WO2008020597A1 - Procédé de production d'un intermédiaire pour la production de 1-méthylcarbapenem - Google Patents

Procédé de production d'un intermédiaire pour la production de 1-méthylcarbapenem Download PDF

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WO2008020597A1
WO2008020597A1 PCT/JP2007/065896 JP2007065896W WO2008020597A1 WO 2008020597 A1 WO2008020597 A1 WO 2008020597A1 JP 2007065896 W JP2007065896 W JP 2007065896W WO 2008020597 A1 WO2008020597 A1 WO 2008020597A1
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group
compound
formula
hydrogen atom
general formula
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PCT/JP2007/065896
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Japanese (ja)
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Masayuki Okue
Masaaki Takahashi
Ichiro Ishikawa
Nobuo Ito
Hitoshi Yamaguchi
Shinjiro Sumi
Keiichi Ajito
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Meiji Seika Kaisha, Ltd.
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Priority to JP2008529869A priority Critical patent/JPWO2008020597A1/ja
Publication of WO2008020597A1 publication Critical patent/WO2008020597A1/fr

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    • 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 System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • 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 System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages

Definitions

  • the present invention relates to a method for producing a azetidinone derivative useful as an intermediate for producing 1-methylcarbapenems having excellent antibacterial activity.
  • 1-methylcarbapenems which have excellent antibacterial activity and have high safety / safety, are extremely useful clinically as antibacterial substances for injection.
  • it has been developed as an oral administration agent, and is one of the substances that are expected to receive more and more attention in the future.
  • R 1 represents a hydrogen atom or a protecting group for a hydroxyl group
  • R 6 represents a protecting group for a hydrogen atom or a carboxyl group
  • OR 8 represents a leaving group.
  • R 1 represents a protecting group for a hydrogen atom or a hydroxyl group
  • R 2 represents a protecting group for a hydrogen atom or an amino group
  • R 5 represents a hydrogen atom or a nitrogen atom
  • R 6 represents a hydrogen atom or a carboxyl group. Represents a protecting group for the group.
  • the compound represented by the general formula ( ⁇ ) is described as an intermediate for the production of the general formula (V) in the method disclosed in JP-A-6-321946. That is, it is represented by the following general formula ( ⁇ ′) disclosed in Japanese Patent No. 3220985, Japanese Patent No. 3450193, and Tetrahedron 52, 331-357, 1996, etc., and is commercially available.
  • a compound such as a 4-acetoxyzetidinone derivative and a compound of the following formula ( ⁇ ) having an auxiliary group are subjected to a stereoselective carbon-carbon bond forming reaction to give a compound of the following general formula (VI):
  • a variety of methods for obtaining compounds have been proposed.
  • R 1 represents a protecting group for a hydrogen atom or a hydroxyl group
  • R 2 represents a protecting group for a hydrogen atom or an amino group
  • R 5 represents a hydrogen atom or a nitrogen atom
  • R 6 represents a hydrogen atom or a carboxyl group.
  • OR 8 represents a leaving group
  • R 9 represents an auxiliary group.
  • R 1 represents a hydrogen atom or a protecting group for a hydroxyl group
  • R 2 represents a protecting group for a hydrogen atom or an amino group
  • R 5 represents a hydrogen atom or a nitrogen atom
  • R 6 represents a hydrogen atom.
  • OR 8 represents a leaving group
  • R 9 represents an auxiliary group
  • R 1Q , R U , R 12 , and R 13 are the same or different and are hydrogen or substituted. May represent a group! / Represents a lower alkyl group
  • X and Y represent an oxygen atom or a sulfur atom
  • the present invention provides 1-methylcarbapenems or 1 ⁇ having excellent antibacterial activity.
  • the purpose of the present invention is to provide an industrially superior method for producing a azetidinone derivative that is useful as an intermediate for the production of methyl carbapenems and using an inexpensive auxiliary group without going through complicated steps. ! /
  • R 1 represents a hydrogen atom or a hydroxyl protecting group
  • R 2 represents a hydrogen atom or a protecting group for an amino group
  • R 5 represents a hydrogen atom or a nitrogen atom
  • R 6 represents a hydrogen atom or a protecting group for a carboxyl group.
  • R 3 represents an aryl group which may have a substituent
  • R 4 represents an aryl group that may have a substituent, an aralkyl group that may have a substituent, or an alkyl group that may have a substituent.
  • step (b) characterized in that it further comprises diazotization of the compound obtained in step (a) when a compound of formula ( ⁇ ) wherein R 5 is a nitrogen atom is desired It is.
  • R 1 and R 2 are as defined above,
  • R 7 represents a rualkylcarbonyl-oxy group.
