WO2007020960A1 - Process for producing carbapenem derivatives through reactions without isolating intermediates - Google Patents

Process for producing carbapenem derivatives through reactions without isolating intermediates Download PDF

Info

Publication number
WO2007020960A1
WO2007020960A1 PCT/JP2006/316140 JP2006316140W WO2007020960A1 WO 2007020960 A1 WO2007020960 A1 WO 2007020960A1 JP 2006316140 W JP2006316140 W JP 2006316140W WO 2007020960 A1 WO2007020960 A1 WO 2007020960A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
solvate
protecting group
reaction
solvent
Prior art date
Application number
PCT/JP2006/316140
Other languages
French (fr)
Japanese (ja)
Inventor
Kenji Kanamoto
Original Assignee
Shionogi & Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Publication of WO2007020960A1 publication Critical patent/WO2007020960A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for producing a force rubapenem derivative.
  • a pyrrolidylthio-rubapenem derivative (compound (VI)) having a broad antibacterial spectrum is known as a useful antibiotic (Reference: Patent Document 1).
  • the following TCE is known as the synthetic intermediate.
  • a continuous method in which EL P PNB is isolated or not isolated using the following keto as a starting material is also known (see: Patent Document 2).
  • keto forms can be synthesized by cyclizing diazo forms (see Patent Documents 3, 4, 5, etc.).
  • Patent Document 1 Japanese Patent Laid-Open No. 05-294970
  • Patent Document 2 JP 2003-26680 A
  • Patent Document 3 JP-A-57-123182
  • Patent Document 4 JP-A 64-25779
  • Patent Document 5 JP-A-6-321946
  • TCE pyrrolidylthio-rubapenem derivative
  • compound (VI) pyrrolidylthio-rubapenem derivative
  • Step 1 A step of reacting compound (I) with a metal catalyst in a solvent
  • Step 3 Step of synthesizing Compound (V) by mixing the reaction solution obtained in Step 2 and Compound (IV) or a salt thereof;
  • a process for producing compound (V), a solvate thereof or a solvate crystal characterized by comprising:
  • R 1 represents a carboxy protecting group
  • R 2 represents hydrogen or a hydroxy protecting group
  • R 3 represents hydrogen or an amino protecting group.
  • Step 1 Compound (I) is reacted with a metal catalyst in a solvent to form compound ( ⁇ ). About;
  • Step 3 Step of synthesizing Compound (V) by mixing the reaction solution obtained in Step 2 containing Compound (III) and Compound (IV) or a salt thereof;
  • R 1 represents a carboxy protecting group
  • R 2 represents a hydrogen or hydroxy protecting group
  • R 3 represents a hydrogen or amino protecting group
  • reaction solvent in the first step and the second step is dichloromethane and the reaction solvent in the third step is dichloromethane and N, N dimethylacetamide.
  • the first step is performed at 20 to 60 ° C
  • the second step is performed at 30 to 0 ° C
  • the third step is performed at 30 to 0 ° C. Manufacturing method.
  • the compound (V) can be easily produced in a high yield by a one-pot method.
  • the compound (VI), which is an antibacterial agent can be industrially efficiently produced through the production method.
  • carboxy protecting group those used in the field of 13-ratata compounds can be used, such as methyl, ethyl, n-propyl, isopropyl, n-, iso-, sec-, tert-butyl, n-hexyl groups, etc. C1-6 alkyl group, bromo-tert-butyl, trichlorodiethyl etc.
  • halogens eg, chlorine, bromine, fluorine, iodine etc. 1 to 3 substituted C1-6 alkynole group, benzinore, p-nitrobenzole O-trobenzinole, p-methoxybenzinole, p-t -tro, such as butylbenzyl, C1-4 alkoxy (eg methoxy, ethoxy, etc.) or C1-4 alkyl (eg methyl, ethyl, n- or iso-propyl, n-, iso-, sec or tert butyl, etc.), etc., which may be substituted by 1 or 2 C7-14 aralkyl group, acetoxymethyl, propionyloxymethyl, n-, i so-, butyryloxymethyl, valeryloxymethyl, bivalyloxymethyl, 1 (or 2—) acetoxetyl, 1— (or 2 or 3—) acetoxypropyl,
  • C1-6 alkoxy group such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, etc.
  • C1-4 alkylthio such as (2 methylthio) ethyl, C1-4 alkyl group, 3 —Methyl-2-butyr group, 5-indanyl group, 3 phthalid Group or the like is used, preferably, nitro, more preferably 1 or 2 optionally substituted C7-14 Ararukiru group force such C1-4 Al Kill group p —Nitrobenzil (hereinafter also referred to as PNB) is used.
  • hydroxy protecting group those used in the field of / 3-ratata compounds can be used, such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, butyryl, 4 toluoyl, C1-7 acyl group optionally substituted with 1 to 3 halogens such as 4-anisol, 4-trobenzoyl, 2-trobenzoyl group (eg, chlorine, bromine, fluorine, etc.) or -toro, such as benzyl, 1 to 3 substituents such as 4-methoxybenzyl, 2nitrobenzyl, 4-12 benzyl, diphenylmethyl, triphenylmethyl, etc.
  • halogens such as 4-anisol, 4-trobenzoyl, 2-trobenzoyl group (eg, chlorine, bromine, fluorine, etc.) or -toro, such as benzyl, 1 to
  • C1-4 alkoxy eg methoxy, ethoxy, etc.
  • -toro may be substituted! ! /, C7_19 aralkyl group, for example, methoxycarbon, ethoxycarbonyl, t-butoxycarbonyl, 2, C1-4 alkoxy (eg, methoxy, ethoxy, etc.), halogen (eg, chlorine, bromine, etc.) or tri-C1-4 alkylsilyl (eg, 1 to 3 substituted with, for example, limethylsilyl etc.!, May!
  • halogen eg, chlorine, bromine, etc.
  • tri-C1-4 alkylsilyl eg, 1 to 3 substituted with, for example, limethylsilyl etc.!, May!
  • Cl-6 alkyloxy carbo yl groups such as benzyloxy carbo yl, 4-methoxy benzyloxy carbo ol, 3, Substituted with C1-4 alkoxy (eg methoxy, ethoxy, etc.) or -tro group such as 4-dimethoxybenzyloxycarbonyl, 2 nitrobenzyloxycarbonyl, 4 nitrobenzyloxycarbonyl group, etc.
  • C7-19 aralkyloxycarbonyl groups for example, C2-6 alkoxycarboxyl groups such as buruloxycarbol groups, aralkyloxycarbol groups, for example methoxy Substituted with halogens such as til, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethyl ethoxymethyl (eg, chlorine, bromine, fluorine, etc.) C1-4 alkoxy ( C1-4 alkoxy (for example, methoxy, ethoxy, etc.) such as 1 or 3 substituted methyl groups such as methoxy, ethoxy, etc., for example, 1 ethoxyethyl, 1-methyl-1-methoxyethyl, 2,2,2-trichlorodiethyl group, etc.
  • halogens such as til, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethyl ethoxymethyl (eg,
  • halogen for example, chlorine, bromine, fluorine, etc.
  • 1 to 3 substituted ethyl groups such as trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, t-butyldimethylsilyl, triisopropylpropylsilyl C1-4 alkylsilyl groups, such as diphenylmethylsilyl, diphenyl-ruethylsilyl groups, etc.
  • Group preferably a C7-19 aralkyloxycarboxyl group (benzyloxycarboxyl- Group), C2-6 alkyl carboxy group (such as butyl group), tri-C1-4 alkylsilyl group (trimethylsilyl group, etc.), and more preferably tri-C1-4 alkylsilyl.
  • Group eg, t-butyldimethylsilyl group or the like is used.
  • amino-protecting group examples include carboxylic acid, carbonic acid, sulfonic acid, and an aliphatic acylic group derived from rubamic acid, and an aliphatic acryl group substituted with an aromatic group.
  • Aliphatic acyl groups are saturated or unsaturated acyclic or cyclic acyl groups such as, for example, lower alkanol groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, bivaloyl, hexanoyl and the like.
  • Alkanoyl groups such as mesyl, ethylsulfol, propylsulfol, isopropylsulfol, butinolesnorehoninole, isobutinoresnorehoninore, pentinoresnorehoninore, hexinoresnorephonyl, etc.
  • Alkylsulfol groups such as lower alkylsulfol groups, rubamoyl groups such as N-alkyl rubamoyl groups such as methylcarbamoyl, ethylcarbamoyl, etc., such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl , Tertiary butoxy Alkoxycarbon groups such as lower alkoxy carbo groups such as rubols, for example, alkke groups such as lower alkoxy carboxy groups such as buroxy carboxy and aralkyl carboxylic groups.
  • Alkoxyl groups such as alkoxyl groups such as lower alkenyl groups such as acryloyl, methacryloyl, crotonol, etc.
  • Cyclo (lower) alkanecarbox such as cyclopropanecarbol, cyclopentanecarbol and cyclohexanecarbol.
  • cycloalkane carbo yl group such as -l group.
  • Examples of the aliphatic acyl group substituted with an aromatic group include aralkoxycarbons such as vinyl (lower) alkoxycarbonyl groups such as benzyloxycarbol and phenoxycarboxyl. Group. These acyl groups may be further substituted with one or more suitable substituents such as -tro group. Preferred V acyl groups having such a substituent include, for example, -trobenzyloxycarboxyl. And -troaralkoxy carbonyl group such as -l.
  • the amino protecting group is preferably a protecting group which is difficult to be removed during the coupling reaction, and particularly preferably a substituted benzyloxycarbol (eg, 4-trobendi).
  • the salt is preferably a pharmaceutically acceptable salt.
  • Inorganic base salts eg, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt); organic base salts (eg, triethylamine salt, pyridine) Salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, ⁇ , ⁇ '-dibenzylethylenediamine salt); hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • organic base salts eg, triethylamine salt, pyridine
  • organic base salts eg, triethylamine salt, pyridine
  • picoline salt ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, ⁇ , ⁇ '-dibenzylethylenediamine salt
  • hydrochloride hydrobromide, sulfate, phosphate, etc.
  • Acid addition salts Organic acid addition salts such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate; arginine, aspartic acid, glucose Examples include salts with basic amino acids or acidic amino acids such as thamic acid, and inner salts (solvates).
  • Solvates include hydrates (eg monohydrate, dihydrate, trihydrate, tetrahydrate) and alcoholates (examples of alcohol: methanol, 2-propanol, 2 -Pentanol, 1-pentanol, tamyl alcohol, 1 propanol, n propanol, t-butanol, isobutanol, n-butanol, cyclohexanol, benzyl alcohol) are examples.
  • R 1 represents a carboxy protecting group
  • R 2 represents hydrogen or a hydroxy protecting group
  • R 3 represents hydrogen or an amino protecting group.
  • Compound (II) is produced by reacting compound (I) with a metal catalyst in a solvent.
  • the compound ( ⁇ ) is subjected to the next step as it is without being isolated.
