%w/w. In some embodiments, Compound A (iii) is present and is present at not more than about 0.15%w/w. In some embodiments, Compound A (iii) is present at not more than about 0.05%w/w. In some embodiments, Compound A (iii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (iii) is present at about 0.05 to about 0.15%w/w.
  • Compound A (iv) is present at about 0.05 to about 0.3%w/w. In some embodiments, Compound A (iv) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (iv) is present at not more than aboaut 0.15%w/w. In some embodiments, Compound A (iv) is present and is present at not more than about 0.15%w/w.
  • Compound A (v) is present at about 0.05 to about 0.25%w/w. In some embodiments, Compound A (v) is present at about 0.05 to about 0.2%w/w. In some embodiments, Compound A (v) is present at not more than about 0.25%w/w. In some embodiments, Compound A (v) is present and is present at not more than about 0.25%w/w.
  • Compound A (vi) is present at not more than about 0.15%w/w. In some embodiments, Compound A (vi) is present at not more than about 0.05%w/w. In some embodiments, Compound A (vi) is present at about 0.01 to about 0.15%w/w or at about 0.01 to about 0.05%w/w. In some embodiments, Compound A (vi) is present and is present at not more than about 0.15%w/w.
  • Compound A (vii) is present at not more than about 0.15%w/w. In some embodiments, Compound A (vii) is present at not more than about 0.05%w/w. In some embodiments, Compound A (vii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (viii) is present and is present at not more than about 0.15%w/w.
  • Compound A (viii) is present at about 0.05 to about 0.3%w/w. In some embodiments, Compound A (viii) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (viii) is present at not more than about 0.4%w/w. In some embodiments, Compound A (viii) is present at about 0.05 to about 0.4%w/w. In some embodiments, Compound A (viii) is present and is present at not more than about 0.4%w/w.
  • Compound A (ix) is present at about 0.05 to about 0.25%w/w. In some embodiments, Compound A (ix) is present at about 0.05 to about 0.1%w/w. In some embodiments, Compound A (ix) is present at not more than about 0.25%w/w. In some embodiments, Compound A (ix) is present and is present at not more than about 0.25%w/w.
  • Compound A (x) is present at less than about 0.15%w/w. In some embodiments, Compound A (x) is present at less than about 0.05%w/w. In some embodiments, Compound A (x) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w.
  • Compound A (xi) is present at not more than about 0.4%w/w. In some embodiments, Compound A (xi) is present and is present at not more than about 0.4%w/w. In some embodiments, Compound A (xi) is present at not more than about 0.25%w/w. In some embodiments, Compound A (xi) is present and is present at not more than about 0.25%w/w. In some embodiments, Compound A (xi) is present at about 0.05 to about 0.25%w/w.
  • Compound A (xii) is present at about 0.05 to about 0.4%w/w. In some embodiments, Compound A (xii) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (xii) is present at not more than about 0.4%w/w.
  • Compound A (xiii) is present at about 0.05 to about 0.4%w/w. In some embodiments, Compound A (xiii) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (xiii) is present at not more than about 0.4%w/w.
  • Compound A (xiv) is present at not more than about 0.15%w/w. In some embodiments, Compound A (xiv) is present at not more than about 0.05%w/w. In some embodiments, Compound A (xiv) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (xiv) is present and is present at not more than about 0.15%w/w.
  • Compound A (xv) is present at not more than about 0.5%w/w. In some embodiments, Compound A (xv) is present and is present at not more than about 0.5%w/w. In some embodiments, Compound A (xv) is present at about 0.05 to about 0.5%w/w.
  • Compound A (xvi) is present at not more than about 0.15%w/w. In some embodiments, Compound A (xvi) is present at not more than about 0.05%w/w. In some embodiments, Compound A (xvi) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (xvi) is present and is present at not more than about 0.15%w/w.
  • Compound A (xvii) is present at not more than about 0.25%w/w. In some embodiments, Compound A (xviii) is present and is present at not more than about 0.25%w/w. In some embodiments, Compound A (xvii) is present at about 0.05 to about 0.25%w/w.
  • Compound A (xviii) is present at not more than about 0.15%w/w. In some embodiments, Compound A (xviii) is present at not more than about 0.05%w/w. In some embodiments, Compound A (xviii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (xviii) is present and is present at not more than about 0.15%w/w.
