[go: up one dir, main page]

US20230139731A1 - Process for preparing mannose derivatives - Google Patents

Process for preparing mannose derivatives Download PDF

Info

Publication number
US20230139731A1
US20230139731A1 US18/083,674 US202218083674A US2023139731A1 US 20230139731 A1 US20230139731 A1 US 20230139731A1 US 202218083674 A US202218083674 A US 202218083674A US 2023139731 A1 US2023139731 A1 US 2023139731A1
Authority
US
United States
Prior art keywords
compound
alkyl
group
formula
membered ring
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.)
Abandoned
Application number
US18/083,674
Inventor
Denis Viktorovich Arefyev
Michael P. Cruskie
Chaminda Priyapushpa Gamage
Joseph Chase CHEWNING
Marc Labelle
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.)
Enterome SA
Original Assignee
Enterome SA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Enterome SA filed Critical Enterome SA
Priority to US18/083,674 priority Critical patent/US20230139731A1/en
Assigned to ENTEROME reassignment ENTEROME ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LABELLE, MARC, AREFYEV, Denis Viktorovich, CHEWNING, Joseph Chase, CRUSKIE, MICHAEL P., GAMAGE, CHAMINDA PRIYAPUSHPA
Publication of US20230139731A1 publication Critical patent/US20230139731A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/083—Syntheses without formation of a Si-C bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/06—Heterocyclic radicals
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • 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 provides a process for preparing mannose derivatives and their intermediates which are useful for the treatment or prevention of bacterial infections, such as urinary tract infection (UTI) and inflammatory bowel disease (IBD).
  • UMI urinary tract infection
  • IBD inflammatory bowel disease
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • IBD is a multifactorial disease that results from a combination of predisposing genetic factors, environmental triggers, dysbiosis of the gastrointestinal microbiota and an inappropriate inflammatory response (Man et al., 2011, Nat Rev Gastroenterol Hepatol, March 8(3):152-68).
  • AIEC adherent-invasive E. coli
  • WO 2014/100158 and WO 2016/199105 describe mannose derivatives which are useful for the treatment or prevention of bacterial infections, in particular urinary tract infection, inflammatory bowel disease, ulcerative colitis or Crohn's disease.
  • mannose derivatives are of particular interest for use in pharmaceutical industry, it is necessary to be able to synthesize these compounds efficiently on a large scale and at low cost with a minimum of steps and good yields.
  • mannose derivatives which comprise a triple bond on the anomeric position of mannose are of particular interest. They are synthesized by Sonogashira coupling between compound (I′) and an aromatic (di)halide (see FIG. 1 ). In particular, three intermediates (I′a), (I′b) and (I′c) are used (see FIG. 2 ).
  • Compound (I′c) is obtained in 3 steps from 2,3,4,6-Tetra-O-benzyl-D-mannopyranose (B), which is not readily available and requires a multistep synthesis.
  • compound (I′d) is obtained by alkynylation of 1,4,6-tri-O-acetyl-2,3-O-isopropylidene-D-mannopyranoside (C).
  • This starting material is not commercially available and its synthesis requires multiple steps of protection/deprotection from mannose. Additionally, the alkynyl iodide used is substituted with a phenyl which cannot be removed and alkynyl iodide is usually more expensive than terminal alkynes.
  • alkynylation of carbohydrate derivatives has also been described using organotin acetylides (for example with glucose derivatives in U.S. 2005/222048).
  • organotin acetylides for example with glucose derivatives in U.S. 2005/222048.
  • tin reagents are toxic and their use is avoided in pharmaceutical industry.
  • the glucose derivative used as starting material is obtained through several steps of protection/deprotection.
  • the present invention relates to a process to prepare a compound of the following formula (I):
  • P represents a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing an aryl or a (C 1 -C 6 )alkyl,
  • R represents a hydrogen atom or a protective group of a terminal alkyne, from mannose, comprising the following steps:
  • the protective group P is a —COR 1 group with R 1 representing an aryl group, preferably a phenyl group.
  • R is a —SiR 2 R 3 R 4 group with R 2 , R 3 and R 4 representing independently from each other a (C 1 -C 6 )alkyl group or a biphenyl group, preferably R 2 , R 3 and R 4 represent a methyl group.
  • step b) is performed in the presence of a base, an alkylaluminum halide and optionally a Lewis acid, preferably in the presence n-Butyl lithium, diethyl aluminium chloride and aluminium chloride.
  • step (b) is divided into three sub-steps:
  • the invention also relates to a process to prepare a compound of formula (III):
  • Y represents a group
  • R′′ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing an aryl or a (C 1 -C 6 )alkyl, from mannose, comprising the following steps:
  • the compound of formula (III) is a compound of formula (IIIa)
  • R 10 representing a hydrogen, a (C 1 -C 6 )alkyl, —SO 2 R 6 , —C(O)R 6 or —C(O)OR 6 , with R 6 , R′′ and X being as described above.
  • R 10 is a —C(O)R 6 group with R 6 representing an aryl or a (C 1 -C 6 )alkyl, preferably R 6 is a methyl group.
  • steps (c) and (d) occur in a one-pot process.
  • R 10 is a compound of formula (IVa) wherein R 10 and is a —COMe group and is obtained from compound of formula (IVa) with R 10 being a protective group of an amine function different from —COMe by deprotection and acetylation in a one-pot process.
  • the invention also relates to a process to prepare a compound of formula (V):
  • R 11 represents:
  • R′′ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing an aryl or a (C 1 -C 6 )alkyl, from mannose, comprising the following steps:
  • R 11 is a pyridinone substituted or not by a (C 1 -C 6 ) alkyl.
  • the compound of formula (V) is a compound of formula (Va)
  • steps (c) and (d) occur in a one-pot process.
  • the present invention also relates to a compound of formula (IIIa):
  • R 10 represents a hydrogen, a (C 1 -C 6 )alkyl, —SO 2 R 6 , —C(O)R 6 or —C(O)OR 6 , with R 6 being a hydrogen or a radical selected from a (C 1 -C 6 )alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C 1 -C 6 ) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl or a 3-8 membered ring heterocycloalkyl, a halogen, —NR 8 R 9 , —CN, —C(O)OR 8 , —C(O)NR 8 R 9 or —OR 8 , with R 8 and R 9 being independently a hydrogen atom or a (C 1 -C 6
  • FIG. 1 illustrates the synthesis of mannose derivatives as described in WO 2014/100158 and WO 2016/199105 via Sonogashira coupling starting from compound (I′) with R ⁇ H, and P 1 , P 2 , P 3 and P 4 are protective groups of hydroxyl function.
  • FIG. 2 illustrates the synthetic routes for the preparation of compounds of formula (I′) such as compounds (I′a), (I′b) and (I′c) according to the prior art.
  • the applicants have developed a process to prepare mannose derivatives which are useful for the treatment or prevention of bacteria infections, such as urinary tract infection (UTI) and inflammatory bowel disease (IBD).
  • UMI urinary tract infection
  • IBD inflammatory bowel disease
  • the process comprise the preparation of biologically active compounds of formula (III) or (V), and preparation of key intermediates such as compounds of formula (I).
  • halogen refers to a fluorine, bromine, chlorine or iodine atom.
  • (C 1 -C 6 )alkyl refers to a saturated straight or branched hydrocarbon chain containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • (C 2 -C 6 )alkenyl refers to an unsaturated straight or branched hydrocarbon chain containing from 2 to 6 carbon atoms comprising at least one carbon-carbon double bond including, but not limited to, ethenyl, n-propenyl, iso-propenyl, n-butenyl, n-pentenyl, n-hexenyl, and the like.
  • aryl refers to an aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or several fused rings, such as, for example, a phenyl or naphtyl group.
  • aryl is a phenyl group.
  • heteroaryl refers to an aromatic heterocycle as defined above. It can be is more particularly an aromatic monocyclic or bicyclic heterocycle, each cycle comprising 5 or 6 members, such as a pyrrole, a furane, a thiophene, a thiazole, an isothiazole, an oxazole, an isoxazole, an imidazole, a pyrazole, a triazole, a pyridine, a pyrimidine, a pyridazine, a pyrazine, a triazine (such as 1, 3, 5-triazine), an indole, a benzofurane, a benzothiophene, a benzothiazole, a benzoxazole, a benzimidazole, an indazole, a benzotriazole, a quinoline, an isoquinoline, a quinazoline or a qui
  • cycloalkyl refers to a saturated mono-, bi- or tri-cyclic alkyl group as defined above comprising between 3 and 12 carbon atoms. It also includes fused, bridged or spiro-connected cycloalkyl groups.
  • cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.
  • heterocycloalkyl refers to saturated cycloalkyl group as defined above further comprising at least one heteroatom such as nitrogen, oxygen or sulphur.
  • heterocycloalkyl includes, but is not limited to, pyranyl, piperidyl, piperidinyl, piperazinyl, 1,4-dioxanyl, morpholinyl, tetrahydrofuranyl, oxetanyl, pyrrolidinyl or pyrrolidyl.
  • cycloalkenyl refers to unsaturated mono- or bi-cyclic alkenyl group as defined above comprising between 3 and 12 carbon atoms.
  • cycloalkenyl includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
  • oxo refers to the functional group ‘ ⁇ O’ (a substituent oxygen atom connected to another atom by a double bond).
  • Protective groups of amine function are well known to persons skilled in the art. These groups protect the amine functions of undesirable reactions. For example, a chemical reaction can be performed selectively at another reactive site which is not protected.
  • the protective groups of the amine functions can be such as those described in “Protective Groups In Organic synthesis”, (John Wiley & Sons, New York (1981)) and Harrison et al. “Compendium of Synthetic Organic Methods”, Vols. 1 to 8 (J. Wiley & Sons, 1971 to 1996).
  • the protective groups of amine functions comprise carbamates, amides, amino acetal derivatives, N-benzyl derivatives, imine derivatives and N-heteroatom derivatives.
  • a protective group of amine function is a Boc group or an acetyl group.
  • Protective groups of hydroxyl function are well known to those skilled in the art. These groups protect the hydroxyl functions against undesirable reactions.
  • the protective groups of hydroxyl functions can be such as described in Greene, “Protective Groups In Organic synthesis”, (John Wiley & Sons, New York (1981)) and Harrison et al. “Compendium of Synthetic Organic Methods”, Vols. 1 to 8 (J. Wiley & Sons, 1971 to 1996).
  • the protective groups of hydroxyl functions comprise substituted or unsubstituted methyl or alkyl ethers or esters e.g.
  • benzyloxymethyl methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl) ethoxymethyl, t-butyl, benzyl and triphenylmethyl, benzyl ethers (substituted or unsubstituted), tetrahydropyranyl ethers, allyl ethers, substituted ethyl ethers e.g. 2,2,2-trichloroethyl, silyl ethers or alkylsilyl ethers, e.g.
  • esters prepared by reaction of the hydroxyl group with a carboxylic acid e.g. tert-butyl, benzyl or methyl esters, carbonates in particular benzyl or halogenalkyl carbonate, acetate, propionate, benzoate and the like.
  • carboxylic acid e.g. tert-butyl, benzyl or methyl esters, carbonates in particular benzyl or halogenalkyl carbonate, acetate, propionate, benzoate and the like.
  • Protective groups of a terminal alkyne are well known to those skilled in the art. These groups protect the terminal alkyne functions against undesirable reactions.
