WO2007142207A1 - Procédé de production de dérivés de l'azétidinone à substitution en 4 - Google Patents

Procédé de production de dérivés de l'azétidinone à substitution en 4 Download PDF

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WO2007142207A1
WO2007142207A1 PCT/JP2007/061320 JP2007061320W WO2007142207A1 WO 2007142207 A1 WO2007142207 A1 WO 2007142207A1 JP 2007061320 W JP2007061320 W JP 2007061320W WO 2007142207 A1 WO2007142207 A1 WO 2007142207A1
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group
carbon atoms
substituted
optionally substituted
alkyl group
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Tatsuya Honda
Nobuo Nagashima
Ikuhiro Suzuki
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Kaneka Corp
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Kaneka Corp
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a method for producing a 4-substituted azetidinone derivative which is important as a synthetic intermediate for a powerful rubapenem compound.
  • R 1 is a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, substituted !, or an optionally substituted aralkyl group having 7 to 20 carbon atoms! Or an aryl group having 6 to 20 carbon atoms, an optionally substituted alkenyl group having 2 to 10 carbon atoms, or an optionally substituted carbon group having 2 to: an alkynyl group having LO.
  • R 4 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms.
  • R 7 represents an electron withdrawing group
  • R 8 represents an alkyl group having 1 to 12 carbon atoms, a alkenyl group having 2 to 5 carbon atoms, an optionally substituted silyl group
  • An optionally substituted aryl group having 6 to 10 carbon atoms, an optionally substituted carbon atom 7 to: represents an aralkyl group having L 1
  • R 1 and R 4 are the same as described above, and R 7 and R 8 may be combined with an adjacent nitrogen atom to form a heterocyclic ring.
  • Patent Document 1 JP-A-7-70116
  • Patent Document 2 JP-A-7-82248
  • Patent Document 3 Japanese Patent Fair 5—58630
  • Patent Document 4 Japanese Patent Fair 5-57264 Patent Document 5: Japanese Patent Fair 7-107072
  • Patent Document 6 Japanese Patent Laid-Open No. 61-18791
  • Patent Document 7 Japanese Patent Laid-Open No. 63-233989
  • Non-Patent Document 1 Journal of Synthetic Organic Chemistry, 57th No. 5, No. 387 (1999)
  • Non-Patent Document 2 Chem. Parm. Bull, 29, 2899 (1981)
  • Non-Patent Document 3 Tetrahedron, 39, 2399 (1983)
  • Non-Patent Document 4 Tetrahedron Lett., 23, 2293 (1982)
  • a toxic heavy metal compound such as mercury acetate or lead tetraacetate is introduced in order to introduce an acetoxy group at the 4-position of the j8-ratata ring.
  • peracid which has a risk of explosion, is used, and it is difficult to say that these methods are industrially advantageous production methods.
  • the method (V) which is an industrially suitable production method, is a relatively expensive and bad-smelling pyridine in the process of introducing a hydroxyl group at the 4-position of the ⁇ -lactam ring. Since an excessive amount is used, it is not economically advantageous.
  • the present invention aims to provide a process for producing a rubonic acid derivative (11) or a precursor thereof which is more efficient and economical and can be suitably carried out industrially. It is what.
  • R 1 is a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, substituted !, or an optionally substituted aralkyl group having 7 to 20 carbon atoms! Or an aryl group having 6 to 20 carbon atoms, an alkenyl group having 2 to 10 carbon atoms which may be substituted, or an alkynyl group having 2 to 10 carbon atoms which may be substituted;
  • R 2 is an optionally substituted silyl group, a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, an optionally substituted aralkyl group having 7 to 20 carbon atoms, and a substituted group.
  • Alkyl group having 6 to 20 carbon atoms may be substituted, or may be substituted with an alkyl group having 2 to 10 carbon atoms, or may be substituted with an alkyl group having 2 to 10 carbon atoms.
  • R 3 is a 4-substituted O carboxymethyl ⁇ peptidase histidinol non derivative represented by a protecting group for a hydrogen atom or a N.
  • 4 ⁇ Seto carboxymethyl ⁇ peptidase histidinol non derivative This has led to the invention a method that can be converted to 4-substituted Azechijinon derivatives Kotonagu 1 step to convert to general formula (12)).
  • the present invention relates to a 4-substituted oxazetidinone derivative represented by the above formula (1) and a general formula (2):
  • R 4 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms
  • R 5 is substituted with V, or an alkyl group with 1 to 10 carbon atoms is substituted!
