WO2022077154A1 - Synthèse de modulateurs de l'egfr - Google Patents

Synthèse de modulateurs de l'egfr Download PDF

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Publication number
WO2022077154A1
WO2022077154A1 PCT/CN2020/120339 CN2020120339W WO2022077154A1 WO 2022077154 A1 WO2022077154 A1 WO 2022077154A1 CN 2020120339 W CN2020120339 W CN 2020120339W WO 2022077154 A1 WO2022077154 A1 WO 2022077154A1
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Prior art keywords
compound
admixing
reagent
nitrogen
iia
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PCT/CN2020/120339
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English (en)
Inventor
Jason Christopher Rech
Mukesh K Nyati
Fan FANG
Lei Zhang
Julian Paul Henschke
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The Regents Of The University Of Michigan
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Application filed by The Regents Of The University Of Michigan filed Critical The Regents Of The University Of Michigan
Priority to PCT/CN2020/120339 priority Critical patent/WO2022077154A1/fr
Priority to EP21880871.5A priority patent/EP4225304A1/fr
Priority to PCT/US2021/054485 priority patent/WO2022081514A1/fr
Priority to CN202180083317.4A priority patent/CN116997551A/zh
Priority to US18/031,219 priority patent/US20240018144A1/en
Publication of WO2022077154A1 publication Critical patent/WO2022077154A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present disclosure relates to processes for synthesizing 2- ( (3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] deca-1, 3-dien-2-yl) thio) -N- (quinolin-3-yl) acetamide (Compound A) and salts thereof:
  • Compound A is a modulator of EGFR useful in treating or preventing diseases or disorders associated with aberrant EGFR activity, e.g., cancer.
  • TKI small molecule tyrosine kinase inhibitors
  • erlotinib, gefitinib, and afatinib have been most successful as single agents in the treatment of lung adenocarcinomas that have somatic mutations (such as L858R or deletion in exon 19, i.e. E746-A750) that confer sensitivity to this class of drugs, which occur in 7-20%of patients depending on ethnicity and gender.
  • somatic mutations such as L858R or deletion in exon 19, i.e. E746-A750
  • responses rarely last more than a year because virtually all patients develop resistance to therapy.
  • a third-generation irreversible inhibitor, osimertinib (AZD9291) , is effective in treating as well as patients who have acquired resistance to first or second generation TKIs.
  • C797S EGFR kinase domain
  • R is methyl or a nitrogen-protecting group and Z is a halogen or a sulfonate group.
  • R is methyl.
  • R is a nitrogen-protecting group.
  • R is t-butyloxycarbonyl (Boc) , benzyloxycarbonyl (Cbz) , benzyl, or p-methoxybenzyl (PMB) .
  • Z is a sulfonate group.
  • the sulfonate group is triflate, mesylate, tosylate, benzenesulfonate, or nosylate. In some cases, the sulfonate group is triflate.
  • Compound II is synthesized by admixing Compound I and a halogenation reagent.
  • the halogenation reagent is a chlorination reagent.
  • the chlorination reagent comprises oxalyl chloride, SOCl 2 or POCl 3 .
  • Compound II is synthesized by admixing Compound I and a sulfonylation reagent.
  • the sulfonylation reagent is selected from triflic anhydride, mesyl chloride, mesic anhydride, tosyl chloride, tosic anhydride, nosyl chloride, and a perfluoroalkylsulfonic anhydride.
  • the sulfonylation reagent is triflic anhydride.
  • Compound II is synthesized by admixing Compound I and a halogenation or a sulfonylation reagent in an organic solvent. In some cases, Compound II is synthesized by admixing Compound I and a halogenation or a sulfonylation reagent in a mixture of organic solvents. In some cases, Compound II is synthesized by admixing Compound I and a halogenation or a sulfonylation reagent in a mixture of dichloromethane and ethyl acetate.
  • the processes further comprise synthesizing Compound A by (ii) (a) admixing Compound II and Compound III in the presence of a base to form Compound A:
  • X is Br or Cl. In some cases, X is Cl.
  • the processes comprise synthesizing Compound A by admixing Compound II and Compound III in the presence of a base to form Compound A.
  • the base is NaH, NaOH, KOH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide.
  • the processes comprise synthesizing Compound A by (b) (I) admixing Compound II and a nucleophilic sulfuration reagent to form Compound IIA, then (II) admixing Compound IIA with Compound IIIA in the presence of a base to form Compound A.
  • the nucleophilic sulfuration reagent comprises a hydrate of Na 2 S.