  • the protective groups of terminal alkyne functions can be such as described in Greene, “Protective Groups in Organic synthesis”, (John Wiley & Sons, New York (1981)) and Harrison et al. “Compendium of Synthetic Organic Methods”, Vols. 1 to 8 (J. Wiley & Sons, 1971 to 1996).
  • the protective groups of terminal alkyne functions comprise silyl groups such as a —SiR 2 R 3 R 4 group with R 2 , R 3 and R 4 representing independently from each other a (C 1 -C 6 )alkyl group or a biphenyl group.
  • alkylaluminum halide refers to a compound of formula R a n AlX 3-n with R a representing a (C 1 -C 6 )alkyl group, n being a whole number between 1 and 2 and X representing a halogen.
  • room temperature designates typically a temperature ranging from 18° C. to 25° C.
  • one-pot process refers to a process wherein a reactant is subjected to successive chemical reactions in just one reactor.
  • the invention deals with a process to prepare a compound of the following formula (I):
  • P represents a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing an aryl group or a (C 1 -C 6 )alkyl group,
  • R represents a hydrogen atom or a protective group of a terminal alkyne, from mannose, comprising the following steps:
  • the protective group P is a —COR 1 group with R 1 representing an aryl group, preferably R 1 is a phenyl group.
  • R is a —SiR 2 R 3 R 4 group with R 2 , R 3 and R 4 representing independently from each other a (C 1 -C 6 )alkyl group or a biphenyl group, preferably R 2 , R 3 and R 4 represent a methyl group.
  • Protecting the 5 hydroxyl groups of the mannose by a protective group P can be obtained by esterification of mannose.
  • Esterification can be conducted under conditions well known to skilled persons.
  • mannose can react with a carboxylic acid or its derivatives such as an anhydride acid or an acyl chloride.
  • mannose reacts with acyl chloride, notably benzoyl chloride (BzCl), in the presence of a base.
  • acyl chloride notably benzoyl chloride (BzCl)
  • the reaction occurs in the presence of at least 6 molar equivalents of acyl chloride, more advantageously between 6 and 10 molar equivalents.
  • the base is an amine, notably triethylamine (TEA), diisopropylethylamine (DIPEA), piperidine or pyridine.
  • the base is pyridine.
  • the base is the solvent.
  • the protection reaction can be catalysed by a catalyst such as dimethylaminopyridine (DMAP).
  • DMAP dimethylaminopyridine
  • the protection reaction is conducted at room temperature for at least 1 hour, notably for at least 2 hours.
  • Coupling the protected mannose obtained at step (a) with a compound of formula (II) comprising a terminal alkyne can be performed in the presence of a base and an alkylaluminum halide, and optionally a Lewis acid.
  • the base is selected among an organolithium reagent R b Li or a Grignard reagent R c MgX a with R b and/or R c representing a (C 1 -C 6 )alkyl group and X a representing a halogen.
  • the base is an organolithium reagent, notably n-butyl lithium (nBuLi).
  • organolithium reagent notably n-butyl lithium (nBuLi).
  • the alkylaluminum halide is a dialkylaluminum halide, in particular diethylaluminium chloride (Et 2 AlCl) or dimethylaluminium chloride (Me 2 AlCl).
  • Et 2 AlCl diethylaluminium chloride
  • Me 2 AlCl dimethylaluminium chloride
  • the alkylaluminum halide is Et 2 AlCl.
  • step (b) occurs in the presence of at least another Lewis acid.
  • the Lewis acid is preferably selected among BF 3 , BCl 3 , BBr 3 , TiCl 4 , PF 5 , SbF 5 , SnCl 2 , SnCl 4 , ZnCl 2 , aluminium halide or mixture thereof.
  • the Lewis acid is selected among boron trihalide and aluminium halide or mixture thereof.
  • aluminium halide is chosen among AlCl 3 and AlBr 3 , more preferably it is AlCl 3 .
  • step (b) is performed in the presence of an alkylaluminum halide and another Lewis acid. More preferably, step (b) is performed in the presence of an alkylaluminum halide and an aluminium halide. Even more preferably, step (b) is performed in the presence of Et 2 AlCl AlCl 3 . In particular, step (b) is performed in the presence of AlCl 3 , Et 2 AlCl and nBuLi.
  • step (b) is conducted in apolar solvent such as toluene, xylene or dichloroethane. More preferably, step (b) is conducted in a mixture toluene/THF.
  • apolar solvent such as toluene, xylene or dichloroethane. More preferably, step (b) is conducted in a mixture toluene/THF.
  • step (b) is divided into three sub-steps:
  • Deprotonation of the compound of formula (II) is preferably performed with a base selected among organolithium reagent or a Grignard reagent, more preferably, with an organolithium reagent, notably n-butyl lithium nBuLi.
  • addition of the base is carried out at a temperature below ⁇ 30° C. and the mixture is stirred at 0° C. for at least 10 minutes, in particular at least 20 minutes.
  • Step (b2) is a transmetallation reaction.
  • addition of an alkylaluminium halide to the deprotonated compound obtained at step (b1) is carried out at a temperature below 0° C., more preferably below ⁇ 20° C., and the mixture is stirred at room temperature for at least 10 minutes.
  • step (b3) is performed by adding a Lewis acid and the product obtained at step (a), i.e. the protected mannose, at a temperature below ⁇ 20° C. and the mixture is stirred at at least 50° C. for at least 10 hours, more preferably, at least 20 hours.
  • compounds of formula (I) can be obtained using the following synthetic route:
  • step (b) is followed by step (c) deprotecting the terminal alkyne of the compound obtained at step (b) to obtain compound of formula (I) in which R ⁇ H.
  • Deprotecting terminal alkyne is conducted under conditions well known to skilled persons.
  • step (c) is conducted in a polar solvent such as DMA, DMF, DMSO, THF, dioxane, acetonitrile or NMP.
  • a polar solvent such as DMA, DMF, DMSO, THF, dioxane, acetonitrile or NMP.
  • the invention also deals with a process to prepare a compound of formula (III):
  • Y represents an atom S, an atom O, a
  • R′′ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing an aryl or a (C 1 -C 6 )alkyl, from mannose, comprising the following steps:
  • step (e) occurs after step (c) and before step (d).
  • R′′ represents a protective group P as described above.
  • the protective group P is a —COR 1 group with R 1 representing an aryl group, preferably R 1 is a phenyl group.
  • Y represents a
  • R′ is as described above.
  • Y represents a
  • a and B are as described above.
  • a and B represent independently of each other a hydrogen, a hydroxyl or a (C 1 -C 6 )alkyl substituted or not by a —OR 5 group or —OC(O)R 5 group, R 5 representing a hydrogen or a (C 1 -C 6 )alkyl,
  • a and B form together with the carbon atom to which they are bound a 3-7 membered saturated monocyclic ring having 0, 1 or 2 heteroatoms selected from O, N and S, one or several carbon or nitrogen of the ring being optionally substituted by an oxo, a (C 1 -C 6 )alkyl, —OR 6 , —NR 6 R 7 , —SO 2 R 6 —C(O)R 6 or —C(O)OR 6 , with R 6 and R 7 representing independently a hydrogen or a radical selected from a (C 1 -C 6 )alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C 1 -C 6 ) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl, a 3-8 membered ring
  • the compound of formula (III) is a compound of formula (IIIa)
  • R 10 representing a hydrogen, a (C 1 -C 6 )alkyl, —SO 2 R 6 , —C(O)R 6 or —C(O)OR 6 , with R 6 and R′′ being as described above.
  • R 10 representing a hydrogen, a (C 1 -C 6 )alkyl, —SO 2 R 6 , —C(O)R 6 or —C(O)OR 6 , with X being a halogen atom.
  • R 10 is a —C(O)R 6 group with R 6 representing an aryl or a (C 1 -C 6 )alkyl, preferably R 6 is a methyl group.
  • Steps (a), (b) and (c) can be performed as described above.
  • X in compound of formula (IV) is a bromine or an iodine, more preferably, a bromine.
  • Sonogashira coupling can be performed in the presence of a palladium catalyst, or a system of palladium/copper catalyst.
  • Pd and Pd/Cu catalysts include Pd(PPh 3 ) 4 , Pd(PPh 3 ) 4 /CuI PdCl 2 (dppf)/CuI, PdCl 2 (PPh 3 )/CuI.
  • Sonogashira coupling occurs in the presence of a base, such as an amine.
  • a base such as an amine.
  • the amine is trimethylamine (TEA), diisopropylethylamine (DIPEA), piperidine, morpholine or pyridine. More preferably, the base is DIPEA.
  • Sonogashira coupling is conducted in a polar solvent.
  • DMSO, DMF, DMA, THF, dioxane, acetonitrile or NMP can be used as solvent.
  • Sonogashira coupling is performed under nitrogen or under argon at a temperature above room temperature, notably above 50° C., for at least 10 hours, preferably at least 20 hours.
  • steps (c) and (d) occur in a one-pot process.
  • steps (c) and (d) occur in the same reactor without isolation of the intermediate obtained after step (c).
  • steps (c) and (d) occur in the same solvent.
  • deprotection occurs in the presence of a base such as a hydroxide or an alkoxide.
  • the base is an alkoxide, preferably a methoxide, more preferably sodium methoxide.
  • the reaction can be performed in an alcohol, preferably corresponding to the alkoxide used.
  • deprotection occurs in methanol.
  • the reaction can be performed at room temperature for at least 1 hour.
  • Compound of formula (III) with R′′ ⁇ H can be purified by recrystallization in an alcohol, preferably isopropanol.
  • compound of formula (IVa) wherein R 10 is a —COMe group is obtained from compound of formula (IVa) with R 10 being a protective group of an amine function different from —COMe, notably a Boc group, by deprotection and acetylation in a one-pot process.
  • R 10 being a protective group of an amine function different from —COMe, notably a Boc group, by deprotection and acetylation in a one-pot process.
  • compound of formula (IVa) is obtained through the following synthetic route:
  • compound of formula (IIIa)-3 is prepared with the following synthetic route:
  • the desired product (IIIa)-3 is obtained with a global yield starting from mannose in the order of 35% to 40%.
  • the invention also deals with a process to prepare a compound of formula (V):
  • R 11 represents:
  • R′′ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing an aryl or a (C 1 -C 6 )alkyl, from mannose, comprising the following steps:
  • step (e) occurs after step (c) and before step (d).
  • R 11 represents a radical selected from an aryl and a heteroaryl, said radical being substituted or not by a (C 1 -C 6 ) alkyl, an aryl, a heteroaryl, a halogen, —C(O)OR a , —C(O)NR a R b , —SO 2 R a , —SO 2 NR a R b , —NR a R b , —OR a , —CN or —NO 2 , with R a and R b being independently a hydrogen atom or a (C 1 -C 6 ) alkyl.
  • R 11 represents a heteroaryl substituted or not by a (C 1 -C 6 ) alkyl, an aryl, a heteroaryl, a halogen, —C(O)OR a , —C(O)NR a R b , —SO 2 R a , —SO 2 NR a R b , —NR a R b , —OR a , —CN or —NO 2 , with R a and R b being independently a hydrogen atom or a (C 1 -C 6 ) alkyl. Even more preferably, R 11 represents a pyridinone substituted or not by a (C 1 -C 6 ) alkyl group.
  • the compound of formula (V) is a compound of formula (Va)
  • Steps (a), (b) and (c) can be performed as described above.
  • Steps (d) can be performed as described above.
  • R 11 represents an aryl or a heteroaryl
  • X′ represents advantageously a halogen
  • step (d′) between step (d) and step (e) can be performed.
  • Step (d′) is a Suzuki coupling between the product obtained at step (d) and an aryl- or heteroaryl-boron derivative.
  • the boron derivative can be a boronic acid derivative, a boronic ester derivative or a trifluoroborate derivative.
  • the radical aryl or heteroaryl of the aryl- or heteroaryl-boron derivative correspond to the group R 11 .
  • the boron derivative is a boronic acid derivative, its formula is R 11 —B(OH) 2 .