  • reaction solvent examples include hydrocarbon solvents such as benzene, toluene and cyclohexane, ester solvents such as ethyl acetate, halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran and dioxane. And ether solvents such as alcohol (eg, methanol, ethanol), dioxane, acetone, and acetonitrile. Halogenated hydrocarbon solvents such as dichloromethane are preferred from the standpoints of the solubility of compound (I), the influence on the catalyst, and the stability of compound (II).
  • hydrocarbon solvents such as benzene, toluene and cyclohexane
  • ester solvents such as ethyl acetate
  • halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran and
  • metal catalyst examples include rhodium reagent (rhodium acetate, rhodium otatanoate), palladium acetate, bis (acetylacetate) Cu (II), CuS04, Cu and the like.
  • the use ratio (molar ratio) of the compound (I) to the catalyst is 0.05 to 5 mol%, preferably 0.1 to 3 mol%.
  • the reaction time is usually 0.5 to 20 hours, preferably 1 to 5 hours.
  • the reaction temperature is usually about 10 to about 100 ° C, preferably about 15 to about 80 ° C, more preferably about 20 to about 60. C, particularly preferably about 35 to about 45 ° C.
  • this reaction may be performed in an inert gas atmosphere such as nitrogen gas or argon gas in order to avoid the adverse effects of moisture. (Second process)
  • Compound (III) is formed by mixing the reaction solution obtained in the first step, diphenylphosphochloridate, and a base. Preferably, compound (III) is subjected to the next step as it is without being isolated. According to this step, compound (II) and diphenylphosphochloridate react in the presence of a base to produce compound (III). Compound (III) is preferably not crystallized in the reaction vessel.
  • reaction solvent examples include hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene, and cyclohexane, ether solvents such as tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, dichloromethane, chloroform, tetrachloride. Carbon, trichlorethylene, A halogenated hydrocarbon solvent such as 1,2-dichloroethane, or a highly apolar solvent such as dimethylformamide or acetononitrile is used. Preferably, for example, tetrahydrofuran, dichloromethane or acetonitrile is used. From the viewpoints of improving the reaction yield, avoiding solidification of the reaction system by crystallization of compound (III), shortening the reaction time, etc., the reaction solvent of the first step, particularly dichloromethane, is used as it is.
  • hydrocarbon solvents such as benzene, toluene, x
  • Examples of the base include trimethylamine, triethylamine, ⁇ , ⁇ diisopropylethylamine, tributylamine, trioctylamine, triallylamine, dimethylbenzylamine, tetramethyl-1,3 diaminopropane, ⁇ ⁇ ⁇ methylmorpholine, ⁇ ⁇ ⁇ methylpyrrolidine.
  • ⁇ -Methylbiperidine ⁇ , ⁇ Dimethylaline, 1,8 Diazabicyclo [5,4,0] undeca 7 (DBU), 1,5-Diazabicyclo [4,3,0] Nona 5 ) And the like, and secondary amines such as diisopropylamine, pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, isoquinoline and other aromatic amines.
  • it is 1 with a C1-4 alkyl group such as ⁇ , ⁇ diisopropylethylamine, etc., and a trisubstituted tertiary aliphatic amine, 4 diC1-4 alkylamino such as dimethylaminopyridine, etc. Pyridine substituted with a group is used.
  • a C1-4 alkyl group such as ⁇ , ⁇ diisopropylethylamine, etc.
  • a trisubstituted tertiary aliphatic amine, 4 diC1-4 alkylamino such as dimethylaminopyridine, etc. Pyridine substituted with a group is used.
  • the use ratio (molar ratio) of diphenylphosphochloridate is 1: 1 to 5, preferably 1: 1 to 3 with respect to compound (II) in the reaction solution.
  • the reaction time is 10 minutes to 10 hours, preferably 0.5 to 3 hours.
  • the reaction temperature is 70 to 40 ° C., preferably ⁇ 40 to 10 ° C., more preferably ⁇ 30 to 0 ° C.
  • this reaction may be carried out in an inert gas atmosphere such as nitrogen gas or argon gas in order to avoid the adverse effects of moisture.
  • the reaction of the compound (III) proceeds smoothly without crystallization.
  • the use ratio of dichloromethane and N, N dimethylacetamide is preferably 1: 1 to 1:10, more preferably 1: 4 to 1: 6.
  • the compound (III) crystallizes, and as a result, the reaction system becomes suspended or solidified. A phenomenon was also seen.
  • Compound (V), a solvate thereof, or a solvate crystal can be obtained by mixing the reaction solution obtained in the second step and compound (IV) or a salt thereof. Through this step, the compound (III) reacts with the compound (IV).
  • the reaction is preferably performed in the presence of a base.
  • a base primary amine, secondary amine, or tertiary amine is used, and the base used in the second step can be preferably used.
  • the solvent used in the second step can be used as it is, but an amide polar solvent (eg, dimethylformamide, N, N-dimethylacetamide) is more preferably used in order to promote the reaction. Even ⁇ .
  • an amide polar solvent eg, dimethylformamide, N, N-dimethylacetamide
  • N, N-dimethylacetamide is particularly preferable as the amide polar solvent. That is, the present invention relates to a compound (V), a solvate thereof, characterized by reacting the compound (III) and the compound (IV) or a salt thereof in a solvent containing N, N-dimethylacetamide. Also provided is a method for producing a product or solvate crystal.
  • the reaction temperature in the third step is usually ⁇ 40 ° C. to room temperature, preferably about ⁇ 30 to 0 ° C.
  • the reaction time is usually several tens of minutes to several tens of hours, preferably 1 to 5 hours.
  • the amount of compound (III) and compound (IV) used is 10: 1 to 1:10, preferably 1: 1 to L: 5.
  • the hydroxy protecting group represented by R 2 is optionally removed. May be protected.
  • the deprotection reaction is preferably performed by a hydrolysis reaction with addition of an acid.
  • the acid include halogen hydrofluoric acids (hydrochloric acid, hydrofluoric acid, etc.), inorganic acids such as sulfuric acid and phosphoric acid, organic acids such as acetic acid, etc., preferably halogen hydrofluoric acids such as hydrochloric acid, etc. Is used.
  • this hydrolysis reaction may be carried out by adding water, a lower alcohol solvent such as methanol or ethanol, or an ether solvent such as tetrahydrofuran or dioxane to the reaction system.
  • a lower alcohol solvent such as methanol or ethanol
  • an ether solvent such as tetrahydrofuran or dioxane
  • Compound (V) produced by the above method may be isolated from the reaction system as a solvate or a crystal thereof.
  • the solvate is exemplified by the alcohol solvate.
  • the compound (V) in which R 2 is hydrogen, R 1 is PNB, and R 3 is PNZ is preferably a 2-methanol solvate It can be isolated as crystals.
  • Compound (V) which is H) can preferably be isolated as benzyl alcohol solvate crystals
  • the alcohol solvate crystals After the third step, add the alcohol, and optionally other organic solvents and Z or seed crystals to the reaction solution, and optionally at 10 ° C to room temperature for several hours. It can be obtained by stirring and washing for several days, standing or standing, and filtering, washing, and drying by ordinary methods.
  • the seed crystal for example, a 2-methanol solvate crystal of TCE isolated according to the method of JP-A-2003-26680 is used.
  • a seed crystal of benzyl alcohol monohydrate can also be used.
  • compound (V), a solvate thereof or a crystal thereof can be obtained by a one-pot reaction including a continuous three-step reaction of compound (I) and a desired crystallization reaction.
  • the one-pot reaction is a continuous reaction that does not require operations such as extraction, concentration, and drying of intermediates during the reaction, and is very useful as an industrial production method.
  • Compound (VI) is preferably a hydrate crystal (eg, monohydrate, dihydrate, 2.5 hydrate), particularly a monohydrate crystal.
  • a noble metal catalyst such as a nickel catalyst, a cobalt catalyst, an iron catalyst, a copper catalyst, a platinum catalyst and a palladium catalyst is used.
  • Palladium catalyst and nickel catalyst are preferably used, and palladium carbon, tetrakis (triphenylphosphine) palladium, acetic acid (triphenylphosphine) palladium and acetic acid (triethylphosphite) palladium are preferable.
  • an additive preferably triphenylphosphine, etc.
  • a reducing agent for reducing and removing the protective group or a nucleophilic reagent may be used in combination with the palladium catalyst.
  • the reducing agent include hydrogen, metal hydride, and the like, preferably hydrogenated tributyl tin.
  • carboxylates for example, sodium 2-ethylhexanoate
  • 1,3-dicarboxyl compounds for example, Meldrum's acid, dimedone and malonic acid esters
  • secondary amines for example, jetylamine
  • aromatic amines Arin, N-methyla) Diphosphorus, Nethylaniline, ⁇ , ⁇ dimethylaniline, 0—, m— or ⁇ toluidine, 0—, m— or p-acidin).
  • the reaction temperature is about 20-50 ° C.
  • the reaction time is usually several minutes to several tens of hours.
  • PNB 4-trobenzyl
  • PNZ 4-nitrobenzyloxycarbol
  • Ph phenol
  • TCE Allyl Diazo compound (lO.Og) is charged with dichloromethane (20 ml) and rhodium (II) acetate (360 mg) and heated to 40 ° C and stirred for 1 hour under reflux conditions. After cooling the reaction solution to 20 ° C, add diphenylphosphochloridate (9.5 g) and diisopropylethylamine (3.6 g) and stir at -20 ° C for 2 hours. Add N, N-dimethylacetamide (50 ml) and thiolpyrrolidine (SPL-Allo C ) (11.7 g) at the same temperature, and stir at 20 ° C for 2 hours.
  • TCE-Allyl 100 mg is dissolved in ethyl acetate (0.1 ml), benzyl alcohol (0.3 ml) is added, stirred at room temperature for 1 hour, then at 5 ° C. Left for 2 days. The precipitated crystals were separated by filtration and air-dried to obtain benzyl alcohol solvate crystals (79 mg) of TCE-Allyl.
  • TCE '2 methanol solvate crystal (20.0 g) obtained in Example 1 was added to tetrahydrofuran (120 ml), water (80 ml), 10% palladium carbon (10 g as a dry base), and magnesium chloride hexahydrate. (3.4 g) was added. The mixture was stirred for 3 hours at 17 to 33 ° C in a hydrogen atmosphere (about 0.5 MPa). Palladium on carbon was filtered and washed with 60 vol% tetrahydrofuran (60 ml). Salt ⁇ in the filtrate Magnesium hexahydrate (0.8 g) and tetrahydrofuran (600 mL) were added, and the aqueous layer was separated and cooled to 5 ° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

