WO2022007502A1 - Fabrication de composés et de compositions pour inhiber shp2 - Google Patents

Fabrication de composés et de compositions pour inhiber shp2 Download PDF

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WO2022007502A1
WO2022007502A1 PCT/CN2021/094139 CN2021094139W WO2022007502A1 WO 2022007502 A1 WO2022007502 A1 WO 2022007502A1 CN 2021094139 W CN2021094139 W CN 2021094139W WO 2022007502 A1 WO2022007502 A1 WO 2022007502A1
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formula
compound
yield
group
protecting group
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PCT/CN2021/094139
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English (en)
Inventor
Zhongbo FEI
Wei Li
Huangchao YU
Huanqing JIA
Jianhua Wang
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Novartis Ag
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Priority to AU2021305970A priority Critical patent/AU2021305970B2/en
Priority to EP21740209.8A priority patent/EP4178962A1/fr
Priority to CA3183946A priority patent/CA3183946A1/fr
Priority to JP2023500286A priority patent/JP2023532748A/ja
Priority to CN202180043650.2A priority patent/CN115916786A/zh
Priority to KR1020237001046A priority patent/KR20230038197A/ko
Priority to IL298350A priority patent/IL298350A/en
Priority to TW110124805A priority patent/TW202216723A/zh
Priority to US18/004,313 priority patent/US20230374029A1/en
Priority to PCT/IB2021/056057 priority patent/WO2022009098A1/fr
Publication of WO2022007502A1 publication Critical patent/WO2022007502A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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 invention relates to a process for the manufacture of a compound capable of inhibiting the activity of SHP2 and intermediates useful therein.
  • the Src Homolgy-2 phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance and migration. SHP2 is involved in signaling through the Ras-mitogen-activated protein kinase, the JAK-STAT or the phosphoinositol 3-kinase-AKT pathways.
  • the Src Homolgy-2 phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance and migration. SHP2 is involved in signaling through the Ras-mitogen-activated protein kinase, the JAK-STAT or the phosphoinositol 3-kinase-AKT pathways.
  • SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2) , a catalytic domain (PTP) , and a C-terminal tail.
  • the two SH2 domains control the subcellular localization and functional regulation of SHP2.
  • the molecule exists in an inactive, self-inhibited conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. Stimulation by, for example, cytokines or growth factors leads to exposure of the catalytic site resulting in enzymatic activation of SHP2.
  • SHP2 Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human diseases, such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. SHP2, therefore, represents a highly attractive target for the development of novel therapies for the treatment of various diseases.
  • the compound that can be manufactured according to the present invention fulfills the need of small molecules to that inhibit the activity of SHP2.
  • WO 2020/065452 A1 describes three methods for the manufacture of the compound of the formula I which can be characterized by the following reaction schemes (for further details see WO 2020/065452 A1) :
  • the HCl salt compound A17 (equivalent to B10, C10 and D10) is then converted into the compound of the formula I as follows:
  • the compound Z17a is made according to the following route (variant (iii) ) :
  • the present invention overcomes both the large quantities of material requirement and the thermo safety risk by manufacturing B4 using a new intermediate B3’ with a chemical structure uniquely distinct from B3 and C3.
  • a further improvement of the synthesis of the compound of formula I disclosed in WO 2020/065452 A1 relates to the variant (i) for the manufacture of the compound Y7c (above) .
  • the anhydrous Na 2 S used in this reaction is pyrophoric and not commercially available in large scale.
  • the use of the tetrabutylammonium salt required for work-up is poorly biodegradable.
  • the present invention provides a method for the manufacture of a compound of Formula I as mentioned above, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof.
  • the present invention provides a method for the manufacture of a compound of Formula I as mentioned above, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof (these varaints are also included where subsequently only a compound of the formula I is referred to) , said method comprising reacting a compound of the formula II with a compound of the formula III according to the following reaction scheme:
  • LG is a leaving group, especially chloro
  • A is the anion of a protic acid, especially a Cl anion
  • n, m and p are integers, preferably 1, 2 or 3, so that the salt of the formula II is electrically neutral, preferably m is 1, n is 1 and p is 2; where the compound of the formula II is preferably obtained either (i) by deprotecting or (ii) by reducing a compound of the formula IV:
  • R 1 is a secondary amino protecting group (meaning a protecting group protecting secondary amino) , especially tert-butoxycarbonyl, and R 2 is a protected amino group, especially acetylamino or tert-butoxycarbonylamino, and R 3 is hydrogen, or in case (ii) R 1 is a secondary amino protecting group, preferably tert-butoxycarbonyl, R 2 is amino and R 3 is hydroxyl, and if required (that is, if the acid is not already present for example due to the deprotection) reacting the resulting compound of the formula II*:
  • the manufacturing of a compound of the formula II in a first step preferably followed by the further steps defined by further invention embodiments defined below, comprises reacting a compound of the formula V:
  • R 1 is a secondary amino protecting group, especially tert-butoxycarbonyl
  • R 4 is a carboxyl (-COOH) protecting group, especially alkyl, such as ethyl, in the presence of a strong base with L-lactide of the formula:
  • R 1 is as defined for a compound of the formula IV and R 5 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl, especially ethyl.