  • Suzuki coupling can be performed in the presence of a palladium catalyst such as Pd(PPh 3 ) 4 .
  • Suzuki coupling occurs in the presence of a base, such as a carbonate, an acetate or an amine.
  • R 10 represents advantageously a —C(O)R 6 group with R 6 representing an aryl or a (C 1 -C 6 )alkyl, preferably R 6 is a methyl group.
  • R′′ represents —COR 1 group with R 1 being an aryl, such as a phenyl, or a (C 1 -C 6 )alkyl, such as a methyl. More preferably, R′′ represents a benzoyl group of formula —COPh, wherein Ph is the abbreviation for the phenyl group.
  • compound of formula (IIIa) is the compound of the following formula (IIIa-2):
  • n-BuLi (2.5 M in hexanes, 2.0 equiv.) is added to a solution of trimethylsilyl acetylene (2.1 equiv.) in toluene (6.6 vol.) at a temperature below ⁇ 30° C.
  • the reaction mixture is stirred at 0° C. for 20 min.
  • the mixture is cooled and diethyl aluminium chloride is added at a temperature below ⁇ 20° C.
  • the reaction is stirred at room temperature for 10 min.
  • the mixture is cooled at ⁇ 30° C. and THF (2.0 equiv.), aluminium chloride (2.0 equiv.) and compound a-1 (1.0 equiv.) are successively added.
  • the reaction mixture is stirred at 60° C.
  • compound (IVa)-3 1.0 equiv.
  • potassium fluoride 8.0 equiv.
  • the reaction mixture is stirred under vacuum at room temperature for 30 min. N,N-diisopropylethylamine (4.0 equiv.) is added. Nitrogen is bubbled into the reaction mixture for 30 min.
  • the reaction mixture is heated at 50° C. and tetrakis(triphenylphosphine)palladium (0.05 equiv.) and copper iodide (0.1 equiv.) are added successively.
  • the reaction mixture is stirred at 60° C. for 24 hours.
  • the reaction mixture is cooled at 10° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a process to prepare a compound of the following formula (I):
Figure US20230139731A1-20230504-C00001
    • in which
    • P represents a protective group of a hydroxyl function which is a —COR1 group with R1 representing an aryl or a (C1-C6)alkyl,
    • R represents a hydrogen atom or a protective group of a terminal alkyne, from mannose, comprising the following steps:
      • (a) protecting the 5 hydroxyl groups of the mannose by a protective group P;
      • (b) coupling the protected mannose obtained at step (a) with a compound of the following formula (II)
Figure US20230139731A1-20230504-C00002
The present invention also relates to a compound of formula (IIIa):
Figure US20230139731A1-20230504-C00003
    • wherein R10 represents a hydrogen, a (C1-C6)alkyl, —SO2R6, —C(O)R6 or —C(O)OR6, with R6 being a hydrogen or a radical selected from a (C1-C6)alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C1-C6) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl or a 3-8 membered ring heterocycloalkyl, a halogen, —NR8R9, —CN, —C(O)OR8, —C(O)NR8R9 or —OR8, with R8 and R9 being independently a hydrogen atom or a (C1-C6) alkyl, or R8 and R9 form together with the nitrogen to which they are bound a 3-8 membered ring heterocycloalkyl, and
    • R″ represents —COR1 group with R1 being an aryl or a (C1-C6)alkyl.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a Continuation of copending application Ser. No. 17/263,012, filed Jan. 25, 2021, which is the National Phase under 35 U.S.C. § 371 of International Application No. PCT/EP2019/070276, filed Jul. 26, 2019, which claims the benefit under 35 U.S.C. § 119(a) to European Patent Application No. 18306013.6 filed Jul. 26, 2018, all of which are hereby expressly incorporated by reference into the present application.
    • FIELD OF THE INVENTION
  • The present invention provides a process for preparing mannose derivatives and their intermediates which are useful for the treatment or prevention of bacterial infections, such as urinary tract infection (UTI) and inflammatory bowel disease (IBD).
    • STATE OF THE ART
  • Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder, with the two more common forms being ulcerative colitis (UC) and Crohn's disease (CD). IBD is a multifactorial disease that results from a combination of predisposing genetic factors, environmental triggers, dysbiosis of the gastrointestinal microbiota and an inappropriate inflammatory response (Man et al., 2011, Nat Rev Gastroenterol Hepatol, March 8(3):152-68).
  • Several pathogens have been proposed as causative agents. In particular, adherent-invasive E. coli (AIEC) has been reported to be more prevalent in CD patients than in controls. It has also been demonstrated recently that FimH antagonists are potentially effective in treating urinary tract infections.
  • WO 2014/100158 and WO 2016/199105 describe mannose derivatives which are useful for the treatment or prevention of bacterial infections, in particular urinary tract infection, inflammatory bowel disease, ulcerative colitis or Crohn's disease.
  • As mannose derivatives are of particular interest for use in pharmaceutical industry, it is necessary to be able to synthesize these compounds efficiently on a large scale and at low cost with a minimum of steps and good yields.
  • In WO 2014/100158 and WO 2016/199105, mannose derivatives which comprise a triple bond on the anomeric position of mannose are of particular interest. They are synthesized by Sonogashira coupling between compound (I′) and an aromatic (di)halide (see FIG. 1 ). In particular, three intermediates (I′a), (I′b) and (I′c) are used (see FIG. 2 ).
  • The synthesis of compounds (I′a) and (I′b) is described in Vasella and coll. Helvetica Chimica Acta 2001, 84, 2355-2367. Compounds (I′a) and (I′b) are obtained in 3 and 4 steps successively starting from 1,6-anhydro-R-D-mannopyranose (A), which is not readily available and requires a multistep synthesis.
  • Compound (I′c) is obtained in 3 steps from 2,3,4,6-Tetra-O-benzyl-D-mannopyranose (B), which is not readily available and requires a multistep synthesis.
  • In an article from Lubin-Germain and coil, Org. Lett. 2008, 10, 725-728, compound (I′d) is obtained by alkynylation of 1,4,6-tri-O-acetyl-2,3-O-isopropylidene-D-mannopyranoside (C). This starting material is not commercially available and its synthesis requires multiple steps of protection/deprotection from mannose. Additionally, the alkynyl iodide used is substituted with a phenyl which cannot be removed and alkynyl iodide is usually more expensive than terminal alkynes.
  • In general, alkynylation of carbohydrate derivatives has also been described using organotin acetylides (for example with glucose derivatives in U.S. 2005/222048). However, tin reagents are toxic and their use is avoided in pharmaceutical industry. Additionally, the glucose derivative used as starting material is obtained through several steps of protection/deprotection.
  • To this extent, a need remains for the development of a process to synthesize compounds of formula (I) more efficiently on a large scale, at low cost, with a minimum of steps, good yields and starting from readily available and cheap starting material.
  • Similarly, it is necessary to develop an efficient process to prepare compounds of formula (III) and of formula (V) which are mannose derivatives useful for the treatment or prevention of bacterial infections.
    • SUMMARY OF THE INVENTION
  • The present invention relates to a process to prepare a compound of the following formula (I):
  • Figure US20230139731A1-20230504-C00004
  • in which
  • P represents a protective group of a hydroxyl function which is a —COR1 group with R1 representing an aryl or a (C1-C6)alkyl,
  • R represents a hydrogen atom or a protective group of a terminal alkyne, from mannose, comprising the following steps:
      • (a) protecting the 5 hydroxyl groups of the mannose by a protective group P;
      • (b) coupling the protected mannose obtained at step (a) with a compound of the following formula (II)
  • Figure US20230139731A1-20230504-C00005
  • In particular, the protective group P is a —COR1 group with R1 representing an aryl group, preferably a phenyl group.
  • Preferably, R is a —SiR2R3R4 group with R2, R3 and R4 representing independently from each other a (C1-C6)alkyl group or a biphenyl group, preferably R2, R3 and R4 represent a methyl group.
  • Advantageously, step b) is performed in the presence of a base, an alkylaluminum halide and optionally a Lewis acid, preferably in the presence n-Butyl lithium, diethyl aluminium chloride and aluminium chloride.
  • Preferably, step (b) is divided into three sub-steps:
      • (b1) deprotonation of the compound of formula (II) with a base,
      • (b2) addition of an alkylaluminium halide, preferably diethyl aluminium chloride,
      • (b3) coupling the product obtained at step (a) with the product of step (b2) in the presence of a Lewis acid, preferably aluminium chloride.
  • The invention also relates to a process to prepare a compound of formula (III):
  • Figure US20230139731A1-20230504-C00006
  • in which
  • Y represents a group
  • Figure US20230139731A1-20230504-C00007
  • or a group
  • Figure US20230139731A1-20230504-C00008
      • with A and B representing independently of each other a hydrogen, a hydroxyl, an amine or a radical selected from a (C1-C6)alkyl and an aryl, said radical being substituted or not by a (C1-C6)alkyl, a 3-8 membered ring cycloalkyl, —OR5, —OC(O)R5 or —COOR5, R5 representing a hydrogen or a (C1-C6)alkyl,
      • or A and B form together with the carbon atom to which they are bound a 3-7 membered saturated monocyclic ring having 0, 1 or 2 heteroatoms selected from O, N and S, one or several carbon or nitrogen of the ring being optionally substituted by an oxo, a (C1-C6)alkyl, —OR6, —NR6R7, —SO2R6—C(O)R6 or —C(O)OR6, with R6 and R7 representing independently a hydrogen or a radical selected from a (C1-C6)alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C1-C6) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl or a 3-8 membered ring heterocycloalkyl, a halogen, —NR8R9, —CN, —C(O)OR8, —C(O)NR8R9 or —OR8, with R8 and R9 being independently a hydrogen atom or a (C1-C6) alkyl, or R8 and R9 form together with the nitrogen to which they are bound a 3-8 membered ring heterocycloalkyl,
      • with R′ representing a hydrogen atom or a radical selected from a (C1-C6) alkyl, an aryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C1-C6) alkyl, a 3-8 membered ring cycloalkyl, a 3-8 membered ring heterocycloalkyl, —C(O)ORa, —C(O)NRaRb or —ORa, with Ra and Rb being independently a hydrogen atom or a (C1-C6) alkyl optionally substituted by a 3-8 membered ring heterocycloalkyl, or Ra and Rb form together with the nitrogen a 3-8 membered ring heterocycloalkyl,
  • R″ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR1 group with R1 representing an aryl or a (C1-C6)alkyl, from mannose, comprising the following steps:
      • (a)(b) performing steps (a) and (b) to obtain the compound of formula (I) as described above;
      • (c) optionally deprotecting the terminal alkyne of the compound obtained after steps (a)(b) to obtain compound of formula (I) in which R═H;
      • (d) Sonogashira coupling of the compound obtained at steps (a)(b) or when applicable at step (c) with a compound of the following formula (IV):
  • Figure US20230139731A1-20230504-C00009
      • in which X is a halogen atom;
      • (e) optionally deprotecting the hydroxyl groups protected by a group P to obtain compound of formula (III) in which R″═H;
      • (f) recovering the compound of formula (III) obtained at step (d) or when applicable at step (e).
  • In particular, the compound of formula (III) is a compound of formula (IIIa)
  • Figure US20230139731A1-20230504-C00010
  • advantageously obtained from compound (IVa)
  • Figure US20230139731A1-20230504-C00011
  • with R10 representing a hydrogen, a (C1-C6)alkyl, —SO2R6, —C(O)R6 or —C(O)OR6, with R6, R″ and X being as described above.
  • Advantageously, R10 is a —C(O)R6 group with R6 representing an aryl or a (C1-C6)alkyl, preferably R6 is a methyl group.