  • auxiliary group one N (R 3 ) SO R 4 ) employed in the present invention is required in the conventional method.
  • auxiliary groups having a specific cyclic structure and the like can be easily produced at low cost, are industrially suitable, and further effectively function as a leaving group. That is, the auxiliary group employed in the present invention (an N (R 3) SO R 4 ) is a general purpose such Anirin acids and sulfonic acid derivatives
  • the two bodies are versatile, with some being used as industrial raw materials, and can be easily manufactured at low cost. Furthermore, the method according to the present invention is industrially excellent because it does not require a complicated process when the carboxyl group is activated after removing the auxiliary group once!
  • the above method according to the present invention has the advantageous effect that always high stereoselectivity can be obtained, especially when carried out in the presence of a zirconium reagent.
  • the lower alkyl group as a group or a part of the group represents a chain, branched, or cyclic alkyl group having preferably 1 to 6 carbon atoms.
  • Specific examples thereof include a methyl group, Ethyl group, n-propyl group, i-propyl group, cyclopropyl, n-butyl group, i-butanol group, sec-butyl group, t-butyl group, cyclobutyl group, n-pentyl group, cyclopentyl group, n-hexyl group, cyclohexyl group Groups and the like.
  • the aryl group is an aromatic cyclic compound, and examples thereof include a phenyl group, a naphthyl group, and a pyridyl group.
  • the aralkyl group represents an arylalkyl group, and in the group, the alkyl group portion is preferably
  • the lower alkyl group is represented, and the aryl group represents the aryl group. Therefore, specific examples thereof include benzyl group, phenethyl group, 3-phenylpropyl group, naphthylmethyl group, pyridylmethyl group and the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • a compound of the general formula (I) is reacted with imidazole to give an imidazolide compound, and then reacted with a malonic ester to give a compound of formula ( ⁇ ) in which R 5 is a hydrogen atom. obtain.
  • R 1 is a hydrogen atom or a hydroxyl protecting group
  • R 2 is a protecting group of hydrogen atom or Amino group
  • R 6 is hydrogen atom or a protecting group of a carboxyl group
  • the protective groups for the hydroxyl group, amino group, and carboxyl group respectively, commonly used protective groups described in PROT ECTVE GROUPS in ORGANIC SYNTHESIS THIRD EDITION (WILEY) can be used.
  • Specific examples of the hydroxyl protecting group include silyl protecting groups such as trimethylsilyl group, triethylsilyl group, and t-butyldimethylsilyl group.
  • the amino protecting group includes trimethylsilyl group, triethylsilyl group, and t-butyl group.
  • examples include silyl protecting groups such as dimethylsilyl group, benzyl protecting groups such as benzyl group, noramethoxybenzyl group, paranitrobenzyl group, benzhydryl group, etc.
  • Benzylic protecting groups such as paranitrobenzyl group, benzhydryl group, bivalloyloxymethinole group, 1- (cyclohexinole xycanoleponinole xy) ethinole group, acetoxymethinole group, 1- (isopropyloxy group) Carbonyloxy) ethyl group, 1- (ethoxycal Benzyloxy) ethyl, cyclohexyloxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyloxy) -2-methylpropane-1-yl, isopropyloxycarbonyloxymethyl, phthalidyl And ester groups that can be hydrolyzed in vivo, such as groups.
  • R 2 is a hydrogen atom, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a benzyl group, a nonamethoxybenzyl group, or a paranitro group.
  • R 6 includes a benzyl group, a paramethoxybenzyl group, a parabitrobenzyl group, a benzhydryl group, a bivalyloxymethyl group, 1 -(Cyclohexylcarbonyloxy) ethyl group, acetoxymethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, cyclohexyloxycarbonyloxymethyl group, ester group that can be hydrolyzed in the body, etc. More preferred examples include a paranitrobenzyl group and a paramethoxybenzyl group.
  • R 3 may have a substituent! /,
  • An aryl group and preferred examples of the aryl group include aromatic cyclic compounds such as a phenyl group, a naphthyl group, and a pyridyl group.
  • Substituents include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, methyl group, trifunoleolomethinole group, trichloromethinole group, ethyl group, n-propyl group and i-propyl group.
  • N butyl group i butyl group, sec butyl group, t butyl group, lower alkyl group, methoxy group, ethoxy group and other lower alkyl group, amino group, monoalkyl which may be substituted with halogen atoms
  • Examples include amino groups (for example, monomethylamino group and monoethylamino group), and dialkylamino groups (for example, dimethylamino group, jetylamino group), amino groups such as cyano group and nitro group.