  • the nucleophilic sulfuration reagent comprises Na 2 S 4H 2 O.
  • the processes comprise synthesizing Compound A by (b) (I) admixing Compound II and a nucleophilic sulfuration reagent in an organic solvent to form Compound IIA. In some cases, the processes comprise synthesizing Compound A by (b) (I) admixing Compound II and a nucleophilic sulfuration reagent in a mixture of organic solvents to form Compound IIA. In some cases the processes comprise synthesizing Compound A by (b) (I) admixing Compound II and a nucleophilic sulfuration reagent in a mixture of dichloromethane and ethyl acetate to form Compound IIA.
  • the processes comprise synthesizing Compound A by (II) admixing Compound IIA with Compound IIIA in the presence of a base to form Compound A.
  • the base is K 2 CO 3 .
  • the processes comprise synthesizing Compound A by (II) admixing Compound IIA with Compound IIIA in the presence of a base in an organic solvent to form Compound A.
  • the organic solvent is isopropanol.
  • the processes further comprise synthesizing compound A by (iii) optionally, when R is a nitrogen-protecting group, removing the nitrogen-protecting group and methylating the resulting deprotected amine to form Compound A wherein R is methyl.
  • R is a nitrogen-protecting group.
  • step (iii) is performed between steps (ii) (b) (I) and (ii) (b) (II) .
  • the process further comprises removing the nitrogen-protecting group from Compound IIA and methylating the resulting deprotected amine to form Compound IIA wherein R is methyl.
  • removing the nitrogen-protecting group comprises admixing in the presence of acid
  • the deprotected amine is methylated by admixing with NaBH (OAc) 3 , CH 2 O, and acetic acid.
  • processes for synthesizing EGFR modulators and salts thereof are provided herein.
  • processes for synthesizing 2- ( (3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] deca-1, 3-dien-2-yl) thio) -N- (quinolin-3-yl) acetamide (Compound A) and salts thereof are provided:
  • the ’358 application generally describes a procedure for making compounds such as Compound A as shown in Scheme 1, below, which is adapted from the disclosure at paragraph [0090] (General Procedure A) of the ‘358 application.
  • the ’358 application describes that substituted acetamides 7A-G were added to 3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] dec-3-ene-2-thione (labeled as Compound 6) in anhydrous acetonitrile and warmed to 40 °C.
  • the ‘358 application further describes a process for synthesizing intermediate compounds like compound 6 in Scheme 1.
  • Scheme 2, below which is adapted from paragraph [0105] (Examples 15-28) of the ‘358 application, represents the general process of synthesizing substituted 2- (4-bromophenyl) -3-thioxo-1, 4, 8-triazaspiro [4.5] dec-1-ene compounds (e.g., compound 6) as described in the ‘358 application.
  • the process of the ’358 application has several disadvantages for large-scale synthesis.
  • the Lawesson’s reagent used to convert the amide moiety to a thioamide is malodorous and highly moisture-sensitive, and there are potential difficulties in performing the amide to thioamide conversion at the scale of several hundred grams.
  • the process of the ’358 application also employs several column chromatography purification steps, which are impractical for a synthesis at the scale of several hundred grams or larger.
  • the processes described herein avoid the use of Lawesson’s reagent for the preparation of thioamides, and are more practical and higher-yielding.
  • the processes described herein also avoid the necessity of purification by column chromatography.
  • R is methyl or a nitrogen-protecting group and Z is chloride or a sulfonate group
  • the disclosed processes involve formation of 3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] deca-1, 3-diene-2-thioacetamides by the addition of a thiol group to a 3-halo (e.g., 3-chloro) -or 3-sulfonyloxy-1, 4, 8-triazaspiro [4.5] deca-1, 3-diene, or the addition of a chloro-or bromoacetamide to a 1, 4, 8-triazaspiro [4.5] dec-3-ene-2-thione.
  • a thiol group e.g., 3-chloro
  • step (iii) to remove a nitrogen-protecting group for R and replace it with a methyl group for R may precede or follow step (ii) (a) or (ii) (b) .
  • step (iii) can take place between steps (ii) (b) (I) and (ii) (b) (II) .
  • the processes of the disclosure can include synthesizing Precursor V:
  • R is methyl or a nitrogen-protecting group.
  • R is a CD 3 group (i.e., a deuterated methyl group) .