  • the pharmaceutical composition comprises Compound A, or a pharmaceutically acceptable salt thereof, and Compound A impurities.
  • the Compound A impurities are present in a total amount that is about 2%w/w or less, less than about 1%w/w, less than about 0.75%w/w, less than about 0.50%w/w, less than about 0.25%w/w, less than about 0.20%w/w, less than about 0.15%w/w, less than about 0.10%w/w, or less than about 0.05%w/w (relative to Compound A + Compound A impurities) .
  • the pharmaceutical composition comprises Compound A and one or more of Compounds A (i) to A (x) .
  • the pharmaceutical composition comprises Compound A and one or more of Compounds A (i) , A (ii) , A (iii) , A (iv) , A (v) , A (vi) , A (vii) , A (viii) , A (ix) , A (xi) , A (xii) , A (xiii) , A (xiv) , A (xv) , A (xvi) , A (xvii) , and A (xviii) .
  • the pharmaceutical composition comprises Compound A and one, two, three, four, five, or all of Compound A (i) , A (ii) , A (vi) , A (v) , A (viii) , and A (ix) .
  • the pharmaceutical composition comprises Compound A and one, two, three, four, five, or all of Compounds A (ii) , A (v) , A (ix) , A (xi) , A (xv) , and A (xvii) .
  • Compound A (i) is present at about 0.05 to about 0.3%w/w. In some embodiments, Compound A (i) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (i) is present at not more than about 0.15%w/w. In some embodiments, Compound A (i) is present and is present at not more than about 0.15%w/w.
  • Compound A (ii) is present at about 0.05 to about 0.25%w/w. In some embodiments, Compound A (ii) is present at about 0.05 to about 0.2%w/w. In some embodiments, Compound A (ii) is present at not more than about 0.25%w/w. In some embodiments, Compound A (ii) is present and is present at not more than about 0.25%w/w.
  • Compound A (iii) is present at not more than about 0.15%w/w. In some embodiments, Compound A (iii) is present and is present at not more than about 0.15%w/w. In some embodiments, Compound A (iii) is present at not more than about 0.05%w/w. In some embodiments, Compound A (iii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (iii) is present at about 0.05 to about 0.15%w/w.
  • Compound A (iv) is present at about 0.05 to about 0.3%w/w. In some embodiments, Compound A (iv) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (iv) is present at not more than aboaut 0.15%w/w. In some embodiments, Compound A (iv) is present and is present at not more than about 0.15%w/w.
  • Compound A (v) is present at about 0.05 to about 0.25%w/w. In some embodiments, Compound A (v) is present at about 0.05 to about 0.2%w/w. In some embodiments, Compound A (v) is present at not more than about 0.25%w/w. In some embodiments, Compound A (v) is present and is present at not more than about 0.25%w/w.
  • Compound A (vi) is present at not more than about 0.15%w/w. In some embodiments, Compound A (vi) is present at not more than about 0.05%w/w. In some embodiments, Compound A (vi) is present at about 0.01 to about 0.15%w/w or at about 0.01 to about 0.05%w/w. In some embodiments, Compound A (vi) is present and is present at not more than about 0.15%w/w.
  • Compound A (vii) is present at not more than about 0.15%w/w. In some embodiments, Compound A (vii) is present at not more than about 0.05%w/w. In some embodiments, Compound A (vii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (viii) is present and is present at not more than about 0.15%w/w.
  • Compound A (viii) is present at about 0.05 to about 0.3%w/w. In some embodiments, Compound A (viii) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (viii) is present at not more than about 0.4%w/w. In some embodiments, Compound A (viii) is present at about 0.05 to about 0.4%w/w. In some embodiments, Compound A (viii) is present and is present at not more than about 0.4%w/w.
  • Compound A (ix) is present at about 0.05 to about 0.25%w/w. In some embodiments, Compound A (ix) is present at about 0.05 to about 0.1%w/w. In some embodiments, Compound A (ix) is present at not more than about 0.25%w/w. In some embodiments, Compound A (ix) is present and is present at not more than about 0.25%w/w.
  • Compound A (x) is present at less than about 0.15%w/w. In some embodiments, Compound A (x) is present at less than about 0.05%w/w. In some embodiments, Compound A (x) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w.
