[go: up one dir, main page]

WO2020202205A1 - Procédé de préparation de dérivés de 1,1-dialkyléthane-1,2-diols en tant qu'intermédiaires utiles - Google Patents

Procédé de préparation de dérivés de 1,1-dialkyléthane-1,2-diols en tant qu'intermédiaires utiles Download PDF

Info

Publication number
WO2020202205A1
WO2020202205A1 PCT/IN2020/050309 IN2020050309W WO2020202205A1 WO 2020202205 A1 WO2020202205 A1 WO 2020202205A1 IN 2020050309 W IN2020050309 W IN 2020050309W WO 2020202205 A1 WO2020202205 A1 WO 2020202205A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
formula
unsubstituted
compound
aryl
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.)
Ceased
Application number
PCT/IN2020/050309
Other languages
English (en)
Other versions
WO2020202205A4 (fr
Inventor
Sumit Sharma
Riyaz Ahmed
Sushil Raina
Ram Ashrey VISHWAKARMA
Parvinder Pal SINGH
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.)
Council of Scientific and Industrial Research CSIR
Original Assignee
Council of Scientific and Industrial Research CSIR
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 Council of Scientific and Industrial Research CSIR filed Critical Council of Scientific and Industrial Research CSIR
Priority to CN202080027021.6A priority Critical patent/CN113874341B/zh
Publication of WO2020202205A1 publication Critical patent/WO2020202205A1/fr
Publication of WO2020202205A4 publication Critical patent/WO2020202205A4/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/18—Polyhydroxylic acyclic alcohols
    • C07C31/20—Dihydroxylic alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D263/12—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to the field of pharmaceutical industry of antimicrobial agents.
  • the present invention particularly relates to the compounds and methods of making them that are useful as an intermediate for the preparation of active pharmaceutical ingredients, such as: anti-bacterial, anti-cancer, anti-HIV, anti-parasitic, anti-tuberculosis, anti-leishmanasis agents etc., as well as imaging agents. More particularly, the present invention relates to 1,1- dialkylethane-l,2-diols and process for the preparation thereof.
  • Tuberculosis remains a leading infectious cause of death worldwide.
  • the existing treatment of tuberculosis requires a lengthy therapy and often needs a combination of three or four different drugs (first-line drug regimen such as isoniazide, pyrazinamide, and rifampin and several second line drug regimen including ethionamide, para-aminosalicylic acid, kanamycin, amikacin, capreomycin, ciprofloxacin, streptomycin, etc.).
  • first-line drug regimen such as isoniazide, pyrazinamide, and rifampin
  • second line drug regimen including ethionamide, para-aminosalicylic acid, kanamycin, amikacin, capreomycin, ciprofloxacin, streptomycin, etc.
  • nitroimidazole J. Med. Chem. 2017, 60, 7636-7657
  • based drugs have played a very important role in combating infections of various types.
  • One of major outcomes of all these efforts is the discovery and development of Delamanid, a nitro-dihydro-imidazooxazole derivative, for the treatment of multidrug- resistant tuberculosis (MDR-TB).
  • PCT application, W02004033463A1 reports 2,3-dihydro- 6-nitroimidazo[2,l-b]oxazoles, including Delamanid (Compound 1572, page 970 of 1084) and process for the preparation thereof.
  • Delamanid Compound 1572, page 970 of 1084
  • several other nitroimidazole s have also been studied, such as:
  • the halonitroimidazole or dinitroimidazole is coupled with the three- carbon chiral epoxide to prepare the intermediate (D), which is coupled with the phenolic fragment (C) to form intermediate (E) and finally converted to the target molecule, as shown below:
  • the phenolic fragment is first coupled with the chiral three-carbon fragment to generate a diol intermediate (F) which is later coupled with imidazole derivative to form intermediate (E) which in turn is converted to the target molecule, as shown below.
  • WO 2004/033463 and J. Med. Chem. 2006, 49, 7854 describe 2,3-dihydro-6- nitroimidazo[2,l-b]oxazozles derivatives with focus on Delamanid.
  • An epoxide compound of formula (II-l) is treated with the phenol of formula (II-2), wherein R 1 is a hydrogen atom or lower alkyl group, R 2 is a substituted piperidyl group or a substituted piperazinyl group and X 1 is a halogen atom or a nitro group, to produce a tertiary alcohol intermediate (II-3) which is converted to final compound (II-4) as shown in Scheme (II).
  • WO 2011/151320 relating to nitroimidazole derivatives possessing radioactive or non- radioactive halogen atoms, reports treatment of the epoxide (III-l) with 4-halophenol (III-2) to provide the halo containing compound (III-3).
  • WO 2004/035547 describes a process for producing 1-substituted 4-nitroimidazole compounds, an intermediate for various medicines and agricultural chemicals, especially as an intermediate for anti-tubercular agents.
  • Treatment of halonitroimidazole (IV-1) (or corresponding sulfoxide) with an epoxy-sulfonate (IV-2) provide an intermediate (IV-3), which is treated with a nucleophile (IV-4) to provide (IV-5) and finally the target (IV-6).
  • WO 2008/140090 also describes following process of Scheme (V).