  • Preferably, steps (c) and (d) occur in a one-pot process.
  • In particular, compound of formula (IVa)
  • Figure US20230139731A1-20230504-C00012
  • is a compound of formula (IVa) wherein R10 and is a —COMe group and is obtained from compound of formula (IVa) with R10 being a protective group of an amine function different from —COMe by deprotection and acetylation in a one-pot process.
  • The invention also relates to a process to prepare a compound of formula (V):
  • Figure US20230139731A1-20230504-C00013
  • in which
  • R11 represents:
      • a —CONR12R13 group with R12 and R13 representing independently a hydrogen, a (C1-C6)alkyl or R12 and R13 form together with the nitrogen a 3-8 membered ring heterocycloalkyl or cycloalkyl
      • a radical selected from a cycloalkenyl, an aryl and a heteroaryl, said radical being substituted or not by a (C1-C6) alkyl, an aryl, a heteroaryl, a halogen, —C(O)ORa, —C(O)NRaRb, —SO2Ra, —SO2NRaRb, —NRaRb, —ORa, —CN or —NO2, with Ra and Rb being independently a hydrogen atom or a (C1-C6) alkyl,
  • R″ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR1 group with R1 representing an aryl or a (C1-C6)alkyl, from mannose, comprising the following steps:
      • (a)(b) performing steps (a) and (b) to obtain the compound of formula (I) as described above;
      • (c) optionally deprotecting the terminal alkyne of the compound obtained after steps (a)(b) to obtain compound of formula (I) in which R═H;
      • (d) Sonogashira coupling of the compound obtained at steps (a)(b) or when applicable at step (c) with a compound of the following formula (VI):
  • Figure US20230139731A1-20230504-C00014
      • in which X is a halogen atom and X′ is a halogen or a radical R11;
      • (e) optionally deprotecting the hydroxyl groups protected by a group P to obtain compound of formula (V) in which R″═H;
      • (f) recovering the compound of formula (V) obtained at step (d) or when applicable at step (e).
  • Advantageously, R11 is a pyridinone substituted or not by a (C1-C6) alkyl.
  • Preferably, the compound of formula (V) is a compound of formula (Va)
  • Figure US20230139731A1-20230504-C00015
  • In particular, steps (c) and (d) occur in a one-pot process.
  • The present invention also relates to a compound of formula (IIIa):
  • Figure US20230139731A1-20230504-C00016
  • wherein R10 represents a hydrogen, a (C1-C6)alkyl, —SO2R6, —C(O)R6 or —C(O)OR6, with R6 being a hydrogen or a radical selected from a (C1-C6)alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C1-C6) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl or a 3-8 membered ring heterocycloalkyl, a halogen, —NR8R9, —CN, —C(O)OR8, —C(O)NR8R9 or —OR8, with R8 and R9 being independently a hydrogen atom or a (C1-C6) alkyl, or R8 and R9 form together with the nitrogen to which they are bound a 3-8 membered ring heterocycloalkyl, and R″ represents —COR1 group with R1 being an aryl or a (C1-C6)alkyl.
    • FIGURES
  • FIG. 1 illustrates the synthesis of mannose derivatives as described in WO 2014/100158 and WO 2016/199105 via Sonogashira coupling starting from compound (I′) with R═H, and P1, P2, P3 and P4 are protective groups of hydroxyl function.
  • FIG. 2 illustrates the synthetic routes for the preparation of compounds of formula (I′) such as compounds (I′a), (I′b) and (I′c) according to the prior art.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • The applicants have developed a process to prepare mannose derivatives which are useful for the treatment or prevention of bacteria infections, such as urinary tract infection (UTI) and inflammatory bowel disease (IBD).
  • In particular, the process comprise the preparation of biologically active compounds of formula (III) or (V), and preparation of key intermediates such as compounds of formula (I).
  • The process developed by the applicants is adapted for preparation on an industrial scale of active compounds of formula (III) or (V) and present numerous advantages:
      • compounds of formula (I) are obtained in a limited number of steps from a cheap commercially available reagent, i.e. mannose;
      • the synthetic route does not require chiral synthesis since the chiral centres are contained in the starting reagent;
      • the operating conditions are mild and do not use toxic reagents like organotin;
      • the product is obtained with high chiral purity as chirality is controlled since starting material selection as per Mannose specifications and Chirality is assessed through current HPLC method.
      • the global yield of the synthetic route starting from mannose and leading to compound of formula (IIIa)-3 is 35% to 40%.
    Definitions
  • The term “halogen”, as used in the present invention, refers to a fluorine, bromine, chlorine or iodine atom.
  • The term “(C1-C6)alkyl”, as used in the present invention, refers to a saturated straight or branched hydrocarbon chain containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • The term “(C2-C6)alkenyl”, as used in the present invention, refers to an unsaturated straight or branched hydrocarbon chain containing from 2 to 6 carbon atoms comprising at least one carbon-carbon double bond including, but not limited to, ethenyl, n-propenyl, iso-propenyl, n-butenyl, n-pentenyl, n-hexenyl, and the like.
  • The term “aryl”, as used in the present invention, refers to an aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or several fused rings, such as, for example, a phenyl or naphtyl group. Advantageously, it is a phenyl group.
  • The term “heteroaryl” as used in the present invention refers to an aromatic heterocycle as defined above. It can be is more particularly an aromatic monocyclic or bicyclic heterocycle, each cycle comprising 5 or 6 members, such as a pyrrole, a furane, a thiophene, a thiazole, an isothiazole, an oxazole, an isoxazole, an imidazole, a pyrazole, a triazole, a pyridine, a pyrimidine, a pyridazine, a pyrazine, a triazine (such as 1, 3, 5-triazine), an indole, a benzofurane, a benzothiophene, a benzothiazole, a benzoxazole, a benzimidazole, an indazole, a benzotriazole, a quinoline, an isoquinoline, a quinazoline or a quinoxaline.
  • The term “cycloalkyl” as used in the present invention refers to a saturated mono-, bi- or tri-cyclic alkyl group as defined above comprising between 3 and 12 carbon atoms. It also includes fused, bridged or spiro-connected cycloalkyl groups. The term “cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.
  • The term “heterocycloalkyl” as used in the present invention refers to saturated cycloalkyl group as defined above further comprising at least one heteroatom such as nitrogen, oxygen or sulphur. The term “heterocycloalkyl” includes, but is not limited to, pyranyl, piperidyl, piperidinyl, piperazinyl, 1,4-dioxanyl, morpholinyl, tetrahydrofuranyl, oxetanyl, pyrrolidinyl or pyrrolidyl.
  • The term “cycloalkenyl” as used in the present invention refers to unsaturated mono- or bi-cyclic alkenyl group as defined above comprising between 3 and 12 carbon atoms. The term “cycloalkenyl” includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
  • The term “oxo” as used in the present invention refers to the functional group ‘═O’ (a substituent oxygen atom connected to another atom by a double bond).
  • Protective groups of amine function are well known to persons skilled in the art. These groups protect the amine functions of undesirable reactions. For example, a chemical reaction can be performed selectively at another reactive site which is not protected. The protective groups of the amine functions can be such as those described in “Protective Groups In Organic synthesis”, (John Wiley & Sons, New York (1981)) and Harrison et al. “Compendium of Synthetic Organic Methods”, Vols. 1 to 8 (J. Wiley & Sons, 1971 to 1996). The protective groups of amine functions comprise carbamates, amides, amino acetal derivatives, N-benzyl derivatives, imine derivatives and N-heteroatom derivatives. In particular, they can be selected from among acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl (Bn), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, p-nitrobenzyl-oxycarbonyl, trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), 9-Fluorenylmethyloxycarbonyl (Fmoc), trifluoro-acetyl and benzyl carbamates (substituted or unsubstituted) and the like. Preferably, a protective group of amine function is a Boc group or an acetyl group.
  • Protective groups of hydroxyl function are well known to those skilled in the art. These groups protect the hydroxyl functions against undesirable reactions. The protective groups of hydroxyl functions can be such as described in Greene, “Protective Groups In Organic synthesis”, (John Wiley & Sons, New York (1981)) and Harrison et al. “Compendium of Synthetic Organic Methods”, Vols. 1 to 8 (J. Wiley & Sons, 1971 to 1996). The protective groups of hydroxyl functions comprise substituted or unsubstituted methyl or alkyl ethers or esters e.g. methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl) ethoxymethyl, t-butyl, benzyl and triphenylmethyl, benzyl ethers (substituted or unsubstituted), tetrahydropyranyl ethers, allyl ethers, substituted ethyl ethers e.g. 2,2,2-trichloroethyl, silyl ethers or alkylsilyl ethers, e.g. trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, heterocycle ethers; and esters prepared by reaction of the hydroxyl group with a carboxylic acid e.g. tert-butyl, benzyl or methyl esters, carbonates in particular benzyl or halogenalkyl carbonate, acetate, propionate, benzoate and the like.
  • Protective groups of a terminal alkyne are well known to those skilled in the art. These groups protect the terminal alkyne functions against undesirable reactions. The protective groups of terminal alkyne functions can be such as described in Greene, “Protective Groups in Organic synthesis”, (John Wiley & Sons, New York (1981)) and Harrison et al. “Compendium of Synthetic Organic Methods”, Vols. 1 to 8 (J. Wiley & Sons, 1971 to 1996). The protective groups of terminal alkyne functions comprise silyl groups such as a —SiR2R3R4 group with R2, R3 and R4 representing independently from each other a (C1-C6)alkyl group or a biphenyl group.
  • The term “alkylaluminum halide” as used in the present invention refers to a compound of formula Ra nAlX3-n with Ra representing a (C1-C6)alkyl group, n being a whole number between 1 and 2 and X representing a halogen.
  • The expression “room temperature” designates typically a temperature ranging from 18° C. to 25° C.
  • The term “one-pot process”, as used in the present invention, refers to a process wherein a reactant is subjected to successive chemical reactions in just one reactor.
    • Preparation of Compounds of Formula (I)
  • The invention deals with a process to prepare a compound of the following formula (I):
  • Figure US20230139731A1-20230504-C00017
  • in which:
  • P represents a protective group of a hydroxyl function which is a —COR1 group with R1 representing an aryl group or a (C1-C6)alkyl group,
  • R represents a hydrogen atom or a protective group of a terminal alkyne, from mannose, comprising the following steps:
      • (a) protecting the 5 hydroxyl groups of the mannose by a protective group P;
      • (b) coupling the protected mannose obtained at step (a) with a compound of the following formula (II)
  • Figure US20230139731A1-20230504-C00018
  • Preferably, the protective group P is a —COR1 group with R1 representing an aryl group, preferably R1 is a phenyl group.
  • In particular, R is a —SiR2R3R4 group with R2, R3 and R4 representing independently from each other a (C1-C6)alkyl group or a biphenyl group, preferably R2, R3 and R4 represent a methyl group.
    • Step (a)—Protection Step
  • Protecting the 5 hydroxyl groups of the mannose by a protective group P can be obtained by esterification of mannose.