  • the aryl group having 7 to 20 carbon atoms, the aryl group having 6 to 20 carbon atoms which may be substituted, the alkyl group having 2 to 10 carbon atoms which may be substituted, and the substituted group may be substituted.
  • General formula (3) characterized by reacting enolate of the carbo-Louis compound shown: [0021] [Chemical 15]
  • the present invention is characterized by hydrolyzing a 4-substituted azetidinone derivative represented by the above formula (3) obtained by the above-described method:
  • a 4-substituted azetidinone derivative can be synthesized in a shorter process than before, and can be produced industrially advantageously.
  • R 1 represents a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, a substituted Or an aryl group having 7 to 20 carbon atoms, substituted !, an aryl group having 6 to 20 carbon atoms, or an alkenyl group having 2 to 10 carbon atoms which may be substituted. And an optionally substituted alkynyl group having 2 to 10 carbon atoms.
  • substituent for R 1 include a chlorine atom, a bromine atom, a hydroxyl group, a nitro group, a methoxy group, and a methyl group.
  • R 1 examples include, for example, a hydrogen atom, a methyl group, an ethyl group, a hydroxyl group-protected 1-hydroxycetyl group, a vinyl group, a phenyl group, and the like. Groups are preferred.
  • examples of the hydroxyl-protecting group include all hydroxyl-protecting groups usually used in the field of peptide chemistry and ⁇ 8-latatam compounds.
  • silyl groups such as trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, aralkyl groups such as benzyl group, methoxycarbol group, tert-butoxycarbol group, benzyloxycarboro group
  • acetal type protecting groups such as methoxymethyl group, tetrahydrobiranyl group and the like, and alkoxy groups such as alkoxycarbonyl group, acetyl group, bivaloyl group and benzoyl group.
  • alkoxy groups such as alkoxycarbonyl group, acetyl group, bivaloyl group and benzoyl group.
  • a tert-butyldimethylsilyl group which is widely used in the chemistry of strong rubapenem compounds and can be easily and inexpensively deprotected, is preferred.
  • R 2 is an optionally substituted silyl group, an optionally substituted alkyl group having 1 to 10 carbon atoms, an optionally substituted aralkyl group having 7 to 20 carbon atoms, or a substituted group.
  • the substituent for R 2 include a chlorine atom, an bromo atom, a hydroxyl group, a nitro group, a methoxy group, and a methyl group.
  • R 2 include, for example, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a methyl group, an ethyl group, an isopropyl group, a benzyl group, a phenyl group, and the like, and among them, a trimethylsilyl group and a methyl group Is preferred.
  • R 3 represents a hydrogen atom or a protecting group for N.
  • the protecting group for N include all protecting groups commonly used in the field of ⁇ -lactam compounds. That is, for example, silyl group such as trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, benzyl group, 2,4 dimethoxybenzyl group, benzyl group such as di (p-acyl) methyl group, and phenyl group.
  • Aryl groups such as p-acyl group, alkoxy carbonyl groups such as methoxy carbo yl group, tert butoxy carbo yl group, benzyloxy carbo ol group, Acetyl group such as til group, bivaloyl group, benzoyl group, methoxymethyl group, tetrahydrovilla
  • Acetal-type protecting groups such as -l- and acetoxymethyl groups, 2--trifluorosulfol groups, p-toluenesulfol groups, sulfo groups such as chlorosulfol groups, alkoxy such as methoxy and benzyloxy groups Group, hydroxyl group and the like.
  • the method for producing the 4-substituted oxazetidinone derivative (1) used in the present invention is not particularly limited.
  • Examples thereof include a method described in 18 791 and JP-A 63-233989 or a method analogous thereto.
  • Carbonyl compound (2) used in the present invention is carbonyl compound (2) used in the present invention:
  • R 4 in [0035] represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and examples thereof include a hydrogen atom, a methyl group, an ethyl group, and an isopropyl group. Among them, a hydrogen atom or a methyl group is preferable. .
  • R 5 may be an optionally substituted alkyl group having 1 to 10 carbon atoms, may be substituted V, an aralkyl group having 7 to 20 carbon atoms, substituted !, may be carbon An aryl group having 6 to 20 carbon atoms, which may be substituted, an alkyl group having 2 to 10 carbon atoms, or a substituted !, an alkyl group having 2 to 10 carbon atoms, which may be substituted; The amino group which may be substituted, the hydroxyl group which may be substituted, and the thiol group which may be substituted are shown.
  • R 5 is not particularly limited, and examples thereof include a chlorine atom, a bromine atom, a hydroxyl group, a nitro group, a methoxy group, and a methyl group.