An industrially advantageous process for the production of carbapenem derivatives, namely, a process for the production of compounds (V), solvates thereof, or crystals of the solvates, characterized by comprising the first step of reacting a compound (I) with a metal catalyst in a solvent to form a compound (II), the second step of mixing the compound (II) containing reaction fluid obtained in the first step with diphenylphosphochloridate and a base to form a compound (III), and the third step of mixing the compound (III) containing reaction fluid obtained in the second step with a compound (IV) or a salt thereof to form a compound (V): wherein R1 is a carboxyl-protecting group; R2 is hydrogen or a hydroxyl-protecting group; and R3 is hydrogen or an amino -protecting group, with the proviso that neither compound (II) nor compound (III) is isolated.

Description

連続化反応による力ルバぺネム誘導体の製法  Production of force rubapenem derivatives by continuous reaction
技術分野  Technical field
[0001] 本発明は、力ルバぺネム誘導体の製法に関する。  [0001] The present invention relates to a method for producing a force rubapenem derivative.
背景技術  Background art
[0002] 広範囲の抗菌スペクトルを有するピロリジルチオ力ルバぺネム誘導体 (化合物 (VI) )は、有用な抗生物質として知られている (参照:特許文献 1)。その合成中間体として 以下の TCEが公知である。また TCEの製法として以下のケト体を出発原料として EL P PNBを単離または非単離で経由する連続法も公知である (参照:特許文献 2)。 さらにケト体はジァゾ体を環化させて合成され得ることも公知である（参照：特許文献 3、 4、 5等）。  [0002] A pyrrolidylthio-rubapenem derivative (compound (VI)) having a broad antibacterial spectrum is known as a useful antibiotic (Reference: Patent Document 1). The following TCE is known as the synthetic intermediate. In addition, as a method for producing TCE, a continuous method in which EL P PNB is isolated or not isolated using the following keto as a starting material is also known (see: Patent Document 2). Furthermore, it is also known that keto forms can be synthesized by cyclizing diazo forms (see Patent Documents 3, 4, 5, etc.).
[化 1]  [Chemical 1]
Figure imgf000003_0001
Figure imgf000003_0001
ジァゾ体 ケト体 ELP-PNB
Figure imgf000003_0002
Diazo Keto ELP-PNB
Figure imgf000003_0002
TCE ( VI )  TCE (VI)
(式中、 PNBは 4—ニトロベンジル； Phはフエニル； PNZは 4—ニトロべンジルォキシ カルボニルを示す。）  (In the formula, PNB represents 4-nitrobenzyl; Ph represents phenyl; PNZ represents 4-nitrobenzyloxycarbonyl)
しかし、ジァゾ体から TCEまでを連続的にワンポットィ匕反応で合成する方法は報告 されていない。  However, no method for continuously synthesizing from diazo to TCE by one-pot reaction has been reported.
特許文献 1：特開平 05— 294970  Patent Document 1: Japanese Patent Laid-Open No. 05-294970
特許文献 2：特開 2003 - 26680  Patent Document 2: JP 2003-26680 A
特許文献 3 :特開昭 57— 123182 特許文献 4：特開昭 64 - 25779 Patent Document 3: JP-A-57-123182 Patent Document 4: JP-A 64-25779
特許文献 5：特開平 6— 321946  Patent Document 5: JP-A-6-321946
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0003] ピロリジルチオ力ルバぺネム誘導体 (化合物（VI) )の中間体である TCEまたはその 溶媒和物結晶等のさらに好ましい工業的製法の開発が要望されている。 [0003] Development of a more preferable industrial production method for TCE, which is an intermediate of pyrrolidylthio-rubapenem derivative (compound (VI)), or a solvate crystal thereof has been demanded.
課題を解決するための手段  Means for solving the problem
[0004] 本発明者は、上記課題に鑑み鋭意研究を重ねた結果、溶媒、温度条件、中間体の 溶解度や安定性、および各工程での操作性等を種々検討することにより、ジァゾ体 力も TCEまでのワンポットィ匕反応に成功し、以下に示す本発明を完成した。 [0004] As a result of intensive studies in view of the above problems, the present inventor has variously studied the solvent, temperature conditions, solubility and stability of the intermediate, operability in each step, etc. The one-pot reaction up to TCE was successful and the present invention shown below was completed.
(1)以下の工程：  (1) The following processes:
(第 1工程)化合物 (I)と金属触媒を溶媒中で反応させる工程；  (Step 1) A step of reacting compound (I) with a metal catalyst in a solvent;
(第 2工程)第 1工程で得られた反応液、ジフエ-ルホスホクロリデート、および塩基を 混合する工程;および  (Second Step) A step of mixing the reaction solution obtained in the first step, diphenylphosphochloridate, and a base; and
(第 3工程)第 2工程で得られた反応液と化合物 (IV)またはその塩を混合して化合物 (V)を合成する工程；  (Step 3) Step of synthesizing Compound (V) by mixing the reaction solution obtained in Step 2 and Compound (IV) or a salt thereof;
を包含することを特徴とする、化合物 (V)、その溶媒和物または溶媒和物結晶の製 造方法。  A process for producing compound (V), a solvate thereof or a solvate crystal, characterized by comprising:
[化 2]  [Chemical 2]
Figure imgf000004_0001
Figure imgf000004_0001
(式中、 R1はカルボキシ保護基; R2は水素またはヒドロキシ保護基; R3は水素または ァミノ保護基を示す。 ) (Wherein R 1 represents a carboxy protecting group; R 2 represents hydrogen or a hydroxy protecting group; R 3 represents hydrogen or an amino protecting group.)
(2)以下の工程：  (2) The following processes:
(第 1工程)化合物 (I)と金属触媒を溶媒中で反応させて化合物 (Π)を生成させるェ 程； (Step 1) Compound (I) is reacted with a metal catalyst in a solvent to form compound (Π). About;
(第 2工程)ィ匕合物 (Π)を含む第 1工程で得られた反応液、ジフヱニルホスホクロリデ ート、および塩基を混合して化合物（III)を生成させる工程;および  (Second Step) Step of mixing compound (III) with the reaction solution obtained in the first step including compound (ii), diphenylphosphochloride, and base; and
(第 3工程)化合物 (III)を含む第 2工程で得られた反応液と化合物 (IV)またはその塩 を混合して化合物 (V)を合成する工程； (Step 3) Step of synthesizing Compound (V) by mixing the reaction solution obtained in Step 2 containing Compound (III) and Compound (IV) or a salt thereof;
を包含することを特徴とする、上記（1)記載の化合物 (V)、その溶媒和物または溶媒 和物結晶の製造方法。 A process for producing the compound (V), a solvate thereof or a solvate crystal thereof according to the above (1), which comprises:
[化 3] [Chemical 3]
Figure imgf000005_0001
Figure imgf000005_0001
( III )  (III)
(式中、 R1はカルボキシ保護基; R2は水素またはヒドロキシ保護基; R3は水素または ァミノ保護基を示し、化合物 (Π)および化合物 (III)は単離されな!/ヽ。 ) (Wherein R 1 represents a carboxy protecting group; R 2 represents a hydrogen or hydroxy protecting group; R 3 represents a hydrogen or amino protecting group, and compound (化合物) and compound (III) are not isolated! / ヽ).)
(3)1^は 4— -トロべンジルまたは— CH CH=CHである、上記（1)または（2)に記載 (3) 1 ^ is 4--trobenzyl or —CH 2 CH═CH, as described in (1) or (2) above
2 2  twenty two
の製造方法。 Manufacturing method.
(4) R2は水素である、上記（1)または（2)に記載の製造方法。 (4) The production method according to the above (1) or (2), wherein R 2 is hydrogen.
(5) R3はァミノ保護基である、上記（1)または（2)に記載の製造方法。 (5) The production method according to the above (1) or (2), wherein R 3 is an amino protecting group.
(6) R3は 4— -トロべンジルォキシカルボ-ルまたは一 COOCH CH=CHである、上 (6) R 3 is 4--trobenzoxycarbol or one COOCH CH = CH,
2 2 記（1)または（2)に記載の製造方法。  2 2. The production method according to (1) or (2).
(7) 1^は 4— -トロべンジルまたは一 CH CH=CH、 R2は水素、 R3は 4— -トロべンジ (7) 1 ^ is 4—-trobenzyl or one CH CH = CH, R 2 is hydrogen, R 3 is 4—-trovenge
2 2  twenty two
ルォキシカルボ-ルまたは— COOCH CH=CHである、上記（1)または（2)に記載の 製造方法。 Roxycarbonyl or —COOCH CH═CH, as described in (1) or (2) above Production method.
(8)第 1工程および第 2工程の反応溶媒がジクロロメタンであり、かつ第 3工程の反応 溶媒がジクロロメタンおよび N, N ジメチルァセトアミドである、上記（1)〜（7)のい ずれかに記載の製造方法。  (8) Any of (1) to (7) above, wherein the reaction solvent in the first step and the second step is dichloromethane and the reaction solvent in the third step is dichloromethane and N, N dimethylacetamide. The manufacturing method as described in.
(9)第 1工程を 20〜60°C、第 2工程を 30〜0°C、第 3工程を 30〜0 °Cで行う、上 記（1)〜（8)の 、ずれかに記載の製造方法。  (9) The first step is performed at 20 to 60 ° C, the second step is performed at 30 to 0 ° C, and the third step is performed at 30 to 0 ° C. Manufacturing method.
(10)上記（1)〜（9)の 、ずれかに記載の製造方法により化合物 (V)を得た後、アル コール含有溶媒中から結晶化することを特徴とする、化合物 (V)のアルコール和物 結晶の製造方法。  (10) Compound (V) characterized in that after obtaining Compound (V) by the production method according to any one of (1) to (9) above, crystallization from an alcohol-containing solvent Alcohol hydrate A method for producing crystals.
(11)アルコール力メタノールであり、アルコール和物結晶が 2メタノール和物結晶で ある、上記（10)記載の製造方法。  (11) The production method according to the above (10), which is alcohol-powered methanol and the alcohol solvate crystals are dimethanol solvate crystals.
(12)上記（2)記載の化合物（III)と化合物（IV)またはその塩を、 N, N ジメチルァ セトアミドを含有する溶媒中で反応させることを特徴とする、化合物 (V)、その溶媒和 物または溶媒和物結晶の製造方法。  (12) Compound (V), a solvate thereof, characterized by reacting compound (III) described in (2) above with compound (IV) or a salt thereof in a solvent containing N, N dimethylacetamide Product of hydrate or solvate crystal.
(13)上記（1)〜（12)の 、ずれかに記載の製造方法により、化合物 (V)、その溶媒 和物または溶媒和物結晶を得た後、これを脱保護することを特徴とする、式：  (13) The method according to any one of (1) to (12) above, wherein the compound (V), a solvate thereof or a solvate crystal is obtained and then deprotected. The expression:
Figure imgf000006_0001
Figure imgf000006_0001
で示される化合物 (VI)、その製薬上許容される塩、またはそれらの溶媒和物の製造 方法。  Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
発明の効果  The invention's effect