  • Esterification can be conducted under conditions well known to skilled persons.
  • Notably, mannose can react with a carboxylic acid or its derivatives such as an anhydride acid or an acyl chloride.
  • In particular, mannose reacts with acyl chloride, notably benzoyl chloride (BzCl), in the presence of a base.
  • Advantageously, the reaction occurs in the presence of at least 6 molar equivalents of acyl chloride, more advantageously between 6 and 10 molar equivalents.
  • In particular, the base is an amine, notably triethylamine (TEA), diisopropylethylamine (DIPEA), piperidine or pyridine. Preferably, the base is pyridine.
  • Advantageously, the base is the solvent.
  • The protection reaction can be catalysed by a catalyst such as dimethylaminopyridine (DMAP).
  • Preferably, the protection reaction is conducted at room temperature for at least 1 hour, notably for at least 2 hours.
    • Step (b)—Alkynylation
  • Coupling the protected mannose obtained at step (a) with a compound of formula (II) comprising a terminal alkyne can be performed in the presence of a base and an alkylaluminum halide, and optionally a Lewis acid.
  • In particular, the base is selected among an organolithium reagent RbLi or a Grignard reagent RcMgXa with Rb and/or Rc representing a (C1-C6)alkyl group and Xa representing a halogen.
  • Preferably, the base is an organolithium reagent, notably n-butyl lithium (nBuLi).
  • Advantageously, the alkylaluminum halide is a dialkylaluminum halide, in particular diethylaluminium chloride (Et2AlCl) or dimethylaluminium chloride (Me2AlCl). Preferably, the alkylaluminum halide is Et2AlCl.
  • In particular, in addition to the alkylaluminum halide, which is a Lewis acid, step (b) occurs in the presence of at least another Lewis acid. The Lewis acid is preferably selected among BF3, BCl3, BBr3, TiCl4, PF5, SbF5, SnCl2, SnCl4, ZnCl2, aluminium halide or mixture thereof. Advantageously, the Lewis acid is selected among boron trihalide and aluminium halide or mixture thereof.
  • Preferably aluminium halide is chosen among AlCl3 and AlBr3, more preferably it is AlCl3.
  • Preferably, step (b) is performed in the presence of an alkylaluminum halide and another Lewis acid. More preferably, step (b) is performed in the presence of an alkylaluminum halide and an aluminium halide. Even more preferably, step (b) is performed in the presence of Et2AlCl AlCl3. In particular, step (b) is performed in the presence of AlCl3, Et2AlCl and nBuLi.
  • Preferably, step (b) is conducted in apolar solvent such as toluene, xylene or dichloroethane. More preferably, step (b) is conducted in a mixture toluene/THF.
  • In a specific embodiment, step (b) is divided into three sub-steps:
      • (b1) deprotonation of the compound of formula (II) with a base,
      • (b2) addition of an alkylaluminium halide, preferably diethyl aluminium chloride,
      • (b3) coupling the product obtained at step (a) with the product obtained at step (b2) in the presence of a Lewis acid, preferably aluminium chloride.
  • Deprotonation of the compound of formula (II) is preferably performed with a base selected among organolithium reagent or a Grignard reagent, more preferably, with an organolithium reagent, notably n-butyl lithium nBuLi.
  • Advantageously, addition of the base is carried out at a temperature below −30° C. and the mixture is stirred at 0° C. for at least 10 minutes, in particular at least 20 minutes.
  • Step (b2) is a transmetallation reaction. Preferably, addition of an alkylaluminium halide to the deprotonated compound obtained at step (b1) is carried out at a temperature below 0° C., more preferably below −20° C., and the mixture is stirred at room temperature for at least 10 minutes. In particular, step (b3) is performed by adding a Lewis acid and the product obtained at step (a), i.e. the protected mannose, at a temperature below −20° C. and the mixture is stirred at at least 50° C. for at least 10 hours, more preferably, at least 20 hours.
  • In particular, compounds of formula (I) can be obtained using the following synthetic route:
  • Figure US20230139731A1-20230504-C00019
  • Preferably, compounds of formula (I) can be obtained using the following synthetic route:
  • Figure US20230139731A1-20230504-C00020
    • Step (c)—Deprotection of the Terminal Alkyne
  • In a specific embodiment, when R represents a protective group of a terminal alkyne, step (b) is followed by step (c) deprotecting the terminal alkyne of the compound obtained at step (b) to obtain compound of formula (I) in which R═H.
  • Deprotecting terminal alkyne is conducted under conditions well known to skilled persons.
  • In particular, when R is a —SiR2R3R4 group, deprotection can occur in the presence of fluoride ion, notably in the presence of potassium fluoride, tetra-n-butyl ammonium fluoride or silver fluoride. Preferably, step (c) is conducted in a polar solvent such as DMA, DMF, DMSO, THF, dioxane, acetonitrile or NMP.
  • In particular, compounds of formula (I) can be obtained using the following synthetic route:
  • Figure US20230139731A1-20230504-C00021
    • Preparation of Compounds of Formula (III)
  • The invention also deals with a process to prepare a compound of formula (III):
  • Figure US20230139731A1-20230504-C00022
  • in which
  • Y represents an atom S, an atom O, a
  • Figure US20230139731A1-20230504-C00023
  • group or a
  • Figure US20230139731A1-20230504-C00024
  • group,
      • with A and B representing independently of each other a hydrogen a hydroxyl, an amine or a radical selected from a (C1-C6)alkyl and an aryl, said radical being substituted or not by a (C1-C6)alkyl, a 3-8 membered ring cycloalkyl, —OR5, —OC(O)R5 or —COOR5, R5 representing a hydrogen or a (C1-C6)alkyl, or A and B form together with the carbon atom to which they are bound a 3-7 membered saturated monocyclic ring having 0, 1 or 2 heteroatoms selected from O, N and S, one or several carbon or nitrogen of the ring being optionally substituted by an oxo, a (C1-C6)alkyl, —OR6, —NR6R7, —SO2R6—C(O)R6 or —C(O)OR6, with R6 and R7 representing independently a hydrogen or a radical selected from a (C1-C6)alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C1-C6) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl, a 3-8 membered ring heterocycloalkyl, a halogen, —NR8R9, —CN, —C(O)OR8, —C(O)NR8R9 or —OR8, with R8 and R9 being independently a hydrogen atom or a (C1-C6) alkyl, or R8 and R9 form together with the nitrogen to which they are bound a 3-8 membered ring heterocycloalkyl,
      • with R′ representing a hydrogen atom or a radical selected from a (C1-C6) alkyl, an aryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C1-C6) alkyl, a 3-8 membered ring cycloalkyl, a 3-8 membered ring heterocycloalkyl, —C(O)ORa, —C(O)NRaRb or —ORa, with Ra and Rb being independently a hydrogen atom or a (C1-C6) alkyl optionally substituted by a 3-8 membered ring heterocycloalkyl, or Ra and Rb form together with the nitrogen a 3-8 membered ring heterocycloalkyl,
  • R″ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR1 group with R1 representing an aryl or a (C1-C6)alkyl, from mannose, comprising the following steps:
      • (a)(b) performing steps (a) and (b) to obtain the compound of formula (I) as described in any of the preceding claims;
      • (c) optionally deprotecting the terminal alkyne of the compound obtained after steps (a)(b) to obtain compound of formula (I) in which R═H;
      • (d) Sonogashira coupling of the compound obtained at steps (a)(b) or when applicable at step (c) with a compound of the following formula (IV):
  • Figure US20230139731A1-20230504-C00025
      • in which X is a halogen atom;
      • (e) optionally deprotecting the hydroxyl groups protected by a group P to obtain compound of formula (III) in which R″═H;
      • (f) recovering the compound of formula (III) obtained at step (d) or when applicable at step (e).
  • In an alternative embodiment, step (e) occurs after step (c) and before step (d).
  • In particular, R″ represents a protective group P as described above.
  • Preferably, the protective group P is a —COR1 group with R1 representing an aryl group, preferably R1 is a phenyl group.
  • In a first embodiment, Y represents a
  • Figure US20230139731A1-20230504-C00026
  • group.
  • In particular, R′ is as described above.
  • In a second embodiment, Y represents a
  • Figure US20230139731A1-20230504-C00027
  • group.
  • In particular, A and B are as described above.
  • Advantageously, A and B represent independently of each other a hydrogen, a hydroxyl or a (C1-C6)alkyl substituted or not by a —OR5 group or —OC(O)R5 group, R5 representing a hydrogen or a (C1-C6)alkyl,
  • or A and B form together with the carbon atom to which they are bound a 3-7 membered saturated monocyclic ring having 0, 1 or 2 heteroatoms selected from O, N and S, one or several carbon or nitrogen of the ring being optionally substituted by an oxo, a (C1-C6)alkyl, —OR6, —NR6R7, —SO2R6—C(O)R6 or —C(O)OR6, with R6 and R7 representing independently a hydrogen or a radical selected from a (C1-C6)alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C1-C6) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl, a 3-8 membered ring heterocycloalkyl, a halogen, —NR8R9, —CN, —C(O)OR8, —C(O)NR8R9 or —OR8, with R8 and R9 being independently a hydrogen atom or a (C1-C6) alkyl, or R8 and R9 form together with the nitrogen to which they are bound a 3-8 membered ring heterocycloalkyl.
  • Preferably, the compound of formula (III) is a compound of formula (IIIa)
  • Figure US20230139731A1-20230504-C00028
  • with R10 representing a hydrogen, a (C1-C6)alkyl, —SO2R6, —C(O)R6 or —C(O)OR6, with R6 and R″ being as described above.
  • Compound (IIIa) is advantageously obtained from compound (IVa)
  • Figure US20230139731A1-20230504-C00029
  • with R10 representing a hydrogen, a (C1-C6)alkyl, —SO2R6, —C(O)R6 or —C(O)OR6, with X being a halogen atom.
  • Preferably, R10 is a —C(O)R6 group with R6 representing an aryl or a (C1-C6)alkyl, preferably R6 is a methyl group.
    • Step (a), (b) and (c)
  • Steps (a), (b) and (c) can be performed as described above.
    • Step (d)—Sonogashira Coupling
  • Sonogashira coupling of compound of formula (I) with R═H and compound of formula (IV) is conducted under conditions well known to skilled persons.
  • Preferably, X in compound of formula (IV) is a bromine or an iodine, more preferably, a bromine. Sonogashira coupling can be performed in the presence of a palladium catalyst, or a system of palladium/copper catalyst.
  • Some suitable examples of Pd and Pd/Cu catalysts include Pd(PPh3)4, Pd(PPh3)4/CuI PdCl2(dppf)/CuI, PdCl2(PPh3)/CuI.
  • In particular, Sonogashira coupling occurs in the presence of a base, such as an amine. Preferably, the amine is trimethylamine (TEA), diisopropylethylamine (DIPEA), piperidine, morpholine or pyridine. More preferably, the base is DIPEA.
  • Advantageously, Sonogashira coupling is conducted in a polar solvent. In particular, DMSO, DMF, DMA, THF, dioxane, acetonitrile or NMP can be used as solvent.
  • Preferably, Sonogashira coupling is performed under nitrogen or under argon at a temperature above room temperature, notably above 50° C., for at least 10 hours, preferably at least 20 hours.
  • In particular, steps (c) and (d) occur in a one-pot process. Thus steps (c) and (d) occur in the same reactor without isolation of the intermediate obtained after step (c). Preferably, steps (c) and (d) occur in the same solvent.
    • Step (e)—Deprotection of the Hydroxyl Groups of the Mannose Moiety
  • Compounds of formula (III) with R″ representing a protective group P obtained following step (d) can be subjected to deprotection of the hydroxyl groups of the mannose moiety.