  • Nitrogen-protecting groups are generally known in the art. Nonlimiting examples of nitrogen-protecting groups include carbobenzyloxy (Cbz) groups, acetyl groups, t-butyloxycarbonyl (Boc) groups, and 9-fluorenylmethyloxycarbonyl (Fmoc) groups.
  • an ⁇ -aminoamide (Precursor III) can be reacted with a piperidin-4-one (Precursor IV) to form a substituted 1, 4, 8-triazaspiro [4.5] decan-2-one (Precursor V) :
  • Precursor V is carried out in an organic solvent.
  • Organic solvents are generally known in the art. Nonlimiting examples of organic solvents that can be used throughout the processes described herein include ethyl acetate, acetonitrile, toluene, benzene, xylene, chlorobenzene, fluorobenzene, naphthalene, benzotrifluoride, tetrahydrofuran (THF) , tetrahydropyran, dimethylformamide (DMF) , tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE) , 2-methyltetrahydrofuran (2-MeTHF) , dimethyl sulfoxide (DMSO) , 1, 2-dimethoxyethane (1, 2-DME) , 1, 2-dichloroethane (1, 2-DCE)
  • the formation of Precursor V is carried out in ethanol. In some embodiments, the formation of Precursor V is carried out at elevated temperature. In some embodiments, the formation of Precursor V is carried out at a temperature of 20 °C to 100 °C, for exampl e, at least 20, 30, 40, 50, 60, 70, 80, 90, or 100 °C and/or up to 60, 70, 80, 90, or 100 °C, such as 20 °C to 80 °C, 40 °C to 80 °C, 50°C to 90°C, 60 °C to 80 °C, 75°C to 85°C, or 70 °C to 80 °C. In some embodiments, the formation of Precursor V occurs at a temperature of 80 °C.
  • the processes of the disclosure can include synthesizing Compound I.
  • Precursor V can be oxidized to form Compound I.
  • Compound I is formed via an addition-elimination reaction.
  • Compound I is formed by treating Precursor V with 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) .
  • Compound I is formed by treating Precursor V with an ⁇ -bromination reagent, followed by elimination of an equivalent of HBr.
  • Compound I is formed by treating Precursor V with N-bromosuccinimide (NBS) , followed by heating to form Compound I.
  • NBS N-bromosuccinimide
  • Compound I is formed by treating Precursor V with NBS in the presence of UV light to form Compound I.
  • Compound I is formed by treating Precursor V with NBS in the presence of UV light and with heating to form Compound I.
  • the UV light has a wavelength of 365 nm.
  • Compound I is formed by treating Precursor V with NBS in an organic solvent.
  • Compound I is formed by treating Precursor V with NBS in DCM.
  • Compound I is formed in the presence of a base.
  • Non-limiting examples of bases include alkylamines, such as mono-, di, or trialkylamines (e.g., monoethylamine, diethylamine, triethylamine, and N, N-diisopropylethylamine (DIPEA) ) , pyridines, such as collidine and 4-dimethylaminopyridine (DMAP) , and imidazoles, such as N-methylimidazole, as well as benzylamine, methylbenzylamine, morpholine, piperidine, picoline, dicyclohexylamine, N, N'-dibenzylethylenediamine, 2- hydroxyethylamine, bis- (2-hydroxyethy) amine, tri- (2-hydroxyethyl) amine, procaine, dibenzylpiperidine, dehydroabietylamine, N, N'-bisdehydroabietylamine, glucamine, N-methylglucamine,
  • the base is a trialkylamine (e.g., triethylamine or N, N-diisopropylethylamine (DIPEA) ) , lutidine, collidine, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , CaCO 3 , LiH, NaH, or KH.
  • DIPEA N, N-diisopropylethylamine
  • the formation of Compound I is carried out at elevated temperature.
  • the formation of Compound I is carried out at a temperature of 20 °C to 50 °C, for example, at least 20, 25, 30, 35, 40, 45, or 50 °C and/or up to 20, 25, 30, 35, 40, 45, or 50 °C, such as 20 °Cto 50 °C, 30 °C to 50 °C, 40 °C to 50 °C, or 30 °C to 40 °C.
  • the formation of Compound I occurs at a temperature of 35 °C to 45 °C or 35°C to 40°C. In some embodiments, the formation of Compound I occurs at a temperature of about 40 °C.
  • the processes of the disclosure can include synthesizing Compound II:
  • Z is a halogen or a sulfonate group. In some cases, Z is chloride. In some cases, Z is triflate.
  • Compound I can be admixed with a halogenation reagent or a sulfonylation reagent to form Compound II.
  • Halogenation reagents and sulfonylation reagents are generally known in the art.