[0006] 本製法によって化合物 (V)をワンポットィ匕法で簡便に収率よく製造できる。また該製 法を経由して抗菌剤である化合物 (VI)等を工業的に効率よく製造できる。  [0006] By this production method, the compound (V) can be easily produced in a high yield by a one-pot method. In addition, the compound (VI), which is an antibacterial agent, can be industrially efficiently produced through the production method.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0007] 本発明の製法を以下に示す。  [0007] The production method of the present invention is described below.
(保護基) カルボキシ保護基としては 13—ラタタム化合物の分野で用いられるものを用いること ができ、メチル、ェチル、 n—プロピル、イソプロピル、 n- , iso—， sec- , tert ブチ ル、 n—へキシル基等の C1-8アルキル基、ブロモー tーブチル、トリクロ口ェチル等の ハロゲン (例えば、塩素、臭素、フッ素、ヨウ素等）で 1ないし 3置換された C1-6アルキ ノレ基、ベンジノレ、 p 二トロべンジノレ、 o 二トロべンジノレ、 p—メトキシベンジノレ基、 p —t ブチルベンジル等の-トロ、 C1-4アルコキシ基（例えばメトキシ、エトキシ等）ま たは C1-4アルキル基（例えばメチル、ェチル、 n—又は iso プロピル、 n—、 iso—、 sec 又は tert ブチル等）等で 1または 2置換されていてもよい C7-14ァラルキル基 、ァセトキシメチル、プロピオニルォキシメチル、 n—， iso- ,ブチリルォキシメチル、 バレリルォキシメチル、ビバロイルォキシメチル、 1 （または 2—）ァセトキシェチル， 1— (または 2 または 3—)ァセトキシプロピル， 1— (または 2 または 3 または 4— )ァセトキシブチル， 1— (または 2—)プロピオ-ルォキシェチル， 1— (または 2—ま たは 3 )プロピオ-ルォキシプロピル， 1 （または 2 )ブチリルォキシェチル， 1 (または 2—)イソブチリルォキシェチル， 1— (または 2—)ビバロイルォキシェチル， 1 （または 2—）へキサノィルォキシェチル、イソブチリルォキシメチル、 2—ェチルブ チリルォキシメチル， 3, 3 ジメチルブチリルォキシメチル、 1 （または 2 ）ペンタノ ィルォキシェチル等の C1-4アルカノィルォキシ C1-4アルキル基、例えば 2—メシ ルェチル基等の C 1-4アル力ンスルホ-ル C 1-4アルキル基，例えばメトキシカルボ ニルォキシメチル，エトキシカルボニルォキシメチル，プロポキシカルボニルォキシメ チル，第三級ブトキシカルボ-ルォキシメチル， 1 （または 2—）メトキシカルボ-ル ォキシェチル， 1 （または 2—）エトキシカルボ-ルォキシェチル， 1 （または 2—） イソプロポキシカルボニルォキシェチル等の C1-4アルコキシカルボニルォキシー C1 -4アルキル基、 tーブチルジメチルシリル、トリメチルシリル等のトリ C1-4アルキルシリ ル基、ァリル、メタァリル等の C2-6ァルケ-ル基、メトキシメチル、エトキシメチル、プ 口ポキシメチル、イソプロポキシメチル等の C1-4アルコキシ メチル基、（2 メチル チォ） ェチル等の C1-4アルキルチオ C1-4アルキル基、 3—メチルー 2 ブテュル 基、 5—インダニル基、 3 フタリジル基等が用いられ、好ましくは、ニトロ、 C1-4アル キル基等で 1または 2置換されていてもよい C7-14ァラルキル基等力 より好ましくは p —ニトロべンジル（以下、 PNBとも表示する）ゃァリルが用いられる。 (Protecting group) As the carboxy protecting group, those used in the field of 13-ratata compounds can be used, such as methyl, ethyl, n-propyl, isopropyl, n-, iso-, sec-, tert-butyl, n-hexyl groups, etc. C1-6 alkyl group, bromo-tert-butyl, trichlorodiethyl etc. halogens (eg, chlorine, bromine, fluorine, iodine etc.) 1 to 3 substituted C1-6 alkynole group, benzinore, p-nitrobenzole O-trobenzinole, p-methoxybenzinole, p-t -tro, such as butylbenzyl, C1-4 alkoxy (eg methoxy, ethoxy, etc.) or C1-4 alkyl (eg methyl, ethyl, n- or iso-propyl, n-, iso-, sec or tert butyl, etc.), etc., which may be substituted by 1 or 2 C7-14 aralkyl group, acetoxymethyl, propionyloxymethyl, n-, i so-, butyryloxymethyl, valeryloxymethyl, bivalyloxymethyl, 1 (or 2—) acetoxetyl, 1— (or 2 or 3—) acetoxypropyl, 1— (or 2 or 3 or 4 —) Acetoxybutyl, 1— (or 2—) propio-loxychetyl, 1— (or 2—or 3) propio-loxypropyl, 1 (or 2) butyryloxychetyl, 1 (or 2—) isobutyryl Quichetil, 1- (or 2-) Bivaloyloxetyl, 1 (or 2-) Hexanoyloxychetyl, Isobutyryloxymethyl, 2-Ethylbutyryloxymethyl, 3, 3 Dimethyl C1-4 alkanoyloxy C1-4 alkyl group such as butyryloxymethyl, 1 (or 2) pentanoyloxychetyl, for example, C 1-4 alkylsulfonyl, such as 2-mesylethyl group C 1-4 Kill groups such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, tertiary butoxycarboxoxymethyl, 1 (or 2-) methoxycarboxoxyl, 1 (or 2-) ethoxycarboxoxyl , 1 (or 2-) C1-4 alkoxycarbonyloxy such as isopropoxycarbonyloxetyl C1-4 alkyl group, tri C1-4 alkylsilyl group such as t-butyldimethylsilyl, trimethylsilyl, aryl, methallyl, etc. C1-6 alkoxy group such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, etc., C1-4 alkylthio such as (2 methylthio) ethyl, C1-4 alkyl group, 3 —Methyl-2-butyr group, 5-indanyl group, 3 phthalid Group or the like is used, preferably, nitro, more preferably 1 or 2 optionally substituted C7-14 Ararukiru group force such C1-4 Al Kill group p —Nitrobenzil (hereinafter also referred to as PNB) is used.
ヒドロキシ保護基としては、 /3—ラタタム化合物の分野で用いられるものを用いること ができ、例えばホルミル、ァセチル、クロロアセチル、ジクロロアセチル、トリクロロアセ チル、トリフルォロアセチル、プロピオニル、ブチリル、 4 トルオイル、 4ーァニソィル 、 4 -トロベンゾィル、 2 -トロベンゾィル基等のハロゲン（例えば塩素、臭素、フッ 素等）または-トロ等で 1〜3個置換されていてもよい C1-7ァシル基、例えばべンジ ル、 4—メトキシベンジル、 2 ニトロベンジル、 4一二トロベンジル、ジフエニルメチル 、トリフエ-ルメチル基等の C1-4アルコキシ (例えばメトキシ、エトキシ等）または-トロ 等で 1〜3個置換されて!、てもよ!/、C7_19ァラルキル基、例えばメトキシカルボ-ル、 エトキシカルボニル、 t ブトキシカルボニル、 2,2,2—トリクロ口エトキシカルボニル、 2 トリメチルシリルエトキシカルボ-ル基等の C1-4アルコキシ（例えばメトキシ、エト キシ等）、ハロゲン (例えば塩素、臭素等)またはトリ— C1-4アルキルシリル (例えばト リメチルシリル等）等で 1〜3個置換されて!、てもよ!/、Cl-6アルキルォキシ カルボ- ル基、例えばべンジルォキシカルボ-ル、 4ーメトキシベンジルォキシカルボ-ル、 3, 4ージメトキシベンジルォキシカルボニル、 2 二トロべンジルォキシカルボニル、 4 ニトロべンジルォキシカルボ-ル基等の C1-4アルコキシ（例えばメトキシ、エトキシ等 )または-トロ基等で置換されていてもよい、 C7-19ァラルキルォキシ カルボ-ル 基、例えばビュルォキシカルボ-ル、ァリルォキシカルボ-ル基等の C2-6ァルケ- ルォキシ—カルボ-ル基、例えばメトキシメチル、 t—ブトキシメチル、 2—メトキシエト キシメチル、 2,2,2—トリクロ口エトキシメチル基等のハロゲン (例えば塩素、臭素、フッ 素等）で置換されて 、てもよ ヽ C1-4アルコキシ (例えばメトキシ、エトキシ等）等で 1な いし 3置換されたメチル基、例えば 1 エトキシェチル， 1ーメチルー 1ーメトキシェチ ル、 2,2,2—トリクロ口ェチル基等の C1-4アルコキシ (例えばメトキシ、エトキシ等）また はハロゲン (例えば、塩素、臭素、フッ素等)等で 1ないし 3置換されたェチル基、例え ばトリメチルシリル、トリェチルシリル、ジメチルイソプロビルシリル、 t—ブチルジメチル シリル、トリイソプロビルシリル基等のトリー C1-4アルキルシリル基、例えばジフエ-ル メチルシリル、ジフヱ-ルェチルシリル基等のジフヱ-ルー C1-4アルキルシリル基が 用いられ、好ましくは C7-19ァラルキルォキシカルボ-ル基（ベンジルォキシカルボ- ル基等）、 C2-6ァルケ-ルォキシカルボ-ル基（ビュルォキシカルボ-ル基等）、トリ — C1-4アルキルシリル基（トリメチルシリル基等）等力 より好ましくはトリ— C1-4アル キルシリル基 (例： t -ブチルジメチルシリル基)等が用 ヽられる。 As the hydroxy protecting group, those used in the field of / 3-ratata compounds can be used, such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, butyryl, 4 toluoyl, C1-7 acyl group optionally substituted with 1 to 3 halogens such as 4-anisol, 4-trobenzoyl, 2-trobenzoyl group (eg, chlorine, bromine, fluorine, etc.) or -toro, such as benzyl, 1 to 3 substituents such as 4-methoxybenzyl, 2nitrobenzyl, 4-12 benzyl, diphenylmethyl, triphenylmethyl, etc. C1-4 alkoxy (eg methoxy, ethoxy, etc.) or -toro may be substituted! ! /, C7_19 aralkyl group, for example, methoxycarbon, ethoxycarbonyl, t-butoxycarbonyl, 2, C1-4 alkoxy (eg, methoxy, ethoxy, etc.), halogen (eg, chlorine, bromine, etc.) or tri-C1-4 alkylsilyl (eg, 1 to 3 substituted with, for example, limethylsilyl etc.!, May! /, Cl-6 alkyloxy carbo yl groups such as benzyloxy carbo yl, 4-methoxy benzyloxy carbo ol, 3, Substituted with C1-4 alkoxy (eg methoxy, ethoxy, etc.) or -tro group such as 4-dimethoxybenzyloxycarbonyl, 2 nitrobenzyloxycarbonyl, 4 nitrobenzyloxycarbonyl group, etc. C7-19 aralkyloxycarbonyl groups, for example, C2-6 alkoxycarboxyl groups such as buruloxycarbol groups, aralkyloxycarbol groups, for example methoxy Substituted with halogens such as til, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethyl ethoxymethyl (eg, chlorine, bromine, fluorine, etc.) C1-4 alkoxy ( C1-4 alkoxy (for example, methoxy, ethoxy, etc.) such as 1 or 3 substituted methyl groups such as methoxy, ethoxy, etc., for example, 1 ethoxyethyl, 1-methyl-1-methoxyethyl, 2,2,2-trichlorodiethyl group, etc. ) Or halogen (for example, chlorine, bromine, fluorine, etc.) 1 to 3 substituted ethyl groups such as trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, t-butyldimethylsilyl, triisopropylpropylsilyl C1-4 alkylsilyl groups, such as diphenylmethylsilyl, diphenyl-ruethylsilyl groups, etc. Group, preferably a C7-19 aralkyloxycarboxyl group (benzyloxycarboxyl- Group), C2-6 alkyl carboxy group (such as butyl group), tri-C1-4 alkylsilyl group (trimethylsilyl group, etc.), and more preferably tri-C1-4 alkylsilyl. Group (eg, t-butyldimethylsilyl group) or the like is used.
ァミノ保護基としては、カルボン酸、炭酸、スルホン酸および力ルバミン酸力 誘導さ れた脂肪族ァシル基や、芳香族基で置換された脂肪族ァシル基等が挙げられる。 脂肪族ァシル基としては飽和または不飽和の非環式または環式ァシル基、その例 として、例えばホルミル、ァセチル、プロピオニル、ブチリル、イソブチリル、バレリル、 イソバレリル、ビバロイル、へキサノィル等の低級アルカノィル基のようなアルカノィル 基、例えばメシル、ェチルスルホ -ル、プロピルスルホ -ル、イソプロピルスルホ-ル 、ブチノレスノレホニノレ、イソブチノレスノレホニノレ、ペンチノレスノレホニノレ、へキシノレスノレホニ ル等の低級アルキルスルホ-ル基のようなアルキルスルホ-ル基、力ルバモイル基、 例えばメチルカルバモイル、ェチルカルバモイル等の N—アルキル力ルバモイル基、 例えばメトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ブトキシカル ボ -ル、第三級ブトキシカルボ-ル等の低級アルコキシカルボ-ル基のようなアルコ キシカルボ-ル基、例えばビュルォキシカルボ-ル、ァリルォキシカルボ-ル等の低 級ァルケ-ルォキシカルボ-ル基のようなァルケ-ルォキシカルボ-ル基、例えばァ クリロイル、メタクリロイル、クロトノィル等の低級アルケノィル基のようなアルケノィル基 、例えばシクロプロパンカルボ-ル、シクロペンタンカルボ-ル、シクロへキサンカル ボ-ル等のシクロ（低級）アルカンカルボ-ル基のようなシクロアルカンカルボ-ル基 等が挙げられる。  Examples of the amino-protecting group include carboxylic acid, carbonic acid, sulfonic acid, and an aliphatic acylic group derived from rubamic acid, and an aliphatic acryl group substituted with an aromatic group. Aliphatic acyl groups are saturated or unsaturated acyclic or cyclic acyl groups such as, for example, lower alkanol groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, bivaloyl, hexanoyl and the like. Alkanoyl groups such as mesyl, ethylsulfol, propylsulfol, isopropylsulfol, butinolesnorehoninole, isobutinoresnorehoninore, pentinoresnorehoninore, hexinoresnorephonyl, etc. Alkylsulfol groups such as lower alkylsulfol groups, rubamoyl groups such as N-alkyl rubamoyl groups such as methylcarbamoyl, ethylcarbamoyl, etc., such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl , Tertiary butoxy Alkoxycarbon groups such as lower alkoxy carbo groups such as rubols, for example, alkke groups such as lower alkoxy carboxy groups such as buroxy carboxy and aralkyl carboxylic groups. Alkoxyl groups such as alkoxyl groups such as lower alkenyl groups such as acryloyl, methacryloyl, crotonol, etc. Cyclo (lower) alkanecarbox such as cyclopropanecarbol, cyclopentanecarbol and cyclohexanecarbol. And cycloalkane carbo yl group such as -l group.