  • Deprotection of hydroxyl groups protected by a group P is conducted under conditions well known to skilled persons and depends on the protective group.
  • When P is a —COR1 group, deprotection consists in a saponification. Saponification is well known to skilled persons.
  • In particular, deprotection occurs in the presence of a base such as a hydroxide or an alkoxide. In particular, the base is an alkoxide, preferably a methoxide, more preferably sodium methoxide. The reaction can be performed in an alcohol, preferably corresponding to the alkoxide used. In particular, deprotection occurs in methanol.
  • The reaction can be performed at room temperature for at least 1 hour.
    • Step (f)—Recovery of Compound of Formula (III)
  • Compound of formula (III) with R″═H can be purified by recrystallization in an alcohol, preferably isopropanol.
  • In particular, compounds of formula (III) can be obtained using the following synthesis scheme:
  • Figure US20230139731A1-20230504-C00030
  • Compound of formula (IIIa) is obtained by Sonogashira coupling of compound of formula (I) and compound of formula (IVa):
  • Figure US20230139731A1-20230504-C00031
  • In a specific embodiment, compound of formula (IVa) wherein R10 is a —COMe group is obtained from compound of formula (IVa) with R10 being a protective group of an amine function different from —COMe, notably a Boc group, by deprotection and acetylation in a one-pot process. In particular, compound of formula (IVa) is obtained through the following synthetic route:
  • Figure US20230139731A1-20230504-C00032
  • In one embodiment of the present invention, compounds of formula (IIIa) are prepared with the following synthesis scheme:
  • Figure US20230139731A1-20230504-C00033
  • In one embodiment of the present invention, compound of formula (IIIa)-3 is prepared with the following synthetic route:
  • Figure US20230139731A1-20230504-C00034
  • The desired product (IIIa)-3 is obtained with a global yield starting from mannose in the order of 35% to 40%.
    • Preparation of Compounds of Formula (V)
  • The invention also deals with a process to prepare a compound of formula (V):
  • Figure US20230139731A1-20230504-C00035
  • in which
  • R11 represents:
      • a —CONR12R13 group with R12 and R13 representing independently a hydrogen or a (C1-C6)alkyl or R12 and R13 form together with the nitrogen a 3-8 membered ring heterocycloalkyl or cycloalkyl,
      • a radical selected from a cycloalkenyl, an aryl and a heteroaryl, said radical being substituted or not by a (C1-C6) alkyl, an aryl, a heteroaryl, a halogen, —C(O)ORa, —C(O)NRaRb, —SO2Ra, —SO2NRaRb, —NRaRb, —ORa, —CN or —NO2, with Ra and Rb being independently a hydrogen atom or a (C1-C6) alkyl,
  • R″ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR1 group with R1 representing an aryl or a (C1-C6)alkyl, from mannose, comprising the following steps:
      • (a)(b) performing steps (a) and (b) to obtain the compound of formula (I) as described in any of the preceding claims;
      • (c) optionally deprotecting the terminal alkyne of the compound obtained after steps (a)(b) to obtain compound of formula (I) in which R═H;
      • (d) Sonogashira coupling of the compound obtained at steps (a)(b) or when applicable at step (c) with a compound of the following formula (VI):
  • Figure US20230139731A1-20230504-C00036
      • in which X is a halogen atom and X′ is a halogen or a radical R11;
      • (e) optionally deprotecting the hydroxyl groups protected by a group P to obtain compound of formula (V) in which R″═H;
      • (f) recovering the compound of formula (V) obtained at step (d) or when applicable at step (e).
  • In an alternative embodiment, step (e) occurs after step (c) and before step (d).
  • In particular, R11 represents a radical selected from an aryl and a heteroaryl, said radical being substituted or not by a (C1-C6) alkyl, an aryl, a heteroaryl, a halogen, —C(O)ORa, —C(O)NRaRb, —SO2Ra, —SO2NRaRb, —NRaRb, —ORa, —CN or —NO2, with Ra and Rb being independently a hydrogen atom or a (C1-C6) alkyl. More preferably, R11 represents a heteroaryl substituted or not by a (C1-C6) alkyl, an aryl, a heteroaryl, a halogen, —C(O)ORa, —C(O)NRaRb, —SO2Ra, —SO2NRaRb, —NRaRb, —ORa, —CN or —NO2, with Ra and Rb being independently a hydrogen atom or a (C1-C6) alkyl. Even more preferably, R11 represents a pyridinone substituted or not by a (C1-C6) alkyl group.
  • In a specific embodiment, the compound of formula (V) is a compound of formula (Va)
  • Figure US20230139731A1-20230504-C00037
    • Step (a), (b), (c), (e) and (f)
  • Steps (a), (b) and (c) can be performed as described above.
    • Step (d)—Sonogashira Coupling
  • Steps (d) can be performed as described above.
  • In a specific embodiment, when R11 represents an aryl or a heteroaryl, then X′ represents advantageously a halogen.
  • In this embodiment, an additional step (d′) between step (d) and step (e) can be performed.
  • Step (d′) is a Suzuki coupling between the product obtained at step (d) and an aryl- or heteroaryl-boron derivative.
  • Suzuki coupling is conducted under condition known to skilled persons.
  • The boron derivative can be a boronic acid derivative, a boronic ester derivative or a trifluoroborate derivative. The radical aryl or heteroaryl of the aryl- or heteroaryl-boron derivative correspond to the group R11. Thus, when the boron derivative is a boronic acid derivative, its formula is R11—B(OH)2.
  • Suzuki coupling can be performed in the presence of a palladium catalyst such as Pd(PPh3)4.
  • In particular, Suzuki coupling occurs in the presence of a base, such as a carbonate, an acetate or an amine.
  • In particular, compounds of formula (V) can be obtained using the following synthesis scheme
  • Figure US20230139731A1-20230504-C00038
  • In one embodiment of the present invention, compounds of formula (V) are prepared with the following synthesis scheme:
  • Figure US20230139731A1-20230504-C00039
  • Compound of Formula (Ilia)
  • According to the present invention, in the compound of the following formula (IIIa):
  • Figure US20230139731A1-20230504-C00040
  • R10 represents advantageously a —C(O)R6 group with R6 representing an aryl or a (C1-C6)alkyl, preferably R6 is a methyl group.
  • Preferably, R″ represents —COR1 group with R1 being an aryl, such as a phenyl, or a (C1-C6)alkyl, such as a methyl. More preferably, R″ represents a benzoyl group of formula —COPh, wherein Ph is the abbreviation for the phenyl group.
  • According to a preferred embodiment, compound of formula (IIIa) is the compound of the following formula (IIIa-2):
  • Figure US20230139731A1-20230504-C00041
    • EXAMPLES Abbreviation
    • Bz benzoyl
    • n-BuLi n-butyl lithium
    • MTBE methyl tert-butyl ether
    • DMA dimethylacetamide
    • THF tetrahydrofuran
    Preparation of Compound a-1
  • D-mannose (1.0 equiv.) and dimethylaminopyridine (0.1 equiv.) are dissolved in pyridine (20 vol). Benzoyl chloride (8.0 equiv.) is added at −15° C., The reaction mixture is stirred at room temperature for 2 hours. Ethyl acetate is added. The mixture is cooled to −15° C. and a solution of hydrochloric acid (3 M) is added until pH<7. The organic phase is isolated and washed with a solution of sodium bicarbonate, and then a solution of sodium chloride. The organic phase is then dried on anhydrous sodium sulfate and evaporated under reduced pressure. Ethanol is added to precipitate compound a-1. The mixture is filtered and the filter cake is washed with ethanol. The filter cake is dried under vacuum and compound a-1 is obtained as a white solid with a purity above 95% by HPLC and a yield ranging from 70 to 90%. 1H NMR (400 MHz, DMSO) δ 7.95-8.25 (m, 8H), 7.36-7.82 (m, 17H), 6.58 (s, 1H), 5.91-6.17 (m, 3H), 4.82-4.84 (m, 1H), 4.52-4.67 (m, 2H). ESI-MS m/z calc. 700.1, found (M+Na)+: 723.4.
    • Preparation of Compound (1)-1
  • n-BuLi (2.5 M in hexanes, 2.0 equiv.) is added to a solution of trimethylsilyl acetylene (2.1 equiv.) in toluene (6.6 vol.) at a temperature below −30° C. The reaction mixture is stirred at 0° C. for 20 min. The mixture is cooled and diethyl aluminium chloride is added at a temperature below −20° C. The reaction is stirred at room temperature for 10 min. The mixture is cooled at −30° C. and THF (2.0 equiv.), aluminium chloride (2.0 equiv.) and compound a-1 (1.0 equiv.) are successively added. The reaction mixture is stirred at 60° C. for 20 hours. The mixture is cooled at −30° C. and MTBE (10 vol.) and a solution of hydrochloric acid (2 M) are added successively. The organic phase is isolated and washed with a solution of sodium bicarbonate, and then a solution of sodium chloride. The organic phase is then dried on anhydrous sodium sulfate. DMA (2.9 vol.) is added. The organic solvents except DMA are evaporated. Compound (I)-1 in solution in DMA is ready for next step at a purity >60% and an estimate yield ranging from 80 to 90%. 1H NMR (400 MHz, DMSO) δ 7.40-8.20 (m, 20H), 5.90-6.05 (m, 2H), 5.74-5.79 (m, 1H), 5.30-5.33 (m, 1H), 4.53-4.72 (m, 3H), 0.35 (s, 9H). ESI-MS m/z calc. 676.2, found (M+Na)+: 699.5.
    • Preparation of Compound (IVa)-3
  • To a solution of compound (IVa)-1 (1 equiv.) in acetic acid is added acetic anhydride (2.0 equiv.) and acetyl chloride (2.0 equiv.) at room temperature. The reaction mixture is stirred at 100° C. for 7 hours. The reaction mixture is cooled at room temperature and stirred for 6 hours. Sodium acetate (2.5 equiv.) is added followed by water at room temperature and stirred for 3 hours. The reaction mixture is filtered. The filer cake is washed with water and dried under vacuum. Compound (IVa)-3 is obtained with a yield ranging from 85 to 100%. 1H NMR (400 MHz, DMSO) δ 8.01 (s, 2H), 7.86-7.89 (d, 2H, J=8.0 Hz), 7.59-7.62 (d, 2H, J=8.0 Hz), 3.80-3.85 (m, 4H), 2.12 (s, 3H), 1.73-1.90 (m, 4H). ESI-MS m/z calc. 432.9, found (M+Na)+: 456.0.
    • Preparation of Compound (IIIa)-2
  • To a solution of compound (1)-1 (2.5 equiv.) in DMA is added compound (IVa)-3 (1.0 equiv.) and potassium fluoride (8.0 equiv.). The reaction mixture is stirred under vacuum at room temperature for 30 min. N,N-diisopropylethylamine (4.0 equiv.) is added. Nitrogen is bubbled into the reaction mixture for 30 min. The reaction mixture is heated at 50° C. and tetrakis(triphenylphosphine)palladium (0.05 equiv.) and copper iodide (0.1 equiv.) are added successively. The reaction mixture is stirred at 60° C. for 24 hours. The reaction mixture is cooled at 10° C. and acetic acid (8.0 equiv.), methanol (12 vol.) and N-acetyl-cysteine (2.0 equiv.) are added successively. The reaction mixture is stirred at 30° C. for 48 hours. The reaction mixture is filtered. The filer cake is washed with methanol and dried under vacuum. Compound (IIIa)-2 is obtained as a white solid with a purity above 85 to 90% by HPLC and a yield ranging from 85 to 95%. 1H NMR (400 MHz, DMSO) δ 7.37-8.17 (m, 46H), 6.00-6.12 (m, 4H), 5.91-5.92 (m, 2H), 5.57-5.58 (m, 2H), 4.72-4.84 (m, 4H), 4.59-4.62 (m, 2H), 3.95-4.00 (m, 4H), 2.14 (s, 3H), 1.88-1.89 (m, 4H). ESI-MS m/z calc. 1481.5, found (M+Na)+: 1505.6.
    • Preparation of Compound (IIIa)-3
  • To a solution of compound (IIIa)-2 (1.0 equiv.) in THF are added successively methanol and sodium methoxide, 25% in methanol (1.1 equiv.) at a temperature below 20° C. The reaction mixture is stirred at room temperature for 16 hours. Isopropanol is added. The reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is filtered. The filter cake is washed with isopropanol and dried under vacuum. Compound (IIIa)-3 is obtained as a brown solid with a purity above 95% by HPLC and a yield ranging from 90 to 100%. 1H NMR (400 MHz, DMSO) δ 7.93-7.95 (d, 2H, J=8.0 Hz), 7.85 (s, 2H), 7.50-7.52 (d, 2H, J=8.0 Hz), 4.98-4.99 (d, 2H), 4.72-4.82 (m, 6H), 4.49-4.52 (m, 2H), 3.85-3.95 (m, 6H), 3.71-3.80 (m, 4H), 3.42-3.61 (m, 6H), 2.13 (s, 3H). ESI-MS m/z calc. 649.3, found (M+Na)+: 672.4.

