WO1983003827A1 - 4-cyano-2-azetidinone derivatives and process for their preparation - Google Patents

4-cyano-2-azetidinone derivatives and process for their preparation Download PDF

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Publication number
WO1983003827A1
WO1983003827A1 PCT/JP1982/000141 JP8200141W WO8303827A1 WO 1983003827 A1 WO1983003827 A1 WO 1983003827A1 JP 8200141 W JP8200141 W JP 8200141W WO 8303827 A1 WO8303827 A1 WO 8303827A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
azetidinone
acid
reaction
Prior art date
Application number
PCT/JP1982/000141
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English (en)
French (fr)
Japanese (ja)
Inventor
Michihiko Ochiai
Taisuke Matsuo
Shoji Kishimoto
Original Assignee
Takeda Chemical Industries, Ltd.
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 Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1982/000141 priority Critical patent/WO1983003827A1/ja
Priority to IL67451A priority patent/IL67451A/xx
Priority to EP82111744A priority patent/EP0083039B1/en
Priority to AU91642/82A priority patent/AU557575B2/en
Priority to DE8282111744T priority patent/DE3270045D1/de
Priority to AT82111744T priority patent/ATE18665T1/de
Priority to US06/451,323 priority patent/US4560508A/en
Priority to GB08236247A priority patent/GB2114977B/en
Priority to NO824312A priority patent/NO160996C/no
Priority to IE3036/82A priority patent/IE54682B1/en
Priority to CA000418377A priority patent/CA1212112A/en
Priority to DK570082A priority patent/DK570082A/da
Priority to NZ202907A priority patent/NZ202907A/en
Priority to HU824159A priority patent/HU192780B/hu
Priority to KR8205807A priority patent/KR890003423B1/ko
Priority to ES518562A priority patent/ES518562A0/es
Priority to JP58073470A priority patent/JPS591465A/ja
Publication of WO1983003827A1 publication Critical patent/WO1983003827A1/ja
Priority to US06/791,998 priority patent/US4684724A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • 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
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the present invention is an intermediate which is advantageous for the synthesis of an optically active form of a 4-substituted 12-azetidinone derivative, and has a novel 4-cyano 1-2 which has an antibacterial action and a ⁇ -lactamase inhibitory action.
  • the present invention relates to azetidinone derivatives, a method for producing the same, and a method for using the compound as an intermediate.
  • the present invention provides a new formula
  • R 1 represents an amino group which may be acylated or protected
  • X represents hydrogen or a methoxy group
  • W represents hydrogen or a sulfo group.
  • X represents a group represented by 2), and X and W have the same meanings as defined above).
  • a compound represented by the formula: is reacted with a cyano compound, and if necessary, the protective group is removed to give 4-cyano-2-azetidinone.
  • Derivative [I] is obtained, and the obtained compound [I] is an intermediate which is advantageous for the synthesis of 4-substituted 12-azetidinone derivatives, particularly for the synthesis of optically active compounds.
  • the protecting group is removed by subjecting
  • examples of the acyl group in the acylated amino group represented by R 1 , R 2 and R 4 include, for example, an acyl group substituted on the 6-position amino group of a conventionally known penicillin derivative, An acyl group substituted for the 7-amino group of the cephalosporin derivative is used.
  • an acyl group for example, the formula (1)
  • R. represents a lower alkyl, a phenyl which may have a substituent or a heterocyclic group which may have a substituent.
  • R 6 is hydrogen, an amino acid residue which may have a substituent, an amino-protecting group
  • R 8 represents an amino group, a heterocyclic group which may have a substituent, a phenyl which may have a substituent or a lower alkyl group which may have a substituent
  • R 7 represents hydrogen, lower alkyl optionally having substituent (s), phenyl optionally having substituent (s), or group having substituent (s).
  • a heterocyclic group or a chloroalkenyl group which may have a substituent, respectively;
  • R 9 is the formula R 11 — C— ⁇ where R 11 is
  • the N-0-R 12 which may have a substituent group a heterocyclic group, or a substituent optionally off Eniru group optionally having, R 12 is hydrogen, optionally phenyl may have a substituent, a lower A Syl, lower alkyl or a group represented by the formula: R 13 —R 14 (wherein, R 13 represents a lower alkylene or a lower alkylene, and R 14 represents a carboxyl group or an ester thereof).
  • R 1 G is a mere bond or a formula —CO—NH—CH— (wherein R 15 is lower alkyl and has a substituent
  • R 15 also represents a good heterocyclic group), a group represented by each)), a group represented by (4)
  • R 16 represents a hydroxyl, carboxyl, sulfo, formyloxy, halogen or azide group
  • R 17 represents a hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy group, respectively
  • H L8 is Shiano, phenyl which may have a substituent, which may have a substituent phenoxy, lower alkyl which may have a substituent, have a substituent And alkenyl or a heterocyclic group which may have a substituent, and R 19 represents a mere bond or 1 S—, respectively.
  • lower alkyl includes, for example, methyl, ethynole, n-propyl, isopropyl, n-butyl, isobutynole, sec-butyl, tert — Alkyl having 1 to 6 carbon atoms, such as butynole, pentynole, isopentinole, hexyl, and isohexyl, is used.