  • the bonding position is selected from the 2,3, 2,4, 2,5, 2,6, 3, 4 or 3,5 position, and beyond
  • a position selected from any conceivable position may be substituted. If the substituent is adjacent disubstitution, the ends of both substituents may be integrated. In that case, an aliphatic ring to which propylene, butylene, or the like is bonded, methylenedioxy, ethylenedioxy, or the like is bonded. The thing which formed the cyclic ether compound is mentioned.
  • preferable R 3 includes phenyl group, bromophenyl group, fluorophenyl group, chlorophenyl group, methylphenyl group, dimethylphenyl group, ethenylphenyl group, i-propylphenyl group. , T-butylphenyl group, methyl-methoxyphenyl group, chloro-methylphenyl group, trifluoromethylphenyl group, methoxyphenyl group, cyanophenyl group, nitrophenyl group, methoxycarbonylphenyl group, methylenedioxyphenyl group, ethylenedioxy group A phenyl group etc. are mentioned, The position of the substituent on a phenyl group is as above-mentioned, respectively.
  • R 4 is an aryl group, aralkyl group, or alkyl group which may have a substituent, and examples of the substituent include the same substituents as those described above for R 3 .
  • An alkyl group is a lower alkyl group that may be substituted with a halogen atom or the like.
  • a methyl group, a trifunoleolomethinole group, a trichloromethinole group, an ethyl group, an n-propyl group, an i-propyl group Examples include n-butyl group, i-butyl group, sec-butyl group, and t-butyl group.
  • the aryl group which may have a substituent is a force having the same meaning as described above, for example, a phenyl group, a methylphenyl group, a naphthyl group, a pyridyl group and the like.
  • the aralkyl group has the same meaning as described above, and examples thereof include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a naphthylmethyl group, and a pyridylmethyl group.
  • Preferred R 4 phenyl group, main Chirufueniru group, a benzyl group, or the like methyl.
  • R 5 is a hydrogen atom or a nitrogen atom.
  • the malonic acid ester to be reacted after reacting the compound of formula (I) with imidazole is preferably a malonic acid monoester, and the ester portion of the malonic acid monoester corresponds to. Accordingly, this ester moiety is preferably selected from those listed for R 6 , and specific examples of malonic acid monoesters include malonic acid monobenzil ester, malonic acid mono-p-nitrobenzinoreestenole, malonic acid monoester. Examples thereof include pivaloino reoxymethino ester, and preferably, malonic acid mono-p nitrobenzil ester and the like.
  • Step (a) that is, the reaction for obtaining a compound in which R 5 is a hydrogen atom among the compounds represented by the general formula ( ⁇ ), is carried out under an inert gas atmosphere such as nitrogen or argon as the first step.
  • an inert gas atmosphere such as nitrogen or argon
  • imidazole is allowed to act in the presence or absence of a base catalyst.
  • any solvent that is not involved in the reaction can be used as long as it is an inert solvent.
  • Hydrocarbon solvents such as methylene chloride, chlorine solvents such as 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene, chloroform benzene, toluene and xylene, jetyl ether, diisopropyl ether, dimethoxy Organic solvents such as ether solvents such as ethane, tetrahydrofuran, 1,4 dioxane and cyclopentyl methyl ether, acetate solvents such as ethyl acetate and butyl acetate, or aprotic polar solvents such as acetonitrile , Can be used by appropriately mixing a plurality of types, preferably methylene chloride, ethyl acetate, Tonitoriru and the like.
  • Base catalysts include pyridine, 4 dimethylaminopyridine, 2 picoline, 3 picoline, 4 picoline, aniline, N methylaniline, N, N dimethylaniline, 2,3-tidine, 2,4,6-collidine, 1, Organic bases such as 4-diazabicyclo [2.2.2] octane, 1,5 diazabicyclo [4 ⁇ 3.0] nona 5-ene, 1,8 diazabicyclo [5.4.0] Examples include 4-dimethylaminopyridine.
  • the use ratio (weight / volume ratio) of the general formula (I) and the solvent is usually from 1: 5 to 100, and preferably from 1:10 to 50.
  • the use ratio (molar ratio) of the general formula (I) to the base catalyst is usually from 1: 0.0 to 0.5, preferably 1: 0 ⁇ 05-0.2.
  • the use ratio (molar ratio) of the general formula (I) and imidazole is usually 1: 1 to 10 and preferably 1 :;! To 5.
  • the reaction temperature is generally ⁇ 30 to; 100 ° C., preferably 30 to 60 ° C.
  • the reaction usually proceeds in 0.5 to 48 hours, preferably 2 to 24 hours, and 3 to 6 hours is preferable.
  • the imidazolide compound obtained by this reaction can be isolated by a general separation and purification method. Since the compound is unstable, it is usually convenient to directly apply to the next step. .