  • R 5 include, for example, a methyl group, a tert-butyl group, a methoxycarbonyl methyl group, a p--trobenzyloxycarbonylmethyl group, 1-diazo-1- (p--trobenzyloxy) (Carbonyl) methyl group, isobutyloxycarboxoxymethyl group etc. may be substituted, alkyl group, benzyl group etc. may be substituted !, may!
  • Aralkyl group phenol group
  • aryl group dibenzylamino group, diph N- ((R) — 1-phenethyl) -N-ethoxycarbo-lamino group, which may be substituted, such as amino group, methoxy group, phenoxy group, p--trophenoxy group, etc. May be substituted with a hydroxyl group, a methylthio group, a phenolthio group, a p--trifluorophenol group, a p-chlorophenol group, etc., and a thiol group may be mentioned. But I prefer the amino group.
  • R 7 represents an electron-withdrawing group, for example, an acetyl group such as a acetyl group, a bivaloyl group, a benzoyl group, an ethoxycarbol group, a tert-butoxycarbol group, or a benzyloxycarbol.
  • a alkoxy group such as a group, a methanesulfol group, a benzenesulfol group, a sulfol group such as a p-toluenesulfol group, the following formula (19):
  • X is an oxygen atom, a sulfur atom or NR 12 group
  • R 1 2 is hydrogen atom, an alkyl group, or Hue 1 to 4 carbon atoms
  • Y represents an oxygen atom, a sulfur atom, an NR 13 group (R 13 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a phenyl group), or may be substituted.
  • R 9 , R 1Q , and R 11 are each an alkyl group having 1 to 12 carbon atoms, an alkyl group having 2 to 5 carbon atoms, and may be substituted V ⁇ 6 to 10 carbon atoms
  • Alkenyl group such as 2-butyl group, phenol group, 4-phenyl group, naphthyl group and other aryl groups, benzyl group, 1-phenethyl group Aralkyl groups such as.
  • substituent represented by the formula (19) include alkoxy carbo ol groups such as an ethoxy carbo ol group, a tert-butoxy carbo ol group, and a benzyloxy carbo ol group.
  • substituent represented by the formula (20) include an acyl group such as an acetyl group, a bivaloyl group, and a benzoyl group.
  • substituent represented by the formula (21) examples thereof include sulfonyl groups such as methanesulfol groups, benzenesulfol groups, and p-toluenesulfol groups. Of these, a bivaloyl group, a benzoyl group, and an ethoxycarbo yl group are preferable from an economical viewpoint.
  • R 8 is an alkyl group having 1 to 12 carbon atoms, an alkyl group having 2 to 5 carbon atoms, an optionally substituted silyl group, or a substituted group.
  • Isopropyl groups alkenyl groups such as 2-butyl group, silyl groups such as trimethylsilyl group, tert-butyldimethylsilyl group, aryl groups such as phenol group, naphthyl group, benzyl group, 1 phenethyl group Aralkyl groups such as.
  • tert butyl group, cyclohexyl group, tert-butyldimethylsilyl group, phenyl group, and 1-phenethyl group are preferred from the viewpoint of performing a stereoselective reaction! /.
  • R 7 and R 8 together with the adjacent nitrogen atom form a ring! It is an aspect that is highly preferred.
  • R 7 is a substituent represented by the above formulas (19) to (21)
  • R 9 , R 1Q and R 11 may be joined together with R 8 to form a ring.
  • R 7 is a substituent represented by the general formula (19):
  • carbocyclic compound (2) having the substituent of [0052] include, for example, N isopropyl N propionyl carbamate, N cyclohexyl N propionyl, carbyl ethyl, N-tert butyl-N propio N- ((R) — 1-Phenethyl) N— (P (R) — 1-Phenethyl) N— (P (R) — 1-Phenethyl) —N— (Propio) N- ((R) — 1-phenethyl) —N tert-butyl propio-carbamate, N— ((S) -1-phenethyl) —N-propio-carbamate tert-butyl, N-isopropyl Examples thereof include —N-propiothiol strength ethyl rubamate, N — ((R) 1-phenethyl) N-propio-
  • R 7 is a substituent represented by the general formula (20).
  • carbocyclic compound (2) having a substituent of [0055] include, for example, N isopropyl N propiolupenamide, N-cyclohexyl-N-propiolupentamide, N-tert butyl-N- Propiorpene amide, N—Phenol-N, Propyl benzamide, N— ((R) — 1-Phenethyl) —N—Propio-Lupenamide, N One ((S) — 1-Phenethyl) —N—Propio-Lupenamide , N—Isopropyl N— Pivalolpropionamide, N Cyclohexyloo N Pivaloylpropionamide, N tert Butyl N Pivalolpropionamide, N Phenyl N Pivaloylpropionamide, N— ((R) — 1—Phenethyl) —N —Bivaloylpro
  • R 7 is a substituent represented by the general formula (20).