  • 1,4-cyclohexanedione (V- 2) is treated with a piperidine derivative (V-l) in the presence of PTSA to provide a salt of phenol (V-3).
  • the phenol (V-3) is treated with epoxide (V-4) to provide another epoxide (V-5) which finally provided (V-7), when treated with nitroimidazole derivative (V-6).
  • WO/2011/093529 describes an organic sulfonyloxy group containing compound of formula (VI-4).
  • a diol compound (VI-1) is coupled with a piperidine derivative (VI-2) in the presence of catalytic amounts of Pd2dba3 and l BuXPhos along with sodium tert-butoxide in toluene.
  • the resulting diol (VI-3) is converted to the epoxide (VI-5).
  • Coupling of epoxide (VI-5) with halonitroimidazole (VI-6) provided the target molecule (VI-8) via an intermediate (VI-7).
  • the diol intermediate (F), as mentioned above, can alternatively be prepared by allylation of the phenol (C) to generate an intermediate of type (G) followed by asymmetric dihydroxylation reaction. This type of reaction is the subject matter of the present invention.
  • the diol compounds of type (F) can be further converted to the targeted nitrodihydroimidazooxazole molecule s .
  • the main objective of the invention is to provide a novel and practical route of synthesis of intermediates and derivatives of 6-nitro-2,3-dihydroimidazo[2,l-b]oxazoles that are useful for the treatment of various bacterial and parasitic infections.
  • Another objective of the invention is to provide route of synthesis for preparation of the derivatives of chiral 1,1 -dialky lethane- 1,2-diols.
  • Yet another objective of the invention is to provide a practical and novel route of synthesis of Delamanid.
  • the present invention provides a compound of general Formula (I), or a salt or an isomer thereof
  • Y is substituted or unsubstituted carbon, nitrogen, oxygen or a sulfur atom
  • R is substituted or unsubstituted alkyl
  • Ar is substituted or unsubstituted aryl
  • the compounds of general Formula (I) are 1,1 -dialky lethane-l,2-diols.
  • the present invention provides a process for the preparation of compound of general Formula (I), or a salt or an isomer thereof
  • the present invention provides a process of making the diol compounds of Formula (I), from corresponding alkene compounds of Formula (IA) employing asymmetric dihyroxylation.
  • the present invention provides a process of making the diol compounds of Formula (I), from corresponding alkene compounds of Formula (IA) employing Sharpless asymmetric dihyroxylation; wherein the alkene (IA) is allowed to react with a suitable asymmetric catalyst in a suitable solvent at a suitable temperature for a suitable time period.
  • the present invention provides a process for the preparation of alkene compounds of Formula (IA), comprising: alkylation/allylation of corresponding phenol with methallyl halide or other suitable allyl halide derivatives in presence of a suitable base and a suitable solvent.
  • l,l-dialkylethane-l,2-diols of Formula (I) are selected from the group, comprising compounds of following formula:
  • the present invention provides use of compound of general Formula (I) for the preparation of 6-nitro-2,3-dihydroimidazo[2,l-b]oxazole derivatives of following formula (H):
  • 6-nitro-2,3-dihydroimidazo[2,l-b]oxazole derivatives of formula (H) are selected from the group, comprising of following compounds, and the like:
  • the present invention provides compound of following formula:
  • the present invention provides antibacterial compounds of following formula:
  • the present invention provides compounds of formula (003R) and (003S) for the treatment of mycobacterial infections.
  • the present invention provides antitubercular pharmaceutical composition of compounds of formula (003R) and (003S). BRIEF DESCRIPTION OF DRAWINGS
  • Figure 1 HPLC chromatogram of crude reaction mixture of compound of Formula (009) for determination of % ee.
  • Figure 2 HPLC chromatogram of crude reaction mixture of compound of Formula (017) for determination of %ee.
  • Figure 3 Anti-TB In vivo efficacy data of compound 003(R) in mice model of infection
  • the present invention provides a compound of general Formula (I), or a salt or an isomer thereof
  • Y is substituted or unsubstituted carbon, nitrogen, oxygen or a sulfur atom
  • Z is substituted or unsubstituted alkyl, aryl, or heteroaryl group, wherein a substituent is independently selected from groups such as H, X, NO2, CN, COOH, COOR, OH, OR, OAr, OHetAr, SH, S(0) n R, SAr, SHetAr, substituted or unsubstituted alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl, NH 2 , NHR, NHAr, NH-HetAr, NR 2 , NAr 2 , NHetAn, CONR 3 ⁇ 4 OC(0)OR, OC(0)NR; wherein
  • X F, Cl, Br or I
  • R is substituted or unsubstituted alkyl
  • Ar is substituted or unsubstituted aryl
  • the Z in Formula (I) can be an aryl group independently substituted by N-Het group, wherein N-Het represents and is independently selected from one of the N- containing alkyl or aryl system such as acridine, azabenzotriazole, azaindole, azepane, azepine, azetidine, aziridine, benzimidazole, benzotriazole, carbazole, cinnoline, cyclopenta[b]pyridine, deazapurine, diazepine, dihydropyridine, imidazopyridine, imidazole, imidazolidine, imidazopyridazine, imidazopyridine, imidazopyrimidine, indazole, indole, indoline, indolizine, isoindole, isoquinoline, naphthyridine, oxindole, phenanthroline, phenazine, phthalazin