芳香族基で置換された脂肪族ァシル基としては、例えばべンジルォキシカルボ- ル、フエネチルォキシカルボ-ル等のフエ-ル（低級）アルコキシカルボ-ル基のよう なァラルコキシカルボ-ル基が挙げられる。これらのァシル基はさらに-トロ基のよう な適当な置換基 1個以上で置換されていてもよぐそのような置換基を有する好まし Vヽァシル基としては、例えば-トロベンジルォキシカルボ-ル等の-トロアラルコキシ カルボニル基等が挙げられる。  Examples of the aliphatic acyl group substituted with an aromatic group include aralkoxycarbons such as vinyl (lower) alkoxycarbonyl groups such as benzyloxycarbol and phenoxycarboxyl. Group. These acyl groups may be further substituted with one or more suitable substituents such as -tro group. Preferred V acyl groups having such a substituent include, for example, -trobenzyloxycarboxyl. And -troaralkoxy carbonyl group such as -l.
ァミノ保護基として好ましくは、カップリング反応中に脱離しにくい保護基であり、特 に好ましくは、置換されて 、てもよ 、ベンジルォキシカルボ-ル（例： 4 -トロベンジ ルォキシカルボ-ル（以下、 PNZとも表示する） )ゃァルケ-ルォキシカルボ-ル基（ 例： COOCH CH=CH (以下、 Allocとも表示する）である。 塩としては好ましくは製薬上許容される塩であり、無機塩基塩 (例:ナトリウム塩、カリ ゥム塩等のアルカリ金属塩;カルシウム塩、マグネシウム塩等のアルカリ土類金属塩； アンモ-ゥム塩）；有機塩基塩 (例：トリェチルァミン塩、ピリジン塩、ピコリン塩、ェタノ ールァミン塩、トリエタノールアミン塩、ジシクロへキシルァミン塩、 Ν,Ν' —ジベンジ ルエチレンジァミン塩）；塩酸塩、臭化水素酸塩、硫酸塩、燐酸塩等の無機酸付加塩 ；ギ酸塩、酢酸塩、トリフルォロ酢酸塩、マレイン酸塩、酒石酸塩、メタンスルホン酸塩 、ベンゼンスルホン酸塩等の有機酸付加塩；アルギニン、ァスパラギン酸、グルタミン 酸等の塩基性アミノ酸または酸性アミノ酸との塩、または分子内塩が挙げられる。 (溶媒和物） The amino protecting group is preferably a protecting group which is difficult to be removed during the coupling reaction, and particularly preferably a substituted benzyloxycarbol (eg, 4-trobendi). Roxy carbonyl (hereinafter also referred to as PNZ)) is a alkenyl carboxy group (eg COOCH CH = CH (hereinafter also referred to as Alloc). The salt is preferably a pharmaceutically acceptable salt. , Inorganic base salts (eg, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt); organic base salts (eg, triethylamine salt, pyridine) Salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, Ν, Ν'-dibenzylethylenediamine salt); hydrochloride, hydrobromide, sulfate, phosphate, etc. Acid addition salts: Organic acid addition salts such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate; arginine, aspartic acid, glucose Examples include salts with basic amino acids or acidic amino acids such as thamic acid, and inner salts (solvates).
溶媒和物としては、水和物（例： 1水和物、 2水和物、 3水和物、 4水和物）やアルコ 一ル和物（アルコールの例：メタノール、 2—プロパノール、 2—ペンタノール、 1ーぺ ンタノール、 tーァミルアルコール、 1 プロパノール、 n プロパノール、 tーブタノ一 ル、イソブタノール、 n—ブタノール、シクロへキサノール、ベンジルアルコール）が例 示される。  Solvates include hydrates (eg monohydrate, dihydrate, trihydrate, tetrahydrate) and alcoholates (examples of alcohol: methanol, 2-propanol, 2 -Pentanol, 1-pentanol, tamyl alcohol, 1 propanol, n propanol, t-butanol, isobutanol, n-butanol, cyclohexanol, benzyl alcohol) are examples.
(化合物 (V)の製法） (Production method of compound (V))
[化 5] [Chemical 5]
Figure imgf000010_0001
Figure imgf000010_0001
Figure imgf000010_0002
(式中、 R1はカルボキシ保護基; R2は水素またはヒドロキシ保護基; R3は水素または ァミノ保護基を示す。 )
Figure imgf000010_0002
(Wherein R 1 represents a carboxy protecting group; R 2 represents hydrogen or a hydroxy protecting group; R 3 represents hydrogen or an amino protecting group.)
(第 1工程） (First step)
化合物 (I)と金属触媒を溶媒中で反応させることにより、化合物 (II)が生成する。好 ましくは、化合物（Π)は単離されずに反応液のまま次工程に付される。  Compound (II) is produced by reacting compound (I) with a metal catalyst in a solvent. Preferably, the compound (Π) is subjected to the next step as it is without being isolated.
反応溶媒としては、ベンゼン、トルエン、シクロへキサン等の炭化水素系溶媒、酢酸 ェチル等のエステル系溶媒、ジクロロメタン、クロ口ホルム、 1,2—ジクロルェタン等の ハロゲン化炭化水素系溶媒、 テトラヒドロフラン、ジォキサン等のエーテル系溶媒、ァ ルコール（例：メタノール、エタノール）、ジォキサン、アセトン、ァセトニトリル等が例示 される。化合物 (I)の溶解度、触媒への影響、化合物 (II)の安定性等の点力もは、ジ クロロメタン等のハロゲンィ匕炭化水素系溶媒が好ましい。  Examples of the reaction solvent include hydrocarbon solvents such as benzene, toluene and cyclohexane, ester solvents such as ethyl acetate, halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran and dioxane. And ether solvents such as alcohol (eg, methanol, ethanol), dioxane, acetone, and acetonitrile. Halogenated hydrocarbon solvents such as dichloromethane are preferred from the standpoints of the solubility of compound (I), the influence on the catalyst, and the stability of compound (II).
金属触媒としては、ロジウム試薬 (酢酸ロジウム、ロジウムオタタノエート）、酢酸パラ ジゥム、ビス（ァセチルァセトナート） Cu (II)、 CuS04、 Cu等が例示される力 好ましく はロジウム試薬である。  Examples of the metal catalyst include rhodium reagent (rhodium acetate, rhodium otatanoate), palladium acetate, bis (acetylacetate) Cu (II), CuS04, Cu and the like.
化合物（I)と触媒との使用割合 (モル比）は 0.05〜5モル％、好ましくは 0.1〜3モル %である。反応時間は、通常、 0.5〜20時間、好ましくは 1〜5時間である。反応温度 は、通常、約 10〜約 100°C、好ましくは約 15〜約 80°C、より好ましくは約 20〜約 60 。C、特に好ましくは約 35〜約 45°Cである。また本反応は、水分による悪影響を避け るために、例えば窒素ガス、アルゴンガス等の不活性ガス雰囲気下で行ってもよい。 (第 2工程）  The use ratio (molar ratio) of the compound (I) to the catalyst is 0.05 to 5 mol%, preferably 0.1 to 3 mol%. The reaction time is usually 0.5 to 20 hours, preferably 1 to 5 hours. The reaction temperature is usually about 10 to about 100 ° C, preferably about 15 to about 80 ° C, more preferably about 20 to about 60. C, particularly preferably about 35 to about 45 ° C. In addition, this reaction may be performed in an inert gas atmosphere such as nitrogen gas or argon gas in order to avoid the adverse effects of moisture. (Second process)
第 1工程で得られた反応液、ジフエ-ルホスホクロリデート、および塩基を混合する ことにより、化合物 (III)が生成する。好ましくは、化合物 (III)は単離されずに反応液 のまま次工程に付される。当該工程により、前記化合物（II)とジフエ-ルホスホクロリ デートが塩基存在下で反応して化合物 (III)が生成する。化合物 (III)は好ましくは、 反応容器内にぉ 、て晶析しな 、。  Compound (III) is formed by mixing the reaction solution obtained in the first step, diphenylphosphochloridate, and a base. Preferably, compound (III) is subjected to the next step as it is without being isolated. According to this step, compound (II) and diphenylphosphochloridate react in the presence of a base to produce compound (III). Compound (III) is preferably not crystallized in the reaction vessel.
反応溶媒としては、例えばベンゼン、トルエン、キシレン、クロルベンゼン、シクロへ キサン等の炭化水素系溶媒、テトラヒドロフラン、ジォキサン、 1,2—ジメトキシェタン 等のエーテル系溶媒、ジクロロメタン、クロ口ホルム、四塩化炭素、トリクロロエチレン、 1,2—ジクロルェタン等のハロゲン化炭化水素溶媒、ジメチルホルムアミド、ァセトニト リル等の高非極プロトン性溶媒が使用され、好ましくは、例えばテトラヒドロフラン、ジ クロロメタン、ァセトニトリル等が用いられる。反応収率の向上、化合物（III)の結晶析 出等による反応系固化の回避、反応時間の短縮等の点からより好ましくは、第 1工程 の反応溶媒、特にジクロロメタンがそのまま使用される。 Examples of the reaction solvent include hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene, and cyclohexane, ether solvents such as tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, dichloromethane, chloroform, tetrachloride. Carbon, trichlorethylene, A halogenated hydrocarbon solvent such as 1,2-dichloroethane, or a highly apolar solvent such as dimethylformamide or acetononitrile is used. Preferably, for example, tetrahydrofuran, dichloromethane or acetonitrile is used. From the viewpoints of improving the reaction yield, avoiding solidification of the reaction system by crystallization of compound (III), shortening the reaction time, etc., the reaction solvent of the first step, particularly dichloromethane, is used as it is.
塩基としては例えば、トリメチルァミン、トリエチルァミン、 Ν,Ν ジイソプロピルェチ ルァミン、トリブチルァミン、トリオクチルァミン、トリアリルァミン、ジメチルベンジルアミ ン、テトラメチルー 1,3 ジァミノプロパン、 Ν メチルモルホリン、 Ν メチルピロリジ ン、 Ν—メチルビペリジン、 Ν,Ν ジメチルァ-リン、 1,8 ジァザビシクロ [5,4,0]ゥ ンデカ 7 ェン（DBU) , 1,5 -ジァザビシクロ [4, 3,0]ノナ 5 ェン（DBN)等の 第 3級脂肪族ァミン、ジイソプロピルアミン等の 2級ァミン、ピリジン、 4 ジメチルーァ ミノピリジン、ピコリン、ルチジン、キノリン、イソキノリン等の芳香族ァミン等が用いられ る。好ましくは、例えば、 Ν,Ν ジイソプロピルェチルァミン等の C1-4アルキル基で 1 な!、し 3置換された第 3級脂肪族ァミン、 4 ジメチルァミノピリジン等のジ C1-4アル キルアミノ基で置換されたピリジン等が用いられる。  Examples of the base include trimethylamine, triethylamine, Ν, Ν diisopropylethylamine, tributylamine, trioctylamine, triallylamine, dimethylbenzylamine, tetramethyl-1,3 diaminopropane, メ チ ル methylmorpholine, メ チ ル methylpyrrolidine. , Ν-Methylbiperidine, Ν, Ν Dimethylaline, 1,8 Diazabicyclo [5,4,0] undeca 7 (DBU), 1,5-Diazabicyclo [4,3,0] Nona 5 ) And the like, and secondary amines such as diisopropylamine, pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, isoquinoline and other aromatic amines. Preferably, for example, it is 1 with a C1-4 alkyl group such as Ν, Ν diisopropylethylamine, etc., and a trisubstituted tertiary aliphatic amine, 4 diC1-4 alkylamino such as dimethylaminopyridine, etc. Pyridine substituted with a group is used.
ジフ ニルホスホクロリデートの使用割合 (モル比）は反応液中の化合物（II)に対し て 1 : 1〜5、好ましくは 1 : 1〜3である。反応時間は 10分〜 10時間、好ましくは 0.5〜 3時間である。反応温度は、 70〜40°C、好ましくは— 40〜10°C、より好ましくは— 30〜0°Cである。また本反応は、水分による悪影響を避けるために、例えば窒素ガス 、アルゴンガス等の不活性ガス雰囲気下で行ってもよ 、。  The use ratio (molar ratio) of diphenylphosphochloridate is 1: 1 to 5, preferably 1: 1 to 3 with respect to compound (II) in the reaction solution. The reaction time is 10 minutes to 10 hours, preferably 0.5 to 3 hours. The reaction temperature is 70 to 40 ° C., preferably −40 to 10 ° C., more preferably −30 to 0 ° C. In addition, this reaction may be carried out in an inert gas atmosphere such as nitrogen gas or argon gas in order to avoid the adverse effects of moisture.
また第 1工程でジクロロメタンを使用しかつ第 2工程時に N, N -ジメチルァセトアミ ドを添加した場合に、化合物（III)が晶析せずに反応力スムーズに進行することも本 発明の特徴の 1つである。第 2工程の反応系において、ジクロロメタンと N, N ジメチ ルァセトアミドの使用割合は、好ましくは1 : 1〜1 : 10、より好ましくは 1 :4〜1 : 6である 。なお、第 1工程でテトラヒドロフランや酢酸ェチルを使用し、第 2工程で N, N ジメ チルァセトアミドを添加した場合には、化合物（III)が晶析し、その結果、反応系が懸 濁したり固化する現象も見られた。  In addition, when dichloromethane is used in the first step and N, N-dimethylacetamide is added in the second step, the reaction of the compound (III) proceeds smoothly without crystallization. One of the features. In the reaction system of the second step, the use ratio of dichloromethane and N, N dimethylacetamide is preferably 1: 1 to 1:10, more preferably 1: 4 to 1: 6. Note that when tetrahydrofuran or ethyl acetate is used in the first step and N, N-dimethylacetamide is added in the second step, the compound (III) crystallizes, and as a result, the reaction system becomes suspended or solidified. A phenomenon was also seen.
(第 3工程） 第 2工程で得られた反応液と化合物 (IV)またはその塩を混合することにより、化合 物 (V)、その溶媒和物または溶媒和物結晶が得られる。当該工程により、前記化合 物 (III)と化合物 (IV)が反応する。 (3rd process) Compound (V), a solvate thereof, or a solvate crystal can be obtained by mixing the reaction solution obtained in the second step and compound (IV) or a salt thereof. Through this step, the compound (III) reacts with the compound (IV).
当該反応は好ましくは塩基存在下で行われる。塩基としては、 1級ァミン、 2級ァミン 、または 3級ァミンが使用されるが、好ましくは第 2工程で使用した塩基が使用可能で ある。  The reaction is preferably performed in the presence of a base. As the base, primary amine, secondary amine, or tertiary amine is used, and the base used in the second step can be preferably used.
反応溶媒としては、好ましくは第 2工程で使用した溶媒がそのまま使用できるが、反 応を促進させるためにより好ましくはアミド系極性溶媒 (例：ジメチルホルムアミド、 N, N -ジメチルァセトアミド）を併用してもょ ヽ。  As the reaction solvent, the solvent used in the second step can be used as it is, but an amide polar solvent (eg, dimethylformamide, N, N-dimethylacetamide) is more preferably used in order to promote the reaction. Even ヽ.
本発明では、アミド系極性溶媒として、特に N, N—ジメチルァセトアミドが好ましい ことも見出した。即ち、本発明は、化合物（III)と化合物（IV)またはその塩を、 N, N— ジメチルァセトアミドを含有する溶媒中で反応させることを特徴とする、化合物 (V)、 その溶媒和物または溶媒和物結晶の製造方法も提供する。  In the present invention, it has also been found that N, N-dimethylacetamide is particularly preferable as the amide polar solvent. That is, the present invention relates to a compound (V), a solvate thereof, characterized by reacting the compound (III) and the compound (IV) or a salt thereof in a solvent containing N, N-dimethylacetamide. Also provided is a method for producing a product or solvate crystal.
第 3工程の反応温度は、通常— 40°C〜室温、好ましくは約— 30〜0°Cである。 反応時間は、通常、数十分〜数十時間、好ましくは 1〜5時間である。  The reaction temperature in the third step is usually −40 ° C. to room temperature, preferably about −30 to 0 ° C. The reaction time is usually several tens of minutes to several tens of hours, preferably 1 to 5 hours.
化合物 (III)と化合物 (IV)の使用量は、 10 : 1〜1： 10、好ましくは 1： 1〜： L： 5である 上記反応後、所望により R2で示されるヒドロキシ保護基を脱保護してもよい。脱保護 反応は、好ましくは酸を添加して加水分解反応により行われる。酸としては、例えば、 ハロゲンィ匕水素酸 (塩酸、フッ化水素酸等）、硫酸、リン酸等の無機酸、酢酸等の有 機酸等であり、好ましくは例えば塩酸等のハロゲンィ匕水素酸等が用いられる。本加水 分解反応は、所望により、反応系に水、メタノール、エタノール等の低級アルコール 系溶媒、テトラヒドロフラン、ジォキサン等のエーテル系溶媒等を添加して行ってもよ V、。酸の使用割合 (モル比）は、化合物 (V, R2=ヒドロキシ保護基）に対して好ましくは 1 : 0.5〜10、より好ましくは 1 : 1〜5である。 The amount of compound (III) and compound (IV) used is 10: 1 to 1:10, preferably 1: 1 to L: 5. After the above reaction, the hydroxy protecting group represented by R 2 is optionally removed. May be protected. The deprotection reaction is preferably performed by a hydrolysis reaction with addition of an acid. Examples of the acid include halogen hydrofluoric acids (hydrochloric acid, hydrofluoric acid, etc.), inorganic acids such as sulfuric acid and phosphoric acid, organic acids such as acetic acid, etc., preferably halogen hydrofluoric acids such as hydrochloric acid, etc. Is used. If desired, this hydrolysis reaction may be carried out by adding water, a lower alcohol solvent such as methanol or ethanol, or an ether solvent such as tetrahydrofuran or dioxane to the reaction system. The use ratio (molar ratio) of the acid is preferably 1: 0.5 to 10, more preferably 1: 1 to 5 with respect to the compound (V, R 2 = hydroxy protecting group).
上記方法により生成した化合物 (V)は、反応系中より溶媒和物またはその結晶とし て単離してもよい。溶媒和物として好ましくは、前記アルコール和物が例示される。例 えば、 R2が水素、 R1が PNB、 R3が PNZである化合物（V)は、好ましくは 2メタノール和物 結晶として単離され得る。また R2が水素、 R1がァリル、 R3力 lloc (：— COOCH CH=C Compound (V) produced by the above method may be isolated from the reaction system as a solvate or a crystal thereof. Preferably, the solvate is exemplified by the alcohol solvate. For example, the compound (V) in which R 2 is hydrogen, R 1 is PNB, and R 3 is PNZ is preferably a 2-methanol solvate It can be isolated as crystals. R 2 is hydrogen, R 1 is allyl, R 3 force lloc (: —COOCH CH = C
2 2
H )である化合物 (V)は、好ましくはべンジルアルコール和物結晶として単離され得るCompound (V) which is H) can preferably be isolated as benzyl alcohol solvate crystals
2 2
。アルコール和物結晶を単離するには、第 3工程終了後、反応液に該アルコール、 および所望によりその他の有機溶媒および Zまたは種晶を添加した後、所望により 10°C〜室温で数時間〜数日、攪拌および Zまたは静置させ、常法により濾取、洗 浄、乾燥すること〖こより得られる。種晶としては、例えば、特開 2003— 26680の方法 に従って単離される TCEの 2メタノール和物結晶が使用される。またべンジルアルコ 一ル和物結晶の種晶も使用可能である。  . To isolate the alcohol solvate crystals, after the third step, add the alcohol, and optionally other organic solvents and Z or seed crystals to the reaction solution, and optionally at 10 ° C to room temperature for several hours. It can be obtained by stirring and washing for several days, standing or standing, and filtering, washing, and drying by ordinary methods. As the seed crystal, for example, a 2-methanol solvate crystal of TCE isolated according to the method of JP-A-2003-26680 is used. A seed crystal of benzyl alcohol monohydrate can also be used.
本反応により、化合物（I)力 連続 3工程の反応および所望の結晶化反応を含むヮ ンポットィ匕反応によって、化合物 (V)、その溶媒和物またはその結晶を得ることができ る。ワンポットィ匕反応は、反応途中での中間体の抽出、濃縮、乾燥等の操作が不要 な連続反応であり、工業的製法として非常に有用である。  By this reaction, compound (V), a solvate thereof or a crystal thereof can be obtained by a one-pot reaction including a continuous three-step reaction of compound (I) and a desired crystallization reaction. The one-pot reaction is a continuous reaction that does not require operations such as extraction, concentration, and drying of intermediates during the reaction, and is very useful as an industrial production method.
上記製法により得られた化合物 (V)、その溶媒和物またはその結晶を、特開平 05 294970、特開 2003— 26680、 WO2004/72073等【こ記載の方法【こ準じて脱 保護することにより、抗菌剤として有用な化合物 (VI)、その製薬上許容される塩、ま たはそれらの溶媒和物が得られる。化合物 (VI)として好ましくは、水和物結晶（例： 1 水和物、 2水和物、 2. 5水和物）、特に 1水和物結晶である。  By deprotecting the compound (V) obtained by the above production method, its solvate or its crystal, according to the method described in JP-A-05-294970, JP-A-2003-26680, WO2004 / 72073, etc. A compound (VI) useful as an antibacterial agent, a pharmaceutically acceptable salt thereof, or a solvate thereof is obtained. Compound (VI) is preferably a hydrate crystal (eg, monohydrate, dihydrate, 2.5 hydrate), particularly a monohydrate crystal.
脱保護反応は、ニッケル触媒、コバルト触媒、鉄触媒、銅触媒、白金触媒およびパ ラジウム触媒等の貴金属系触媒等が用いられる。好ましくは、パラジウム触媒および ニッケル触媒等が用いられ、より好ましくは、パラジウムカーボン、テトラキス（トリフエ -ルホスフィン)パラジウム、酢酸（トリフエ-ルホスフィン)パラジウムおよび酢酸（トリ ェチルホスファイト)パラジウム等である。ノ《ラジウムをカロえた混合溶液に添加物 (好ま しくはトリフエ-ルホスフィン等）を加えても良 、。またパラジウム触媒に保護基を還元 除去する還元剤や求核試薬 (ァリル基のトラップ剤）を併用してもよい。還元剤として 、水素、金属水素化物等であり、好ましくは水素化トリー n プチルスズ等である。求 核試薬として、カルボキシレート (例えば、ナトリウム 2—ェチルへキサノエート等）、 1, 3—ジカルボ二ルイ匕合物（例えば、メルドラム酸、ジメドンおよびマロン酸エステル等） 、 2級ァミン (例えば、ジェチルァミン等）、および芳香族ァミン (ァ-リン、 N—メチルァ 二リン、 N ェチルァニリン、 Ν,Ν ジメチルァニリン、 0—、 m—または ρ トルイジン 、 0—、 m—または p ァ-シジン）が例示される。 For the deprotection reaction, a noble metal catalyst such as a nickel catalyst, a cobalt catalyst, an iron catalyst, a copper catalyst, a platinum catalyst and a palladium catalyst is used. Palladium catalyst and nickel catalyst are preferably used, and palladium carbon, tetrakis (triphenylphosphine) palladium, acetic acid (triphenylphosphine) palladium and acetic acid (triethylphosphite) palladium are preferable. . It is also possible to add an additive (preferably triphenylphosphine, etc.) to the mixed solution containing radium. Further, a reducing agent for reducing and removing the protective group or a nucleophilic reagent (aryl group trapping agent) may be used in combination with the palladium catalyst. Examples of the reducing agent include hydrogen, metal hydride, and the like, preferably hydrogenated tributyl tin. As nucleophiles, carboxylates (for example, sodium 2-ethylhexanoate), 1,3-dicarboxyl compounds (for example, Meldrum's acid, dimedone and malonic acid esters), secondary amines (for example, jetylamine) Etc.), and aromatic amines (Arin, N-methyla) Diphosphorus, Nethylaniline, Ν, Ν dimethylaniline, 0—, m— or ρ toluidine, 0—, m— or p-acidin).