  • carbocyclic compound (2) having the substituents of [0058] include, for example, N isopropyl-N-p toluenesulfol propionamide, N-cyclohexyl N- p toluenesulfol propion.
  • R 7 is a compound represented by the general formulas (19) to (21) in the substituent represented by the formula (7)
  • R 8 is R 9 , R 1Q or R
  • Examples of the force sulfonyl compound (2) in the case of forming a heterocyclic ring with 11 include substituents represented by the following general formulas (14) to (18).
  • R ′′, R 15 , R 16 , R ′′, R 18 and R 19 are each an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, and may be substituted.
  • C6-C10 aryl group, optionally substituted C7-: L 1 aralkyl group, X and Y are the same as above, R "and R 15 , R 16 and R 17 , R 18 and R 19 may be joined together to form a ring R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and the two adjacent carbons at the base of these substituents You can form a ring with an atom, or the substituent force shown by) can be one selected! /.
  • R ′′, R 15 , R 16 , R ′′, R 18 , R 19 are, for example, methyl groups, isopropyl groups, tert butyl groups, cyclohexyl groups and other alkyl groups, isopropyl groups, 2-butyr Alkenyl groups such as alkenyl groups, phenyl groups, chloro groups, naphthyl groups, benzyl groups, 1 phenethyl And an aralkyl group such as a ru group.
  • R 14 and R 15 , R 16 and R 17 , R 18 and R 19 may be joined together to form a ring such as a cyclohexane ring.
  • R 14 , R 15 , R 16 , R ", R 18 , R 19 bonded to two adjacent carbon atoms and the two adjacent carbon atoms at the base of these substituents
  • a cyclohexane ring which may have a substituent, a substituent, or a ring such as a benzene ring may be formed.
  • Specific examples of the carbonyl compound (2) having a substituent represented by the general formula (14) include, for example, 4, 4 dimethyl-3 propionyloxazolidin-2-one, (S) -4 Fenuluo 3 propio-loxazolidine 2-one, (S) -4-tert-Butyl-3 propio-loxazolidine 2-on, (S) -4 monobenzyl 3 propio-loxazolidine 2-one, (S) — 4-methyl-3 propio -Luoxazolidine-2-one, (S) —4-ethyl-3-propio-loxazolidine-2-one, (S) —4 Isopropyl-3-propio-loxazolidine-2-one, (4S, 5R) —Dipheo-Lu-3 propio-loxazolidine 2 ON, 4, 4 dimethyl-3 propionyloxazolidine 2-thione, 4, 4 dimethyl-3 propionyl thiazolidine 2 ON, 4, 4 dimethyl 3 propionyl
  • carbonyl compound (2) having a substituent represented by the general formula (15) include, for example, 4, 4 dimethyl 1 3 propionyl 1 tetrahydro 1 1, 3-oxazine 1 2 — ON, 1-propio-Lu 1,4-dihydro-2H— 3, 1 benzoxazine 2 ON.
  • Specific examples of the carbonyl compound (2) having a substituent of the general formula (16) include, for example, 5, 5 dimethyl-3 propionyl 2, 2 pentamethylene 1, 3 oxazine-4-one, 1 propio-rubiperidin 2-one and the like.
  • carbocyclic compound (2) having a substituent represented by the general formula (17) include, for example, N propio-lubornane 1,2-sultam and the like.
  • Specific examples of the carbonyl compound (2) having a substituent represented by the general formula (18) include, for example, N-propio-luo 2, 1-benzothiazine 1, 2, 2-dioxide and the like.
  • the method for producing compound (2) is not particularly limited, and examples thereof include the method described in JP-A-7-97381 and JP-B-5-58630, or a method analogous thereto.
  • R 4 of the carbonyl compound (2) is a lower alkyl group having 1 to 4 carbon atoms
  • a 4-substituted azetidinone derivative (3) synthesized:
  • R 1 , R 3 , R 4 and R 5 are the same as above.
  • the 1-position on the 4-position side chain is an asymmetric carbon.
  • the configuration is not particularly limited, and the R configuration, the S configuration, or a mixture thereof may be used.
  • As a synthetic intermediate of the force rubapenem compound the following general formula (6):
  • R 1 is a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, and an optionally substituted aralkyl having 7 to 20 carbon atoms.