  • the present invention provides a compound of general Formula (I), selected from the group, comprising:
  • the compounds of general Formula (I) are l, l-dialkylethane- l,2-diols, selected from the group.
  • the present invention provides a process for the preparation of compound of general Formula (I), or a salt or an isomer thereof
  • the present invention provides a process of making the diol compounds of Formula (I), from corresponding alkene compounds of Formula (IA) employing asymmetric dihyroxylation.
  • Formula (IA) wherein A, W, Y, Z and n are as defined above.
  • the present invention provides a compound of Formula (IA), selected from the group, comprising:
  • the present invention provides a process of making the diol compounds of Formula (I), from corresponding alkene compounds of Formula (IA) employing Sharpless asymmetric dihyroxylation; wherein the alkene (IA) is allowed to react with a suitable asymmetric catalyst in a suitable solvent at a suitable temperature for a suitable time period
  • Formula (IA) Formula (I) wherein A, W, Z and n are as defined above.
  • Suitable asymmetric catalysts include, but are not limited to, AD-mix a [(DHQ)2PHAL, the phthalazine adduct with dihydroquinine] or AD-mix b [(DHQD)2PHAL, the phthalazine adduct with dihydroquinidine], or the like.
  • Suitable solvents include, but are not limited to, polar solvents, preferably polar-protic solvents.
  • the suitable solvents include, water, acetone, butanone, methanol, ethanol, isopropanol, butanol, tert-butanol , or the like, or mixture thereof.
  • the suitable solvent is a mixture of tert-butyl alcohol and water.
  • the suitable temperature for the reaction is about - 30 °C to 40 °C.
  • the suitable temperature range is - 5 °C to 25 °C.
  • the suitable time period for the reaction is 4 hrs to 24 hrs, though it is variable with respect to reactants and reaction conditions.
  • l,l-dialkylethane-l,2-diols of Formula (I) are compounds of following formula:
  • the present invention provides use of compound of general Formula (I) for the preparation of 6-nitro-2,3-dihydroimidazo[2,l-b]oxazole derivatives of following formula (H):
  • 6-nitro-2,3-dihydroimidazo[2,l-b]oxazole derivatives of formula (H) are selected from the group, comprising of following compounds, and the like:
  • the present invention provides compound of following formula:
  • the present invention provides antibacterial compounds of following formula:
  • the present invention provides compounds of formula (003R) and (003S) for the treatment of mycobacterial infections.
  • the present invention provides antitubercular pharmaceutical composition of compounds of formula (003R) and (003S).
  • the present invention provides a process for the preparation of alkene compounds of Formula (IA), comprising: alkylation/allylation of corresponding phenol with methallyl halide (for e.g. Methallyl chloride, Methallyl bromide, Methallyl iodide or other suitable allyl halide (e.g. allyl bromide, allyl chloride or allyl iodide) derivatives in presence of a suitable base (e.g. potassium carbonate, Cesium carbonate or sodium hydride) and a suitable solvent (e.g. acetonitrile, acetone, DMF) at a suitable temperature (range from 60-70 °C) for a suitable time period (2-4 hrs.)
  • methallyl halide for e.g. Methallyl chloride, Methallyl bromide, Methallyl iodide or other suitable allyl halide (e.g. allyl bromide, allyl chloride
  • the allylation step serves as a protecting group for the phenolic OH for subsequent reactions as well as attachment of the three carbon fragment to the molecule thereby saving two steps of protection and deprotection that are required otherwise.
  • the alkenes of Formula (IA), e.g. compounds of Formula ((001), (005) etc.), can be either commercially available or can be prepared by simple synthetic methods.
  • the corresponding phenolic compound is allowed to react with methallyl halide (or any other allyl halide) in the presence of a suitable base, e.g. potassium carbonate etc., in a suitable solvent, e.g. DMF, at about 50-100 °C, preferably at 60-70 °C, for about 6-12 hrs;
  • the processes for the alkenes of Formula (IA), e.g. compounds of Formula (008, Oil, 016 etc.), may be difficult and require multiple steps of preparation.
  • a phenol compound of Formula (007) can be prepared through cycloaddition reaction between 4-azidophenol (R6), prepared by azidation of 4-aminophenol (R5), and l-(prop-2-yn-l-yloxy)-4-(trifluoromethoxy)benzene (R4), prepared by propargylation of 4-trifluoromethoxyphenol (R2) with propargyl halide (R3).
  • a phenol compound of Formula (010) can be prepared through cycloaddition reaction between 4-hydroxybenzaldehyde oxime (Rll), prepared from 4- hydroxy benzaldehyde (R9), and l-(prop-2-yn-l-yloxy)-4-(trifluoromethoxy)benzene (R8), prepared by propargylation of 4-trifluoromethoxyphenol (R7) with propargyl halide (R3).
  • Rll 4-hydroxybenzaldehyde oxime
  • R9 4- hydroxy benzaldehyde
  • R8 l-(prop-2-yn-l-yloxy)-4-(trifluoromethoxy)benzene