  • lower alkoxy examples include carbons such as methoxy, ethoxy, ⁇ -propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy tert-butoxy, pentoxy, isosorboxy, hexyloxy, and isoxyhexyloxy.
  • Alkoxy of numbers 1 to 6 is used.
  • alkenyl for example, vinyl, aryl, isopropyl, 2-methacryl, 2-butenyl, 3-butenyl and the like are used.
  • the chloroalkenyl is preferably a 5- to 6-membered ring, for example, cyclohexenyl, cyclohexenyl, and the like.
  • the lower alkylene one having 1 to 3 carbon atoms is preferable.
  • the lower alkylene include, for example, methylene, dimethylenemethylene, ethylene, methylethylene, and trimethylene.
  • the lower alkenylene is preferably one having 1 to 3 carbon atoms, and examples thereof include vinylene and propenylene.
  • Specific examples of rho and rhogen include chlorine, bromine, iodine, and fluorine.
  • the heterocyclic group for example, a 5- to 8-membered ring containing one to several hetero atoms such as a nitrogen atom (which may be oxidized), an oxygen atom, a sulfur atom or the like or a condensed ring thereof is bonded to a carbon atom.
  • amino acid residues examples include glyceryl, aranyl, zozolyl, leucyl, isoloyl, serinole, threonyl, cystinyl, cistyl, methionyl, naichi or / asnorutyl, a- or r-pertamyl, Lysyl, arginyl, phenylenolaninole, phenylglycinole, tyrosyl, histidyl, tryptofil, prolyl, etc. are used.
  • amino-protecting group those similar to the amino-protecting group described below are used.
  • the lower acetyl group those having 2 to 4 carbon atoms are preferable.
  • acetyl, propionyl, butyryl, isoptyryl and the like are used.
  • substituent of a lower alkyl which may have a substituent and an alkenyl which may have a substituent include, for example, phenyl, carbamoyl, methylcarbamoyl, carboxyl, cyano, halogen, hydroxyl and the like. Is used.
  • the substituent of phenyl which may have a substituent, phenoxy which may have a substituent, and cycloalkenyl which may have a substituent include lower alkyl having 1 to 3 carbon atoms. Lower alkoxy having 1 to 3 carbon atoms, halogen, amino, benzyloxy, hydroxynole, alkoxy having 2 to 10 carbon atoms,
  • ': _ 0 --Aminomethyl, rubamoylaminomethyl, 3-amino-13-carboxypropoxy, etc. are used.
  • substituent of the optionally substituted heterocyclic group include, but are not limited to, an optionally substituted alkyl having 1 to 8 carbon atoms, a lower alkoxy having 1 to 3 carbon atoms, hydroxy, and carboxyl.
  • Oxo monochloroacetamide, aldehyde, trifluoromethyl, amino, halogen, phenyl which may have a substituent as described above (eg, 2,6-dichlorophenyl, etc.), coumarin-3-carbonyl , 4-formyl-1-pyrazinyl, pyro-inorealidino, furanaldino, thiophenaldino, mesyl, meramino, a protecting group for an amino group, having 2 to 4 carbon atoms which may be substituted by halogen ⁇ ⁇ is used.
  • amino-protecting group those similar to the amino-protecting group described below are used.
  • substituent of the amino acid residue which may have a substituent include, for example, amino, an amino-protecting group, carpamoyl, metercarpamoyl, benzyl and the like.
  • amino-protecting group those similar to the amino-protecting group described below are used.
  • Examples of the carboxy ester represented by R 14 include, for example, methyl ester. ⁇ Pinole Esthenole, t-butynole ester, benzoyl benzoyl ester, 2-trime J / i / ryl ether ester, etc.
  • ⁇ ⁇ ⁇ , ⁇ -tricycloethyl, ⁇ -nitrobenzil, tertiary butyl, 2-trimethylsilylethyl, and ⁇ -methoxybenzylka are preferred.
  • the protecting group for the hydroxyl group any one which can be used as a protecting group for the hydroxyl group in the field of lactam and organic chemistry can be used, and for example, ester residues such as acetyl, chloroacetyl, ⁇ , ⁇ , and Esterified carbonyl groups such as liquid ethoxycarbonyl and 2-trimethylsilylethoxycarbonyl, tert-butyl, "benzinole, P-nitrobenzil, tritinole, methylthiomethenole- Ether residues such as methoxetoxymethyl, silyl ether residues such as trimethylsilyl and tert-butylmethylsilyl, acetal residues such as 2-tetrahydrobi
  • acyl group represented by the formula R 5 —CO— [A] is, for example, 3- (2,6-dichloromethylphenyl) -15-me
  • acyl group represented by the formula R 6 —NH—CH—CO— [B] include:
  • acyl group represented by the formula R 9 — R 10 — CO— [C] include, for example, N— [2- (2-aminothiazolyl-14-yl) -12-methoxyminoacetyl] 1-D-alanil, 2- (2-chloroacetamidothiazole-1-41) -1-2-methoxyminoacetyl, 2- (2-aminothiazo-l 4-yl) -1-2-isopropoxyminoacetyl, 2- (2-aminothiazolyl-4-yl) 2-methoxyminoacetyl, 2- (2-aminothiazoyl-4-yl) -1-2-oxyminoacetyl, 2-cheloni-2-yl 2-Minoacetyl, 2-furyl-2-methoxyminoacetyl, 2- (4-hydroxyphenyl) -12-methoxyminoacetyl, 2-phenyl-2-methoxyminoacetil, 2-Chenol-2
  • na-sulfofifenacetyl na-hydroxy phenyl- acetyl, na-formyloxy-phenyl-acetyl, na-sulfur oxyphenyl-acetyl, 2-bromo-12-phenyl-acetyl, 2-azido-one 2-phenylacetyl is used.