Claims (8)

1. A compound of formula (IIIa):
Figure US20230139731A1-20230504-C00042
wherein R10 represents a hydrogen, a (C1-C6)alkyl, —SO2R6, —C(O)R6 or —C(O)OR6, with R6 being a hydrogen or a radical selected from a (C1-C6)alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C1-C6) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl or a 3-8 membered ring heterocycloalkyl, a halogen, —NR8R9, —CN, —C(O)OR8, —C(O)NR8R9 or —OR8, with R8 and R9 being independently a hydrogen atom or a (C1-C6) alkyl, or R8 and R9 form together with the nitrogen to which they are bound a 3-8 membered ring heterocycloalkyl and R″ represents —COR1 group with R1 being an aryl.
2. The compound of claim 1, wherein R10 represents a hydrogen, a (C1-C6)alkyl, —SO2R6, —C(O)R6 or —C(O)OR6.
3. The compound of claim 2, wherein R10 represents —C(O)R6.
4. The compound of claim 3, wherein R6 is an aryl.
5. The compound of claim 3, wherein R6 is a (C1-C6)alkyl.
6. The compound of claim 5, wherein R6 is a methyl group.
7. The compound of claim 1, wherein R1 is a phenyl.
8. The compound of claim 1, being of formula (IIIa)-2:
Figure US20230139731A1-20230504-C00043
US18/083,674 2018-07-26 2022-12-19 Process for preparing mannose derivatives Abandoned US20230139731A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US18/083,674 US20230139731A1 (en) 2018-07-26 2022-12-19 Process for preparing mannose derivatives