脱保護反応に用いられる溶媒は、好ましくは、アセトン、ァセトニトリル、酢酸ェチル 、ジクロロメタン、テトラヒドロフラン、メタノール、エタノール及び水等である。これらの 溶媒は単独で使用しても、 2種以上を混合して使用してもよい。特に好ましくはテトラ ヒドロフランと水の組合せであり、好ましくはテトラヒドロフラン:水 = 1： 1〜10： 1の割 合で使用される。 反応温度は約 20〜50°Cである。反応時間は通常数分から数十 時間である。  The solvent used for the deprotection reaction is preferably acetone, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran, methanol, ethanol, water or the like. These solvents may be used alone or in combination of two or more. Particularly preferred is a combination of tetrahydrofuran and water, preferably tetrahydrofuran: water = 1: 1 to 10: 1. The reaction temperature is about 20-50 ° C. The reaction time is usually several minutes to several tens of hours.
以下に実施例を示す。  Examples are shown below.
(略号） (Abbreviation)
PNB = 4 -トロベンジル； PNZ =4-ニトロべンジルォキシカルボ-ル； Ph =フエ- ル； Allyl= CH CH=CH； Alloc= COOCH CH=CH  PNB = 4-trobenzyl; PNZ = 4-nitrobenzyloxycarbol; Ph = phenol; Allyl = CH CH = CH; Alloc = COOCH CH = CH
2 2 2 2  2 2 2 2
実施例 1 Example 1
4—-トロべンジル (4R, 5S, 6S)— 6— [(1R)— 1—ヒドロキシェチル] 4—メチル 3— [ [(3S, 5S)— 1— (4— -トロべンジルォキシカルボ-ル)一 5 (スルファモイルアミノメチ ノレ)ピロリジン一 3—ィノレ]チォ]—7—ォキソ 1—ァザビシクロ [3. 2. 0]ヘプト一 2 ェ ンー2—カルボキシレート（チォピロリジン力ルバぺネムエステル、 TCE)の合成  4-—Trobendyl (4R, 5S, 6S) — 6— [(1R) — 1-Hydroxyethyl] 4-methyl 3— [[(3S, 5S) — 1— (4-—Trobenziro Xycarbol) 1-5 (sulfamoylaminomethinole) pyrrolidine 1-3-ynole] thio] -7-oxo 1-azabicyclo [3.2.0] hept-2-en-2-carboxylate (thiopyrrolidine strength ruba) (Penem ester, TCE)
[化 6] [Chemical 6]
Figure imgf000015_0001
Figure imgf000015_0001
TCE  TCE
(注） （ ）内の中間体は非単離である。  (Note) Intermediates in parentheses are not isolated.
ジァゾ体（l.Og)にジクロロメタン (5.0ml)およびロジウム (II)アセテート（28mg)を加え -^Ο) ( ¾V- 3っ丄） 4—
Figure imgf000016_0001
Add dichloromethane (5.0 ml) and rhodium (II) acetate (28 mg) to diazo compound (l.Og) -^ Ο) (¾V-3) 4—
Figure imgf000016_0001
(S3 'SS)]j - S - - ^ - {Λ^^^ ^ - ΐ - (Η ΐ)] - 9 - (S9 'se ' ) / -f (S3 'SS)] j-S--^-{Λ ^^^ ^-ΐ-(Η ΐ)]-9-(S9' se ') / -f
CHORDS 'ZHS'S = f 'Ηΐ S6"S '(HO HD2 = f 'HS 'P) SV£ '
Figure imgf000016_0002
O -Z 'ZHS'8 = f Ήΐ 'Ρ) IZ'S ¾D OD-2 'ZHS'8 = f Ήΐ 'Ρ) ΐΖ"Ζ ^HD Oつ N— 'ε 'ΖΗ8〜 = f 'Ηΐ 'P ^q) 99· Z '
Figure imgf000016_0003
CHORDS 'ZHS'S = f' Ηΐ S6 "S '(HO HD2 = f' HS 'P) SV £'
Figure imgf000016_0002
O -Z ' Z HS'8 = f Ήΐ' Ρ) IZ'S ¾D OD-2 ' Z HS'8 = f Ήΐ' Ρ) ΐΖ "Ζ ^ HD O N— 'ε' ΖΗ8〜 = f 'Ηΐ' P ^ q) 99Z '
Figure imgf000016_0003
D-Z 'ζΗ6·εΐ = f Ήΐ 'Ρ) V
Figure imgf000016_0004
DZ 'ζΗ6 · εΐ = f Ήΐ' Ρ) V
Figure imgf000016_0004
Ν-,ε 'ΖΗ6·εΐ = f 'Ηΐ 'Ρ) fZ' '(^HDOD- 'ZH6"ST = f 'Ηΐ 'Ρ) S '(H- 'S '^ΗΘ •Z 'Ζ'β = f 'Ηΐ 'PP)W '(H— 'ΖΗ0" '6 ΐ = f 'ΡΡ) Ο^ '(Η―' 'Ηΐ 'ω) ΐ0· '((Η〇 Ν-, ε 'ΖΗ6 · εΐ = f' Ηΐ 'Ρ) fZ' '(^ HDOD-' ZH6 "ST = f 'Ηΐ' Ρ) S '(H-' S '^ ΗΘ • Z' Ζ'β = f 'Ηΐ' PP) W '(H—' ΖΗ0 "'6 ΐ = f' ΡΡ) Ο ^ '(Η―' 'Ηΐ' ω) ΐ0 · '((Η〇
)HD HD-9 'Ηΐ 'ω) 66·ε '(Η- 'ΐ 'Ηΐ 'ω) '(Η― 'ΖΗ9 'Ζ'β = f '¾Ρ) SSTヾ ΗΝ ^OSHN Ηつ—'， 'Ηΐ 'ω) Ζ£'£ '(Η— 9 'ΖΗ9 'ε·9 =Γ 'Ηΐ 'ΡΡ) SZ'£ '(Η— 'Ηΐ 'ω) FS) HD HD-9 'Ηΐ' ω) 66 · ε '(Η-' ΐ 'Ηΐ' ω) '(Η―' ΖΗ9 'Ζ'β = f' ¾Ρ) SST ヾ ΗΝ ^ OSHN Η つ — ',' Ηΐ 'ω) Ζ £' £ '(Η— 9' Ζ Η9 'ε · 9 = Γ' Ηΐ 'ΡΡ) SZ' £ '(Η—' Ηΐ 'ω) FS
' HN。SHN つ-' 'ΖΗ6·9 '6 ΐ = f 'Ηΐ '^Ρ) ΖΟΤ '(Η- 'S 'Ηΐ 'ω) OS '(Η- 'S 'HI 'ω) ΐ6·ΐ '(SHつ— = f Ήε 'Ρ)8ΐ·ΐ '((ΗΟ)Ηつ SHつ— 9 'ZHS'9 = f Ήε 'Ρ)9ΐ·ΐ 9 'HN. SHN Tsu- '' ΖΗ6 · 9 '6 ΐ = f' Ηΐ '^ Ρ) ΖΟΤ' (Η- 'S' Ηΐ 'ω) OS' (Η- 'S' HI 'ω) ΐ6 · ΐ' ( S H -= F Ήε 'Ρ) 8ΐ · ΐ' ((ΗΟ) Η S H-- 9 ' Z HS'9 = f Ήε' Ρ) 9ΐ · ΐ 9
Η顺- Ητ Η 顺-Η τ
°(%ζ·° (% ζ
S9 ¾ί翥講 3っ丄） 呦 Π /—,^^ ·3っ丄ェっ粼¾ （Ρ¾·9) /—, S9 ¾ί 翥 Lecture 3) 呦 Π / —, ^^ · 3 っ 丄 粼 ¾ (Ρ¾ · 9) / —,
機
Figure imgf000016_0005
Machine
Figure imgf000016_0005
— っ丄 / エマ ベ；^ fi ^^^ ェ (V) Q)  — っ 丄 / Emmabe; ^ fi ^^^ (V) Q)
«0oe-¾WH
Figure imgf000016_0006
-、ェ" ¥Hf ( ' Cws)ベ ίίΰ。;Μ/—
Figure imgf000016_0007
、エ^ «0 o e-¾WH
Figure imgf000016_0006
-、 E "\ Hf ('Cws) Be ίίΰ.; Μ / —
Figure imgf000016_0007
, D ^
QC^ (Su¾8S)ベ ^ ^エ / ci l ;^ ?ί (SuiZeZ) 4— ^fici^ / -ェ
Figure imgf000016_0008
QC ^ ( Su ¾8S) Be ^^ E / ci l; ^? Ί ( Sui ZeZ) 4— ^ fici ^ /-
Figure imgf000016_0008
0M9TC/900Zdf/X3d 0960Z0/.00Z OAV 0M9TC / 900Zdf / X3d 0960Z0 / .00Z OAV
Figure imgf000017_0001
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0002
TCE Allyl ジァゾ体（lO.Og)にジクロロメタン (20ml)およびロジウム (II)アセテート（360mg)をカロ えて 40°Cに加熱し、還流条件下 1時間攪拌する。反応液を 20°Cに冷却した後に、 ジフエ-ルホスホクロリデート（9.5g)およびジイソプロピルェチルァミン（3.6g)をカロえ て、—20°Cで 2時間攪拌する。同温度で N, N-ジメチルァセトアミド（50ml)およびチォ ールピロリジン (SPL-AlloC)(11.7g)を加えて、 20°Cで 2時間攪拌する。反応液を濃縮 した後に、酢酸ェチル (150ml)を加え、水洗 (X 4)する。有機層を脱水濃縮後、ベンジ ルアルコール（12.9g)、チォピロリジン力ルバぺネムエステル (TCE-Allyl)の種晶およ びトルエン (85g)を加えて、氷冷下で 2時間攪拌する。得られたスラリーをろ過、洗浄（ トルエン（15ml) )、乾燥して TCE-Allylのべンジルアルコール和物結晶を得る。 TCE Allyl Diazo compound (lO.Og) is charged with dichloromethane (20 ml) and rhodium (II) acetate (360 mg) and heated to 40 ° C and stirred for 1 hour under reflux conditions. After cooling the reaction solution to 20 ° C, add diphenylphosphochloridate (9.5 g) and diisopropylethylamine (3.6 g) and stir at -20 ° C for 2 hours. Add N, N-dimethylacetamide (50 ml) and thiolpyrrolidine (SPL-Allo C ) (11.7 g) at the same temperature, and stir at 20 ° C for 2 hours. Concentrate the reaction mixture, add ethyl acetate (150 ml), and wash with water (X 4). After dehydrating and concentrating the organic layer, add benzyl alcohol (12.9 g), thiopyrrolidine strength rubapenem ester (TCE-Allyl) seed crystals and toluene (85 g), and stir for 2 hours under ice cooling. The obtained slurry is filtered, washed (toluene (15 ml)) and dried to obtain TCE-Allyl benzyl alcohol solvate crystals.
(TCE-Allylの種晶の調製法） (Preparation method of TCE-Allyl seed crystal)
非晶質で粉末状の TCE-Allyl (100 mg)を酢酸ェチル (0.1 ml)に溶解さし、ベンジ ルアルコール（0.3 ml)をカ卩え、室温にて 1時間攪拌後、 5°Cで 2日間放置した。析出し た結晶を濾別し、風乾して、 TCE-Allylのべンジルアルコール和物結晶（79mg)を得 た。  Amorphous and powdered TCE-Allyl (100 mg) is dissolved in ethyl acetate (0.1 ml), benzyl alcohol (0.3 ml) is added, stirred at room temperature for 1 hour, then at 5 ° C. Left for 2 days. The precipitated crystals were separated by filtration and air-dried to obtain benzyl alcohol solvate crystals (79 mg) of TCE-Allyl.
実施例 3 (脱保護工程） Example 3 (Deprotection process)
実施例 1で得られた TCE' 2メタノール和物結晶（20.0 g)にテトラヒドロフラン (120 ml) 、水（80 ml)、 10%パラジウム炭素（ドライベースとして 10 g)、及び塩化マグネシウム六 水和物（3.4 g)を加えた。水素雰囲気下（約 0.5 MPa) 17〜33°Cで 3時間攪拌した。 パラジウム炭素をろ過し、 60 vol%テトラヒドロフラン（60 ml)で洗浄した。ろ液に塩ィ匕 マグネシウム六水和物（0.8 g)及びテトラヒドロフラン（600 mL)を加え、水層を分取し て 5°Cに冷却した。メタノール (30 ml)及び W095Z29913号に記載の化合物 (VI) の結晶（20 mg)をカ卩えて 5分間晶析し、さらにメタノール (50 ml)を加え、 0°Cで晶析し た。有機層に塩ィ匕マグネシウム六水和物（1.4 g)を加えて水層を分取し、先の晶析ス ラリーに加えた。この操作を再度繰り返した後、晶析スラリーにメタノール（150 ml)を 加え、— 10°Cに冷却して 62分攪拌し、晶析した。得られた結晶をろ過し、メタノール ( 20 ml)および 2-プロパノール（40 ml)で順次洗浄した。結晶に 30 vol% 2-プロパノー ル（60 ml)を加え、 18°Cで 30分間撹拌した。 5°Cまで冷却後、 2-プロパノール（24 ml) を 30分かけて加え、 5°Cで 25分間撹拌した。更に 2-プロパノール（56 ml)を 63分かけ て加え、 0°Cで 65分撹拌し、晶析した。得られた結晶をろ過し、 80 vol% 2-プロパノー ル（48 ml)で洗浄後、乾燥して化合物 (VI)の 1水和物結晶（7.4g)を得た。 TCE '2 methanol solvate crystal (20.0 g) obtained in Example 1 was added to tetrahydrofuran (120 ml), water (80 ml), 10% palladium carbon (10 g as a dry base), and magnesium chloride hexahydrate. (3.4 g) was added. The mixture was stirred for 3 hours at 17 to 33 ° C in a hydrogen atmosphere (about 0.5 MPa). Palladium on carbon was filtered and washed with 60 vol% tetrahydrofuran (60 ml). Salt 塩 in the filtrate Magnesium hexahydrate (0.8 g) and tetrahydrofuran (600 mL) were added, and the aqueous layer was separated and cooled to 5 ° C. Methanol (30 ml) and crystals of compound (VI) described in W095Z29913 (20 mg) were collected and crystallized for 5 minutes. Methanol (50 ml) was further added and crystallized at 0 ° C. To the organic layer, magnesium chloride hexahydrate (1.4 g) was added, and the aqueous layer was separated and added to the crystallization slurry. After repeating this operation again, methanol (150 ml) was added to the crystallization slurry, cooled to −10 ° C., stirred for 62 minutes, and crystallized. The obtained crystals were filtered and washed successively with methanol (20 ml) and 2-propanol (40 ml). 30 vol% 2-propanol (60 ml) was added to the crystals and stirred at 18 ° C for 30 minutes. After cooling to 5 ° C, 2-propanol (24 ml) was added over 30 minutes, and the mixture was stirred at 5 ° C for 25 minutes. Further, 2-propanol (56 ml) was added over 63 minutes, and the mixture was stirred at 0 ° C for 65 minutes for crystallization. The obtained crystals were filtered, washed with 80 vol% 2-propanol (48 ml), and dried to obtain monohydrate crystals (7.4 g) of compound (VI).