  • a compound of the formula VI as just described is cyclized with hydroxylamine, or a salt thereof, to yield a hydroxylamine compound of the formula VII, respectively:
  • R 1 is as defined for a compound of the formula IV.
  • a compound of the formula VII is either (a-i) hydrogenated to yield an amino compound of the formula VIII:
  • R 1 is as defined for a compound of the formula IV, or (a-ii) acylated (with an amino protecting group inserting agent, e.g. an acetic anhydride or di-tertbutyl dicarbonate) under reducing conditions to yield a compound of the formula VIII*:
  • an amino protecting group inserting agent e.g. an acetic anhydride or di-tertbutyl dicarbonate
  • a compound of the formula VIII is either (b-i) reduced to yield a compound of the formula IX:
  • R 1 is as defined for a compound of the formula IV, preferably tert-butoxycarbonyl, which compound is a compound of the formula IV wherein R 1 is a secondary amino protecting group, especially tert-butyoxycarbonyl, R 2 is amino and R 3 is hydroxyl;
  • the reducing step (ii) mentioned for a compound of the corresponding formula IV above falling under the definition of the compound of formula IX is preferably in a further step, conducted using a trialkylsilane, to yield, after subsequent addition of an acid of the formula H n A as defined above, especially HCl, a compound of the formula II as described above;
  • the compound of the formula VIII is, as a further invention embodiment, in a further step reacted with an amino protecting group inserting compound, especially (Boc) 2 O, to yield a compound of the formula X:
  • R 1 is as defined for a compound of the formula IV and R 2 is a protected amino group, especially tert-butoxycarbonylamino, which compound of formula X is, preferably in a further step, reduced to a compound of the formula XI:
  • R 1 is as defined for a compound of the formula IV and R 2 is a protected amino group, especially tert-butoxycarbonylamino; which compound of formula XI, preferably in a further step, is reacted at the hydroxy of the hydroxymethyl group (directly bound to the ring) with a leaving group forming agent of the formula LG*-X in which LG*is an electrophilic radical capable, with the hydroxy to which it is bound, of forming a leaving group LG2, especially tosyloxy or preferably 2, 4, 6-triisopropylbenzenesulfonyl) oxy, and X is halogen, especially chloro, to yield a compound of the formula XII:
  • R 1 is as defined for a compound of the formula IV
  • R 2 is a protected amino group, especially tert-butoxycarbonylamino
  • LG2 is a leaving group, especially tosyloxy or preferably 2, 4, 6-triisopropylbenzenesulfonyl) oxy;
  • R 1 is a secondary amino protecting group, especially tert-butoxycarbonyl
  • R 2 is a protected amino group, especially tert-butoxycarbonylamino, which is a compound of the formula IV wherein R 1 is a secondary amino protecting group, especially tert-butyoxycarbonyl, and R 2 is a protected amino group, especially tert-butoxycarbonylamino, and R 3 is hydrogen
  • the deprotecting step (i) mentioned for a compound of the corresponding formula IV above of the compound of formula XIII is preferably, in a further invention embodiment, in a further step conducted using an acid H n A as defined for a compound of the formula II to yield a compound of the formula II as described above.
  • a compound of the formula VIII* is in a further reaction (b-ii) hydrogenated in the presence of a chiral hydrogenation catalyst to yield a compound of the formula X*:
  • R 1 is as defined for a compound of the formula IV and *R 2 is an acylated amino group, especially acetylamino, which compound of formula X*is, in a further invention embodiment, in a further step reduced to a compound of the formula XI*:
  • R 1 is as defined for a compound of the formula IV and *R 2 is an acylated amino group, especially acetylamino;
  • R 1 is as defined for a compound of the formula IV, R 2 is a protected amino group, especially acetylamino, and LG2 is a leaving group, especially tosyloxy;
  • R 1 is a secondary amino protecting group, especially tert-butoxycarbonyl
  • the deprotecting step (i) mentioned for a compound of the corresponding formula IV above (where deprotecting here means deacylating) of the compound of formula XIII* is preferably, in a further invention embodiment, in a further step conducted using an acid H n A as defined for a compound of the formula II to yield a compound of the formula II as described above.
  • R 1 is as defined for a compound of the formula IV, especially tert-butoxycarbonyl, and R 5 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl, especially ethyl; or a salt thereof.