  • the halogenation reagent is a chlorination reagent.
  • Nonlimiting examples of chlorination reagents that can be used throughout the processes described herein include SOCl 2 , POCl 3 , Vilsmeier reagents, oxalyl chloride, PCl 5 , SOBr 2 , and POBr 3 .
  • Nonlimiting examples of sulfonylation reagents that can be used throughout the processes described herein include triflic anhydride, mesyl chloride, mesic anhydride, tosyl chloride, tosic anhydride, benzenesulfonyl chloride, benzenesulfonic anhydride, nosyl chloride, and perfluoroalkylsulfonic anhydrides.
  • Compound I is admixed with a halogenation reagent to form Compound II.
  • Compound I is admixed with a chlorination reagent to form Compound II.
  • Compound I is admixed with a sulfonylation reagent to form Compound II.
  • Compound I is admixed with triflic anhydride to form Compound II.
  • Compound II is formed by admixing Compound I with a halogenation or sulfonylation reagent in an organic solvent. In some embodiments, Compound II is formed by admixing Compound I with a halogenation or sulfonylation reagent in DCM. In some embodiments, Compound II is formed by admixing Compound I with a halogenation or sulfonylation reagent in ethyl acetate. In some embodiments, Compound II is formed by admixing Compound I with a halogenation or sulfonylation reagent in a mixture of organic solvents.
  • Compound II is formed by admixing Compound I with a halogenation or sulfonylation reagent in a mixture of DCM and ethyl acetate. In some embodiments, Compound II is formed by admixing Compound I with a chlorination or sulfonylation reagent in an organic solvent. In some embodiments, Compound II is formed by admixing Compound I with a chlorination or sulfonylation reagent in a mixture of organic solvents. In some embodiments, Compound II is formed by admixing Compound I with a chlorination or sulfonylation reagent in a mixture of DCM and ethyl acetate.
  • DCM and ethyl acetate are present in a volume ratio of 2: 1, 1.9: 1, 1.8: 1, 1.7: 1, 1.6: 1, 1.5: 1, 1.4: 1, 1.3: 1, 1.2: 1, 1.1: 1, or 1: 1. In some embodiments, DCM and ethyl acetate are present in a volume ratio of 1.5: 1.
  • Compound II is formed by admixing Compound I with a chlorination or sulfonylation reagent in a mixture of DCM and ethyl acetate in the presence of a base.
  • bases include alkylamines, such as trialkylamines (e.g., triethylamine, or N, N-diisopropylethylamine (DIPEA) ) , pyridines, such as collidine and 4-diethylaminopyridine (DMAP) , and imidazoles, such as N-methylimidazole, as well as dimethylbenzylamine, N-methylmorpholine, N-methylpiperidine, picoline, N-methyldicyclohexylamine, N, N'-dibenzylethylenediamine, tri- (2-hydroxyethyl) amine, procaine, dibenzylpiperidine, dehydroabietylamine, N, N'-bisde
  • the base is a trialkylamine (e.g., triethylamine or N, N-diisopropylethylamine (DIPEA) ) , lutidine, collidine, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , CaCO 3 , LiH, NaH, or KH.
  • the base is a trialkyl amine, or more specifically, comprises triethylamine or DIPEA.
  • Compound II is formed by admixing Compound I with a chlorination or sulfonylation reagent in a mixture of DCM and ethyl acetate in the presence of DIPEA.
  • the base and Compound I are present in a molar ratio of 2: 1, 1.9: 1, 1.8: 1, 1.7: 1, 1.6: 1, 1.5: 1, 1.4: 1, 1.3: 1, 1.2: 1, 1.1: 1, or 1: 1. In some embodiments, the base and Compound I are present in a molar ratio of 1.5: 1. In some embodiments, DIPEA and Compound I are present in a molar ratio of 1.5: 1.
  • Compound II is formed by admixing Compound I with a chlorination or sulfonylation reagent in the presence of di-tert-butyl dicarbonate (Boc 2 O) , and optionally a base as described above. In some embodiments, Compound II is formed by admixing Compound I with a chlorination or sulfonylation reagent in a mixture of DCM and ethyl acetate in the presence of DIPEA and Boc 2 O.
  • Boc 2 O and Compound I are present in a molar ratio of 2: 1, 1.9: 1, 1.8: 1, 1.7: 1, 1.6: 1, 1.5: 1, 1.4: 1, 1.3: 1, 1.2: 1, 1.1: 1, or 1: 1. In some embodiments, Boc 2 O and Compound I are present in a molar ratio of 1: 1.