  • the reaction mixture containing the imidazolide compound thus obtained is usually subsequently subjected to the next step, but can be appropriately cooled and stored.
  • the cooling temperature for storage is ⁇ 80 to 0 ° C., preferably ⁇ 30 to ⁇ 10 ° C. Also, The storage period is from several hours to two days, preferably within 24 hours.
  • step (a) that is, the reaction to obtain a compound in which R 5 is a hydrogen atom among the compounds represented by the general formula ( ⁇ )
  • imidazole acts on the compound of the formula (I) as the second step. And then add malonic acid ester.
  • the reaction is carried out in the presence of a magnesium compound.
  • the magnesium compound include magnesium chloride, magnesium bromide, magnesium bromide ether complex, magnesium iodide, magnesium methoxide. , Magnesium ethoxide and the like are used, and preferably magnesium chloride is used.
  • the reaction is carried out in the presence of a base.
  • the base include trimethylamine, triethylamine, tributylamine, trioctylamine, diisopropyl pyrethylamine, ⁇ methyl Pyrrolidine, ⁇ -methylpiperidine, ⁇ methylmorpholine, pyridine, 4 dimethylaminopyridine, 2 picoline, 3 picoline, 4-picoline, aniline, ⁇ methylaniline, ⁇ , ⁇ -dimethylaniline, 2,3 lutidine, 2, 4 lutidine, 2,5 lutidine, 2,6 lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5 diazabicyclo [ 4.3.0] —Nonah 5 and 1,8 diazabicyclo [5.4.0] —Undecar 7—en,
  • reaction mixture containing an imidazolide compound obtained separately is added to a mixture obtained by reacting a magnesium compound, a base group, and a malonic ester in an organic solvent.
  • a magnesium compound, a base and malonic acid monoester is usually 1: 0 ⁇ 5 to 3, preferably 1: 0 ⁇ 7 to!
  • the use ratio (molar ratio) of the general formula (I) to the base is usually 1: 1 to 6, preferably 1: 1.5 to 3.
  • the use ratio (molar ratio) of the general formula (I) to the malonic acid monoester is usually 1:;!-3, and preferably 1:;!-2.
  • the temperature at which the magnesium compound, base and malonic acid monoester are added is usually from -80 to 0 ° C, preferably from -30 to -10 ° C.
  • the reaction temperature after adding all necessary reagents is -30 to 100 ° C, preferably 30 to 6 0 ° C.
  • the reaction usually proceeds in 0.5 to 20 hours, preferably 1 to 5 hours.
  • reaction mixture is worked up according to a conventional method, and is isolated by a general separation and purification method to obtain the general formula (II) (wherein R 5 is a hydrogen atom). I can do it.
  • step (a) If a compound of formula (II) in which R 5 is a nitrogen atom is desired, the compound obtained in step (a) is further diazotized.
  • the general formula ( ⁇ ) (wherein R 5 is a hydrogen atom) obtained in the step (a) is diazotized as it is without isolating the general formula ( ⁇ ) ( In the formula, R 5 is a nitrogen atom).
  • the organic solvent used at this time is an ability to use an inert solvent that does not participate in the aforementioned reaction.
  • a hydrocarbon solvent, a chlorinated solvent, an aromatic hydrocarbon which are convenient for use in the post-treatment of the reaction.
  • System solvents and acetic acid-sterol solvents are used, and ⁇ -heptane, methylene chloride, toluene, ethyl acetate, etc. are preferably used.
  • An azide compound and a base are used for diazotization.
  • the azide compound sulfonyl azides such as methanesulfonyl azide, toluenesulfonyl azide, ⁇ -carboxybenzenesulfonyl azide and dodecylbenzenesulfonyl azide are used, and preferably dodecylbenzenesulfonyl azide and the like.
  • Bases include trimethylamine, triethylamine, tributylamine, trioctylamine, diisopropylethylamine, ⁇ -methylpyrrolidine, ⁇ -methylpiperidine, ⁇ -methinole monoreforin, pyridine, 4-dimethylaminopyridine, 2 —Picoline, 3-Picoline, 4-Picoline, Aniline, ⁇ -Methylaniline, ⁇ , ⁇ -Dimethylaniline, 2,3-Lutidine, 2,4-Lutidine, 2,5-Lutidine, 2,6-Lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] —noner-5-ene, 1, 8-Zazabicyclo [5.4.0] -undecar 7-en and the like are used, and preferred is triethyl
  • the use ratio (molar ratio) of the general formula (I) to the azide compound is usually from 1: 0.7 to 2, preferably;!:;! To 1 ⁇ 5.