  • Group, substituted V may be an aryl group having 6 to 20 carbon atoms, substituted !, may be an alkenyl group having 2 to 10 carbon atoms, may be substituted 2 to 2 carbon atoms 10 represents an alkyl group, R 3 represents a hydrogen atom or a protecting group for N, R 4 represents a lower alkyl group having 1 to 4 carbon atoms, R 5 is substituted!
  • Alkyl group having 2 to 10 carbon atoms Represents an amino group which may be substituted, a hydroxyl group which may be substituted, or a thiol group which may be substituted.
  • An optically active 4-substituted azetidinone derivative having a configuration shown by (2) is preferred.
  • metal enolate is preferred as enolate, for example, lithium enolate, sodium enolate, magnesium enolate, zinc enolate, titanium enolate, zirconium enolate, hafnium enolate, iron enolate, stannolate, antimony enolate, silyl enolate, boron enolate. And aluminum enolate.
  • titanium enolate is preferred from the viewpoint of yield and economy.
  • the method for generating the enolate is not particularly limited, and for example, a metal base can be used.
  • metal bases include alkyl metal compounds such as ⁇ -butyllithium, t-butyllithium, and phenyllithium, n-butylmagnesium bromide, and glycine compounds such as t-butylmagnesium bromide, lithium diisopropylamide, sodium bis (trimethylsilyl) amide, and the like.
  • metal amide compounds metal hydrides such as sodium hydride, and metal alkoxides such as sodium ethoxide and potassium tert-butoxide.
  • the amount of the metal base used is not particularly limited, but the reaction can usually be carried out using 1 mol or more per 1 mol of the carbonyl compound (2). In view of economy, it is generally preferable to use 10.0 mol or less, but more preferably 8.0 mol or less.
  • the desired metal enolate can also be formed by using various metal compounds and bases.
  • general formula (4) As a metal compound to be used, general formula (4):
  • Titanium compounds iron compounds such as iron trichloride, zinc compounds such as zirconium tetrachloride, aluminum compounds such as aluminum chloride, tin compounds such as tin tetrachloride, pentamonium antimony Antimony compounds such as tetrachloride and hafnium, magnesium compounds such as salt and magnesium, zinc compounds such as salt and zinc, silyl such as trimethylsilyl chloride Boron compounds such as compounds and jetyl boron triflate Among them, a titanium compound is preferable from the viewpoint of yield and economy in terms of yield and economy.
  • X represents a halogen atom, and examples thereof include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Bromine atom is preferred.
  • R 6 is a lower alkyl group having 1 to 4 carbon atoms, a lower alkyloxy group having 1 to 4 carbon atoms, a phenoxy group which may have a substituent, an alkylsulfo-oxy group, an arylsulfonyl group, or Cyclopentadienyl group, for example, methoxy group, ethoxy group, isopropoxy group, phenoxy group, trifluoromethanesulfol group, methanesulfol group, p-toluenesulfol group, cyclopentagel Among them, a trifluoromethanesulfol group, a methanesulfol group, and a p-toluenesulfonyl group are preferable from the viewpoints of yield and economy.
  • titanium compound (4) examples include, for example, tetrachloro titanium, tetrabromo titanium, diisopropyl dichloro titanium, isopropyl trichloro titanium and the like. From the viewpoint of economy, tetrachloro titanium or tetrabromo titanium. Tan is preferred. Two or more of these may be used in combination. When mixing, there is no particular limitation on the mixing ratio. Examples of the compound represented by the formula (4) include tetrachloro titanium, tetrabromo titanium, isopropyl trichloro titanium and the like.
  • Examples of the base include primary amines such as ethylamine, lin, and benzylamine, secondary amines such as dimethylamine, diisopropylamine, piperidine, morpholine, and imidazole, trimethylamine, and triethylamine.
  • Examples include tertiary amines such as 7-ene and 1,4-diazabicyclo [2, 2, 2] octane.
  • triethylamine and tri-n-butylamine are preferred from the viewpoint of yield and economy.
  • Tertiary amines such as diisopropylethylamine are preferred.
  • the amount of the metal compound to be used is not particularly limited, but the reaction can usually be carried out using 1 mol or more per 1 mol of the carbonyl compound (2). Preferably it is 2.5 mol or more, more preferably 3 mol or more, and especially 4 mol or more. In general, it is preferably used in an amount of 10.0 mol or less from the viewpoint of economy, but more preferably 8. 0 mol or less.
  • the amount of the base used is not particularly limited, but the reaction can usually be carried out using 1 mol or more per 1 mol of the carbonyl compound (2). Preferably it is 2.5 mol or more, more preferably 3 mol or more, and especially 4 mol or more. In view of economy, it is generally preferred to use 10.0 mol or less, but more preferably 8.0 mol or less.