  • Compound A (xi) is present at not more than about 0.4%w/w. In some embodiments, Compound A (xi) is present and is present at not more than about 0.4%w/w. In some embodiments, Compound A (xi) is present at not more than about 0.25%w/w. In some embodiments, Compound A (xi) is present and is present at not more than about 0.25%w/w. In some embodiments, Compound A (xi) is present at about 0.05 to about 0.25%w/w.
  • Compound A (xii) is present at about 0.05 to about 0.4%w/w. In some embodiments, Compound A (xii) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (xii) is present at not more than about 0.4%w/w.
  • Compound A (xiii) is present at about 0.05 to about 0.4%w/w. In some embodiments, Compound A (xiii) is present at about 0.05 to about 0.15%w/w. In some embodiments, Compound A (xiii) is present at not more than about 0.4%w/w.
  • Compound A (xiv) is present at not more than about 0.15%w/w. In some embodiments, Compound A (xiv) is present at not more than about 0.05%w/w. In some embodiments, Compound A (xiv) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (xiv) is present and is present at not more than about 0.15%w/w.
  • Compound A (xv) is present at not more than about 0.5%w/w. In some embodiments, Compound A (xv) is present and is present at not more than about 0.5%w/w. In some embodiments, Compound A (xv) is present at about 0.05 to about 0.5%w/w.
  • Compound A (xvi) is present at not more than about 0.15%w/w. In some embodiments, Compound A (xvi) is present at not more than about 0.05%w/w. In some embodiments, Compound A (xvi) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (xvi) is present and is present at not more than about 0.15%w/w.
  • Compound A (xvii) is present at not more than about 0.25%w/w. In some embodiments, Compound A (xviii) is present and is present at not more than about 0.25%w/w. In some embodiments, Compound A (xvii) is present at about 0.05 to about 0.25%w/w.
  • Compound A (xviii) is present at not more than about 0.15%w/w. In some embodiments, Compound A (xviii) is present at not more than about 0.05%w/w. In some embodiments, Compound A (xviii) is present at about 0.01 to about 0.05%w/w, or at about 0.01 to about 0.15%w/w. In some embodiments, Compound A (xviii) is present and is present at not more than about 0.15%w/w.
  • GMP guidelines outline acceptable contamination levels of active therapeutic agents, such as, for example, the amount of residual solvent in the final product.
  • Preferred solvents are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) , “Impurities: Guidelines for Residual Solvents, Q3C (R3) , (November 2005) .
  • compositions comprising Compound A, or a pharmaceutically acceptable salt thereof, and an organic solvent.
  • the composition comprises a residual amount of an organic solvent.
  • the residual amount of organic solvent is detectable.
  • the solvent is a Class 3 solvent as defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) , “Impurities: Guidelines for Residual Solvents, Q3C (R3) , (November 2005) .
  • the Class 3 solvent is acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, or tetrahydrofuran.
  • the Class 3 solvent is ethyl acetate, isopropyl acetate, tert-butylmethylether, heptane, isopropanol, or ethanol.
  • the residual amount of organic solvent is less than about 1%, and the solvent is acetone, dichloromethane, 1, 2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, isopropanol, heptane, or 2-propanol.
  • the solvent is MTBE, EtOH, IPA, MeOH, DCM, THF, 1, 2-dichlorobenzene, or a mixture thereof.
  • the residual amount of solvent is less than about 5000 parts per million (ppm) . In some embodiments, the residual amount of solvent is less than about 5000 ppm, less than about 4000 ppm, less than about 3000 ppm, less than about 2000 ppm, less than about 1000 ppm, less than about 500 ppm, or less than about 100 ppm.
  • the process may comprise reducing the amount of transition metal materials, such as palladium-based materials, from a reaction product or a subsequent reaction product.
  • the reducing is performed on Compound A, or a pharmaceutically acceptable salt thereof, or an intermediate in the synthetic process, so that Compound A, or a pharmaceutically acceptable salt thereof, meets transition metal or palladium specification guidelines ( “Guideline on the Specification Limits for Residues of Metal Catalysts” European Medicines Agency Preauthorisation Evaluation of Medicines for Human Use, London, January 2007, Doc. Ref. CPMP/SWP/QWP/4446/00 corr) .
  • the process comprises reducing the amount of palladium in the reaction product from Step 4.5a in Scheme B-1, Step 5a in Scheme B-2, or Step 5c in Scheme B-3, or from Compound A, or a pharmaceutically acceptable salt thereof, after the coupling shown of Compound 10 and Compound 16 shown in Scheme A.