  • acyl group represented by the formula R 18 —R 19 —CHg—CO— [E] include, for example, cyanoacetyl, phenylacetyl, phenoxyacetyl, trifluoromethylthioacetel, cyanomethyltheoacetyl , 1 H—tetrazoyl 1-acetyl, 2-cerylacetyl, 2— (2-aminothiazole 1 4
  • protecting group of the protected Amino groups represented by 1 2 Oyobi 1 4 those used for this purpose in the field of lactam and peptide synthesis is employed for convenience.
  • those used for this purpose in the field of lactam and peptide synthesis is employed for convenience.
  • Aromatic acyl groups such as zensulfonyl, toluenesulfonyl and the like, for example, formyl, acetyl, propionole, monochloroacetyl, dichloroacetyl, trichloroacetinole, methanesulfonole, ethanesulfonole, trifluoroacetyl, maloylacetyl
  • Aliphatic sacyl groups such as succinyl and succinyl, for example, benzyloxycarbonyl, P-dimethoxybenzyloxycarbonyl, P-methoxybenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl , Methoxycarbonyl radicals, and furthermore, for example, trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, di- or trialkylyl, t-butyldimethyllyl,
  • the choice of the protecting group is not particularly limited as in the case of the carboxy protecting group, but in particular, it is preferably monochloroacetic acid, benzyloxycarbinole, P-methoxy / benzinoleoxyca.
  • Luponinole, 2 — trimethylsilyl ketone i / force norboninole, P-2 troben ziroxycarbonyl are preferred.
  • Y is a halogen or one of the formulas OCOR 3 , one SCOR 3 or one S—R 3 (R 3 is
  • n 1 or 2
  • chlorine, fluorine, iodine and bromine are used as halogens.
  • the hydrocarbon group include lower alkyl, alkenyl, and cycloalkenyl which may have a substituent as described in R 5 to R 19 , and the like.
  • C3 to C10 e / cycloalkyl groups such as cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl, for example, phenyl, tolyl, xylyl, biphenyl, naphthyl, anthryl, phenanthate
  • Aryl groups such as benzyl, benzyl and phenyl;
  • Aralkyl groups such as enethyl, phenylpropyl, and naphthylmethyl are used. These chloroalkyl, aryl and aralkyl groups may have a substituent. Examples of such a substituent include R 5 to! The same substituents as for phenyl or phenyl described for i 19 are used. In particular, good results are obtained when Y represents, for example, lower acyloxy (for example, acetoxy, propionyloxy, etc.) or lower alkylsulfonyl (for example, methylsulfur, dimethylsulfonyl, etc.). X represents hydrogen or a methoxy group. w represents hydrogen or a sulfo group.
  • compound [I] can be obtained by reacting compound [ ⁇ ] with a cyano compound and removing a protecting group as necessary.
  • Compound [II] has substituents at the 3-position and the cis-trans isomer, and the carbons at the 3- and 4-positions are asymmetric carbons.
  • salt of the compound [] 1] when a sulfo group is present at the 1-position and a carboxyl group is present at R 2 , for example, ⁇ -cations such as sodium and potassium, arginine, ornithine, lysine, histidine
  • ⁇ -cations such as sodium and potassium, arginine, ornithine, lysine, histidine
  • a salt with a basic amino acid such as -methinoregolemin, diethanolanolamine, triethanolanolamine, polyhydroxyalkylamine such as trishydroxymethylaminomethane or the like is used.
  • R 2 contains a basic group
  • salts with organic acids such as acetic acid, tartaric acid, and methanesulfonic acid
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid
  • acidic amino acids such as arginine, aspartic acid, and glutamic acid.
  • R 2 may be used as an ester derivative (two-conversion may be used. In such a case, the ester group may be, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl, n-one).
  • Alkoxymethyl such as methoxethyl, naethoxyethoxy, etc., monoalkoxy monosubstituted methyl group such as naalkoxyethyl, alkylthiomethyl group such as methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, and vivaloyl Oxymethyl groups such as ethoxymethyl, acetic acid butyl, etc. or carboxylic acid mono-substituted methyl groups, ethoxy carbonyl dioxomethyl, ethoxy carbonyl dioxymethyl, etc.
  • the silyl agents for example, the formula P 1 -!?? 32 'in 3 ⁇ Si .Eal [wherein, P 1, 2, to JP 3, for example 1 -C respective 4 lower Arukiru (e.g. methylation, Echiru , N-propyl, i-propyl, n-butyl, etc.) a hydrocarbon group such as aryl (for example, phenyl, tolyl, etc.), Hal represents a halogen, preferably chloro, bromo, and: P 1 and? 2,? 53 are two 1 That other of the halogen preferably chloro, bromo, P 1,! 52, one of the P 3 is represented by may be a hydrogen atom] the compound force Used.