  • the 4-substituted oxazetidinone derivative (1) has a weak functional group in a Lewis acid such as an alkylsilyloxy group, from the viewpoint of yield, the titanium compound (4) and It is preferable to use equimolar amounts of bases.
  • the amount of the carbonyl compound (2) used is not particularly limited, but usually the reaction is performed using 1 mol or more per 1 mol of the 4-substituted oxazetidinone derivative (1). Can be implemented.
  • the economical surface power is preferably 10.0 mol or less, more preferably 5.0 mol or less, and still more preferably 3.0 mol or less.
  • reaction of the compound represented by the formula (1) and the enolate of the carbonyl compound (2) in the present invention proceeds by mixing in a solvent, but separately in the formula (4) It is preferable to react in the presence of the compound represented and the aforementioned base.
  • the titanium compound (4) and the base are used for the enolate formation of the carbonyl compound (2), the titanium compound (4) and the base are combined with the carbonyl compound from the viewpoint of yield.
  • This is an excess molar amount than (2).
  • the molar amount of the excess (a value obtained by subtracting the molar amount of the carbonyl compound (2) from the molar amount of the titanium compound (4) or base) is 2 moles per mole of the 4-substituted oxazetidinone derivative (1).
  • preferably 3 mol or more, particularly 4 mol or more is preferred.
  • the upper limit is preferably 20 mol or less, more preferably 15 mol or less.
  • the amount of the compound represented by the formula (4) to be separately present in the reaction is not particularly limited. However, 2 moles or more is preferable with respect to 1 mole of the 4-substituted oxazetidinone derivative (1), more preferably 3 moles or more, and particularly preferably 4 moles or more. The upper limit is 20 moles 15 moles or less are more preferred.
  • the reaction solvent in the reaction of the present invention is not particularly limited as long as it does not inhibit the reaction including the preparation of the enolate of compound (2).
  • halogens such as methylene chloride, 1,2-dichloroethane, black form, carbon tetrachloride, black benzene, etc.
  • hydrocarbon hydrocarbon solvents and aromatic hydrocarbon solvents such as toluene, benzene and xylene.
  • two or more of these solvents may be mixed and used.
  • the mixing ratio is not particularly limited.
  • the order of addition of the 4-substituted oxazetidinone derivative (1), the enolate of compound (2), and the reaction solvent is not limited.
  • the enoler is dissolved in the reaction solvent in which compound (1) and compound (2) are dissolved.
  • the reaction may be started by adding a reagent for preparing the compound, or the compound (1) may be added to the solution in which the enolate of the compound (2) is prepared.
  • Compound (1) is added to a solution prepared with an enolate of compound (2), in which the addition order is not limited even when compound (4) and a base are used in the reaction of compound (1) and compound (2) enolate.
  • compound (4) and a base may be further added, followed by sequential addition or divided addition.
  • the concentration of the 4-substituted oxazetidinone derivative (1) during the reaction varies depending on the reaction solvent used. Generally, the reaction should be carried out at 1 to 50% (gZml, the same shall apply hereinafter). It is preferably 3 to 30%.
  • the reaction temperature during the reaction varies depending on the reactivity of the enolate of the carbonyl compound (2) and the type of the reaction solvent, but usually the freezing point force of the reaction solvent used is in the range below the boiling point. In order to complete the reaction in a short time, it is better to carry out at a higher temperature to suppress side reactions. Therefore, it is better to set the temperature low. Generally, it is ⁇ 40 to 100 ° C., more preferably 20 to 40 ° C.
  • reaction time during the reaction varies depending on the reactivity of the enolate of the carbonyl compound (2), the type of reaction solvent, and the reaction temperature, but is usually 1 to 30 when the reaction temperature is carried out at -20 to 40 ° C. It is about time.
  • the order of mixing the 4-substituted oxazetidinone (1), carbonyl compound (2) or its enolate, titanium compound (4), base, reaction solvent, etc. used in this reaction is arbitrary. Yes, for example, even if 4-substituted oxazetidinone (1) is added to a mixture of carbonyl compound (2), titanium compound (4) and base. Alternatively, a mixture of the carbonyl compound (2), the titanium compound (4) and the base may be added to the 4-substituted oxazetidinone (1).
  • a general treatment for obtaining a reaction fluid product may be performed.
  • water, hydrochloric acid, alkaline water or the like is added to the reaction solution after completion of the reaction, and the extraction operation is performed using a common extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane or the like.
  • a common extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane or the like.
  • the reaction solvent and the extraction solvent are distilled off under reduced pressure from the obtained extract, the desired product is obtained.
  • the product thus obtained may be further purified by performing general purification such as silica gel chromatography, distillation, recrystallization and the like.
  • R 5 may be an amino group which may be substituted, a hydroxyl group which may be substituted, or a thiol group which may be substituted.
  • the general formula (5) the general formula (5):
  • R 1 is a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, substituted !, or an optionally substituted aralkyl group having 7 to 20 carbon atoms! Or an aryl group having 6 to 20 carbon atoms, an optionally substituted alkenyl group having 2 to 10 carbon atoms, an optionally substituted carbon group having 2 to: an alkyl group of LO.
  • R 3 represents a hydrogen atom or a protecting group for N
  • R 4 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms
  • a base may be added to accelerate the reaction rate.
  • the base to be used include hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide, and magnesium hydroxide, and carbonates such as sodium carbonate and potassium carbonate. Above all, from the viewpoint of yield and economy. Therefore, sodium hydroxide and lithium hydroxide are preferable.
  • the amount of the base used is not particularly limited, but the reaction can usually be carried out using 1 mol or more per 1 mol of the 4-substituted azetidinone derivative (3). In view of economy, it is generally preferred to use no more than 10.0 mol, but more preferably no more than 4.0 mol.
  • hydrogen peroxide may be added to improve the yield.
  • the amount of hydrogen peroxide is not particularly limited, but the reaction can usually be carried out using 1 mol or more per 1 mol of the 4-substituted azetidinone derivative (3). Economic Aspect In general, it is preferably used in an amount of 10.0 mol or less, more preferably 5.0 mol or less.
  • the reaction solvent in this reaction does not inhibit the reaction, and is not particularly limited as long as it is a solvent.
  • a solvent for example, alcohol solvents such as methanol, ethanol and isopropanol, ketone solvents such as acetone, pentane, Hydrocarbon solvents such as hexane, heptane, cyclohexane, methylcyclohexane and petroleum ether, ester solvents such as ethyl acetate and methyl acetate, aromatic hydrocarbon solvents such as toluene, benzene and xylene, acetonitrile , -Tolyl solvents such as propio-tolyl, ether solvents such as tert-butyl methyl ether, jetyl ether, diisopropyl ether, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N dimethylacetamide, etc.
  • alcohol solvents such as
  • Amide solvents such as dimethyl sulfoxide, Ren, 1, 2-dichloroethane, black hole Holm
  • sulfoxide solvents such as dimethyl sulfoxide, Ren, 1, 2-dichloroethane, black hole Holm
  • halogenated hydrocarbon solvents such as carbon tetrachloride and black benzene
  • water Among them, alcohol solvents such as methanol, ethanol and isopropanol, and ketone solvents such as acetone from the viewpoint of reaction yield. Or water is preferred. Further, two or more of these solvents may be mixed and used. When using a mixed solvent, the mixing ratio is not particularly limited
  • the concentration of the 4-substituted azetidinone derivative (3) during the reaction varies depending on the reaction solvent to be used, but the reaction can generally be carried out at 1 to 50%, preferably 3 to 30%. .
  • the reaction temperature during the reaction varies depending on the type and amount of the base used and the type of the reaction solvent, the freezing point force of the reaction solvent used is usually in the range of the boiling point or less. In order to complete the reaction in a short time, it is better to increase the temperature. From the viewpoint of suppressing side reactions, it is better to set the temperature lower. Generally, it is ⁇ 40 to 100 ° C., more preferably ⁇ 20 to 40 ° C.
  • reaction time during the reaction varies depending on the type and amount of the base used, the type of reaction solvent, and the reaction temperature. is there
  • the order of mixing the 4-substituted azetidinone derivative (3), base, hydrogen peroxide, reaction solvent, etc. used in this reaction is not particularly limited.
  • a general treatment for obtaining a reaction fluid product may be performed.
  • water, hydrochloric acid, alkaline water, or the like is added to the reaction solution after completion of the reaction, and the extraction operation is performed using a common extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane, or the like.
  • a common extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane, or the like.
  • the reaction solvent and the extraction solvent are distilled off under reduced pressure from the obtained extract, the desired product is obtained.
  • the product thus obtained may be further purified by performing general purification such as silica gel chromatography, distillation, recrystallization and the like. Moreover, you may use for next reaction as it is, without isolating.
  • R 5 H produced in the hydrolysis reaction can be separated from the carboxylic acid derivative (5) and recovered.
  • the carboxylic acid derivative (5) is converted to a metal salt such as sodium or lithium, dissolved in water, and then R 5 H is crystallized from the aqueous solution.
  • a method of separating the R3 ⁇ 4 from the aqueous layer by performing an extraction operation using a common extraction solvent such as ethyl acetate, jetyl ether, methylene chloride, toluene, hexane and the like. It is done.
  • the R 5 H thus obtained may be further purified by general purification such as silica gel chromatography, distillation or recrystallization, if necessary. Moreover, you may use for next reaction as it is, without isolating.
  • the carbonyl compound (2) can be produced by reacting R 5 H recovered by the above method with an acylating agent.
  • the method for producing the carbonyl compound (2) using R 5 H is not particularly limited. For example, the method described in JP-A-7-97381 and JP-B-5-58630 or a method analogous thereto is used. Can be mentioned.
  • the aqueous layer was further extracted three times with 10 ml of dichloromethane, and the organic layers were combined.
  • the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 251 .Omg of a crude product.
  • the aqueous layer was further extracted three times with 10 ml of dichloromethane, and the organic layers were combined.
  • the organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 247.8 mg of a crude product.
  • N ((S) — 1-phenethyl) - ⁇ -propio-carbamate ethyl (112.5 mg, 0.45 mmol) in methylene chloride (1.5 ml) in titanium tetrachloride (351.9 mg, 1.
  • a solution of 80 mmol) methylene chloride (0.5 ml) was added at 0 ° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne la production de manière efficace et aisée d'un dérivé de l'azétidinone à substitution en 4 à partir d'un dérivé de 4-(substitution hydroxy)azétidinone par un procédé industriellement avantageux. Ce but peut être atteint en remplaçant l'étape conventionnelle de conversion d'un dérivé de 4-(substitution hydroxy)azétidinone en un dérivé 4-acétoxyazétidinone suivie par la conversion du dérivé de 4-acétoxyazétidinone en un dérivé de l'azétidinone à substitution en 4 par une étape de réaction entre un dérivé de 4-(substitution hydroxy)azétidinone et un énolate d'un composé carbonyle afin de convertir le dérivé en un dérivé de l'azétidinone à substitution en 4. Selon l'invention, un dérivé de 4-(substitution hydroxy)azétidinone peut être converti en un dérivé de l'azétidinone à substitution en 4 en une seule étape. En particulier, l'utilisation d'un énolate de titane préparé à partir d'un composé de titane et d'une base permet d'obtenir une réaction ayant un rendement élevé.
PCT/JP2007/061320 2006-06-06 2007-06-04 Procédé de production de dérivés de l'azétidinone à substitution en 4 Ceased WO2007142207A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61275267A (ja) * 1985-03-29 1986-12-05 メルク　エンド　カムパニ−　インコ−ポレ−テツド １−β−メチルカルバペネム抗生物質中間体の鏡像異性選択的製造方法
JPS62258353A (ja) * 1986-04-30 1987-11-10 Kanegafuchi Chem Ind Co Ltd ４−アセトキシ−３−ヒドロキシエチルアゼチジン−２−オン誘導体の製造方法
WO1993013064A1 (fr) * 1991-12-26 1993-07-08 Nippon Soda Co., Ltd. Procede de production d'un derive d'azetidinone substitue en position 4
JPH0770116A (ja) * 1993-06-30 1995-03-14 Tanabe Seiyaku Co Ltd ４−置換アゼチジノン誘導体の製造方法
JPH0782248A (ja) * 1993-06-30 1995-03-28 Nippon Soda Co Ltd ４−置換アゼチジノン誘導体の製造方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61275267A (ja) * 1985-03-29 1986-12-05 メルク　エンド　カムパニ−　インコ−ポレ−テツド １−β−メチルカルバペネム抗生物質中間体の鏡像異性選択的製造方法
JPS62258353A (ja) * 1986-04-30 1987-11-10 Kanegafuchi Chem Ind Co Ltd ４−アセトキシ−３−ヒドロキシエチルアゼチジン−２−オン誘導体の製造方法
WO1993013064A1 (fr) * 1991-12-26 1993-07-08 Nippon Soda Co., Ltd. Procede de production d'un derive d'azetidinone substitue en position 4
JPH0770116A (ja) * 1993-06-30 1995-03-14 Tanabe Seiyaku Co Ltd ４−置換アゼチジノン誘導体の製造方法
JPH0782248A (ja) * 1993-06-30 1995-03-28 Nippon Soda Co Ltd ４−置換アゼチジノン誘導体の製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KALUZA Z. ET AL.: "4-substituted 2-azetidinones, new building blocks for the synthesis of beta-lactams", SYNLETT., no. 9, 1996, pages 895 - 896, XP003020193 *

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