  • a phenol compound of Formula (016) can be prepared by allylation of a phenol compound of Formula (013) using methallyl chloride as an allylating reagent, followed by Cul mediated N-arylation using unprotected 4-hydroxypiperidine as an amine source to provide alcohol of Formula (015), and finally O-arylation under the Mitsunobu reaction conditions.
  • the compound of Formula (016) can also be prepared by N-arylation of compound of Formula (014) using commercially available 4-(4- (trifluoromethoxy)phenoxy)piperidine as an amine source.
  • Figure 1 illustrates HPLC chromatogram of crude reaction mixture of compound of Formula (009) for determination of % ee.
  • Part-A of the Figure 1 shows the peaks of racemic isomer
  • RS optically pure R-isomer of compound of Formula (009).
  • Part-B shows the peaks of optically pure R-isomer of compound of Formula (009).
  • Part-C shows the predominant peak of optically pure S-isomer of compound of Formula (009).
  • Figure 2 illustrates HPLC chromatogram of crude reaction mixture of compound of Formula (017) for determination of % ee.
  • Part-A of the Figure 2 shows the peaks of racemic isomer (RS) of compound Formula (017).
  • Part-B shows the peaks of optically pure R-isomer of compound of Formula (017).
  • Part-C shows the predominant peak of optically pure S-isomer of compound of Formula (017).
  • the modifier "about” should be considered as disclosing the range defined by the absolute values of the two endpoints.
  • the expression “from about 1 to about 4" also discloses the range “from 1 to 4.”
  • the term “about” may refer to ⁇ 10% of the said number including the indicated number.
  • “about 10%” may cover a range of 9% to 11%, and “about 1” means from 0.9-1.1.
  • alkyl refers to an organic group derived from alkane. It also refers, by itself or as part of another substituent, to a straight or branched monovalent hydrocarbon containing up to 1-20 carbon atoms; an “alkyl” group may also be represented as -(CRlR2)n-, where R1 and R2 are independently hydrogen or are independently absent, and for example, m is 1 to 8, and such representation is also intended to cover both saturated and unsaturated alkyl groups; number designators indicate the number of carbon atoms in any substituent, like, C1-C20 means one to twenty carbon atoms; variables or substituents such as Rl, R2, R3, R4, R5 that each of the R groups can be independently defined by any one of the alkyl groups and can be either the same of different groups; the term“substituted alkyl” refers to such straight or branched chain radicals of 1 to 7 carbons wherein one or more hydrogens have been replaced by a hydroxy, amino,
  • the term“lower alkyl” refers to straight or branched chain radicals having one to four carbons
  • the term“substituted lower alkyl” refers to such straight or branched chain radicals having one to four carbons wherein one hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, -NH(lower alkyl),— N(lower alkyl)2, lower alkoxy, lower alkylthio, or carboxy
  • the term“alkenyl” refers to straight or branched chain radicals of 3 to 7 carbon atoms having one or two double bonds; it also refers to a straight or branched monovalent hydrocarbon containing 2-20 carbon atoms (e.g., C2-C10 or C
  • the term“substituted alkenyl” refers to such straight or branched radicals of 3 to 7 carbons having one or two double bonds wherein a hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, — NH(lower alkyl), — N(lower alkyl)2, lower alkoxy, lower alkylthio, or carboxy;
  • the term“alkynyl” refers to a straight or branched monovalent hydrocarbon containing 2-20 carbon atoms (e.g., C2-C10) and one or more triple bonds.
  • alkynyl examples include, but are not limited to, ethynyl, 1-propynyl, 1- and 2-butynyl, and l-methyl-2-butynyl; the term“alkoxy” refers to an -O-alkyl radical.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy; the terms“lower alkoxy” and“lower alkylthio” refer to such lower alkyl groups as defined above attached to an oxygen or sulfur; the term“acyloxy” refers to an -0-C(0)-R radical in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; the term“amino” refers to NH2, alkylamino, or arylamino; the term“alkylamino” refers to an -N(R)-alkyl radical in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl,
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,4-cyclohexylene, cycloheptyl, cyclooctyl, and adamantyl; the term“cycloalkenyl” refers to a monovalent non-aromatic hydrocarbon ring system having 3 to 20 carbons (e.g., C3-C20) and one or more double bonds.
  • heterocycloalkyl refers to a monovalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se).
  • heterocycloalkenyl refers to a monovalent nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se) and one or more double bonds
  • heterocycloalkenyl groups include, but are not limited to, pyranyl, dihydrobenzimidazolyl and l,3-dihydrospiro[benzo[d]imidazol-2, 1 '-cyclopentane] -4-yl
  • aryl refers to phenyl, 1 -naphthyl, and 2-naphthyl; it also refers to a monovalent 6- carbon
  • Examples include, but are not limited to, phenyl (“Ph”), naphthyl, pyrenyl, anthryl, and phenanthryl.