  • the process comprises reducing the amount of palladium mixed with Compound 10 obtained from Step 4.5a in Scheme B.
  • the process comprises reducing the amount of palladium mixed with Compound 10 after Step 5a in Scheme B.
  • the process comprises reducing the amount of palladium mixed with Compound 10 obtained from Step 5c in Scheme B.
  • the process comprises reducing the amount of palladium mixed with Compound A obtained from the coupling shown in Scheme A.
  • reducing the amount of palladium mixed with a reaction product comprises treating the reaction product/transition metal mixture with an adsorbing agent, and extracting agent, or a crystallizing agent, or a combination thereof.
  • reducing the amount of palladium comprises treating the reaction product with an extracting agent and then treating the resulting material with an adsorbing agent.
  • the reaction product may be treated once, more than once, or twice with an adsorbing agent.
  • adsorbing agents include, but are not limited to, trimercaptotriazine (TMT) , a TMT derivative (such as solid TMT, polystyrene-bound TMT, silica gel-bound TMT, DMT, or mercapto-porous polystyrene-bound TMT) , derivatized silica gel (such as silica gel-linker-thiol, silica gel- (CH 2 ) 3 -SH, silica gel- (CH 2 ) 3 -S- (CH 2 ) 2 -SH, or such as silica gel-linker-amine, such as silica gel- (CH 2 ) 3 -NH 2 , or silica gel- (CH 2 ) 3 - [NH- (CH 2 ) 2 ] 1-2 -NH 2 , or silica gel- (CH 2 ) 3 -NHC (S) NHCH 3 , such as metal scavengers) , polyst
  • crystallizing agents include, but are not limited to, N-acetylcysteine, thiourea, a hemi-maleate salt, or Bu 3 P.
  • extracting agents include, but are not limited to, N-acetylcysteine, L-cysteine, and Bu 3 P in lactic acid. See, e.g., Garrett et al., Adv. Synth. Catal. 2004, 346, 889-900.
  • Compound A as obtained from the coupling of Compound 10 and Compound 16 is treated with N-acetylcysteine (e.g., 0.02 to 0.2 w/w, or 0.1 w/w, compared to Compound A) and Na 2 CO 3 (e.g., 0.02 to 0.2 w/w, or 0.1 w/w, compared to Compound A) in water, extracted into organic solvent, and the resulting solution is treated with Si-thiol (e.g., 0.02 to 0.2 w/w, or 0.1, w/w compared to Compound A) .
  • N-acetylcysteine e.g., 0.02 to 0.2 w/w, or 0.1 w/w, compared to Compound A
  • Na 2 CO 3 e.g., 0.02 to 0.2 w/w, or 0.1 w/w, compared to Compound A
  • the amount of palladium in the reaction product is about 100 ppm or less, or about 10 ppm, or is undetectable.
  • the presence and/or amount of residual heavy metal (e.g., palladium) impurities is determined using methods known in the art.
  • the presence and/or amount of residual heavy metal (e.g., palladium) impurities is determined using inductively coupled plasma mass spectrometry (ICP-MS) .
  • ICP-MS inductively coupled plasma mass spectrometry
  • the presence and/or amount of residual heavy metal (e.g., palladium) impurities is determined using techniques described in U.S. Pharmacopeia General Chapter ⁇ 232> Elemental Impurities-Limits. EXAMPLES
  • Abbreviations used herein include: ethyl (Et) , molar (M) , methyl (Me) , Normal, e.g., 6 Normal NaOH solution (N) , volume, e.g., for reaction volume or ratio of solvents (vol. ) , weight ratio (w/w) , and mass equivalents (wt) .
  • Step 1 To a stirred suspension of NaH (859.9 g, 21.497 mol) in THF (10.0 L) at 0 °C, was added a pre-mixed solution of 3-nitro-o-xylene (Compound 1; 2.5 kg, 16.536 mol) , diethyl oxalate (3.162 L, 23.151 mol) , and tert-amyl alcohol (182.2 mL, 1.653 mol) in DMF (2.5 L) at 0 to 5 °C. The reaction mixture was stirred for 30 hours (h) at 20-25 °C (alternatively, the reaction time may be reduced, for example, to from 7 to 30 h, or approximately 8 h) .