  • the formation of Compound II is carried out at elevated temperature. In some embodiments, the formation of Compound II is carried out at a temperature of 20 °C to 50 °C, for example, at least 20, 25, 30, 35, 40, 45, or 50 °C and/or up to 20, 25, 30, 35, 40, 45, or 50 °C, such as 20 °C to 50 °C, 30 °C to 50 °C, 40 °C to 50 °C, or 30 °C to 40 °C. In some embodiments, the formation of Compound II occurs at a temperature of 35 °C to 40 °C. In some embodiments, the formation of Compound II occurs at a temperature of 40 °C.
  • Compound I and/or Compound II is present as a salt.
  • a salt of Compound I, Compound II, or any other compound described herein can be prepared, for example, by reacting the compound in its free form with a suitable organic or inorganic acid, and optionally isolating the salt thus formed.
  • Nonlimiting examples of suitable acid salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfonate, camphorsulfonate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate salts, and amino acid salts.
  • the processes of the disclosure can include synthesizing Compound A via reaction of Compound II and Compound III (via step (ii) (a) ) when R is methyl.
  • the same process synthesizes Compound IV when R is a nitrogen-protecting group.
  • the processes of the disclosure can include admixing Compound II and Compound III in the presence of a base to form Compound A either directly or indirectly via Compound IV:
  • the base is LiH, NaH, KH, LDA, KHMDS, NaHMDS, LiHMDS, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, LiOH, KOH, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide.
  • the base is NaH.
  • the base and Compound III are present in a molar ratio of 2: 1, 1.9: 1, 1.8: 1, 1.7: 1, 1.6: 1, 1.5: 1, 1.4: 1, 1.3: 1, 1.2: 1, 1.1: 1, or 1: 1.
  • the base and Compound III are present in a molar ratio of 1: 1.
  • Compound II and Compound III are present in a molar ratio of 2: 1, 1.9: 1, 1.8: 1, 1.7: 1, 1.6: 1, 1.5: 1, 1.4: 1, 1.3: 1, 1.2: 1, 1.1: 1, or 1: 1. In some embodiments, Compound II and Compound III are present in a molar ratio of 1: 1.
  • Compound A is formed by admixing Compound II, Compound III, and a base in an organic solvent.
  • the organic solvent is ethyl acetate, dichloromethane (DCM) , acetonitrile, tetrahydrofuran (THF) , tetrahydropyran, dimethylformamide (DMF) , diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE) , 2-methyltetrahydrofuran (2-MeTHF) , dimethyl sulfoxide (DMSO) , 1, 2-dimethoxyethane (1, 2-DME) , or 1, 4-dioxane, or a combination thereof.
  • the processes of the disclosure can include synthesizing Compound A via formation of Compound IIA then reaction with Compound IIIA (step (ii) (b) ) when R is methyl.
  • the same process synthesizes Compound IV when R is a nitrogen-protecting group.
  • the processes of the disclosure can include admixing Compound II and a nucleophilic sulfuration reagent source to form Compound IIA then admixing Compound IIA with Compound IIIA in the presence of a base to form Compound A either directly or indirectly via Compound IV:
  • the processes of the disclosure can include synthesizing Compound IIA:
  • Compound II can be admixed with a nucleophilic sulfuration reagent to form Compound IIA.
  • Compound IIA is formed by treating Compound II with Na 2 S.
  • Compound IIA is formed by treating Compound II with a hydrate of Na 2 S.
  • Compound IIA is formed by treating Compound II with Na 2 S 4H 2 O.
  • admixing Compound II and a nucleophilic sulfuration reagent occurs in the presence of a phase transfer catalyst.
  • phase transfer catalysts include tetrabutylammonium chloride (TBACl) , tetrabutylammonium bromide (TBAB) , and tetrabutylammonium iodide (TBAI) .
  • TBACl tetrabutylammonium chloride
  • TBAB tetrabutylammonium bromide
  • TBAI tetrabutylammonium iodide
  • the nucleophilic sulfuration reagent and Compound II are present in a molar ratio of 2: 1, 1.9: 1, 1.8: 1, 1.7: 1, 1.6: 1, 1.5: 1, 1.4: 1, 1.3: 1, 1.2: 1, 1.1: 1, or 1: 1.
  • the nucleophilic sulfuration reagent and Compound II are present in a molar ratio of 1.5: 1.
  • Compound IIA is formed by admixing the nucleophilic sulfuration reagent and Compound II in a mixture of organic solvents.
  • Compound IIA is formed by admixing the nucleophilic sulfuration reagent and Compound II in a mixture of DCM and ethyl acetate.
  • DCM and ethyl acetate are present in a volume ratio of 2: 1, 1.9: 1, 1.8: 1, 1.7: 1, 1.6: 1, 1.5: 1, 1.4: 1, 1.3: 1, 1.2: 1, 1.1: 1, or 1: 1.
  • DCM and ethyl acetate are present in a volume ratio of 1.5: 1.
  • the processes of the disclosure can include synthesizing Compound A via step (ii) (b) .
  • the processes of the disclosure can include admixing Compound IIA and Compound IIIA to form Compound A:
  • X is halogen. In some embodiments, X is I, Br, or Cl. In some embodiments, X is Br, or Cl In some embodiments, X is Cl.
  • Compound IIA can be admixed with Compound IIIA to form Compound A.
  • Compound A is formed by admixing Compound IIA and Compound IIIA in the presence of a base.
  • the base is NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, LiOH, or KOH, or a combination thereof.
  • the base comprises K 2 CO 3 .
  • the base is a trialkylamine, pyridine, a pyridine derivative, or combinations thereof.
  • the base is a trialkylamine.
  • the trialkylamine is triethylamine or DIPEA.
  • the base and Compound IIA are present in a molar ratio of 5: 1, 4: 1, 3: 1, 2: 1, or 1: 1.
  • the base and Compound IIA are present in a molar ratio of 2: 1.
  • Compound IIA, Compound IIIA, and a base are admixed in an organic solvent.
  • the organic solvent is ethyl acetate, dichloromethane (DCM) , 2-butanone, acetonitrile, tetrahydrofuran (THF) , tetrahydropyran, dimethylformamide (DMF) , tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE) , 2-methyltetrahydrofuran (2-MeTHF) , dimethyl sulfoxide (DMSO) , 1, 2-dimethoxyethane (1, 2-DME) , 1, 4-dioxane, methanol, ethanol, propanol, or 2-propanol, or a combination thereof.
  • the organic solvent comprises 2-propanol.
  • admixing Compound IIA, Compound IIIA, and the base is carried out at elevated temperature.
  • the temperature is 20 °C to 50 °C, for example, at least 20, 25, 30, 35, 40, 45, or 50 °C and/or up to 20, 25, 30, 35, 40, 45, or 50 °C, such as 20 °C to 50 °C, 30 °C to 50 °C, 40 °C to 50 °C, or 30 °C to 40 °C.
  • the temperatu re is 40 °C to 45 °C. In some embodiments, the temperature is 45 °C.
  • the processes of the disclosure can include removing the nitrogen protecting group of R and methylating the intermediate amine to form Compound A where R is methyl (e.g., via step (iii) ) or form a compound intermediate where R is methyl (Compound II or Compound IIA) .
  • This modification of R from nitrogen protecting group to methyl group can occur for Compound II, Compound IIA, or Compound IV, e.g., can occur before or after any step of the disclosed processes.
  • the processes disclosed comprise converting Compound IV to Compound A.
  • Removal of the nitrogen-protecting group can comprise admixing the compound (e.g., Compound II, Compound IIA, or Compound IV) in the presence of acid.
  • suitable acids include hydrobromic, hydrochloric, sulfuric, sulfonic, phosphoric, nitric, acetic, trifluoroacetic, benzoic, and tosic acid.
  • the acid comprises hydrochloric acid.
  • the acid and compound (Compound II, Compound IIA, or Compound IV) are present in a molar ratio of 20: 1, 15: 1, 12: 1, 11: 1, 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: 1, 3: 1, 2: 1, or 1: 1.
  • the acid and compound (Compound II, Compound IIA, or Compound IV) are present in a molar ratio of 10: 1.
  • removal of the nitrogen protecting group can occur in the presence of an acid and an organic solvent.
  • the organic solvent is dichloromethane (DCM) , chloroform, 1, 2-dichloroethane, ethyl acetate, acetonitrile, tetrahydrofuran (THF) , tetrahydropyran, dimethylformamide (DMF) , tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE) , 2-methyltetrahydrofuran (2-MeTHF) , dimethyl sulfoxide (DMSO) , 1, 2-dimethoxyethane (1, 2-DME) , 1, 4-dioxane, methanol, ethanol, propanol, or 2-propanol, or a combination thereof.
  • the organic solvent comprises methanol.