  • P 1, 2, to JP 3 for example 1 -C respective 4 lower Arukiru (e.g. methylation, Echiru , N-propyl, i-propyl, n-butyl, etc.) a hydrocarbon group such as ary
  • silylating agents include: --For example, the formula.
  • Y 1 and Y 2 each represent a lower alkyl, phenyl, benzyl or lower alkoxy group
  • Y 3 represents a t-butyl or isopropyl group
  • Y 4 represents a reactivity which is eliminated from the silylating agent.
  • a lower alkyl group represented by Y 1 or Y 2 can be used as a lower alkyl group such as, for example, meter, chloromethyl, ethyl, n-propyl, isopropyl, ⁇ -butyl, tert-butyl, etc.
  • the reactive group Y 4 which is eliminated from the silylating agent includes halogen (eg, chloro, bromo, etc.), and, for example, N— (trialkylsilyl) trifluorene.
  • halogen eg, chloro, bromo, etc.
  • cetimidyloxy i group Trialkyl t-butyldimethyl), such as formylamino, acetylamino, propionylamino, butylylamino, trifluoroacetylamino, etc .
  • (Trialkylsilyl) amino groups such as silyl) amino, isopropyrdimethylsilylamino, (chloromethyldimethylsilyl) amino, etc .
  • N JN T -dimethylamino, N-methylamino-N-methylamino, N ,; N— N, N-dialkylamino groups such as getylamino, N, N-dipropynoleamino, N-methyl-1-N-ethynoleamino, N-methyl-N-propyl poramino, N-ethyl-N-propylamino; Complex groups such as midazole are used.
  • alkyl group in the reactive group include those having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl.
  • silyl compounds include N, 0-bis (t-butyldimethylsilyl) trifluoracetamide, N, 0-bis (isoso-propyldimethylsilyl) acetate. Mid, bis (dimethylisopropyl propyl) acetamide, isopropyl dimethylsilyl acetoamide, bis (dimethyl tertiary butylsilyl) acetamido, N-methyl-1-N-butyldimethyl Silyl acetamide, N-methyl-1-N-isopropyl dimethyl silyl trifluoroacetamide, N-t-butyldimethylsilyl getylamine, 1,3-bis (chloromethyl) 1-1,1,3,3-tetra I-t-butyldimethyldisilazane, N-isopropyldimethy-noresiliymidazolone, t-butinoresiphenylphenyl
  • the reaction is carried out at a temperature of 50 ° C., preferably up to 38 ° C., usually at room temperature (about 20), and the reaction time is several minutes (about 10 minutes) to 24 hours.
  • the reaction may be, for example, ethyl acetate, dioxane, tetrahydrofuran, N, N-dimethylacetoamide, N, N-dimethylformamide, dichloromethane, chlorophoronolem, benzene, tonolene, acetonone, methylethenolene. It is convenient to carry out the reaction in ton, acetonitrile, etc., or a mixed solvent thereof, or any other solvent which does not participate in this reaction.
  • Inorganic bases such as lithium, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate and potassium carbonate; and trialkylamines such as triethylamine and triptylamine; and trialkylamines such as tribenzylamine.
  • Organic tertiary amines such as lalkylamine, N-methylmorpholine, N-methylbiperidine, N, N-dialkylaniline, N, N-dialkylbenzylamine, pyridine, picolin, lutidine, or 1.5-diazabici 1,4-diazabicyclo [2,2,2] octane, 1.8-diazabicyclo [5.4,4] pentane-17, an organic base such as chloro [4,3.0] non-5-ene.1,4-diazabicyclo [2,2,2] octane
  • the reaction can be carried out in the presence of a base, and a liquid base can be used also as a solvent.
  • the i / lyl derivative of the compound [ ⁇ ] thus obtained is used as a raw material for a reaction with a cyano compound either as a reaction mixture or after isolation and purification by known means as described below.
  • a cyano compound either as a reaction mixture or after isolation and purification by known means as described below.
  • the above R 2 force; in the case of a protected amino group, the protecting group is eliminated, and further subjected to an acylation reaction;
  • a 1-silyl derivative of the desired compound [II] can also be produced.
  • the 3-position acyl conversion reaction can be easily carried out because it proceeds in good yield and the operation is simple, and is extremely useful for the synthesis of various 2-oxoazetidine derivatives substituted with a desired aryl group.
  • the reaction with the compound can be carried out continuously.
  • Z represents an alkali metal or an alkaline earth metal].
  • lithium cyanide, sodium cyanide, calcium cyanide, or the like can be used.
  • this reaction about 1 to 3 mol of the cyano compound is used per 1 mol of the compound [D].
  • One-preferably 1 to 1.1 moles of the reaction are performed.
  • the solvent used include water or ethers such as dioxane, tetrahydrofuran, and ether, esters such as ethyl acetate and ethyl formate, halogenated hydrocarbons such as carbon tetrachloride, chloroform, and dichloromethane, and the like.