  • the use ratio (molar ratio) of the general formula (I) to the base is usually 1: 0 ⁇ ;! ⁇ 1, preferably 1: 0.2 ⁇ 0.5.
  • the reaction normally proceeds at -20-50 ° C, preferably Is 0-50 ° C.
  • the reaction time is usually 0.5 to 48 hours, preferably; !! to 24 hours, 3 to 15 hours is preferred.
  • reaction mixture thus obtained is subjected to work-up according to a general method commonly used by those skilled in the art, and is further isolated by a general separation and purification method to give a general formula ( ⁇ ) (wherein R 5 is a nitrogen atom).
  • a general separation and purification method to give a general formula ( ⁇ ) (wherein R 5 is a nitrogen atom).
  • a sodium hydrogen carbonate aqueous solution, a potassium hydrogen carbonate aqueous solution, a sodium carbonate aqueous solution, a potassium carbonate aqueous solution, a sodium hydroxide aqueous solution, a potassium carbonate aqueous solution, an aqueous ammonia, or the like is used, preferably a sodium hydroxide aqueous solution. It is.
  • the concentration of the dilute alkaline aqueous solution is usually from 0.;! To 3 mol / L, preferably from 0.5 to Imol / L.
  • Separation and purification is a force that can be used by an ordinary general method, preferably a method of forming a precipitate, and can be performed by appropriately concentrating the post-treatment solution.
  • an organic solvent such as n-heptane is appropriately added and further aged, and the resulting precipitate is collected by filtration to give a general formula (1) useful as a production intermediate for 1-methylcarbapenems ( II)
  • a azetidinone derivative represented by the formula (wherein R 5 is a nitrogen atom) can be obtained.
  • R 1 of the obtained general formula (II) When a protective group is present in R 1 of the obtained general formula (II), it is removed by a commonly used deprotection method described in PROTECTVE GROUPS in ORGANIC SYNTHESIS THIRD EDITION (WILEY). As a protection, it can be a azetidinone derivative represented by the general formula ( ⁇ ) (wherein R 1 is a hydrogen atom and R 5 is a hydrogen atom or a nitrogen atom).
  • R 1 is a protecting group of hydroxyl group
  • isolated and purified general formula ([pi) can also be used, after the reaction, including the general formula ([pi)
  • the treatment solution can be used as it is.
  • the organic solvent used is a solvent that does not participate in the reaction, for example, a hydrocarbon solvent such as n-pentane, n-hexane, cyclohexane, n-heptane, or a mixture of isomers thereof.
  • Chlorinated solvents such as methylene chloride, 1,2-dichloroethane, chloroform, aromatic hydrocarbon solvents such as benzene, black benzene, toluene, xylene, jetyl ether, diisopropyl ether, dimethoxyethane , Tetrahydrofuran, 1,4 dioxane, ether solvents such as cyclopentyl methyl ether, acetate solvents such as ethyl acetate, butyl acetate, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, or methanol , Ethanol, 1-prono, 2-prono, 1-butanol, 2-butanol, organic solvents such as isobutyl alcohol, tert-butyl alcohol, etc.
  • aromatic hydrocarbon solvents such as benzene, black benzene, toluene,
  • methyl chloride for example, methyl chloride, acetonitrile, tetrahydrofuran, methanol, and more preferred is a mixture of methylene chloride and methanol as appropriate.
  • the mixing ratio (volume ratio) of methyl chloride and methanol is usually 1: 0 to 0: 1, preferably 1:;! To 4.
  • the desilylating agents include formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, camphorsulfonic acid and other organic acids, hydrochloric acid, Mineral acids such as hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boron trifluoride, boron trifluoride jetyl ether complex, titanium tetrachloride, zirconium tetrachloride, aluminum chloride, ferric chloride, ferric nitrate Lewis acids such as copper and cerium (III) nitrate, alkali hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide, hydrogen fluoride, ammonium fluoride, triethylamine hydrofluoride complex, fluoride Hydrogen pyridine complex, te
  • the use ratio (weight / volume ratio) of the general formula ( ⁇ ) (wherein R 1 is a hydroxyl-protecting group) and the solvent is usually 1: 2 to 50, preferably 1 : 5-20.
  • the amount of desilylating agent used is in the range of stoichiometric to large excess.
  • the reaction temperature is usually 20-60 ° C, preferably 0-40 ° C.
  • the reaction time is usually 0.5 to 24 hours, preferably 1 to 17 hours.
  • the compound of formula (I) used in the production of the compound of formula (II) according to the present invention is known, for example, the above-mentioned Japanese Patent No. 3220985, Japanese Patent No. 3450193, and Tetrahedron 52 331- 357 can be obtained by the method described in 1996.