  • the term“aryloxyl” refers to an -O-aryl; the term“substituted aryl” refers to phenyl, 1-naphthyl; and 2-naphthyl having a substituent selected from lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, trifluoromethyl, amino, -NH(lower alkyl), and -N(lower alkyl)2, di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, hydroxy, and amino; the term“arylamino” refers to an -N(R)-aryl in which R can be H, al
  • heteroaryl refers to phenyl, 1 -naphthyl, and 2-naphthyl; it also refers to a monvalent aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se).
  • heteroaryl groups include pyridyl, pyrrolyl, furyl, imidazolyl, indazolyl, benzimidazolyl, pyrimidinyl, thienyl, oxazolyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, and thiazolyl.
  • this term refers to unsaturated monocyclic rings of 5 or 6 atoms containing one or two O and S atoms and/or one to four N atoms provided that the only other atoms in said monocyclic ring are C atoms and that the total number of O, S and N atoms is four or less and bicyclic rings wherein the five or six membered ring as defined above is fused to a phenyl or pyridyl ring, said heteroaryl ring is attached by way of an available carbon or nitrogen atom; and said monocyclic or bicyclic ring can be substituted at an available carbon atom by lower alkyl of 1 to 4 carbons, halo, hydroxy, benzyl, or cyclohexylmethyl, or can be substituted at an available nitrogen atom by benzyloxymethyl, p-toluene sulfonyl, 2,4- dinitrophenyl, lower alkyl of 1 to 4 carbons, benzyl or
  • alkyl, alkenyl, alkylene, alkenylene, heteroalkylene, heteroalkenylene, or alkynyl include all of the above-recited substituents except C1-C10 alkyl;
  • Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl can also be fused with each other by sharing one or more atoms (e.g., to form a spiro compound); wherein R groups when present, are each independenly a substituent selected from the group consisting of -F. -Cl, -Br, -I, -CH3, -OH, -SH, -SCH3, -NH2, NHR’, -NR’R” (wherein each R’ and R” is independently H or Cl -3 alkyl, -CN, -N02, -OCH3.
  • X, Y, Z are each independently -CH2- or N, provided that at least one of X, Y, and z is N and X is O, S, or NH when X is a divalent group in the ring.
  • mesylated compounds was dissolved in ethyl acetate and DBU (300 pL, 4 mmol) was added and stirred the reaction mixture for a period of 2 h and then water was added to the reaction mixture and extract with ethyl acetate and evaporate the organic layer under rotary evaporator followed by purification over 100-200 silica gel and ethyl acetate: hexane (40:60) as eluent to afford the compound 002-EP as brown gummy liquid. (1.4 gm, yield 85 %).
  • mesylated compounds was dissolved in ethyl acetate and DBU (150 pL, 4 mmol) was added and stirred the reaction mixture for a period of 2 h and then water was added to the reaction mixture and extract with ethyl acetate and evaporate the organic layer under rotary evaporator followed by purification over 100-200 silica gel and ethyl acetate: hexane (40:60) as eluent to afford the compound 002-EPS as brown gummy liquid. (700 mg, yield 82 %).
  • STEP 3 Synthesis of (R)-l-(2-chloro-4-nitro-lH-imidazol-l-yl)-2-methylnonan-2-ol and 2-heptyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,l-b]oxazoles (003R):
  • tert-butyl alcohol water (1:1, 40 ml) and AD-mix-b (gm). Stir the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase should be bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 °C some of the dissolved salts may precipitate).
  • tert-butyl alcohokwater (1: 1, 40 ml) and AD-mix-a (2.81 gm). Stir the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase should be bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 °C some of the dissolved salts may precipitate).
  • Step 5 Ring opening and cyclisation
  • tert-butyl alcohol water (1:1, 40 ml) and AD-mix-a (13.45 gm). Stir the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase should be bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 °C some of the dissolved salts may precipitate).
  • Step 5 Ring opening and cyclisation
  • the starting material 4-Iodophenol (013) (20 gm, 91mmol, 1 equiv.) and K2CO3 (182 mmol, 2 equiv.) were suspended in DMF. Then methallyl chloride (118.3 mmol, 1.3 equiv) was added and the reaction was heated to 70 °C for a period of 2 hrs. After cooling, the mixture was diluted with EtOAc and transferred to a separating funnel. The organic phase was washed twice with H2O and once with brine. Drying over MgSC , filtration, and rotary evaporation provided the crude material.
  • reaction mixture was diluted with 70 mL of a 1M aqueous solution of sodium hydroxide and extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give the desired pure product as solid (015) (20 gm, Yield 88 %).
  • tert-butyl alcohokwater (1:1, 30 ml) and AD-mix-a (12 gm). Stir the mixture at room temperature until two clear phases are produced; the lower (aqueous) phase should be bright yellow. Vigorous stirring is required to dissolve all the AD-mix. The mixture was cooled to 0 °C some of the dissolved salts may precipitate).
  • METHOD MIC was determined by broth dilution method against M. tuberculosis H37RV (ATCC 27294; American Type Culture Collection, Manassas, VA, USA), M. tuberculosis MDR (resistant to isoniazid and rifampicin) and one of the laboratory generated mutant M. tuberculosis Rif R (resistant to rifampicin) 10 using micro-broth dilution method.