  • a further embodiment of the present invention both as separate invention embodiment or as part of the overall synthesis of a compound of the formula (III) and/or the synthesis of a compound of the formula (I) , relates to a new method of manufacture (synthesis) of the intermediate of the formula (III)
  • LG is a leaving group, comprising reacting a compound of the formula (XV) ,
  • LG is a leaving group and Mt is (then especially with regard to charge relatively half an atom of metal per sulfur) is an earth alkaline metal or (preferably) (then especially in the ratio of one Mt to one S) an alkaline metal atom, with a compound of the formula (XVI) ,
  • the reaction of a compound II with a compound of the formula III, wherein LG is a leaving group, preferably halo, especially bromo or more especially chloro, preferably takes place in the presence of a weak base, such as an alkali metal carbonate or metal-hydrogen-carbonate, in a mixed solvent composed of aprotic solvent, such as an N, N-Dialkylamide of an alkanoic acid, for example dimethal acetamide or dimethyl formamide, and water, or in a mixed solvent composed of aprotic solvent such as sulfolane, and alcoholic solvent such as isopropanol, and water, at preferably elevated temperatures, for example in the range from 30 °C to the boiling point of the reaction mixtures, for example from 50 to 100 °C.
  • a weak base such as an alkali metal carbonate or metal-hydrogen-carbonate
  • a mixed solvent composed of aprotic solvent such as an N, N-Dialkylamide of an alkanoic acid, for
  • the deprotecting (i) of a compound of the formula IV wherein R 1 is a secondary amino protecting group and R 2 is a protected amino group and R 3 is hydrogen to yield a compound of the formula II preferably takes place in the presence of a strong acid H n A, such as trifluoroacetic acid, trifluoromethane sulfonic acid or preferably an inorganic acid, for example sulfuric acid, phosphoric acid or especially a hydrogen halide, most especially hydrogen chloride, in a solvent, for example an alcohol, such as ethanol or especially methanol, or a mixture of alcohols (especially if R 2 is a benzyloxycarbonyl or especially alkoxycarbonyl, such as tert-butoxycarbonyl) , , or in an ester solvent such as isopropyl acetate (IPAc, ) or in the presence of water (especially if R 2 is an acyl, especially lower alkanoyl, for example acetyl) at preferred temperatures in the range from
  • the reaction of the compound of the formula V with L-Lactide to yield a compound of the formula VI preferably takes place in the presence of a strong base, especially an alkyl-alkaline metals, such as n-butyllithium, and a nitrogen base, especially di-isopropylamine or diethylamine, in a solvent, such as an acyclic or especially cyclic ether, especially tetrahydrofuran or preferably 2-methyltetrahydrofuran, at preferably low temperatures, for example in the range from -80 to -5 °C.
  • a strong base especially an alkyl-alkaline metals, such as n-butyllithium, and a nitrogen base, especially di-isopropylamine or diethylamine
  • a solvent such as an acyclic or especially cyclic ether, especially tetrahydrofuran or preferably 2-methyltetrahydrofuran, at preferably low temperatures, for example in the range from -80 to
  • the reaction is conducted nearer to -80 to -40°C, especially in the range from -60 to -50 °C, and preferably if the amount of the compound of L-lactide (the L form of the lactide) corresponds to 30 to 70 mol percent, preferably 45 to 65 mol %, more preferably 50 to 60 mol %, in relation to the mol amount of the compound of formula V, that is, roughly about half of the molar amount of the compound of formula V, the result is a compound of the formula VI.
  • Mol % refers to mole percent.
  • the cyclization of a compound of the formula VI with hydroxylamine, or a salt thereof, to the compound of the formula VII preferably takes place with an acid addition salt of hydroxylamine, for example a hydrogen halide salt thereof, such as the hydrochloride salt thereof, in the presence of a weak base, for example an alkali metal alkanoate, such as sodium acetate, in solvent, for example an acyclic or especially cyclic ether, especially tetrahydrofuran or preferably 2-methyltetrahydrofuran, at preferred temperatures in the range from 0 to 80 °C, for example from 10 to 50 °C.
  • an acid addition salt of hydroxylamine for example a hydrogen halide salt thereof, such as the hydrochloride salt thereof
  • a weak base for example an alkali metal alkanoate, such as sodium acetate
  • solvent for example an acyclic or especially cyclic ether, especially tetrahydrofuran or preferably 2-methyltetrahydrofuran
  • the hydrogenation (a-i) of the hydroxylamine compound of the formula VII to the corresponding amine of the formula VIII preferably takes place as heterogeneous hydroge-nation in the presence of a hydrogenation catalyst, for example platinum, palladium, rhodium, or ruthenium or other highly active catalysts, which operate at lower temperatures (for example from 0 to 40 °C) and lower pressures (for example, 1 bar) of H 2 , or non-precious metal catalysts, especially those based on nickel (such as Raney nickel and Urushibara nickel) at elevated temperatures and higher H 2 pressure, for example in the range from 5 to 50 bar, such as from 10 to 20 bar.
  • a hydrogenation catalyst for example platinum, palladium, rhodium, or ruthenium or other highly active catalysts, which operate at lower temperatures (for example from 0 to 40 °C) and lower pressures (for example, 1 bar) of H 2 , or non-precious metal catalysts, especially those based on nickel (such
  • the acylation (a-ii) of the hydroxyl compound of the formula VII under reducing conditions to the compound of the formula VIII* preferably takes place in the presence of an acylating agent, especially an anhydride of a carboxylic acid, such as an alkanoic acid anhydride, especially acetanhydride, in the presence of an ignoble metal, such as zinc (for example as zinc amalgam) or especially iron, and an acid, either an inorganic acid, such as a hydrogen halogenide, for example hydrogen chloride, sulfuric acid or an organic acid, such as the carboxylic acid corresponding to the anhydride, especially an alkanoic acid, especially acetic acid, as reductant, in an inert organic solvent, such as a hydrocarbon or an aromatic compound, for example toluene or xylylene, at preferably elevated temperatures in the range from 25 °C to the boiling point of the reaction mixture, for example in the range from 40 to 80 °C.
  • an acylating agent especially an anhydride
  • the reduction (b-i) of a compound of the formula VIII to a compound of the formula IX preferably takes place with a complex hydride reducing the oxo in formula VIII to the hydroxy in formula IX, such as diisobutylaluminium hydride, in an aprotic solvent, such as an ether or especially a cyclic ether, such as tetrahydrofurane, at preferably low temperatures in the range from -100 to -20 °C, for example from -80 to -70 °C.
  • a complex hydride reducing the oxo in formula VIII to the hydroxy in formula IX
  • an aprotic solvent such as an ether or especially a cyclic ether, such as tetrahydrofurane
  • the reduction preferably takes place with a trialkylsilane, especially triethylsilane, in an acid, especially a strong organic sulfonic acid, such as trifluoromethane sulfonic acid, in an aprotic solvent, such as a hydrocarbon, an ester or especially a nitrile, such as acetonitrile, at preferably elevated temperatures in the range from 30 °C to the boiling point of the reaction mixture, for example from 50 to 95 °C.
  • the subsequent reaction with the acid H n A preferably takes place in a protic, potentially aqueous solvent, such as isopropyl alcohol.
  • the reducing of a compound of the formula X to a compound of the formula XI preferably takes place in the presence of a complex hydride capable of reducing the lactone group in formula X to the open ring in formula XI with two hydroxy groups, such as lithium boro-hydride and/or sodium borohydride, in an aprotic solvent, such as a linear or preferably a cyclic ether, for example tetrahydrofurane or 2-methyl tetrahydrofurane, preferably at a temperature in the range from 0 to 50 °C, for example at 20 to 40 °C.
  • a complex hydride capable of reducing the lactone group in formula X to the open ring in formula XI with two hydroxy groups, such as lithium boro-hydride and/or sodium borohydride
  • an aprotic solvent such as a linear or preferably a cyclic ether, for example tetrahydrofurane or 2-methyl tetrahydrofur
  • the reaction of a compound of the formula XI, leading to introduction of a leaving group of the formula LG2, with a leaving group forming agent LG*-X in which X is halogen, especially chloro, LG*is an electrophilic radical capable, with the hydroxy to which it is bound, of forming a leaving group LG2, especially a sulfonylhalogenide, preferably toluolsolfo-nylchloride or more preferably 2, 4, 6-triisopropylbenzenesulfonyl chloride, to yield a compound of the formula XII preferably takes place in the presence of a base, such as an alkali metal hydroxide, for example sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, or in an ether or especially a cyclic ether, such as tetrahydrofurane, at preferred temperatures in the range fom -10 to 50 °C, for example
  • phase transfer catalyst for example a tetraalkylammonium halogenide, such as tetra-n-butylammoniumbromide, in the presence of a base, especially an alkali metal hydroxide, such as sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, or in an ether or especially a cyclic ether, such as tetrahydrofurane at preferred temperatures in the range fom 0 to 50 °C, for example from 20 to 30 °C.
  • a phase transfer catalyst for example a tetraalkylammonium halogenide, such as tetra-n-butylammoniumbromide
  • a base especially an alkali metal hydroxide, such as sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, or in an ether or especially a
  • the deprotection of a compound of the formula XIII preferably takes place with the acid H n A which is part of the salt of the resulting formula II in a polar solvent, such as an alcohol, for example an alkanol, such as ethanol or especially methanol, or in a ester solvent such as IPAc, at preferred temperatures in the range from 0 to 50 °C, for example at 20 to 30 °C.
  • a polar solvent such as an alcohol, for example an alkanol, such as ethanol or especially methanol
  • IPAc ester solvent
  • the hydrogenation of a compound of the formula VIII*to a compound of the formula X*in the presence of a chiral hydrogenation catalyst preferably takes place with hydrogen under elevated pressure, for example in the range of from 3 to 50 bar, such as 20 to 40 bar, in a polar solvent, especially and 2, 2, 2-trifluoroethanol, at temperatures preferably ranging from 30 to 80 °C, for example from 40 to 60°C.
  • a chiral hydrogenation catalyst usually formed from a precatalyst, for example on Ruthenium (I) basis, such as Bis (norbornadiene) rhodium (I) tetrafluoroborate and a chiral ligand
  • This hydrogenation more generally takes place with hydrogen in the presence of a transition metal catalyst, preferably in the presence of a transition metal catalyst comprising an organometallic complex and a chiral ligand.
  • the reduction may occur under hetero- or homogeneous hydrogenation conditions, preferably under homogeneous hydrogenation conditions.
  • the transition metal is selected from group 9 or 10 of the periodic table. Therefore, the transition metal catalyst comprises, for example, Cobalt (Co) , Rhodium (Rh) , Iridium (Ir) , Nickel (Ni) , Palladium (Pd) and/or Platinum (Pt) .
  • the chiral catalysts all those allowing the hydrogenation of the double bond in the compound of formula VIII*to yield the configuration at the former double bond shown in formula X*are appropriate. It is further preferred that the chiral ligand comprises a chiral ferrocene.
  • a preferred chiral ferrocene has the formula:
  • the active catalyst is formed by mixing 0.9 to 1.2, preferably 1.0 to 1.1, more preferably 1.0 to 1.05 mole of chiral ligand with 1.0 mole of transition metal atoms comprised in the transition metal catalyst.
  • the active catalyst is formed by mixing 0.9 to 1.2, preferably 1.0 to 1.1, more preferably 1.0 to 1.05 mole of chiral ligand with 1.0 mole of transition metal atoms comprised in the transition metal catalyst.
  • a dimer transition metal catalyst is employed, preferably two moles of chiral ligand are reacted with one mole of transition metal catalyst in order to form the "active catalyst" .
  • the chiral ligand is typically added to the reaction mixture in a solution prepared with the same solvent used for the reaction.
  • the reduction of a compound of the formula X*to a compound of the formula XI*under ring opening preferably takes place in the presence of a complex hydride capable of reducing the lactone group in formula X to the open ring in formula XI with two hydroxy groups, such as lithium borohydride, in an aprotic solvent, such as a linear or preferably a cyclic ether, for example tetrahydrofurane, preferably at a temperature in the range from 0 to 50 °C, for example at 20 to 30 °C.
  • a complex hydride capable of reducing the lactone group in formula X to the open ring in formula XI with two hydroxy groups
  • an aprotic solvent such as a linear or preferably a cyclic ether, for example tetrahydrofurane
  • Amino protecting groups are preferably groups that can be cleaved by not too harsh acidic conditions, for example in the presence of a hydrogen halogenide, such as HCl, or in the case where a compound of formula II is the direct reaction product, an acid of the formula H n A as defined for a compound of the formula II, especially wherein n is 1 and A is a halogenide anion, especially a chloride anion.
  • a hydrogen halogenide such as HCl
  • an acid of the formula H n A as defined for a compound of the formula II especially wherein n is 1 and A is a halogenide anion, especially a chloride anion.
  • acyl groups especially alkanoyl groups, e.g. with 2 to 10 carbon atoms, such as acetyl, are also appropriate amino protecting groups.
  • phase transfer catalyst for example a tetraalkylammonium halogenide, such as tetra-n-butylammoniumbromide, in the presence of a base, especially an alkali metal hydroxide, such as sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, at preferred temperatures in the range fom 0 to 50 °C, for example from 20 to 30 °C.
  • a phase transfer catalyst for example a tetraalkylammonium halogenide, such as tetra-n-butylammoniumbromide
  • base especially an alkali metal hydroxide, such as sodium hydroxide
  • aqueous organic solvent such as an aqueous halogenated hydrocarbon, for example dichloromethane
  • the deprotection of a compound of the formula XIII* preferably takes place with the acid H n A which is part of the salt of the resulting formula II in a polar solvent, such as an alcohol, for example an alkanol, such as ethanol or especially methanol, at preferably elevated temperatures in the range from 50 to 120 °C, for example at 100 to 115 °C.
  • a polar solvent such as an alcohol, for example an alkanol, such as ethanol or especially methanol
  • the compound of the formula III can be obtained as described in WO 2020/065452 A1. Preferably, however, it can be prepared as follows:
  • LG is a leaving group as defined for a compound of the formula III, especially halo, more preferably iodo, bromo or in particular chloro, with a metal thiosulfate salt (which may be a hydrate or not) , especially an alkaline metal or earth alkaline metal thiosulfate salt, more preferably an alkaline metal thiosulfate, most preferably with sodium thiosulfate, in the presence of an acid in an appropriate solvent, followed by treatment with an aqueous base, to yield a compound of the formula XV:
  • Mt is (then with regard to charge relatively half an atom of metal per sulfur) an earth alkaline metal or preferably (then in the ratio of one Mt to the one S) an alkaline metal atom, especially a sodium atom, and LG is a leaving group as just defined.
  • This reaction preferably takes place in an appropriate solvent, such as an aqueous alcohol, for example methanol or ethanol in mixture with water, in the presence of an acid, such as an inorganic acid, for example phosphoric acid and/or sodium dihydrogen phosphate, or preferably an organic acid, such as a sulfonic acid or more preferably of a strong carboxylic acid, e.g. a trihaloacetic acid, such as trifluoroacetic acid, or especially a carboxylic acid carrying more than one carboxyl (-COOH) group, e.g.
  • an appropriate solvent such as an aqueous alcohol, for example methanol or ethanol in mixture with water
  • an acid such as an inorganic acid, for example phosphoric acid and/or sodium dihydrogen phosphate
  • an organic acid such as a sulfonic acid or more preferably of a strong carboxylic acid, e.g. a trihaloacetic acid, such as trifluoroacetic acid, or especially
  • citric acid which generates less waste than phosphate buffer 85%H 3 PO 4 /NaH 2 PO 4
  • temperatures in the range from 20 °C to the boiling temperature of the reaction mixture preferably at a temperature in the range from 20 to 100 °C, most preferably in the range form 50 to 90 °C, e.g. at about 85 °C.
  • LG is a leaving group, especially as defined above for a compound of the formula III, most especially chloro.
  • the reaction preferably takes place in the presence of a noble metal complex, especially formed from Pd 2 (dbba) 2 , in the presence of a ligand, such as Xantphos, and of a tertiary nitrogen base, such as diisopropylamine, in an aprotic solvent, such as an ether, for example a cyclic ether, especially dioxane, at preferably elevated temperatures, for example in the range from 30 °C to the bolining point of the reaction mixture.
  • a noble metal complex especially formed from Pd 2 (dbba) 2
  • a ligand such as Xantphos
  • a tertiary nitrogen base such as diisopropylamine
  • an aprotic solvent such as an ether, for example a cyclic ether, especially dioxane
  • the reaction can be conducted under Ullmann type reaction conditions e.g. with copper salt such as copper (I) iodide and diamine ligand such as
  • aqueous alcohol such as aqueous methanol, ethanol, propanol or especially isopropanol
  • aqueous methanol, ethanol, propanol or especially isopropanol at preferred temperatures in the range from 25 to 100 °C, e.g. at 50 to 75 °C.
  • an aqueous alcohol such as aqueous methanol, ethanol, propanol or especially isopropanol
  • an acid such as an inorganic acid, for example phosphoric acid and/or sodium dihydrogen phosphate
  • an organic acid such as an acetic acid or more preferably of a strong carboxylic acid, e.g. a trihaloacetic acid, such as trifluoroacetic acid, or especially a carboxylic acid carrying more than one carboxyl (-COOH) group, e.g.
  • citric acid which has the additional advantage of generating less waste than phosphate buffer 85%H 3 PO 4 /NaH 2 PO 4 )
  • temperatures in the range from 20 °C to the boiling temperature of the reaction mixture preferably at a temperature in the range from 20 to 100 °C, most preferably in the range form 60 to 80 °C.
  • the present variant is highly advantageous especially in larger scale synthesis, e.g. in the more than 1 kg scale.
  • this variant (iv) is characterized by the following reaction scheme:
  • the new reaction is part of the overall manufacture of a compound of the formula (III) with the preceding reaction steps as described herein, especially part of the overall manufacture of the compound of the formula (I) including this particular variant of the manufacture of a compound of the formula (III) as described herein.
  • the compound of formula XVI can preferably be obtained by reacting a compound of the formula XVII:
  • This reaction preferably takes place in the presence of a strong base, especially an alkyl-alkaline metal, such as n-butylllithium, and a nitrogen base, especially di-isopropylamine or diethylamine, in a solvent, such as an acyclic or especially cyclic ether, preferably tetrahyro-furane, at preferably low temperatures, for example in the range from -80 to -5 °C.
  • a strong base especially an alkyl-alkaline metal, such as n-butylllithium, and a nitrogen base, especially di-isopropylamine or diethylamine
  • a solvent such as an acyclic or especially cyclic ether, preferably tetrahyro-furane
  • This reaction then preferably takes place in the presence of free ammonia and an inert polar solvent, such as DMSO, especially at elevated temperatures, preferably in the range from 30 °C to the boiling point of the reaction mixture, for example at 85 to 95 °C.
  • an inert polar solvent such as DMSO
  • Another embodiment of the invention comprises the manufacture of a compound of the formula II and a compound of the formula III as described above, namely a method for the manufacture of a compound of Formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof, said method comprising reacting a compound of formula II with a compound of formula III according to the following reaction scheme:
  • LG is a leaving group
  • A is the anion of a protic acid
  • n, m and p are independently 1, 2 or 3, so that the salt of the formula II is electrically neutral.
  • Unsubstituted (preferred) or substituted alkyl where mentioned is especially C 1 -C 20 -alkyl, preferably C 1 -C 8 -alkyl, and may be linear or branched; preferred are methyl, ethyl, propyl, isopropyl, n-butyl, sec. -butyl or tert-butyl.
  • Unsubstituted (preferred) or substituted cycloalkyl especially refers to a saturated ring having 3 to 20 ring carbon atoms, especially to C 3 -C 8 -cycloalkyl, such as cyclopentyl, cyclohexyl of cycloheptyl.
  • Unsubstituted or substituted aryl especially refers to C 6 -C 22 -aryl, especially phenyl, naphthyl or fluorenyl.
  • substituted preferably refers to substitution with one or more substituents the skilled person knows not to interfere with any of the described reaction, especially moieties selected from C 1 -C 8 -alkoxy, C 1 -C 8 -alkanoyloxy, hydroxyl, carboxy, C 1 -C 8 -alkoxycarbonyl, or (especially in the case of substituted alkyl) phenyl, naphthyl or fluorenyloxymethyl.
  • Step a also a preferred invention embodiment on its own:
  • Step b (also a preferred invention embodiment on its own):
  • Step a and step b together in their sequential arrangement also represent a preferred invention embodiment.
  • Step f
  • Step a and step b are identical to Step a and step b:
  • the suspension was filtered through microcrystalline cellulo se to remove solid residue, which was then washed with EtOAc (150 mL ⁇ 2) .
  • the combined filtrates were cooled in an ice-water bath and washed with 5 wt%NaHCO 3 (300 mL) and 20 wt%brine (300 mL) .
  • the organic layer was separated, dried over Na 2 SO 4 and filtered.
  • the filtrate was evaporated to dryness.
  • Step f
  • n-Bu 4 NBr (65 mg, 0.202 mmol) was added followed by NaOH (94 mg, 2.35 mmol) in water (2.0 mL) . The mixture was then stirred for 16 hrs at 20-25 °C. The organic layer was separated, washed with 20 wt%brine (5 mL) , dried over Na 2 SO 4 and filtered. The filtrate was evaporated to dryness to give C9 as a white solid (500 mg, 81%) .
  • Step g
  • Step a and step b are identical to Step a and step b:
  • Step f
  • n-Bu 4 NBr (9.1 mg, 0.028 mmol) was added followed by NaOH (14 mg, 0.34 mmol) in water (1.0 mL) . The mixture was then stirred for 16 hrs at 20-25 °C. The organic layer was separated, washed with 20 wt%brine (2 mL) , dried over Na 2 SO 4 and filtered. The filtrate was evaporated to dryness to give D9 as a colorless oil (45 mg, 43%) .
  • HRMS m/z calcd for C 19 H 35 N 2 O 5 [M+H] + 371.2540, found 371.2533.
  • Step g
  • Step a and Step b are conducted as desccribed in Example 1, Route ALFA.
  • the mixture was heated to 65 ⁇ 75 °C and a clear solution was obtained.
  • the solution was cooled to 50 ⁇ 60 °C, and stirred for 1.5 h.
  • n-Heptane (3 V) was added dropwise to the solution.
  • the mixture was stirred for 1 h, cooled to 25 ⁇ 35 °C and stirred for additional 1 h.
  • n-heptane (3.5 V) was added dropwise to the mixture.
  • the mixture was cooled to 15 ⁇ 25 °C, stirred for 6 h, and filtered.
  • Step f
  • Step g
  • Step a for variants A and B: _2, 3, 5-trichloropyrazine (70.50 g, 384.36 mmol, 1 equiv) and ammonia solution (25%wt, 364.00 g, 400 mL, 2.68 mol, 6.14 equiv) were added to a 1-L sealed reactor. The mixture was heated to 80 °C and stirred for 24 h, and the reaction was completed. The reaction mixture was cooled to 30 °C and filtered to give a brown filter cake. The brown filter cake was dissolved in acetone (50 mL) , and filtered. To the filtrate was added petroleum ether (300 mL) .
  • Step b for variants A and B (also a preferred invention embodiment on its own):
  • Step c (for variants A and B) :
  • n-BuLi (2M, 7.6 L) was added dropwise to a solution of 3-chloro-2-fluoropyridine (2 kg) in THF (15 L) at -78°C. Then the resultant mixture was stirred for 1h. Then a solution of I 2 (4.82 kg) in THF (6 L) was added dropwise. After addition, the reaction mixture was stirred for 30 min, and then quenched with sat. Na 2 SO 3 (10 L) , and warmed to 20-25°C. Phase was separated. The aqueous phase was extracted with EA (2 x 10 L) . The combined organic phase was washed with sat.
  • Step d (for variants A and B) :
  • Y7c water solution (82.3 g, 12.2 wt%, 54.5 mmol) , water (80 mL) and IPA (150 mL) .
  • the brown solution was degassed with nitrogen for 5 min.
  • Citric acid monohydrate (2.29 g, 10.9 mmol) was added with stirring to get a yellow suspension.
  • Y7b (16.6 g, 65.4 mmol) , CuI (207 mg, 1.1 mmol) and 1,10-phenanthroline (393 mg, 2.2 mmol) was added subsequently.
  • the mixture was heated to 50 °C and stirred for 5 h, then the temperature was raised to 75 °C over 3 h.
  • Step f (for variant B only) :
  • the cake was washed with EA (25L) .
  • the filtrate was extracted with EA (4 x 20 L) .
  • the organic phase was concentrated in vacuum to offer the crude product which was combined with the cake.
  • DCM 60 L was added to the crude product and stirred at 25-30°C for 18h and then filtered.
  • the filter cake was slurried with CH 2 Cl 2 (30 L) for 4 hrs and filtered.
  • the filter cake was slurred in CH 2 Cl 2 (30 L) for 16 hrs and filtered. Then the filter cake was dried in vacuum to give Z17a (9.1 kg, 84 %) as light yellow solid.
  • the filter cake was washed with a mixed solvent of THF/water (75 mL/75 mL) and transferred to another reactor. THF (750 mL) and water (75 mL) was added, and the mixture was stirred at 65 °C for 1 h. The mixture was then cooled to 25 °C and filtered through MCC. MCC was rinsed with a mixed solvent of THF/water (60 mL/6 mL) and the filtrate was concentrated to give a residue of 420 g. The residue was stirred at 65 °C for 0.5 h, water (450 g) was added dropwise over 2 h, the resulting suspension was cooled to 10 °C over 2 h and stirred at this temperature for 1 h.

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Abstract

L'invention concerne un procédé de fabrication d'un composé de formule (I) ou un sel pharmaceutiquement acceptable, un co-cristal d'acide, un hydrate ou un autre solvate de celui-ci, ledit procédé comprenant la réaction d'un composé de formule (II) avec un composé de formule (III) selon le schéma réactionnel suivant : LG, A, n, m et p étant tels que définis dans la description, ladite fabrication comprenant la production et l'utilisation d'un composé de formule (VI) : dans laquelle R1 représente un groupe protecteur amino secondaire et R5 représente alkyle non substitué ou substitué, cycloalkyle non substitué ou substitué ou aryle substitué ou non substitué.
PCT/CN2021/094139 2020-07-08 2021-05-17 Fabrication de composés et de compositions pour inhiber shp2 WO2022007502A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU2021305970A AU2021305970B2 (en) 2020-07-08 2021-07-06 Manufacture of compounds and compositions for inhibiting the activity of SHP2
EP21740209.8A EP4178962A1 (fr) 2020-07-08 2021-07-06 Fabrication de composés et de compositions pour inhiber l'activité de shp2
CA3183946A CA3183946A1 (fr) 2020-07-08 2021-07-06 Fabrication de composes et de compositions pour inhiber l'activite de shp2
JP2023500286A JP2023532748A (ja) 2020-07-08 2021-07-06 Ｓｈｐ２の活性を阻害するための化合物及び組成物の製造
CN202180043650.2A CN115916786A (zh) 2020-07-08 2021-07-06 用于抑制shp2活性的化合物和组合物的制造
KR1020237001046A KR20230038197A (ko) 2020-07-08 2021-07-06 Shp2의 활성 억제를 위한 화합물 및 조성물의 제조
IL298350A IL298350A (en) 2020-07-08 2021-07-06 Production of compounds and preparations to inhibit the activity of shp2
TW110124805A TW202216723A (zh) 2020-07-08 2021-07-06 用於抑制shp2活性的化合物及組成物之製造
US18/004,313 US20230374029A1 (en) 2020-07-08 2021-07-06 Manufacture of compounds and compositions for inhibiting the activity of shp2
PCT/IB2021/056057 WO2022009098A1 (fr) 2020-07-08 2021-07-06 Fabrication de composés et de compositions pour inhiber l'activité de shp2

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015107494A1 (fr) * 2014-01-17 2015-07-23 Novartis Ag Dérivés de 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine et compositions les contenant pour l'inhibition de l'activité de shp2
CN110713447A (zh) * 2019-11-15 2020-01-21 山东国邦药业有限公司 一种对甲硫基苯甲醛的制备方法
WO2020065452A1 (fr) * 2018-09-29 2020-04-02 Novartis Ag Fabrication de composés et de compositions pour inhiber l'activité de shp2
WO2020065453A1 (fr) * 2018-09-29 2020-04-02 Novartis Ag Procédé de fabrication d'un composé pour inhiber l'activité de shp2
WO2020177653A1 (fr) * 2019-03-04 2020-09-10 勤浩医药（苏州）有限公司 Dérivé de pyrazine et son application dans l'inhibition de shp2

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JO3517B1 (ar) * 2014-01-17 2020-07-05 Novartis Ag ان-ازاسبيرو الكان حلقي كبديل مركبات اريل-ان مغايرة وتركيبات لتثبيط نشاط shp2

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015107494A1 (fr) * 2014-01-17 2015-07-23 Novartis Ag Dérivés de 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine et compositions les contenant pour l'inhibition de l'activité de shp2
WO2020065452A1 (fr) * 2018-09-29 2020-04-02 Novartis Ag Fabrication de composés et de compositions pour inhiber l'activité de shp2
WO2020065453A1 (fr) * 2018-09-29 2020-04-02 Novartis Ag Procédé de fabrication d'un composé pour inhiber l'activité de shp2
WO2020177653A1 (fr) * 2019-03-04 2020-09-10 勤浩医药（苏州）有限公司 Dérivé de pyrazine et son application dans l'inhibition de shp2
CN110713447A (zh) * 2019-11-15 2020-01-21 山东国邦药业有限公司 一种对甲硫基苯甲醛的制备方法

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