  • the compound of formula (I) is preferably prepared according to the following scheme, and this method constitutes another embodiment of the present invention.
  • R 1 represents a hydrogen atom or a protecting group of a hydroxyl group
  • R 2 represents a hydrogen atom or a protective group for an amino group
  • R 3 represents an Ariru group which may have a substituent
  • R 4 Represents an aryl group, aralkyl group or alkyl group which may have a substituent
  • R 7 represents an alkyl group or a alkoxyloxy group.
  • the compound represented by the general formula (IV) can be carried out by a known method. For example, an aniline compound (R 3 NH) and a sulfonic acid derivative (R 4 SO X) are reacted to form a sulfonanilide compound (HN).
  • R 1 and R 2 are a hydrogen atom or a protecting group for a hydroxyl group and an amino group, respectively, and the hydroxyl group and the protecting group for an amino group are described in the above-mentioned books and the like.
  • the protecting groups for hydroxyl and amino groups are as defined above, and preferred R 1 is a hydrogen atom or a trimethylsilyl group, a triethylsilyl group, t-butyldimethyl. Examples thereof include a silyl group, and more preferably a t-butyldimethylsilyl group.
  • Preferred R 2 is hydrogen atom, trimethylsilyl group, Toryechirushiriru group, t Buchinore dimethylsilyl group, a benzyl group, p-methoxybenzyl group, para nitro downy Njiru group, such as Ben Zuhidoriru group and the like, more preferably, hydrogen Atoms, paranitrobenzyl groups, etc.
  • R 3 has the same meaning as described above, and R 3 is an aryl group which may have a substituent.
  • the aryl group include aromatic cyclic compounds such as a phenyl group, a naphthyl group, and a pyridyl group.
  • substituents examples include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, a methinore group, a trifunoleolomethinole group, a trichloromethinole group, an ethyl group, an n-propyl group, an i— Propinole group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, lower alkyl group which may be substituted with halogen atom, etc., methoxy group, lower alkyloxy group such as ethoxy group, amino group Monoalkylamino groups (for example, monomethylamino group, monoethylamino group, etc.), dialkylamino groups (for example, dimethylamino group, jetamino group, etc.).
  • a halogen atom such as a fluorine
  • Is) amino group such as, like Shiano and nitro.
  • One or more substituents may be the same or different when there are multiple substituents, and the substitution position is selected from the 2-position, 3-position or 4-position of the bonding position when there is one substituent.
  • substitution positions selected from the 2,3, 2,4, 2,5, 2,6, 3,4, or 3,5 positions of the bond position or more When there is a group, a position selected from any conceivable position may be substituted. If the substituent is adjacent disubstitution, the ends of both substituents may be integrated. In that case, an aliphatic ring to which propylene, butylene, or the like is bonded, methylenedioxy, ethylenedioxy, or the like is bonded.
  • R 4 is an aryl group, aralkyl group or alkyl group which may have a substituent, and the substituent has the same meaning as the substituent described above for R 3 .
  • An alkyl group is a lower alkyl group which may be substituted with a halogen atom or the like, for example, methyl group, trifluoromethylol group, trichloromethyl group, ethyl group, n propyl group, i propyl group, n butynole group, i Examples thereof include a butyl group, a sec butyl group, and a t butyl group.
  • the aryl group which may have a substituent includes a force S as defined above, for example, a phenyl group, a methylphenyl group, a naphthyl group, a pyridyl group and the like.
  • the aralkyl group has the same meaning as described above, and examples thereof include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a naphthylmethyl group, and a pyridylmethyl group.
  • Preferable R 4 includes a phenyl group, a methylphenyl group, a benzyl group, or a methyl group.
  • R 7 represents an alkylcarbonyl group, preferably an acetyloxy group.
  • the reaction is preferably carried out in an organic solvent under an inert gas atmosphere such as nitrogen or argon.
  • an organic solvent any inert solvent that does not participate in the reaction can be used.
  • hydrocarbon solvents such as n-pentane, n-hexane, cyclohexane, n-heptane, or mixtures of these different substances.
  • Solvents such as methylene chloride, 1,2 dichloroethane, chloroform, aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, jetyl ether, diisopropyl ether, dimethoxyethane,
  • a single organic solvent such as an ether solvent such as tetrahydrofuran, 1,4 dioxane, cyclopentyl methyl ether, or the like can be used by appropriately mixing a plurality of types, preferably methylene chloride.
  • Examples of the dinoleconium compound include dinoleconium tetrafluoride, dinoleconium tetrachloride, zirconium tetrabromide, zirconium tetraiodide, zirconium tetra-i-propoxide, and preferably zirconium tetrachloride.