  • Removal of the nitrogen-protecting group can comprise catalytic hydrogenation of the compound (e.g., Compound II, Compound IIA, or Compound IV) .
  • suitable hydrogenation catalysts include nickel catalysts (e.g., Ni/Al 2 O 3 ) , palladium catalysts (e.g., Pd/C) and platinum catalysts (e.g., Pt/C) .
  • the hydrogenation catalyst is Pd/C.
  • removal of the nitrogen protecting group can occur in the presence of hydrogen gas, a hydrogenation catalysts, and an organic solvent.
  • the organic solvent is dichloromethane (DCM) , chloroform, 1, 2-dichloroethane, tetrahydrofuran (THF) , tetrahydropyran, tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE) , 2-methyltetrahydrofuran (2-MeTHF) , 1, 2-dimethoxyethane (1, 2-DME) , 1, 4-dioxane, methanol, ethanol, propanol, or 2-propanol, or a combination thereof.
  • the organic solvent comprises methanol.
  • removal of the nitrogen protecting group is carried out at ambient temperature.
  • the temperature can be 20 °C to 30 °C, for example, at least 20, 25, or 30 °C and/or up to 20, 25, or 30°C, such as 20 °C, 21 °C, 22 °C, 23 °C, 24 °C, 25 °C, 26 °C, 27 °C, 28 °C, 29 °C, or 30 °C.
  • the temperature is 20 °C to 25 °C. In some embodiments, the temperature is 25 °C.
  • Methylation of the deprotected amine can be performed by admixing the deprotected amine with a methylating agent.
  • the processes comprise admixing the deprotected amine compound derived from Compound II, Compound IIA, or Compound IV with a methylating agent, and a base if required.
  • Nonlimiting examples of suitable methylating agents include methyl iodide, dimethyl sulfate, methyl tosylate, methyl bromide, all in the presence of a suitable base, a combination of NaBH 3 CN, CH 2 O, and acetic acid, a combination of NaBH 4 , CH 2 O, and acetic acid, a combination of NaBH (OAc) 3 , CH 2 O, Et 3 N, a combination of NaBH (OAc) 3 , CH 2 O, and acetic acid, or CH 2 O and H 2 in presence of Ni, Pt, or Pd catalysts.
  • the methylating agent is a combination of NaBH (OAc) 3 , CH 2 O, and acetic acid.
  • the combination of NaBH (OAc) 3 , CH 2 O, and acetic acid is present in a molar ratio of 3: 2: 3 NaBH (OAc) 3 : CH 2 O: acetic acid per mole of deprotected amine derived from Compound II, Compound IIA, or Compound IV.
  • the methylation is carried out at low temperature (e.g., a temperature below room temperature, 25°C) .
  • the temperature is 0 °C to 20 °C, for example, at least 0, 5, 10, 15, or 20 °C and/or up to 0, 5, or 10°C, such as 0 °C, 1 °C, 2 °C, 3 °C, 4 °C, 5 °C, 6 °C, 7 °C, 8 °C, 9 °C, or 10 °C.
  • the temperature is 0 °C to 5 °C. In some embodiments, the temperature is 5 °C.
  • Precursor I (2-amino-2- (4-bromophenyl) acetic acid, 1.75 kg, 7.6 mol, 1.0 eq. ) was charged into a 30 L reactor with methanol (12.3 L, 7 volumes) under nitrogen atmosphere. The nitrogen was purged three times, and the reaction mixture was cooled to 0 °C. To this solution was added SOC l 2 (1.36 kg, 11.4 mol, 1.5 eq. ) dropwise to the solution at 10–20 °C. The reaction was stirred at 10–20 °C for 0.5 h, then warmed to 30–35 °C and stirred for 6 h.
  • Precursor II (1.75 kg, 6.2 mol, 1.0 eq. ) was charged into a 20 L reactor with NH 3 ⁇ H 2 O (28%, 8.8 L, 5 v) . The mixture was stirred at 10-15 °C for 20 h, then filtered and the filter cake washed with water (3.5 L, 2 v) . The filter cake was dried under reduced pressure at 50 °C to obtain Precursor III (2-amino-2- (4-bromophenyl) acetamide) with 96 A%purity in an 85%isolated yield.
  • Precursor V (tert-butyl 2- (4-bromophenyl) -3-oxo-1, 4, 8-triazaspiro [4.5] decane-8-carboxylate) was prepared according to the following reaction scheme:
  • Precursor III (2-amino-2- (4-bromophenyl) acetamide, 500.0 g, 2.18 mol, 1.0 eq)
  • Precursor IV 436.7 g, 2.18 mol, 1.0 eq.