  • Step 2 To a stirred suspension of Compound 2 (2.2 kg, 12.559 mol) in DCM (22 L) at 25-30 °C was added oxalyl chloride (2.14 L, 25.118 mol) dropwise followed by DMF (97.12 mL, 1.256 mol) . After stirring for 3 h at 45-50 °C, the reaction mixture was cooled to 0-5 °C and treated with 25%aq. ammonia (22 L) . The resulting mixture was stirred for 16 h at 25-30 °C, and DCM was then removed by distillation. The resulting suspension was diluted with water (22 L) and stirred for 5 h at 25-30 °C.
  • Step 3 To a stirred suspension of Compound 3 (1.7 kg, 9.759 mol) in toluene (34 L) at 25-30 °C was added POCl 3 (3.65 L, 39.037 mol) over 30 min. The resulting mixture was heated to reflux and stirred for 3 h. The mixture was diluted with saturated aq. NaHCO 3 (26 L) at 0-5 °C and stirred for 1 h at 25-30 °C. The organic layer was separated, washed with saturated aq. NaHCO 3 (2 x 10 L) , and washed with saturated aq. NaCl (15 L) .
  • the resulting organic layer was treated with activated carbon (170 g) and silica (340 g) and the mixture was heated to 70 °C for 1 h.
  • the mixture was cooled to 25-30 °C and filtered through a pad of diatomaceous earth, washing with toluene (3.4 L) .
  • the filtrate was distilled under reduced pressure at 50 °C to afford 1.28 kg of Compound 4 as a solid. Yield: 1.28 kg (84%) ; HPLC: 98.28% (a/a) .
  • Step 4c To a stirred solution of Compound 4 (1 equiv) in THF (14 vol) under inert atmosphere at 25 to 30 °C was added Compound 7 (1.3 equiv. ) and TPP (1.5 equiv. ) . The mixture was cooled to 0 to -5 °C and a solution of DIAD (1.5 equiv. ) was added slowly, maintaining the reduced temperature, then rinsing the addition funnel with THF (1 vol) . The reaction mixture was stirred at 0 to -5 °C for 30 min, then for 3 h at 25 to 30 °C. THF was removed by distillation under reduced pressure at ⁇ 45 °C until 8-9 vol remained.
  • the resulting mixture was diluted with THF (3.5 mol) at 35 to 45 °C and stirred for 20 min, then treated with IPA (20 vol) at 35 to 45 °C, cooled to 25 to 30 °C, and stirred at 25 to 30 °C for 16 h.
  • the resulting solid was filtered, washed with IPA (2 vol) , and the filter cake was left under filter vacuum for 3 h.
  • the collected solid was diluted with THF (1 vol) and IPA (9 vol) , heated to 45 to 50 °C, and stirred for 1 h.
  • the mixture was cooled to 25 to 30 °C, stirred for 2 h, and filtered.
  • Step 5b To a stirred solution of Compound 8 (1 equiv. ) , optionally as a mixture with Compound 8-X (at ⁇ 5%, or 2-4% (a/a) ) , in 1, 2-dichlorobenzene (15 vol) at -5 to 0 °C was added TiCl 4 (4 equiv. ) slowly and the resulting mixture was stirred for 30 min at 0 to -5 °C. Distilled dichloromethyl methyl ether (4 equiv. ) was then added slowly at -5 to 0 °C, and the resulting mixture was stirred for 6 h at 0 to 10 °C and then for another 6 h at 25 °C.
  • the mixture was cooled to 0 to 10 °C and diluted with DCM (5 vol) , maintaining the reduced temperature, and then quenched with pre-cooled (-15 to -10 °C) approximately 28%aq. NaOH solution, maintaining the temperature at -15 to 0 °C.
  • the final pH was adjusted to pH 8-10.
  • the resulting biphasic heterogeneous solid mass was filtered, and the solids washed with DCM and filtered.
  • the filtrate was diluted with DCM (5 vol) , the organic layer was separated, and the aqueous layer was back-extracted with DCM (5 vol) .
  • the organic layers were combined, washed with saturated aq.
  • the resulting solid was collected by filtration, washing with cold ACN (1.5 vol) .
  • the collected solid was redissolved in ACN (7.5 vol) , heated to 70-80 °C, and stirred for 30-45 min, then cooled slowly to 25-30 °C and stirred for 2 h, and then cooled to 15-20 °C and stirred for 4 h.
  • the resulting solid was collected by filtration, washing with cold ACN (1.5 vol) .