  • Hydrocarbons such as benzene, toluene, n- ⁇ hexane, amides such as dimethylformamide and dimethylacetamide, methanol, ethanol, isopropanol, and t-butanol
  • amides such as dimethylformamide and dimethylacetamide
  • methanol ethanol
  • ethanol isopropanol
  • t-butanol Ordinary organic solvents such as alkonoles, dimethyl sulfoxide, sulfolane, and hexameterphosphoramide are used alone or in combination.
  • phase transfer catalyst mentioned here promotes the reaction by solubilizing one of the reaction substrates, which exists separately in each of the liquid-liquid two phases, in the other liquid phase in the form of an ion pair.
  • phase transfer medium include a cation (ammonia or cation) in which four identical or different groups selected from an alkyl group, an aryl group, and an aralkyl group are bonded to a nitrogen atom or a phosphorus atom.
  • Phosphonium ions and acid groups (anions such as CT, Br ", I-1, F", CIO ⁇ , B, BH ", HSO4, OH—, HgPOj, etc.) Is used.
  • tetramethylammonium chloride tetraethylammonium chloride, tetra-n-butylammonium chloride,
  • halogenated arylalkyls such as ammonium and phenyltrimethylammonium bromide (total carbon number 9-50) ammonium, benzyldimethyldelammonium chloride, benzyltriethylammonium chloride,
  • alkyl groups, aryl groups, and aralkyl groups such as halogenated aralkyl quilt trialkyls (total number of carbon atoms: 13 to 50) such as salted cesyl benzyl dimethylammonium 4
  • One consisting of an ammonium ion substituted with a single group and a halogen ion force for example, sulfuric acid Tetraalkyl hydrogen sulfate (to)
  • ions and halogen ions are used.
  • phase transfer catalysts are, for compound [ ⁇ ] to 1 mole, from about 0. 0. 1 to: I mole, preferably et used 0 - 0 5-0 2 moles reaction.
  • the solvent in the case of using a phase transfer catalyst may mixtures of organic solvents such water and above are organic ⁇ solvent as a mixed split to water 1 part 0.5 to 5 parts, preferably 0.. 5 to: I A mixture of parts is used.
  • the reaction temperature is usually in the range of 100 to 20 ° C., but is not particularly limited to this condition, and heating and cooling may be appropriately performed as needed.
  • the reaction time is appropriately determined depending on the solvent, temperature and the like to be used, but is usually completed in a short time.
  • the resulting compound [ ⁇ ] can be obtained as an arbitrary-purity compound by known separation and cracking means, such as solvent extraction, recrystallization, and quenching chromatography. It may be used as it is as the next raw material.
  • the protecting group can be removed as necessary. How to remove the protecting group and
  • a commonly used method such as a method using an acid, a method using a base, a method using a reduction, a method using thiourea or sodium sodium dimethyldithiocarbamate is appropriately selected. It can be carried out.
  • the force varies depending on the type of the protecting group and other conditions; as an acid, for example, hydrochloric acid, sulfuric acid, anhydrous acid of fornine, formic acid, acetic acid, and
  • a gas-acid ion exchange resin of an organic acid such as sulfonic acid is used.
  • the strength of the base varies depending on the kind of the protecting group and other conditions, for example, alkali metal such as sodium and potassium or alkaline earth metal such as calcium and magnesium.
  • organic bases such as hydroxides and carbonates, etc.
  • organic bases such as metal alkoxides, aluminums and quaternary ammonium salts, basic ion exchange resins and the like are used.
  • a solvent is used in the above-mentioned method using an acid or a base, a hydrophilic organic solvent, water or a mixed solvent is often used.
  • the strength varies depending on the type of protecting group and other conditions.
  • metals such as tin and zinc or metal compounds such as chromium dichloride and chromium sulphate and acetic acid, propionic acid and hydrochloric acid
  • acids such as organic and inorganic acids
  • the catalyst used in the catalytic reduction method is, for example, platinum wire.
  • Platinum catalysts such as platinum sponge, platinum black, platinum oxide, and colloid platinum
  • palladium catalysts such as palladium sponge, palladium black, palladium oxide, barium palladium sulfate, barium palladium carbonate, palladium carbon, palladium silica gel, and colloid palladium
  • ⁇ Nickel, nickel oxide, Raney nickel, Urushibara nickel, etc. are used.
  • a metal compound such as iron and chromium, an inorganic acid such as hydrochloric acid, and an organic acid such as formic acid, diacid, and propionic acid are used.
  • the reduction method is usually carried out in a solvent.
  • alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, etc., and ethyl thiocyanate are frequently used.
  • water, acetone, and the like are commonly used.
  • the acid is a liquid, the acid body can be used as a solvent.
  • the reaction is usually carried out under cooling or heating.
  • 'Compound obtained [I] n WIFO Can also be used as a raw material for the next reaction as it is, which can be isolated and purified by known means as described above.
  • R 0 CO represents an acyl group as described for R 1 , R 2 and R 4 ], and the compound can be appropriately acylated by reacting with a carboxylic acid or a reactive derivative thereof.
  • the acid anhydride examples include, for example, mixed anhydrides of hydrohalic acids (eg, hydrochloric acid, hydrobromic acid, etc.), mixed anhydrides of monoalkyl carbonic acids, and aliphatic carboxylic acids (eg, acetic acid, pivalic acid, valeric acid). , Isopentanoic acid, trichloroacetic acid, etc.) mixed acid anhydrides, aromatic sulfonic acid (eg, benzoic acid etc.) mixed acid anhydrides, symmetrical acid anhydrides, etc. are used.