  • the bacterial strains were grown for 10 to 15 days in Middlebrook 7H9 broth (Difco Laboratories, Detroit, Mich.) supplemented with 0.5% (v/v) glycerol, 0.25% (v/v) Tween 80 (Himedia, Mumbai India), and 10% ADC (albumin dextrose catalase, Becton Dickinson, Sparks, MD) under shaking conditions at 37 °C in 5% CO2 to facilitate exponential-phase growth of the organism.
  • Bacterial suspension was prepared by suspending M. tuberculosis growth in normal saline containing 0.5% tween 80 and turbidity was adjusted to 1 McFarland (McF) standard which is equivalent to 1.0 x 10 7 CFU/mL.
  • the 2-fold serial dilutions of compounds were prepared in Middle brook 7H9 (Difco laboratories) for M. tuberculosis in 100 pL per well in 96-well U bottom microtitre plates (Tarson, Mumbai, India).
  • the above-mentioned bacterial suspension was further diluted 1:10 in the growth media and 100 pL volume of this diluted inoculum was added to each well of the plate resulting in the final inoculum of 1.0 x 10 6 CFU/mL in the well and the final concentrations of compounds ranged from 0.015 to 32 pg/mL.
  • the plates were incubated at 37 °C for seven days in 5% CO2.
  • REMA method was used for evaluation of results. After incubation, 15 pL of 0.04% resazurin and 12.5 pL of 20% tween 80 was added in each well of plate including media and growth controls. After 48 h incubation, plates were read visually and the minimum concentration of the compound showing no change of colour was recorded as MIC.
  • RV Virulent strain of Mycobacterium tuberculosis ;
  • Compound of formula 003R was dissolved in minimum amount of DMSO and then mixed in alcohol so as to make final volume upto 5% ethanol and 95% PEG 400 (v/v) mixed. Compounds were dissolved to make final concentration of 25 mg/kg while isoniazid was prepared at same concentration of 25 mg/kg. A total of 200 pL volume of respective dose was administered orally (oral gavage) in a bio safety cabinet to each group. Same volume of mixture i.e. 5% ethanol and 95% PEG 400 (v/v) was given to placebo group. A group of mice was kept without dosing which served as control.
  • mice were prepared nine groups, and each group was equipped with four B ALB/c mice with average weight 18- 22 gram.
  • M. tuberculosis H37Rv was grown in 7H9 medium, supplemented with 10% ADC. After 14 days culture was diluted at final strength of 1 McF. 20 pi of this culture was administered through the left nasal route. Dosing was initiated after the first day of infection, and three mice from early control was also dissected on the same time, that allows to enumerate mycobacterium established within the lungs. After two weeks, mice from late control and treated group were sacrificed, and left lung was taken out. It allows to monitor the reduction in bacilli burden after the treatment, and compared with early and late control.
  • the compounds 003R was evaluated for the in vivo efficacy in intranasal mice model of acute infection in Balb/c mice. After one week of post MTB infection, the compounds were orally administered at 25 mg/kg once daily for two weeks. Compound having formula 003R has shown the significant 1.2 log CFU (colony forming unit) reduction compared to the untreated control (late control, group run parallel without drug treatment) and 1.8 log colony forming unit reduction as compared to the early control (group at the start of treatment).
  • CFU colony forming unit
  • the present invention deals with novel process of preparation of chiral l,l-dialkylethane-l,2- diols of Formula (I) as useful intermediates for the synthesis of 6-nitro-2,3- dihydroimidazo[2,l-b]oxazole related compounds.
  • the present invention employs Sharpless dihydroxylation which has many advantages over Sharpless epoxidation (usually employed in the prior art) like simple recipe (single commercially available reagent mixture), reaction conditions (near room temperature instead of -40 to -10 °C for epoxidation), reaction time (2-12 hrs vs ⁇ 2 days), solvent advantage (water/tert-butanol mixture vs anhydrous DCM and absolute anhydrous conditions), as well as ease of operation.
  • the present invention provides a concise route for key intermediate of the TB drug Delamanid while reducing the number of reaction steps and improving the cost effectiveness of the drug molecule.
  • the present invention eliminates the need for the protection groups for halophenol as well as 4-hydroxypiperidine fragment.
  • Halophenol is allylated with methallyl chloride which essentially serves as a protecting group as well as an attachment of three carbon fragment.
  • Cu mediated N-arylation methodology makes it possible to use unprotected piperidine, eliminates the need for use of expensive and toxic palladium based catalyst and also eliminate the need for high temperature reaction conditions for a prolonged period of time.
  • the present invention provides new compounds, such as: l-(4-((2-methylallyl)oxy)phenyl)-4- ((4-(trifluoromethoxy)phenoxy)methyl)-lH- 1,2,3-triazole (008), (R)-2-methyl-3-(4-(4-((4- (trifluoromethoxy)phenoxy)methyl)- 1H- 1 ,2,3 -triazol- 1 -yl)phenoxy)propane- 1 ,2-diol (009),