  • the solid product was dried under vacuum at 55-60 °C to afford Compound 10 as a solid. Yield: 40%.
  • Compound 8-X and the corresponding regioisomer of Compound 10 were not detected by HPLC.
  • Step 5b (alternative procedure): To a stirred solution of Compound 8 (1 equiv. ) , optionally as a mixture with Compound 8-X (at ⁇ 5%, or 2-4% (a/a) ) , in 1, 2-dichlorobenzene (15 vol) was charged vacuum oven-dried (at 80 °C for a least 16 h) molecular sieves (25%w/w) and the mixture was stirred for 2 h at 20-30 °C and then was filtered, washing with 1, 2-dichlorobenzene (0.5 vol) . The filtrate was charged into a reactor, cooled to -5 to 0 °C, and treated at -5 to 0 °C with TiCl 4 (4 equiv.
  • the dry solid was diluted with ACN (7.5 vol based on assay corrected weight of the solid material) and the resulting mixture was heated to 70-80 °C, then cooled slowly to 25-30 °C, and stirred for 2 h, then cooled to 15-20 °C, and stirred for 2 h.
  • the resulting solid was collected by filtration, washing with cold ACN (1.5 vol) .
  • the solid product was dried under vacuum at 55-60 °C.
  • the dry product was charged into a vessel, diluted with ACN (15 vol, based on assay corrected weight of the dry solid) , and the resulting mixture was heated at 50-65 °C to dissolve the solid material. Charcoal (5 wt%) was added and the mixture was stirred for 30 min at 50-65 °C.
  • the mixture was filtered hot through a bed of diatomaceous earth, washing with hot ACN (2 x 1 vol) .
  • the filtrate was distilled ( ⁇ 50 °C) to 6-7.5 vol.
  • the resulting mixture was heated to 70-80 °C and was stirred for 30-45 min, then was cooled slowly to 25-30 °C and stirred for at least 1.5 h, and then was cooled to 15-20 °C and stirred for another 4-6 h.
  • the resulting solid was collected by filtration, washing with cold ACN (1.5 vol) .
  • the solid product was dried under vacuum at 55-60 °C to afford Compound 10 as a solid. Yield: 52%.
  • Detected impurities in Compound 10 as obtained may include one or more of the following:
  • Example 2 Preparation of (S) -5-formyl-4-methyl-1- (2- (4- (methylsulfonyl) piperazin-1- yl) propyl) -1H-indole-2-carbonitrile (Compound 10) Scheme Ex2
  • Step 4a Procedure 1. As shown in Scheme Ex2, Compound 4 (1 equiv. ) in DCM (10 V) was treated with BF 3 ⁇ OEt 2 (3.0 equiv. ) at 0 °C and stirred for 30 min. NIS (1.2 equiv. ) was added in portions at 0 °C. The mixture was stirred at rt for 48 h, or rt for 6 h followed by heating at 45 °C for the remaining time. The mixture was cooled to 0 °C and diluted with 2 N NaOH to adjust the pH to ⁇ 8. DCM was removed by distillation at 45 C. The resulting solid was filtered and dried.
  • NIS 1.2 equiv.
  • Step 4a Procedure 2. Compound 4 (1 equiv. ) in ACN (10 V) was treated with TMSOTf (2.2 to 3 equiv. ) and the mixture was stirred at rt for 30 min. To the mixture was added NIS (0.9 to 1.3 equiv. ) as a solid in portions or dropwise as a solution in ACN (10 V) , and the reaction mixture was stirred at 0 to 5 °C, rt, or 50 to 55 °C for 2 h. The mixture was treated with 2 N NaOH at 0 °C to adjust the pH to ⁇ 8. ACN was removed by distillation at 45 °C. The resulting solid was filtered and dried to afford the desired product (yield, 88%) .
  • Step 4a Procedure 3. To a 0 °C solution of Compound 4 (50 g, 1 equiv. ) in ACN (10 vol) was added TMSOTf (2.2 equiv. ) , followed by NIS (0.9 equiv. ) in 6 batches. The resulting mixture was stirred at 0 °C for 30 min, then was treated with 2 N NaOH to adjust the pH to ⁇ 8. ACN was removed by distillation at 45 C, and the resulting solid was filtered and dried to provide Compound 5-I (80 g, 88%yield, 95%purity by HPLC) . 1 H NMR consistent with above; MS Calcd. for C 10 H 7 IN 2 m/z 281.97, found (M-H) 280.6.
  • Step 4.5a A mixture of P (Cy) 3 ⁇ HBF 4 (0.03 equiv. ) , and Na 2 CO 3 (2 equiv. ) in DMF (20 V) was degassed with N 2 for 20 min and then was treated with Pd (OAc) 2 (0.01 equiv. ) , water (1 equiv. ) , and Compound 5 (5 g) . The resulting mixture was degassed with N 2 for 30 min, treated with Et 3 SiH (2.5 equiv. ) , degassed with CO (3 times) , and then reacted in the presence of CO (0.8 MPa) at 65 to 70 °C for 16 h.
  • Step 4b To a solution of Compound 4 (1 equiv. ) in DCM (20 V) at 0 °C was added TiCl 4 (2.2 equiv. ) and the resulting mixture was stirred at 0 °C for 1 h.
  • Dichloromethyl methyl ether (2.5 equiv. ) was added in portions (5 x 0.5 equiv. ) at 0 °C, and the resulting mixture was stirred at 0 °C for 16 h.
  • Work-up provided the crude product as a solid, which was diluted in 5%DMF in DCM (10 V) and stirred for 30 min at 50 °C and 16 h at rt. The mixture was cooled to 0 to 5 °C and stirred for 30 min.
  • the resulting solid was filtered at 0 to 5 °C and dried to provide Compound 6. Analytical data were consistent with the data provided above.
  • Step 5a Compound 7-OH was reacted with Tf 2 O and DIPEA in DCM to provide Compound 7-OTf, which was mixed with Compound 6 and Cs 2 CO 3 in DMF to provide Compound 10.
  • Example 3 Preparation of (S) -5-formyl-4-methyl-1- (2- (4- (methylsulfonyl) piperazin-1- yl) propyl) -1H-indole-2-carbonitrile (Compound 10) Scheme Ex3
  • Step 4.5b A mixture of Compound 8 (500 mg, 1 equiv. ) and Bu 4 NI (0.1 equiv. ) in AcOH (5 vol) . at rt was treated with NIS (1.5 equiv. ) slowly. The resulting mixture was heated to 55-60 °C and stirred for 2 h. Analysis of the reaction mixture by HPLC showed Compound 9-I (82%) along with the 3-iodo-regioisomer (6%) and a di-iodo product (9%) . Isolation from the reaction mixture provided Compound 9-I. Other iodination conditions provided higher ratios of by-products.
  • Step 5c Procedure A. A mixture of P (Cy) 3 ⁇ HBF 4 (0.03 equiv. ) , and Na 2 CO 3 (2 equiv. ) in DMF (20 V) was degassed with N 2 for 20 min and then was treated with Pd (OAc) 2 (0.01 equiv. ) , water (1 equiv. ) , and Compound 9-I (1 equiv. ) . The resulting mixture was degassed with N 2 for 30 min, treated with Et 3 SiH (2.5 equiv. ) , degassed with CO (3 times) , and then reacted in the presence of CO (0.8 MPa) at 65 to 70 °C for 16 h. HPLC analysis showed 65%Compound 10.
  • Step 5c Procedure B. A mixture of Compound 9-I (1 equiv. ) , Pd (OAc) 2 (0.03 equiv. ) , formic acid (7 equiv. ) , DABCO (2 equiv. ) , and DCC (2 equiv. ) in polyethylene glycol (10 vol) was heated to 100 °C in a sealed tube for 16 h. After suitable workup, HPLC analysis indicated 83%production of Compound 10. Satisfactory analytical data were obtained.
  • Example 4 Preparation of (S) -2- (4- (methylsulfonyl) piperazin-1-yl) propan-1-ol (Compound 7-OH) Scheme Ex4
  • the combined filtrate was concentrated by distillation at 50-60 °C until no further solvent was produced.
  • the resulting mixture was cooled to 30 °C, diluted with EtOH (0.8 vol) and ACN (0.8 vol) , heated to 50 to 60 °C, and stirred for 1 h.
  • the solution was cooled slowly to 25-30 °C, and stirred at that temperature for 1 h.
  • the resulting solid was collected by filtration, washing with EtOH.
  • the resulting solid was dried for 10 h at 50 °C to 60 °C to afford Compound 7-OH (73%yield; >99%purity) as a white solid.
  • Step 6 To thieno [2, 3-d] pyrimidine-2, 4-diol 11 (100.0 g, 399.6 mmol, 1.0 equiv. ) in a 2 L reactor at room temperature (15-25 °C) was added toluene (400.0 mL, 4 vol. ) , tetraethylammonium chloride (1.5 equiv. ) , and POCl 3 (3.0 equiv. ) . The reaction mixture was heated to 100-110 °C and stirred for 10-14 h. The mixture was cooled to 15-25 °C, added to water (5 vol) slowly at 20-30 °C, and stirred for 1 h.
  • Step 7 To the toluene solution of Compound 12 from Step 6 was added DIPEA (2.0 equiv. ) and Compound 13-Boc (1.0 equiv. ) . The reaction mixture was heated to 70-80 °C and stirred for 12 h (alternately at 60-65 °C) . The reaction mixture was cooled to 15-25 °C and stirred for 4 h. The mixture was diluted with water (4 vol. ) and stirred for 2 h. The mixture was filtered and washed (2x) with toluene/heptane (2: 3, 3 vol) .
  • Step 8 To a high-pressure reactor at 10-30 °C was added TEA (5.0 equiv. ) , followed by Compound 14-Boc (1.0 equiv. ) , and a solution of MeNH 2 (7.0 equiv. ) in EtOH. The resulting mixture was heated to 85 °C (80-90 °C) and stirred for 8 h. The mixture was cooled to 15-25 °Cand treated with EtOH (1 vol. ) , and then with H 2 O (4.5 vol. ) at 10-20 °C over 2 h, and the resulting mixture was stirred for 3 h. The resulting precipitate was isolated by filtration and washed with ACN/H 2 O (1: 1, v/v, 1 vol.
  • the wet cake was diluted with ACN (12 vol) and was stirred for 1 h at 45-55 °C.
  • the solid was filtered, washing with ACN (1 vol) .
  • the combined filtrate was concentrated to ⁇ 9 vol at 40-50 °C under reduced pressure.
  • the mixture was stirred for 1 h at 45-55 °C, then treated with H 2 O (4 vol) at the same temperature over at least 2 h, and stirred for 1 h at 45-55 °C.
  • the mixture was cooled to 10-20 °C and stirred for 10 h.
  • the precipitate was isolated by filtration and washed with ACN/H 2 O (1: 1, 1 vol) .
  • Step 9 To a solution of Compound 15-Boc (1.0 equiv. ) in MeOH (9 vol. ) was added 4 M HCl in MeOH (6.0 equiv. ) . The resulting mixture was stirred at 30-40 °C for 2-4 h. Additional MeOH (6 vol. ) was added and stirring was continued until completion of the reaction. The mixture was concentrated to 10-11 vol. and diluted with MTBE (20 vol. ) . The resulting slurry was aged at 15-25 °C for 10 h, then filtered. The wet solid was washed with MTBE (2 vol. ) and dried under vacuum to give Compound 16-2HCl (Yield, 65-96%; Purity (HPLC) , >99%) .
  • Detected impurities in Compound A as obtained may include one or more of the following:
  • Example 6 Preparation of (S) -4-methyl-5- ( (4- ( (2- (methylamino) -6- (2, 2, 2- trifluoroethyl) thieno [2, 3-d] pyrimidin-4-yl) amino) piperidin-1-yl) methyl) -1- (2- (4- (methylsulfonyl) piperazin-1-yl) propyl) -1H-indole-2-carbonitrile (Compound A)
  • Detected impurities in Compound A as obtained may include one or more of the following:

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Abstract

L'invention concerne des procédés de fabrication de l'inhibiteur de ménine-MLL (S)-4-méthyl-5-((4- ((2- (méthylamino)-6-(2, 2, 2-trifluoroéthyl) thiéno [2, 3-d] pyrimidin-4-yl) amino) pipéridin-1-yl) méthyl)-1-(2- (4- (méthylsulfonyl) pipérazin-1-yl) propyl) -1 H-indole-2-carbonitrile (composé A) et des sels pharmaceutiquement acceptables de celui-ci.
PCT/CN2025/093750 2024-05-10 2025-05-09 Procédé de fabrication d'un inhibiteur de ménine-mll Pending WO2025232874A1 (fr)

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CN2024092390 2024-05-10

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WO2025232874A1 true WO2025232874A1 (fr) 2025-11-13

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