  • Examples of the base include dimethylamine, trimethylamine, jetylamine, triethylamine, dibutylamine, tributylamine, trioctylamine, diisopropylethylamine, bistrimethinoresinoleamine, pyrrolidine, N-methylpyrrolidine, Piperidine, N-methylbiperidine, morpholine, N-methylmorpholine, tetramethylethylenediamine, pyridine, 4-dimethylaminopyridine, 2-picoline, 3-picoline, 4-picoline, aniline, N-methylaniline, N, N-dimethyla Nilin, 2,3 lutidine, 2,4 lutidine, 2,5 lutidine, 2,6-norethidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2 ⁇ 2-2] Octane, 1,5 diazabicyclo [4.3.0] Noner 5, 1,8 diaza
  • the order in which the reagents are added is not particularly limited, but is preferably added in the order of the zirconium compound, the base and then the general formula (III) to the solution of the organic solvent of the general formula (IV).
  • the use ratio (weight / volume ratio) of the general formula (III) and the solvent is usually from 1:10 to 100; preferably from 1:10 to 30.
  • the use ratio (molar ratio) of the general formula (III) to the general formula (IV) is usually!:;! ⁇ 3, preferably 1: 1: 2 ⁇ 2.
  • the use ratio (molar ratio) of the zirconium compound is usually 1 ::! To 3, preferably 1: 1.2-2.
  • the use ratio (molar ratio) of the base catalyst is usually 1: 1 to 3, preferably 1: 1.2-2.
  • an aprotic polar solvent such as acetonitrile, ⁇ , ⁇ dimethylformamide, dimethyl sulfoxide, etc. be added as appropriate, thereby improving the reaction yield and / or stereoselectivity.
  • the yield can be further improved by adding a trace amount of a protic solvent such as water and methanol.
  • the reaction temperature is usually from 30 to 50 ° C, preferably from 15 to 30 ° C.
  • the reaction time is usually 0.5 to 24 hours, preferably 1 to 5 hours.
  • reaction mixture is subjected to post-treatment according to a conventional method, and is isolated by a general separation and purification method, for example, purification by silica gel column chromatography or a method of forming a precipitate. ) Can be obtained.
  • a general separation and purification method for example, purification by silica gel column chromatography or a method of forming a precipitate.
  • TBS t butyldimethylsilyl group
  • DIPEA Diisopropylethylamine
  • N propionyl N-phenyl p-toluenesulfonamide derivatives can be produced in the same manner as in Production Example 1.
  • N-propionyl N— (2-trifluoromethylphenol) p-toluenesulfonamide (Compound 3) 22.29 g (60.0 mmol) in methylene chloride (345 mU solution in an ice bath) After cooling at room temperature, 2098 g (90.0 mmol) of zirconium chloride was added and stirred at the same temperature for 30 minutes, and then 16.5 mL (94.7 mmol) of DIPEA was added and stirred at the same temperature for 30 minutes, and then (3R, 4R) — 4 [(R) 1 (tert-butyldimethylsilyloxy) ethyl] 2 azetidinone 17.25 g (60.0 mmol) was added, and the reaction was allowed to proceed for 1 hour while removing the ice bath and raising the temperature to room temperature.
  • N propionyl N— (2-trifluoromethylphenol) p toluenesulfonamide compound 3
  • 26.75 g (72.0 mmol) of methylene chloride (345 mU solution was cooled in an ice bath).
  • Zirconium chloride 21.67 g, 93.0 mmol was added and stirred at the same temperature for 30 minutes, then DIPEA 16.2 mL (93.0 mmol) was added, and the mixture was stirred at the same temperature for 30 minutes.
  • Example 1 1 N [(2R) 2- ⁇ (3S, 4R) 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] — 2 oxoazetidine 4 inole ⁇ propioninole N (3,5 dimethylphenolinole)- p Production of toluenesulfonamide
  • N-propionyl, N— (2-ethylphenyl) methanesulfonamide 1.35 g (5.29 mmol) was used in the same manner as in Example 2 to obtain 0.45 g (yield 21.2%) of the title compound as a white powder.
  • N [(2R) — 2— ⁇ (3S, 4R) — 3— [(1R) — 1 (tert-butyldimethyldimethyloxy) ethinole 2 oxazotidine 4 inole ⁇ propioninore N mono (2 trifluoromethylphenyl) p toluenesulfonamide (compound 4) 600 mg (1.00 mmol) of acetonitrile (9 mU solution with imidazole 200 mg (3.00 mmol) and DMAP 1 2.5 mg (0.102 mmol) ) And allowed to react for 16 hours at 60 ° C.
  • the title compound (Compound 5) is a known substance, and the retention time and 1 H wake R spectrum of the existing product and the HPLC coincided.
  • N [(2R) — 2— ⁇ (3S, 4R) — 3— [(1R) — 1 (tert-butyldimethyldimethyloxy) ethinole 2 oxazotidine 4 inole ⁇ propioninore N- (2 trifluoromethylphenyl) p-toluenesulfonamide (compound 4) 3.0 g (5.00 mmol) of acetonitrile (1.0 m imidazole (15.0 mmol) and DMAP 60 mg (0.491 mmol) added to 9 mU solution) The mixture was allowed to react for 19 hours at 60 ° C.
  • the reaction mixture was cooled in an ice bath and 0.48 g (5.01 mmol) of magnesium chloride, 1.4 mL (10.0 mmol) of TEA and 2.04 g of malonic acid mono-p-nitrobenzyl ester ( 8.53 mmol) was added in order, and the mixture was heated to 50 ° C. and reacted for 2 hours, the reaction mixture was concentrated under reduced pressure, and the concentrated solution was diluted with methylene chloride (48 mL), and 1M hydrochloric acid, water, 5% aqueous sodium bicarbonate and The solution was washed successively with 10% brine, and the resulting solution containing Compound 5 was added to dodecinolebenzenesulfonyl azimuth.
  • N [(2R) — 2— ⁇ (3S, 4R) — 3— [(1R) — 1 (tert-butyldimethylsilyloxy) ethinole] 2 oxazotidine 4 inole ⁇ propionate
  • N phenyl p-toluenesulfonamide
  • 5.32 g (10.0 mmol) of acetonitrile Into an 80 mU solution, 2.05 g (30.1 mmol) of imidazole and 0.12 g (1.00 mmol) of DMAP were added and allowed to react for 6 hours at 60 ° C. The reaction mixture was cooled to 15 ° C.
  • the title compound (Compound 8) is a known substance, and the retention time and 1 H-wake R spectrum of the existing product and the HPLC coincided.

Abstract

La présente invention concerne un procédé de production d'un intermédiaire de production de 1-méthylcarbapenem commercialement viable (II), lequel ne nécessite pas d'étapes complexes et emploie des matières brutes bon marché. L'invention concerne spécifiquement un procédé de production d'un intermédiaire de production de 1-méthylcarbapenem (II) dans lequel un composé représenté par la formule générale (I) ci-dessous est amené à réagir avec de l'imidazole, puis avec un ester d'acide malonique et finalement, au besoin, soumis à une diazotation.
PCT/JP2007/065896 2006-08-15 2007-08-15 Procédé de production d'un intermédiaire pour la production de 1-méthylcarbapenem WO2008020597A1 (fr)

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CN101891666B (zh) * 2010-07-20 2012-09-26 深圳市海滨制药有限公司 一种β甲基碳青霉烯类抗生素中间体的制备方法
CN101906115B (zh) * 2010-08-13 2012-12-05 浙江海翔药业股份有限公司 一种β-甲基碳青霉烯抗生素中间体的制备方法
CN102690282A (zh) * 2011-07-07 2012-09-26 深圳市海滨制药有限公司 晶体形式的1β甲基碳青霉烯类抗生素中间体及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63284176A (ja) * 1987-05-15 1988-11-21 Nippon Redarii Kk （１ｒ，５ｒ，６ｓ）−６−〔（１ｒ）−１−ヒドロキシエチル〕−１−メチルカルバペネム−３−カルボン酸誘導体の高立体選択的製造方法
JPH0543575A (ja) * 1991-12-21 1993-02-23 Mercian Corp アゾール誘導体
WO1993013064A1 (fr) * 1991-12-26 1993-07-08 Nippon Soda Co., Ltd. Procede de production d'un derive d'azetidinone substitue en position 4
JPH0782249A (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法
JPH1087657A (ja) * 1996-09-06 1998-04-07 Nippon Soda Co Ltd アゼチジノン誘導体の製造法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63284176A (ja) * 1987-05-15 1988-11-21 Nippon Redarii Kk （１ｒ，５ｒ，６ｓ）−６−〔（１ｒ）−１−ヒドロキシエチル〕−１−メチルカルバペネム−３−カルボン酸誘導体の高立体選択的製造方法
JPH0543575A (ja) * 1991-12-21 1993-02-23 Mercian Corp アゾール誘導体
WO1993013064A1 (fr) * 1991-12-26 1993-07-08 Nippon Soda Co., Ltd. Procede de production d'un derive d'azetidinone substitue en position 4
JPH0782249A (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法
JPH1087657A (ja) * 1996-09-06 1998-04-07 Nippon Soda Co Ltd アゼチジノン誘導体の製造法

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