  • EtOH 10 L, 20 v
  • the reaction reactor was purged with N 2 three times, and then the reaction mixture was heated to reflux and stirred for 16 h.
  • the mixture was concentrated to ca. 2 v under reduced pressure at 45 °C, and then water (7 L, 7 v) was added and stirred at 15-20 °C for 0.5 h.
  • Precursor V (tert-butyl 2- (4-bromophenyl) -3-oxo-1, 4, 8-triazaspiro [4.5] decane-8-carboxylate, 1.5 kg, 1.0 eq. ) , Na 2 CO 3 (194 g, 0.5 eq. ) and DCM (15 L, 10 v) were charged into a 30 L reactor, which was purged with N 2 three times and cooled to 0 °C. NBS (651.4 g, 1.0 eq. ) was charged in four portions into the mixture. The reaction was stirred at 30-35 °C for 20 h.
  • reaction mixture was irradiated with UV light at 365 nm for 1 h, then stirred at 30-35 °C for 4 h.
  • To this mixture was added 20 wt%aq. Na 2 CO 3 (7.5 L, 5 v) and (Boc) 2 O (80 g, 0.1 eq. ) and the mixture was stirred for 30 min.
  • the reaction mixture was worked up as follows: The aqueous phase was separated and extracted with DCM (15 L x 2, 10 v x 2) . The organic phase was concentrated to dryness under reduced pressure at 35-40 °C. The product was slurried in EtOH (4.5 L, 3 v) , the mixture was filtered, and the filter cake was dried under reduced pressure at 35-40 °C to give Compound I (tert-butyl 2- (4-bromophenyl) -3-oxo-1, 4, 8-triazaspiro [4.5] dec-1-ene-8-carboxylate) with 96.4%HPLC purity in an 81%isolated yield.
  • the filter cake was dissolved in EtOAc (1.5 L, 5 v) and the solution was washed with aq. Na 2 CO 3 (600 mL, 2 v) .
  • the organic phase was separated and washed with brine (1.5 L, 5 v x 2) , and then the organic phase was dried over Na 2 SO 4 (600 g, 2 w) .
  • the solution was filtered, and the filter cake was washed with EtOAc (300 mL x 2, 1 v x 2) .
  • the filtrate was concentrated under reduced pressure at 45 °C to giv e Compound IIIA (2-chloro-N- (quinolin-3-yl) acetamide) with 98.3%LC purity in a 90%isolated yield.

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Abstract

L'invention concerne des procédés de synthèse de composés utilisables comme modulateurs de l'EGFR. En particulier, l'invention concerne des procédés de synthèse du composé A :
PCT/CN2020/120339 2020-10-12 2020-10-12 Synthèse de modulateurs de l'egfr WO2022077154A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/CN2020/120339 WO2022077154A1 (fr) 2020-10-12 2020-10-12 Synthèse de modulateurs de l'egfr
EP21880871.5A EP4225304A1 (fr) 2020-10-12 2021-10-12 Synthèse de modulateurs de l'egfr
PCT/US2021/054485 WO2022081514A1 (fr) 2020-10-12 2021-10-12 Synthèse de modulateurs de l'egfr
CN202180083317.4A CN116997551A (zh) 2020-10-12 2021-10-12 Egfr调节剂的合成
US18/031,219 US20240018144A1 (en) 2020-10-12 2021-10-12 Synthesis of EGFR Modulators

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014176475A2 (fr) * 2013-04-26 2014-10-30 The Regents Of The University Of Michigan Inhibiteurs des egfr et leurs utilisations
WO2019122268A1 (fr) * 2017-12-21 2019-06-27 Astrazeneca Ab Procédés pour la préparation stéréosélective d'inhibiteurs de bace
WO2019165358A1 (fr) * 2018-02-23 2019-08-29 The Regents Of The University Of Michigan Désintégrateurs de dimères egfr et leurs utilisations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014176475A2 (fr) * 2013-04-26 2014-10-30 The Regents Of The University Of Michigan Inhibiteurs des egfr et leurs utilisations
WO2019122268A1 (fr) * 2017-12-21 2019-06-27 Astrazeneca Ab Procédés pour la préparation stéréosélective d'inhibiteurs de bace
WO2019165358A1 (fr) * 2018-02-23 2019-08-29 The Regents Of The University Of Michigan Désintégrateurs de dimères egfr et leurs utilisations

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