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP18306013.6 2018-07-26
EP18306013 2018-07-26
PCT/EP2019/070276 WO2020021113A1 (en) 2018-07-26 2019-07-26 Process for preparing mannose derivatives
US202117263012A 2021-01-25 2021-01-25
US18/083,674 US20230139731A1 (en) 2018-07-26 2022-12-19 Process for preparing mannose derivatives

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2019/070276 Continuation WO2020021113A1 (en) 2018-07-26 2019-07-26 Process for preparing mannose derivatives
US17/263,012 Continuation US11560399B2 (en) 2018-07-26 2019-07-26 Process for preparing mannose derivatives

Publications (1)

Publication Number Publication Date
US20230139731A1 true US20230139731A1 (en) 2023-05-04

Family

ID=63144933

Family Applications (2)

Application Number Title Priority Date Filing Date
US17/263,012 Active US11560399B2 (en) 2018-07-26 2019-07-26 Process for preparing mannose derivatives
US18/083,674 Abandoned US20230139731A1 (en) 2018-07-26 2022-12-19 Process for preparing mannose derivatives

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US17/263,012 Active US11560399B2 (en) 2018-07-26 2019-07-26 Process for preparing mannose derivatives

Country Status (5)

Country Link
US (2) US11560399B2 (en)
EP (1) EP3827003A1 (en)
JP (1) JP7377266B2 (en)
CN (1) CN112771035A (en)
WO (1) WO2020021113A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2021268664A1 (en) 2020-05-05 2022-10-20 Nuvalent, Inc. Heteroaromatic macrocyclic ether chemotherapeutic agents
IL297898A (en) 2020-05-05 2023-01-01 Nuvalent Inc Macrocyclic heteroaromatic chemotherapeutic agents
IL311444A (en) 2021-10-01 2024-05-01 Nuvalent Inc Solid forms, pharmaceutical preparations and preparation of macrocyclic heteroaromatic ether compounds
CN114773511B (en) * 2022-04-19 2023-10-31 上海应用技术大学 Mannose-containing polymer and preparation method thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1964626A (en) 2004-03-31 2007-05-16 纽约大学 Novel synthetic c-glycolipids, their synthesis and use to treat infections, cancer and autoimmune diseases
KR102075885B1 (en) * 2012-12-18 2020-02-11 버텍스 파마슈티칼스 인코포레이티드 Mannose derivatives for treating bacterial infections
WO2016199105A1 (en) 2015-06-12 2016-12-15 Vertex Pharmaceuticals Incorporated Mannose derivatives for treating bacterial infections
DE112018002254T5 (en) 2017-04-28 2020-01-23 Sony Corporation MAGNETIC RECORDING MEDIUM

Also Published As

Publication number Publication date
US20210309682A1 (en) 2021-10-07
EP3827003A1 (en) 2021-06-02
WO2020021113A1 (en) 2020-01-30
US11560399B2 (en) 2023-01-24
JP2021533188A (en) 2021-12-02
JP7377266B2 (en) 2023-11-09
CN112771035A (en) 2021-05-07

Similar Documents

Publication Publication Date Title
US20230139731A1 (en) Process for preparing mannose derivatives
US11713298B2 (en) Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
CA2951138A1 (en) Processes for preparing antiviral compounds
CN102212082A (en) Rosuvastatin calcium intermediate and preparation method thereof
CN112358427B (en) A kind of synthetic method of trifluoromethyl thioester compound
UA53742C2 (en) A process and intermediate products useful for antifolates preparing
US9328100B2 (en) Process for the preparation of β-C-arylglucosides
US9938297B2 (en) Process for the synthesis of everolimus and intermediates thereof
CN101563312A (en) Process for producing intermediate of asenapine synthesis
WO2016147197A1 (en) A novel process for preparing (2s,3r,4r,5s,6r)-2-[4-chloro-3-(4-ethoxybenzyl)pheny 1] -6-(hy droxy methyl)tetrahydro-2h-py ran-3,4,5-triol and its amorphous form
EP3986400B1 (en) Processes and intermediates for producing diazaspiro lactam compounds
NO137550B (en) ANALOGICAL PROCEDURE FOR THE PREPARATION OF ANTI-INFLAMMATORY ACTIVITY 2,4,5-TRISUBSTITUTED OXSAZOLE COMPOUNDS
CA2043817A1 (en) Process and intermediates for beta-lactams having aminothiazole (iminooxyacetic acid) acetic acid sidechains
CN117362316A (en) Synthesis method of tetrahydropyrrolothiazole compound
AU2021301939A1 (en) Method for preparing intermediate of uracil compound containing isoxazoline
WO2017060925A1 (en) Novel pipecolic acid co-crystals of dapagliflozin and process for the preparation thereof
CN112409207B (en) Preparation method of dimoxystrobin
JP7635440B2 (en) Method for producing 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivatives, 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivatives and 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-triones and methods for producing them
JP3855686B2 (en) 3,3-dialkoxy-2-hydroxyimino derivative and process for producing the same
KR101003822B1 (en) Method for preparing docetaxel and novel intermediates for the production of docetaxel
TW202434554A (en) Process for the preparation of isoxazoline derivatives
WO2024249672A1 (en) Process of preparing hiv capsid inhibitor
JPS59222430A (en) Fluorocyclopropane derivative
KR101003820B1 (en) Method for preparing docetaxel and novel intermediates for the production of docetaxel
JPS61293979A (en) Method for producing 3-substituted-2-formylthiophene compound

Legal Events

Date Code Title Description
AS Assignment

Owner name: ENTEROME, FRANCE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:AREFYEV, DENIS VIKTOROVICH;CRUSKIE, MICHAEL P.;GAMAGE, CHAMINDA PRIYAPUSHPA;AND OTHERS;SIGNING DATES FROM 20210401 TO 20221013;REEL/FRAME:062155/0318

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION