WO2006077919A1 - イミダゾチアゾール誘導体およびその製造方法 - Google Patents

イミダゾチアゾール誘導体およびその製造方法 Download PDF

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WO2006077919A1
WO2006077919A1 PCT/JP2006/300729 JP2006300729W WO2006077919A1 WO 2006077919 A1 WO2006077919 A1 WO 2006077919A1 JP 2006300729 W JP2006300729 W JP 2006300729W WO 2006077919 A1 WO2006077919 A1 WO 2006077919A1
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Prior art keywords
compound
formula
thiazole
group
reaction
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PCT/JP2006/300729
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English (en)
French (fr)
Japanese (ja)
Inventor
Eiki Shitara
Kunio Atsumi
Keiichi Ajito
Shinya Ikeda
Tadashi Katoh
Munenori Inoue
Mari Nakatani
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Meiji Seika Kaisha, Ltd.
Sagami Chemical Research Center
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Application filed by Meiji Seika Kaisha, Ltd., Sagami Chemical Research Center filed Critical Meiji Seika Kaisha, Ltd.
Priority to DE602006020545T priority Critical patent/DE602006020545D1/de
Priority to IN833DEN2012 priority patent/IN2012DN00833A/en
Priority to CA002595009A priority patent/CA2595009A1/en
Priority to CN200680008113XA priority patent/CN101137661B/zh
Priority to EP06711975A priority patent/EP1840129B1/en
Priority to AU2006207059A priority patent/AU2006207059A1/en
Priority to JP2006553948A priority patent/JP4964599B2/ja
Publication of WO2006077919A1 publication Critical patent/WO2006077919A1/ja
Priority to KR1020077018745A priority patent/KR101344137B1/ko

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to an imidazothiazole derivative useful as an intermediate for producing a powerful rubapenem derivative having excellent antibacterial activity and a broad antibacterial spectrum, and a method for producing the same.
  • WO2004Z055027 discloses the following scheme B as a method for producing 2-bromoimidazo [5,1-b] thiazole (compound of formula (V ⁇ )).
  • the present inventors have now succeeded in preparing a compound of the formula (I) described later as a synthetic intermediate of a powerful rubapenem derivative of the formula (A).
  • the present inventors By reacting 2,5-dihalogenated thiazole derived from 2-aminonothiazole, which is available at low cost, and isocyanatoacetate, the present inventors have improved the imidazothiazole derivative represented by the formula (I) described below.
  • this method was excellent in operability, could avoid the bromination step, and could synthesize the target compound with higher safety.
  • the present invention is based on strong knowledge.
  • an object of the present invention is to provide a synthetic intermediate that can efficiently produce a strong rubapenem derivative of the formula (A) at a safe and inexpensive production cost. That is, an object of the present invention is to provide a new method for constructing a bicyclic imidazo [5,1-b] thiazole ring.
  • the compound according to the present invention is a compound of the following formula (I).
  • X represents a halogen atom
  • R 1 is COR 2 group
  • R 2 represents an OM group or a C 1-12 alkyloxy group, where M represents a hydrogen atom, an alkali metal, an alkaline earth metal, or a quaternary ammonium
  • the process for producing a compound of formula (I) according to the present invention comprises the following steps (a) and (b): (a) a compound of formula (II) below and a compound of formula (III) React in the presence of
  • R 3 represents a C1 12 alkyl group
  • step (b) If necessary, further comprising subjecting the compound obtained in step (a) to a hydrolysis reaction.
  • X represents a halogen atom
  • M represents a hydrogen atom, an alkali metal, an alkaline earth metal, or a quaternary ammonia
  • the starting material which can be obtained at a lower price than the conventional method and the number of steps can be reduced.
  • a compound of formula (VI), an important intermediate of the compound can be obtained.
  • the process from the raw material compound to the important intermediate can be reduced to less than half of the conventional amount, and the low yield process can be avoided, and the yield of the important intermediate and the total amount of the intermediate can be reduced.
  • the reaction efficiency can be dramatically improved (for example, more than 10 times).
  • the production cost can be reduced, the production control and the like can be greatly improved, and the carbapenem derivative (formula (A) having an excellent antibacterial activity and a wide antibacterial spectrum can be obtained.
  • Compound can be efficiently synthesized.
  • alkyl group as a group or part of a group means an alkyl group in which the group is linear, branched, cyclic, or a combination thereof, unless otherwise specified.
  • C1-12 alkyl group and “C1-12” in this case means that the alkyl group has 1 to 12 carbon atoms.
  • the "C1 12 alkyl group” is preferably a C 1-6 alkyl group, more preferably a C1 4 alkyl group, and still more preferably a C 1-3 alkyl group.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sbutyl, tbutyl, pentyl, hexyl, heptyl, octyl, nor.
  • methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, cyclopropyl group, cyclobutyl group and the like can be mentioned.
  • alkyloxy group as a group or part of a group means an alkyloquine group in which the group is linear, branched, cyclic, or a combination thereof, unless otherwise specified.
  • alkyloxy group and “C1-12” in this case mean that the alkyloxy group has 1 to 12 carbon atoms.
  • the "C1 12 alkyloxy group” is preferably a C1 6 alkyloxy group, more preferably a 14 alkyloxy group, and even more preferably a 13 alkyloxy group.
  • alkyloxy groups include, for example, methyloxy group, ethyloxy group, propoxyloxy group, isopropyloxy group, butyloxy group, isobutyloxy group, s— Examples thereof include a butyroxy group, a t-butyloxy group, a pentyloxy group, and a hexyloxy group.
  • a methyloxy group, an ethyloxy group, a propyloxy group, an isopropyloxy group, a butyloxy group, an isobutyloxy group, an S-butyloxy group, a t-butyloxy group, etc. are mentioned.
  • the alkyl group and the alkyloxy group may be optionally substituted.
  • an alkyl group may be “substituted,” means that one or more hydrogen atoms on the alkyl group are substituted with one or more substituents (which may be the same or different). It means that it may be substituted. It will be apparent to those skilled in the art that the maximum number of substituents can be determined depending on the number of substitutable hydrogen atoms on the alkyl. The same applies to the alkyloxy group.
  • Examples of the group that can substitute the alkyl group and the alkyloxy group include a halogen atom, an alkyloxy group, an amino group, and a hydroxyl group.
  • the halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom, a bromine atom or an iodine atom. More preferably, it is a bromine atom.
  • R 1 is a force as defined above According to one aspect of the present invention,
  • X represents a halogen atom
  • R 1 is COR 2 group
  • R 2 represents an OM group or a C 1-12 alkyloxy group, where M represents a hydrogen atom, an alkali metal, an alkaline earth metal, or a quaternary ammonium
  • R 2 is preferably an OM group or a C16 alkyloxy group, more preferably a hydroxyl group or a C13 alkyloxy group.
  • R 3 is preferably a C1 6 alkyl group, more preferably a C1 4 alkyl group, and even more preferably a C 1-3 alkanoleno group.
  • X is preferably a bromine atom, a chlorine atom, or an iodine atom, and more preferably an aromatic atom.
  • X 1 is preferably a bromine atom, a chlorine atom or an iodine atom, more preferably a bromine atom.
  • M is preferably a hydrogen atom, a sodium atom, or a potassium atom.
  • R 1 is preferably a — COR 2 group (wherein R 2 represents a hydroxyl group or a C 1-6 alkyloxy group).
  • X is preferably a bromine atom.
  • R 1 is more preferably a —COR 2 group (wherein R 2 represents a hydroxyl group or a C 1-4 alkyloxy group).
  • X is preferably a bromine atom.
  • the compound of the formula (I) is preferably a compound of the formula (IV) or the formula (V).
  • R 3 is a methyl group
  • M represents a hydrogen atom
  • X represents a bromine atom
  • the compound according to the present invention may be a salt thereof.
  • Such salts include R of formula (I)
  • the R 2 group forms a carboxylate.
  • such salts include alkali metal salts, alkaline earth metal salts, or quaternary ammonium salts. Those skilled in the art will readily be able to prepare such salts during or after the formation of the compounds according to the invention.
  • the process for producing a compound of formula (I) according to the invention comprises the following steps (a) and (b):
  • step (b) If necessary, further comprising subjecting the compound obtained in step (a) to a hydrolysis reaction.
  • the reaction in the step (a) is performed in a polar solvent at a temperature in the range of 40 ° C. to 50 ° C.
  • the compound of formula (I) obtained is represented by formula (V). It is a compound.
  • a compound of formula (IV) is obtained by reacting a compound of formula (II) with a compound of formula (III) in the presence of a base in step I1.
  • a compound of formula (IV) when R 3 is an ethyl group and X is a bromine atom, the formula (IV) can be represented by the following formula (IVa): [Chemical 10]
  • the compounds of formulas (II) and (III) in step I1 may be synthesized upon use, but commercially available products can also be obtained.
  • some of the compounds of formula (II) are available from Aldrich, and some of the compounds of formula (III) are available from Tokyo Chemical Industry Co., Ltd.
  • a compound of formula (IV) can be obtained by reacting a compound of formula (IV) with a compound of formula (III) in the presence of a base.
  • the solvent used in Step 1-1 is not particularly limited as long as it does not adversely affect the reaction in this step, and can be appropriately selected by those skilled in the art.
  • hydrocarbon solvents such as pentane, hexane, benzene, toluene, xylene, halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, Ether solvents such as tetrahydrofuran, 1, 4 dioxane, dimethoxyethane and cyclopentyl methyl ether, acetonitrile, propio-tolyl, nitromethane, nitroethane, aprotic such as N, N dimethylformamide, N, N dimethylacetamide, dimethyl sulfoxide And a mixed solvent thereof.
  • the solvent includes ether solvents such as jetyl ether, tetrahydrofuran and 1,4 dioxane, polar solvents such as N, N dimethylformamide, and more preferably N, N dimethylformamide, or N, N is a mixed solvent system of dimethylformamide and tetrahydrofuran.
  • ether solvents such as jetyl ether, tetrahydrofuran and 1,4 dioxane
  • polar solvents such as N, N dimethylformamide, and more preferably N, N dimethylformamide, or N, N is a mixed solvent system of dimethylformamide and tetrahydrofuran.
  • Examples of usable bases include alkali metal hydrides such as sodium hydride and potassium hydride, and alkali metals such as potassium t-butoxide and sodium t-butoxide.
  • Alkali metal amides such as alkoxide, lithium diisopropylamide, lithium isopropyl cyclohexylamide, lithium dicyclohexylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide and the like can be mentioned. Two or more of these may be used in combination.
  • Preferred is an alkali metal hydride, and more preferred is sodium hydride.
  • the range of the reaction temperature is a force that can vary depending on the solvent used and the like, and is usually the reflux temperature of the solvent used from 100 ° C. Preferably, it is 40-50 degreeC.
  • the reaction time is a force that can vary depending on the solvent used, the reaction temperature, etc. Usually, it is 10 minutes to 24 hours.
  • the resulting compound of formula (IV) can be subjected to conventional post-treatment.
  • the usual post-treatment is a well-known treatment for those skilled in the art, and examples thereof include Taenti (reaction stop) and extraction.
  • it can be isolated and purified by applying conventional techniques such as precipitation, crystallization, gel filtration, silica gel column chromatography, etc. as necessary.
  • the compound of formula (VI) is obtained by hydrolyzing the compound of formula (IV), preferably in the presence of a base, to obtain a compound of formula (V), which is preferably a solvent. It can be obtained by heating in or by heating the prepared compound of formula (V) preferably directly in a solvent. The compound of formula (VI) can also be obtained by directly heating the compound of formula (IV) in a solvent. Further, as described above, the compound of the formula (IV) can be obtained by reacting the compound of the formula (II) with the compound of the formula (III) in the presence of a base.
  • This step is a hydrolysis reaction of the compound of formula (IV).
  • This step is a hydrolysis reaction of the compound of formula (IV).
  • the compound of V) can be obtained.
  • the solvent used in Step II-1 is not particularly limited as long as it does not adversely affect the reaction in this step, and can be appropriately selected by those skilled in the art.
  • methanol, ethanol, tetrahydrofuran, dioxane, acetonitrile, sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, water and the like can be mentioned. Two or more of these may be mixed and used as a mixed solvent.
  • Preferred are water, methanol, ethanol, and acetonitrile. More preferred are water, methanol, and ethanol.
  • Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like. Preferred are sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like.
  • Examples of the acid include sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid and the like, and preferred sulfuric acid, hydrochloric acid, acetic acid and the like.
  • the range of the reaction temperature is the reflux temperature of the solvent at which the force that can be changed depending on the solvent used is normally 100 ° C force. Preferably it is 0-70 degreeC.
  • the reaction time is a force that can vary depending on the solvent used, the reaction temperature, etc. Usually, it is 10 minutes to 24 hours. Preferably, it is 30 minutes to 24 hours.
  • the resulting compound of formula (V) can be subjected to conventional post-treatment. Furthermore, it can be isolated and purified by applying conventional techniques such as precipitation, crystallisation, gel filtration, silica gel column chromatography, etc., as necessary. It can also be isolated as a carboxylate after hydrolysis.
  • This step is a decarboxylation reaction of the compound of formula (V).
  • the compound of formula (VI) can be obtained by heating the compound of formula (V), preferably in a solvent.
  • the solvent used in Step II-2 is not particularly limited as long as it does not adversely affect the reaction in this step, and can be appropriately selected by those skilled in the art.
  • dimethyl sulfoxide, 1,3 dimethylenoyl 3,4,5,6-tetrahydro-2 (1H) pyrimidinone, 1,2,4 trichlorobenzene, orthodichlorobenzene, xylene, diphenol ether, ethylene glycol, toluene, acetic acid examples include acetic anhydride, phosphoric acid, sulfuric acid, and water.
  • a mixed solvent by mixing two or more kinds.
  • it is a single solvent or a mixed solvent having a boiling point of 100 ° C. or higher.
  • dimethyl sulfoxide 1,2,4-trichlorodiethylbenzene, orthodichlorobenzene, diphenyl ether, ethylene glycol, toluene, acetic acid, acetic anhydride, sulfuric acid, water, and the like
  • 1, 2, 4 Trichlorobenzene benzene dimethyl sulfoxide, diphenyl ether, toluene, ethylene glycol, acetic acid, acetic anhydride, sulfuric acid, water, or a mixture of two or more of these.
  • an additive may be added to the solvent.
  • additives include carboxylic acids such as benzoic acid and acetic anhydride and anhydrides thereof, phenols such as phenol and strength techol, mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, lithium chloride, odor Metal salts such as lithium and lithium iodide, 1,8 diazabicyclo [5. 4. 0] —7 undecene.
  • carboxylic acids such as benzoic acid and acetic anhydride and anhydrides thereof
  • phenols such as phenol and strength techol
  • mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, lithium chloride, odor Metal salts such as lithium and lithium iodide, 1,8 diazabicyclo [5. 4. 0] —7 undecene.
  • sulfuric acid, hydrobromic acid, acetic anhydride, benzoic acid, phenol, 1,8 diazabicyclo [5.4.0] -7 undecene and
  • the range of the reaction temperature is a force that can vary depending on the solvent used, etc., usually 80-350. C. Preferably 100-300. C.
  • the reaction time is a force that can vary depending on the solvent used, the reaction temperature, etc. Usually, it is 10 minutes to 72 hours. Preferably it is 1 to 48 hours.
  • the resulting compound of formula (VI) can be subjected to conventional post-treatment. Furthermore, it can be isolated and purified by applying conventional methods such as precipitation, crystallization, gel filtration, silica gel column chromatography, etc. as necessary. [0051] According to another aspect of the present invention, there is provided a process for preparing a compound of formula (VI) comprising hydrolyzing a compound of formula (IV).
  • This step is a dealkoxycarbonylation reaction of the compound of formula (IV).
  • a compound of formula (VI) can be obtained by heating a compound of formula (IV) in a solvent in the presence of an additive.
  • the solvent used in Step II-3 is not particularly limited as long as it does not adversely affect the reaction in this step, and can be appropriately selected by those skilled in the art.
  • the solvent has a boiling point of 100 ° C or higher.
  • dimethyl sulfoxide 1,2,4 trichlorobenzene, sulfuric acid, acetic acid, propionic acid, water and the like. More preferred are dimethyl sulfoxide, propionic acid, sulfuric acid and water.
  • Examples of usable additives include sulfonic acids such as p-toluenesulfonic acid and benzoic acid, carboxylic acids, phenol, hydrochloric acid, sulfuric acid, hydrobromic acid, lithium chloride, lithium bromide and iodine. And metal salts such as lithium fluoride. Preferred are lithium chloride, lithium bromide, lithium iodide, hydrochloric acid and the like.
  • the range of the reaction temperature is a force that can be changed depending on the solvent used, etc. C. Preferably, 100 to 300. C.
  • the reaction time is a force that can vary depending on the solvent used, the reaction temperature, etc. Usually, it is 10 minutes to 72 hours. Preferably it is 1 to 24 hours.
  • the resulting compound of formula (VI) can be subjected to conventional post-treatment. Furthermore, it can be isolated and purified by applying conventional methods such as precipitation, crystallization, gel filtration, silica gel column chromatography, etc. as necessary.
  • step III and step IV the compound of formula (IV) which is a compound according to the present invention is used as a starting material, and the compound of formula (A) is passed through the compound of formula (VIII). ) Can be manufactured.
  • step III-1 the compound of formula (IV) is subjected to a reduction reaction, followed by acid-acid reaction in step ⁇ -2 to obtain the compound of formula (VIII). be able to.
  • the compound of formula (V) is reacted with a commonly used carboxyl group activator in step IV-1, or the compound of formula (IV) is reacted with an amine in step IV-2.
  • the compound of formula (IX) can be obtained, and then the compound of formula (IX) can be obtained by subjecting the compound of formula (IX) to a reduction reaction in Step IV-3.
  • the activator for the carboxy group include thioyluclide, oxalyl chloride, mixed acid anhydride and the like.
  • the compound of the formula (VI) or the compound of the formula (VIII) synthesized as described above is excellent, for example, through the compound represented by the formula (B) by following the method described in WO2004Z055027. It can be a carbapenem derivative of formula (A) having antibacterial activity and a broad antibacterial spectrum.
  • a compound of formula (I) according to the invention for example a compound of formula (IV) or formula (V), is 7- (1 rubamoyl methyl pyridinium in the 2-position on the force ruba penem ring. 3yl) Carbol imidazo [5, 1-b] It is useful as an intermediate for the production of strong rubapenem derivatives (compound of formula (A)) having a thiazole group.
  • the strength of rubapenem derivative of the formula (A) obtained by using the compound of the formula (I) according to the present invention has a wide and strong antibacterial activity against gram positive bacteria and gram negative bacteria, and MRSA It has strong antibacterial activity against Gram-positive and Gram-negative bacteria, including PRSP, Haemophilus influenzae and j8-lactamase producing bacteria, as disclosed in WO02Z42312. Also, as disclosed in this publication, the compound has high stability against DHP-1, which has low toxicity. This compound is used as a therapeutic agent for infectious diseases caused by various pathogenic bacteria in animals including humans, and the manufacture of pharmaceutical compositions and biological products using this compound. It will be apparent to those skilled in the art by reference to the publication. Example
  • Methyl isocyanoacetate (0.63 ml, 6.9 mmol) in an N, N-dimethylformamide (5 ml) suspension of sodium hydride (containing 60% in mineral oil, 346 mg, 8.6 mmol) under an argon atmosphere was slowly added dropwise and stirred at the same temperature for 2 hours.
  • This solution was added dropwise to a solution of 2,5 dibromothiazole (1. Og, 4. lmmol) in tetrahydrofuran (1 Oml) cooled to -20 ° C (brine ice water) over 15 minutes using force-yuri. The mixture was stirred for 2 hours while the temperature was naturally raised to around ° C.
  • 2-Bromoimidazo [5, 1-b] thiazole-7-carboxylic acid (34.8 g, 141 mmol) was suspended in a mixed solvent of water (320 ml) and acetic acid (480 ml), and concentrated sulfuric acid (29. 5 g, 301 mmol) was added, and the mixture was stirred at 105 ° C. for about 24 hours.
  • sodium carbonate 35. lg, 331 mmol
  • Water (320 ml) was added to the concentrate, and the solvent was distilled off under reduced pressure.
  • 2-Bromoimidazo [5, 1- b] thiazole-7-carboxylic acid (0.52 g, 2. lOmmol) was suspended in a mixed solvent of water (4. Oml) and acetic acid (6. Oml) at room temperature. 48 wt% hydrobromic acid (0.75 g, 4.42 mmol) was added, and the mixture was stirred at 105 ° C. for about 22 hours. After completion of the reaction, ethyl acetate (5 ml), 25 wt% aqueous sodium hydroxide solution (10 ml) and sodium carbonate (1.63 g, 15.38 mmol) were added to the reaction solution, adjusted to pH 6 and separated.
  • the aqueous layer was further extracted twice with 5 ml of ethyl acetate. Thereafter, the organic layers were combined, and the organic layers were washed with 15 wt% saline (5 ml). The washed organic layer was dehydrated with magnesium sulfate, and the organic layer was concentrated to dryness. The concentrated dried product was further dried under reduced pressure with an oil pump, and 2-bromoimidazo [5.1-b] thiazole (0.40 g, yield 93.8%) was obtained as a white solid.
  • 2-Bromoimidazo [5, 1-b] thiazole-7-carboxylic acid (0.52 g, 2. lOmmol) was suspended in a mixed solvent of water (4. Oml) and acetic acid (6. Oml) at room temperature. Concentrated hydrochloric acid (0.30 g, 3.04 mmol) was added, and the mixture was stirred at 105 ° C for about 19 hours. After completion of the reaction, sodium carbonate (0.44 g, 4.15 mmol) was added to the reaction solution, and the solvent was distilled off by concentration under reduced pressure. Water (10 ml) is added to the concentrate, and the solvent is distilled off under reduced pressure.
  • 2-Bromoimidazo [5, l-b] thiazole-7-strength ethyl benzoate (2.00 g, 7.3 mmol) is suspended in a mixed solvent of water (16 ml) and acetic acid (24 ml) and concentrated at room temperature.
  • Sulfuric acid (7.84 g, 80. Ommol) was added and stirred at 105 ° C for about 30 hours.
  • sodium carbonate (9.32 g, 88. Ommol) was added to the reaction solution, and acetic acid was distilled off under reduced pressure.
  • water (10 ml) was added to the concentrated solution, and the solvent was distilled off again under reduced pressure.
  • Example 27 (participant example):
  • Example 28 (reference example):
  • Example 29 (participant example):
  • Example 30 (reference example):
  • Example 31 (reference example):
  • Example 33 (reference example):
  • Example 34 (reference example):
  • Example 35 (participant example):
  • the reaction mixture was filtered through Celite, and after further adding ethyl acetate to the residue and stirring, the operation of performing Celite filtration was repeated several times.
  • Example 36 (reference example):
  • Example 37 (reference example):
  • Example 38 (participant example):
  • N-methoxy N-methyl 2 bromoimidazo [5, l-b] thiazole-7-carboxamide (54 mg, 0.19 mmol) in dichloromethane (5 ml) was cooled to -78 ° C, then dibutylaluminum hydride A toluene solution (1.01 M solution; 0.4 ml, 0.42 mmol) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. After completion of the reaction, a saturated aqueous solution of sodium potassium tartrate was added, and the mixture was stirred at room temperature for 1 hour, and extracted with acetyl acetate (5 ml ⁇ 3).
  • Example 39 (reference example):
  • Example 40 (participant example):
  • Example 41 (participant example):
  • Example 42 (reference example): To a solution of 2-bromoimidazo [5, 1-b] thiazole-7-carboxylic acid (97 mg, 0.39 mmol) in toluene (10 ml) was added dropwise thiol chloride (0.1 ml, 1. 37 mmol) 1.5 Heated to reflux for hours. After removing excess salt of hydrhynyl at normal pressure, the solvent was distilled off under reduced pressure, and 2-bromoimidazo [5, l-b] thiazole-7-strength rubonic acid chloride (104 mg, quantitative) as a light brown solid Obtained.

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PCT/JP2006/300729 2005-01-19 2006-01-19 イミダゾチアゾール誘導体およびその製造方法 WO2006077919A1 (ja)

Priority Applications (8)

Application Number Priority Date Filing Date Title
DE602006020545T DE602006020545D1 (de) 2005-01-19 2006-01-19 Imidazothiazol-derivat und herstellungsverfahren dafür
IN833DEN2012 IN2012DN00833A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2005-01-19 2006-01-19
CA002595009A CA2595009A1 (en) 2005-01-19 2006-01-19 Imidazothiazole derivatives and process for producing the same
CN200680008113XA CN101137661B (zh) 2005-01-19 2006-01-19 咪唑并噻唑衍生物及其制备方法
EP06711975A EP1840129B1 (en) 2005-01-19 2006-01-19 Imidazothiazole derivative and method for producing same
AU2006207059A AU2006207059A1 (en) 2005-01-19 2006-01-19 Imidazothiazole derivative and method for producing same
JP2006553948A JP4964599B2 (ja) 2005-01-19 2006-01-19 イミダゾチアゾール誘導体およびその製造方法
KR1020077018745A KR101344137B1 (ko) 2005-01-19 2007-08-16 이미다조티아졸 유도체 및 그의 제조방법

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JPH08311071A (ja) * 1995-03-10 1996-11-26 Meiji Seika Kaisha Ltd 新規イミダゾ［５，１−ｂ］チアゾール誘導体
WO1998032760A1 (fr) 1997-01-28 1998-07-30 Meiji Seika Kaisha, Ltd. Nouveaux derives de carbapenem
WO2000006581A1 (fr) 1998-07-27 2000-02-10 Meiji Seika Kaisha, Ltd. Nouveaux derives de carbapenem
WO2001053305A1 (fr) * 2000-01-24 2001-07-26 Meiji Seika Kaisha, Ltd. Procédés de préparation de dérivés de carbapenem
WO2004055027A1 (ja) * 2002-12-13 2004-07-01 Meiji Seika Kaisha, Ltd. ２−置換カルバペネム誘導体の中間体および製造方法

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WO1998032760A1 (fr) 1997-01-28 1998-07-30 Meiji Seika Kaisha, Ltd. Nouveaux derives de carbapenem
WO2000006581A1 (fr) 1998-07-27 2000-02-10 Meiji Seika Kaisha, Ltd. Nouveaux derives de carbapenem
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CA2595009A1 (en) 2006-07-27
CN101137661A (zh) 2008-03-05
JP4964599B2 (ja) 2012-07-04
KR20070113205A (ko) 2007-11-28
US7662841B2 (en) 2010-02-16
DE602006020545D1 (de) 2011-04-21
KR101344137B1 (ko) 2013-12-20
AU2006207059A1 (en) 2006-07-27
CN101137661B (zh) 2011-06-15
IN2012DN00833A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2015-06-26
JPWO2006077919A1 (ja) 2008-06-19
EP1840129A1 (en) 2007-10-03
EP1840129B1 (en) 2011-03-09
US20080114164A1 (en) 2008-05-15
EP1840129A4 (en) 2008-10-15
ES2362616T3 (es) 2011-07-08

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