  • hydrohalic acids eg, hydrochloric acid, hydrobromic acid, etc.
  • monoalkyl carbonic acids e.g, aliphatic carboxylic acids
  • aliphatic carboxylic acids eg, acetic acid, pivalic acid, valeric acid
  • aromatic sulfonic acid eg, benzo
  • amides such as imidazole, 4-substituted imidazole, dimethylpyrazol, benzotriazole and the like are used.
  • Active ester is, for example, methyl ester, ethyl ester, methoxymethyl ester, pronogyl ester, 412 ⁇
  • esters such as phenylester, 2,4-dinitrate, phenylenoester, trichlorophenol, pentachlorophenylester, mesinolephenyl ester, etc.
  • Esters of N-hydroxysuccinimide, N-hydroxy-15-norbornene-1,2,3-dicarboxyimide, N-hydroxyphthalimide and the like and the above-mentioned acids such as carboxylic acids are used.
  • the reactive derivative of such an organic acid is appropriately selected depending on the kind of the acid to be used. Further, when a free acid is used as the acylating agent, the reaction is preferably performed in the presence of a condensing agent.
  • the condensing agent include N, —V-cyclohexinolecarbodiimide, N-cyclohexyl—morpholino-ethynolecarbodiimide, N-cyclohexyl N- (4-ethylethylamine) Hexyl mouth) carbodimid, N-ethyl ( ⁇ -dimethelamine knob mouth pill) Carbodimid, etc .; used. '
  • the acylation reaction is usually performed in a solvent.
  • Solvents include water, aceton, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethethyl drone, dimethyl honolemamide, pyridine and other reactions.
  • a common organic solvent is used, and among these, a hydrophilic solvent can be used as a mixture with water.
  • the acylation reaction includes, for example, inorganic bases such as sodium hydroxide, sodium carbonate, sodium carbonate, sodium carbonate, trimethylamiso, triamine, tributylamine, tributylamine, and the like.
  • inorganic bases such as sodium hydroxide, sodium carbonate, sodium carbonate, sodium carbonate, trimethylamiso, triamine, tributylamine, tributylamine, and the like.
  • Trialkylamines such as methyl morpholine and dimethyvidiridine, ⁇ , dialkylayurin, ⁇ , ⁇ -dialkylbenzylamine, pyridine, picolin and lutidine.
  • Non-one 5 Yen, 1,4
  • reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature.
  • the stereoisomer When the compound [I] and the acylating agent [IV] have an asymmetric carbon in the compound in the acylation reaction, the stereoisomer may be used alone or in a mixture. it can. When these isomers are mixedly produced in this reaction, each of them can be obtained by a conventional method such as column chromatography or recrystallization, if necessary. When the thus obtained compound [I] ( ⁇ 2) has a protecting group, it can be removed in the same manner as described above, if necessary. Further, in the compound [I] obtained by the above method, when w represents hydrogen, sulfonation can be performed.
  • the reaction can be carried out in the form of a mixture.
  • sulfur-anhydride-compatible conductor examples include, for example, sulfuric anhydride monobasic complex (for example, anhydrous sulfuric acid monopyridine, anhydrous sulfuric acid trimethylamine, anhydrous sulfuric acid picolin, anhydrous sulfuric acid lutidine, anhydrous sulfuric acid N, N— Adducts such as dimethylformamide), anhydrous dioxane sulfate and anhydrous monosulfonic acid are used. .
  • sulfuric anhydride monobasic complex for example, anhydrous sulfuric acid monopyridine, anhydrous sulfuric acid trimethylamine, anhydrous sulfuric acid picolin, anhydrous sulfuric acid lutidine, anhydrous sulfuric acid N, N— Adducts such as dimethylformamide), anhydrous dioxane sulfate and anhydrous monosulfonic acid are used. .
  • the reaction temperature is from about 180 to about 80 ° C, preferably from about 120 to about 60 ° C.
  • a solvent may be used.
  • the solvent include 7 or ethers such as dioxane, tetrahydrofuran, and dimethyl ether, esters such as ethyl acetate and ethyl formate, chloroform, and dichloromethane.
  • Ordinary hydrides such as hydrides of benzene, toluene, toluene, n- ⁇ »xanane, and amides such as N, N-dimethylformamide and N, N-dimethylacetamide.
  • Organic solvents are used alone or in combination.
  • the compound [I :) (V-SOgH) can be obtained in any purity by subjecting the reaction mixture to purification / separation means known per se such as solvent extraction, recrystallization and chromatography. When a protecting group is present, it can be removed by the method described above.
  • the compound [1] thus obtained When the compound [1] thus obtained is in a free form, it may be converted to a salt or ester as described for the compound [H] by a conventional method, and conversely, when the compound [1] is obtained in a salt or ester form. In addition, it may be converted to the free form by an ordinary method.
  • the compound [.1] is subjected to a hydration reaction, and the compound [I] is produced by removing the ⁇ »group as necessary.
  • the cyano group of the compound [I] is converted to a rubamoyl group.
  • the compound [I] to be used may be in a free form, or may be a compound derived from a salt, ester or i-yl derivative as described for the compound [D].
  • compound [I] has substituents at the 3- and 4-positions, and therefore has ⁇ -trans isomers.
  • the carbons at the 3- and 4-positions are asymmetric carbons, at least the total
  • these stereoisomers can be used either alone or in a mixture. The same applies to the case where the group represented by R 1 has an asymmetric carbon atom, and the resulting stereoisomer can be used alone or in a mixture.
  • This hydration reaction may be performed by any method as long as it can convert the 4-position cyano group of the compound (: I) to a rubamoyl group.
  • a method of reacting an acid or a base with [I], a method of reacting a compound [I] with hydrogen iodide in the presence of a base, and the like are used.
  • a base include hydroxides of lithium metals such as lithium, potassium and sodium or hydroxides of alkaline earth metals such as calcium and magnesium (for example, hydroxides of lithium and potassium).
  • Inorganic bases such as sodium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, etc.
  • organic bases such as ammonium hydroxide, etc., and basic ion exchange resins are used.
  • preferred bases are, for example, hydroxides of alkali metal (for example, sodium hydroxide).
  • the acid include hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, ferric chloride, zinc chloride, manganese dioxide, boron trifluoride, salt OMPI
  • Inorganic acids or salts thereof such as palladium fluoride and titanium tetrachloride, formic acid, acetic acid, ⁇ -toluenesulfonic acid, trifluoroacetic acid, and other acids, silicic acid gels, and acidic ion exchange resins are used.
  • acids such as hydrochloric acid, sulfuric acid, manganese dioxide, palladium chloride, and titanium tetrachloride are preferable.
  • the amount of such a base or acid to be used is generally 0.1 to 4.0 mol, preferably 0.1 to 1.0 mol, per 1 mol of compound [I].
  • ⁇ compounds when using hydrogen peroxide (I) 1 mole 0.0 5 bases against 4 0 mol good Mashiku is 0.0 5:. 1. 0 moles.
  • the amount of hydrogen peroxide to be used is generally 1.0 to 10 mol, preferably 1 to 0 to 4 mol, per 1 mol of the compound [I].
  • This reaction is usually carried out in a solvent.
  • a solvent include water, ether (eg, tetrahydrofuran, dioxane, etc.), and acid amide (eg, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ ).
  • hydrocarbons eg, benzene
  • ketones eg, aceton
  • alcohols eg, methanol, ethanol, propanol, butanol, etc.
  • hydrogenated hydrocarbons eg, Form, dichloromethane, etc.
  • fatty acids eg, formic acid, acetic acid, etc.
  • esters eg, ethyl acetate, etc.
  • dimethylsulfoxide snoreholane, hexamethyltinolephosphoramide, and mixtures thereof.
  • phase transfer catalyst the same one as in the above-described reaction between the compound [U] and the cyano compound is used.
  • phase transfer catalysts are used in a reaction of about 0.1 to 2 mol, preferably 0.5 to 1 mol, per 1 mol of the compound [I].
  • Reaction temperature is usually in the range of 0 to 80
  • the temperature is not limited to this condition, and heating and cooling may be performed as needed. Reaction time is usually short Q
  • the reaction mixture is subjected to a purification and separation method known per se, such as solvent extraction, recrystallization, chromatography, etc., to obtain a compound [I] ′ having an arbitrary purity. It can be used as a raw material for the next reaction as it is.
  • the compound may be isolated by a known means as necessary. If the protecting group is present in the substituent of compound [I], the compound may be unnecessary. Accordingly, it can be removed in the same manner as described above.
  • the compound CI] thus obtained When the compound CI] thus obtained is in a free form, it may be converted into the above-mentioned salt or ester by a conventional method.
  • the compound [I] When the compound [I] is obtained as a salt or an ester, the compound may be converted into a free form by a conventional method. May lead. ..
  • the compound [I] when the compound [I] is reacted with hydrogen sulfide, a compound having —CSNH 2 instead of the 4-position cyano group of the compound [I] is cleaved.
  • this reaction it is preferable to react about 1.0 to 3 moles of hydrogen sulfide with respect to 1 mole of compound .1] or its salt, ester or silyl derivative.
  • the reaction advantageously proceeds at or below room temperature.
  • the reactions are, for example, chloroform, dichloromethane, benzene, ethinole acetate, tetrahydrofuran, dihydrofuran.
  • reaction is usually carried out in a solvent such as oxane, N, N-dimethylformamide, ,, ⁇ -dimethylacetamide, dimethylsulfoxide, acetic acid, or water.
  • a solvent such as oxane, N, N-dimethylformamide, ,, ⁇ -dimethylacetamide, dimethylsulfoxide, acetic acid, or water.
  • the reaction is usually completed in a short time.
  • the compound [I] when the compound [ ⁇ ] is reacted with an alcohol such as methanol or ethanol, the compound [I] has a compound having an alkoxy: xycarbonyl group instead of a cyano group at the 4- position. Manufactured. The reaction is carried out by reversing the compound [I] and the alcohols on this mold.
  • reaction temperature is usually a force in the range of o to 80 ° C; however, the present invention is not particularly limited to this condition, and it is possible to appropriately perform heating and cooling if necessary. Conditions are forces appropriately determined depending on the solvent, temperature, etc.
  • reaction time can be shortened by the coexistence of Lewis acids such as zinc and boron trifluoride.
  • the starting compound [11] of the present invention can be produced, for example, by the method shown below.
  • R 2 , Y, and X have the same meanings as described above, H 2l ⁇ represents a protected amino group, and R 21 represents an acylated amino group.
  • the NMR spectrum was measured with a Varian HA 100 type (100 Hz), and the value is represented by Pm based on tetramethylsilane.
  • S is a singlet
  • br.s is a wide singlet
  • d is a doublet
  • dd is a doublet
  • t is a triplet
  • q is a quartet
  • m is a multiplet
  • ABq is an AB-type quartet
  • J is a join.
  • Constant TH is tetrahydrofuran
  • DMF is dimethylformamide
  • DMSO dimethylsulfoxide
  • br. Or broad broad
  • arom is aromatic I do.
  • silica gel chromatography is referred to as Art. 9 382.
  • 530-400 Mesh Kiesel Ge 1 (Kiesel Ge 1) 60 (Merckner Using ⁇ 3 ⁇ 4)
  • Kiesel Ge 1 Kiesel Ge 1 60 (Merckner Using ⁇ 3 ⁇ 4)
  • a TLC analysis of the crude product before chromatographic purification collects the same Rf-value of the main spot newly appeared on the TLC plate, and collects a fraction with the same value. If not used, detect with a UV detector using Art.5642, HPTLC Kiesel Gel 60 F 254 (manufactured by Merck) plates and the same developing solvent as the solvent used for chromatography.
  • XAD-H (100-200 mesh) column chromatography uses 254 nm absorption (LKB UVI CORD 2, (Swedish) shelf) using water to 20% ethanol water as the developing solvent. Collect fractions with). The collected fractions are freeze-dried to produce purified products.
  • IR- 1 2950, 2920, 2140, 1745,
  • the 4-cyano-2-azetidinone derivative [I] has excellent antibacterial activity and is useful for inhibiting 4-lactamase.
  • [I] which is used as an advantageous synthetic intermediate in synthesizing an optically active derivative and has w as a sulfo group, has an antibacterial activity and a ⁇ -lactamase inhibitory activity by itself, and can be used for humans and dogs.
  • As a therapeutic agent for infectious diseases caused by gram-positive or negative bacteria in mammals including cats, cats, cows, horses, mice, guinea pigs, etc .; as a preservative for animal feed, industrial water, or disinfecting sanitary equipment
  • it can be used as a decomposition inhibitor for the antibiotic.

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PCT/JP1982/000141 1981-12-25 1982-04-27 4-cyano-2-azetidinone derivatives and process for their preparation WO1983003827A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
PCT/JP1982/000141 WO1983003827A1 (en) 1982-04-27 1982-04-27 4-cyano-2-azetidinone derivatives and process for their preparation
IL67451A IL67451A (en) 1981-12-25 1982-12-10 4-cyano-2-azetidinones and production thereof and process for the preparation of 4-carbamoyl-2-azetidinones using them
EP82111744A EP0083039B1 (en) 1981-12-25 1982-12-17 4-cyano-2-azetidinones and production thereof
AU91642/82A AU557575B2 (en) 1981-12-25 1982-12-17 4-cyano-2-azetidinones
DE8282111744T DE3270045D1 (en) 1981-12-25 1982-12-17 4-cyano-2-azetidinones and production thereof
AT82111744T ATE18665T1 (de) 1981-12-25 1982-12-17 4-cyano-2-azetidinone und ihre herstellung.
US06/451,323 US4560508A (en) 1981-12-25 1982-12-20 4-Cyano-2-azetidinones and production thereof
IE3036/82A IE54682B1 (en) 1981-12-25 1982-12-21 4-cyano-2-azetidinones and production thereof
NO824312A NO160996C (no) 1981-12-25 1982-12-21 4-cyano-2-azetidinoner.
GB08236247A GB2114977B (en) 1981-12-25 1982-12-21 4-cyano-2-azetidinone azetidines derivatives represented by the formula
CA000418377A CA1212112A (en) 1981-12-25 1982-12-22 4-cyano-2-azetidinones and production thereof
DK570082A DK570082A (da) 1981-12-25 1982-12-23 4-cyan-2-azetidinoner samt fremgangsmaade til fremstilling af saadanne
NZ202907A NZ202907A (en) 1982-04-27 1982-12-23 4-cyano-2-azetidinone derivatives;pharmaceutical compositions containing them and their use in preparing 4-carbamoyl-2-azetidinones
HU824159A HU192780B (en) 1981-12-25 1982-12-23 Process for preparing-2-azetidinone derivatives
KR8205807A KR890003423B1 (ko) 1981-12-25 1982-12-24 4-시아노-2-아제티디논 유도체의 제조방법
ES518562A ES518562A0 (es) 1981-12-25 1982-12-24 Un metodo de producir un derivado de 4-ciano-2-azetidinona.
JP58073470A JPS591465A (ja) 1982-04-27 1983-04-25 ４―シアノ―２―アゼチジノン誘導体の製造法
US06/791,998 US4684724A (en) 1981-12-25 1985-10-23 4-Cyano-2-azetidinones and production thereof

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