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne une nouvelle voie pratique de synthèse d'intermédiaires diols substitués, et des 1,1-dialkyléthane-1,2-diols utiles pour la préparation de divers médicaments contenant 6-nitro-2,3-dihydroimidazo[2,1-b]oxazole. En particulier, l'invention concerne une nouvelle voie pratique de synthèse d'un intermédiaire qui est utilisé pour la synthèse de delamanid.
PCT/IN2020/050309 2019-04-01 2020-03-31 Procédé de préparation de dérivés de 1,1-dialkyléthane-1,2-diols en tant qu'intermédiaires utiles Ceased WO2020202205A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080027021.6A CN113874341B (zh) 2019-04-01 2020-03-31 制备作为有用中间体的1，1-二烷基乙烷-1，2-二醇的衍生物的方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201911013022 2019-04-01
IN201911013022 2019-04-01

Publications (2)

Publication Number Publication Date
WO2020202205A1 true WO2020202205A1 (fr) 2020-10-08
WO2020202205A4 WO2020202205A4 (fr) 2020-11-26

Family

ID=72666193

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2020/050309 Ceased WO2020202205A1 (fr) 2019-04-01 2020-03-31 Procédé de préparation de dérivés de 1,1-dialkyléthane-1,2-diols en tant qu'intermédiaires utiles

Country Status (2)

Country Link
CN (1) CN113874341B (fr)
WO (1) WO2020202205A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060079697A1 (en) * 2002-10-15 2006-04-13 Fumitake Goto 1-substituted-4-nitroimidazole compound and process for producing the same
WO2011093529A1 (fr) * 2010-01-29 2011-08-04 Otsuka Pharmaceutical Co., Ltd. Intermédiaire synthétique d'un composé oxazole et procédé de production associé
US20180065931A1 (en) * 2015-03-27 2018-03-08 Otsuka Pharmaceutical Co., Ltd. Method for producing 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine or salt thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4787529B2 (ja) * 2004-04-09 2011-10-05 大塚製薬株式会社 医薬組成物
CN108689904B (zh) * 2017-04-12 2022-06-17 轩竹生物科技股份有限公司 手性杂环叔醇中间体的制备方法及其应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060079697A1 (en) * 2002-10-15 2006-04-13 Fumitake Goto 1-substituted-4-nitroimidazole compound and process for producing the same
WO2011093529A1 (fr) * 2010-01-29 2011-08-04 Otsuka Pharmaceutical Co., Ltd. Intermédiaire synthétique d'un composé oxazole et procédé de production associé
US20180065931A1 (en) * 2015-03-27 2018-03-08 Otsuka Pharmaceutical Co., Ltd. Method for producing 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine or salt thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM 25 October 2006 (2006-10-25), "R)-2-Heptyl-2-methyloxirane", XP055746281, Database accession no. CID 10261333 *
DATABASE PUBCHEM 27 October 2006 (2006-10-27), "S)-2-Methylnonane-1,2-diol", XP055746279, Database accession no. CID 11819530 *
SASAKI ET AL.: "Synthesis and Antituberculosis Activity of a Novel Series of Optically Active 6-Nitro-2,3-dihydroimidazo[2,1-b]oxazoles", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, no. 26, 12 June 2006 (2006-06-12), pages 7854 - 7860, XP002656698, DOI: 10.1021/JM060957Y *
XIAOJIN LI ET AL.: "Synthesis and antitubercular activity of 7-(R)- and 7-(S)-methyl-2-nitro-6-(S)-(4- (trifluoromethoxy)benzyloxy)-6,7-dihydro- 5Himidazo[2,1-b] [1,3]oxazines, analogues of PA-824", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, no. 7, 7 March 2008 (2008-03-07), pages 2256 - 2262, XP022574941, DOI: 10.1016/j.bmcl.2008.03.011 *

Also Published As

Publication number Publication date
WO2020202205A4 (fr) 2020-11-26
CN113874341A (zh) 2021-12-31
CN113874341B (zh) 2024-05-31

Similar Documents

Publication Publication Date Title
EP3027615B1 (fr) Composés anti-infectieux
EP2892880B1 (fr) Dérivés d'indole carboxamide et leurs utilisations
JP5400032B2 (ja) ベンズイミダゾール及びその医薬組成物
EP3986902B1 (fr) Inhibiteurs macrocycliques de mcl-1
US20130060027A1 (en) Tetrahydroisoquinolines and intermediates therefor
Mashayekhi et al. Synthesis, antimycobacterial and anticancer activity of novel indole-based thiosemicarbazones
EP2065381A1 (fr) Antagonistes du CGRP
EA030410B1 (ru) Замещенные конденсированные гетероциклы в качестве модуляторов gpr119 для лечения диабета, ожирения, дислипидемии и связанных нарушений
JP2014001227A (ja) キノロン化合物及び医薬組成物
JP7574450B2 (ja) アミノピリジン系化合物及びその使用
EP1122243B1 (fr) Nouveaux imidazoles a activite anti-inflammatoire
CN107810185A (zh) 作为溴结构域抑制剂的二环杂环衍生物
EA037974B1 (ru) Соединение, имеющее мутантную idh ингибирующую активность, способ его получения и применения
JP6588647B2 (ja) 血液悪性腫瘍を治療するための重水素化合物及びその組成物並びに方法
EP2307401A2 (fr) Derives anticancereux de 4-oxo-1,4-dihydro-quinoline, leur preparation et leur application en therapeutique
WO2020202205A1 (fr) Procédé de préparation de dérivés de 1,1-dialkyléthane-1,2-diols en tant qu'intermédiaires utiles
JP5769504B2 (ja) 医薬
JPWO1999024425A1 (ja) ベンズイミダゾール誘導体及びその薬学的に許容される塩
OKADA et al. Synthesis and Structure-Activity Relationships of 7-(3'-Amino-4'-methoxypyrolidin-1'-yl)-1-cyclopropyl-6, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic Acids
WO2021161084A1 (fr) Dérivés de n-(4-fluorophényl)-5-phényl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide et leur synthèse
EP3904348A1 (fr) Composé aminopyridine, son procédé de préparation et son utilisation
EP3423449B1 (fr) Alcaloïdes d'aurone substitués en tant qu'agents anti-mycobactériens
JP2024528073A (ja) 有機ピリジン－ピラゾール化合物及びその使用
KR20220103985A (ko) Mcl-1 억제제로서의 거대환식 술포닐 유도체
EP4168413B1 (fr) Dérivés macrocycliques à liaison de 4-(pyrazol-5-yl)-indole en tant qu'inhibiteurs de mcl-1

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20785153

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20785153

Country of ref document: EP

Kind code of ref document: A1