Claims

請求の範囲 以下の工程： (第 1工程)化合物 (I)と金属触媒を溶媒中で反応させる工程； (第 2工程)第 1工程で得られた反応液、ジフエ-ルホスホクロリデート、および塩基を 混合する工程;および (第 3工程)第 2工程で得られた反応液と化合物 (IV)またはその塩を混合して化合物 (V)を合成する工程； を包含することを特徴とする、化合物 (V)、その溶媒和物または溶媒和物結晶の製 造方法。 The following steps: (First step) A step of reacting compound (I) with a metal catalyst in a solvent; (Second step) The reaction solution obtained in the first step, diphenylphosphochloridate, and Mixing the base; and (third step) synthesizing compound (V) by mixing the reaction solution obtained in the second step with compound (IV) or a salt thereof. , Compound (V), a solvate thereof, or a method for producing a solvate crystal thereof.
[化 1] [Chemical 1]
Figure imgf000019_0001
Figure imgf000019_0001
(式中、 R1はカルボキシ保護基; R2は水素またはヒドロキシ保護基; R3は水素または ァミノ保護基を示す。 ) (Wherein R 1 represents a carboxy protecting group; R 2 represents hydrogen or a hydroxy protecting group; R 3 represents hydrogen or an amino protecting group.)
以下の工程： The following steps:
(第 1工程)化合物 (I)と金属触媒を溶媒中で反応させて化合物 (Π)を生成させるェ 程；  (Step 1) Process of reacting Compound (I) with a metal catalyst in a solvent to form Compound (I);
(第 2工程)ィ匕合物 (Π)を含む第 1工程で得られた反応液、ジフヱニルホスホクロリデ ート、および塩基を混合して化合物（III)を生成させる工程;および  (Second Step) Step of mixing compound (III) with the reaction solution obtained in the first step including compound (ii), diphenylphosphochloride, and base; and
(第 3工程)化合物 (III)を含む第 2工程で得られた反応液と化合物 (IV)またはその塩 を混合して化合物 (V)を合成する工程； (Step 3) Step of synthesizing Compound (V) by mixing the reaction solution obtained in Step 2 containing Compound (III) and Compound (IV) or a salt thereof;
を包含することを特徴とする、請求項 1記載の化合物 (V)、その溶媒和物または溶媒 和物結晶の製造方法。 The method for producing a compound (V), a solvate thereof, or a solvate crystal thereof according to claim 1, wherein
[化 2] [Chemical 2]
Figure imgf000020_0001
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0002
(式中、 R1はカルボキシ保護基; R2は水素またはヒドロキシ保護基; R3は水素または ァミノ保護基を示し、化合物 (Π)および化合物 (III)は単離されな!/ヽ。 ) (Wherein R 1 represents a carboxy protecting group; R 2 represents a hydrogen or hydroxy protecting group; R 3 represents a hydrogen or amino protecting group, and compound (化合物) and compound (III) are not isolated! / ヽ).)
[3] R1は 4— -トロべンジルまたは— CH CH=CHである、請求項 1または 2に記載の製造 [3] The production according to claim 1 or 2, wherein R 1 is 4--trobenzyl or —CH 2 CH═CH.
2 2  twenty two
方法。  Method.
[4] R2は水素である、請求項 1または 2に記載の製造方法。 [4] The production method according to claim 1 or 2, wherein R 2 is hydrogen.
[5] R3はァミノ保護基である、請求項 1または 2に記載の製造方法。 [5] The production method according to claim 1 or 2, wherein R 3 is an amino protecting group.
[6] R3は 4— -トロべンジルォキシカルボ-ルまたは一 COOCH CH=CHである、請求項 [6] R 3 is 4--trobenzoxycarbol or one COOCH CH = CH
2 2  twenty two
1または 2に記載の製造方法。  The production method according to 1 or 2.
[7] R1は 4— -トロべンジルまたは一 CH CH=CH、 R2は水素、 R3は 4— -トロベンジルォ [7] R 1 is 4—trobenzyl or one CH CH═CH, R 2 is hydrogen, R 3 is 4—-trobenzylo
2 2  twenty two
キシカルボ-ルまたは— COOCH CH=CHである、請求項 1または 2に記載の製造方  The production method according to claim 1 or 2, wherein xycarbol or —COOCH CH═CH.
2 2  twenty two
法。  Law.
[8] 第 1工程および第 2工程の反応溶媒がジクロロメタンであり、かつ第 3工程の反応溶 媒がジクロロメタンおよび N, N—ジメチルァセトアミドである、請求項 1〜7のいずれ かに記載の製造方法。  [8] The reaction solvent according to any one of claims 1 to 7, wherein the reaction solvent in the first step and the second step is dichloromethane, and the reaction solvent in the third step is dichloromethane and N, N-dimethylacetamide. Manufacturing method.
[9] 第 1工程を 20〜60°C、第 2工程を—30〜0°C、第 3工程を—30〜0°Cで行う、請求項 1 [9] The first step is performed at 20 to 60 ° C, the second step is performed at -30 to 0 ° C, and the third step is performed at -30 to 0 ° C.
〜8の 、ずれかに記載の製造方法。 The manufacturing method according to any one of 8 to 8.
[10] 請求項 1〜9のいずれかに記載の製造方法により化合物 (V)得た後、アルコール含 有溶媒中から結晶化することを特徴とする、化合物 (V)のアルコール和物結晶の製 造方法。 [10] After the compound (V) is obtained by the production method according to any one of claims 1 to 9, crystallization from an alcohol-containing solvent of the compound (V) is performed. Made Manufacturing method.
[11] アルコール力メタノールであり、アルコール和物結晶が 2メタノール和物結晶である、 請求項 10記載の製造方法。  11. The production method according to claim 10, wherein the alcohol power methanol is used, and the alcohol solvate crystal is a dimethanol solvate crystal.
[12] 請求項 2記載の化合物（III)と化合物（IV)またはその塩を、 N, N—ジメチルァセトアミ ドを含有する溶媒中で反応させることを特徴とする、化合物 (V)、その溶媒和物また は溶媒和物結晶の製造方法。 [12] Compound (V), wherein compound (III) according to claim 2 is reacted with compound (IV) or a salt thereof in a solvent containing N, N-dimethylacetamide, A process for producing the solvate or solvate crystal.
[13] 請求項 1〜12のいずれかに記載の製造方法により、化合物 (V)、その溶媒和物また は溶媒和物結晶を得た後、これを脱保護することを特徴とする、式： [13] The compound according to any one of claims 1 to 12, wherein the compound (V), a solvate or a solvate crystal thereof is obtained and then deprotected. :
[化 3]
Figure imgf000021_0001
[Chemical 3]
Figure imgf000021_0001
で示される化合物 (VI)、その製薬上許容される塩、またはそれらの溶媒和物の製造 方法。  Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
PCT/JP2006/316140 2005-08-19 2006-08-17 Process for producing carbapenem derivatives through reactions without isolating intermediates WO2007020960A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005238243A JP2008303143A (en) 2005-08-19 2005-08-19 Method for producing carbapenem derivative by continuous reaction
JP2005-238243 2005-08-19

Publications (1)

Publication Number Publication Date
WO2007020960A1 true WO2007020960A1 (en) 2007-02-22

Family

ID=37757617

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2006/316140 WO2007020960A1 (en) 2005-08-19 2006-08-17 Process for producing carbapenem derivatives through reactions without isolating intermediates

Country Status (3)

Country Link
JP (1) JP2008303143A (en)
TW (1) TW200738717A (en)
WO (1) WO2007020960A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101613351B (en) * 2008-06-24 2011-10-19 上海医药工业研究院 Methanol solvate of doripenem intermediate and preparation method thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7932381B2 (en) * 2005-02-15 2011-04-26 Shionogi & Co., Ltd. Process for producing carbapenem derivative and intermediate crystal therefor

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57123182A (en) * 1980-12-18 1982-07-31 Merck & Co Inc 6- and 4-substituted-1-azabicyclo(3,1,2,0)heptane- 3,7-dione-2-carboxylate
JPS6425779A (en) * 1987-04-11 1989-01-27 Lederle Japan Ltd (1r,5s,6s)-2-substituted-thio-6-((r)-1-hydroxyethyl)-1-methyl -carbapenem-3-carboxylic acid derivative
JPH05294970A (en) * 1991-08-20 1993-11-09 Shionogi & Co Ltd Pyrrolidylthiocarbapenem derivative
JPH06211858A (en) * 1980-05-01 1994-08-02 Merck & Co Inc Production of intemediate of 1-carbapenem through 4-allylazetidinone
JPH06321946A (en) * 1992-07-08 1994-11-22 Takeda Chem Ind Ltd Production of carbapenems
JPH07196662A (en) * 1993-12-02 1995-08-01 Fujisawa Pharmaceut Co Ltd Bicyclic compound and its production
JP2003026680A (en) * 2001-05-10 2003-01-29 Shionogi & Co Ltd Method for producing acetylthiopyrrolidine derivative

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06211858A (en) * 1980-05-01 1994-08-02 Merck & Co Inc Production of intemediate of 1-carbapenem through 4-allylazetidinone
JPS57123182A (en) * 1980-12-18 1982-07-31 Merck & Co Inc 6- and 4-substituted-1-azabicyclo(3,1,2,0)heptane- 3,7-dione-2-carboxylate
JPS6425779A (en) * 1987-04-11 1989-01-27 Lederle Japan Ltd (1r,5s,6s)-2-substituted-thio-6-((r)-1-hydroxyethyl)-1-methyl -carbapenem-3-carboxylic acid derivative
JPH05294970A (en) * 1991-08-20 1993-11-09 Shionogi & Co Ltd Pyrrolidylthiocarbapenem derivative
JPH06321946A (en) * 1992-07-08 1994-11-22 Takeda Chem Ind Ltd Production of carbapenems
JPH07196662A (en) * 1993-12-02 1995-08-01 Fujisawa Pharmaceut Co Ltd Bicyclic compound and its production
JP2003026680A (en) * 2001-05-10 2003-01-29 Shionogi & Co Ltd Method for producing acetylthiopyrrolidine derivative

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101613351B (en) * 2008-06-24 2011-10-19 上海医药工业研究院 Methanol solvate of doripenem intermediate and preparation method thereof

Also Published As

Publication number Publication date
JP2008303143A (en) 2008-12-18
TW200738717A (en) 2007-10-16

Similar Documents

Publication Publication Date Title
WO2005077916A1 (en) Salts of hmg-coa reductase inhibitors and use thereof
US9233963B2 (en) Method for preparing meropenem using zinc powder
JP7365349B2 (en) Method for producing prostaglandin analogs that donate nitric oxide
ITMI20102390A1 (en) PROCEDURE FOR THE PREPARATION OF LINAGLIPTIN
JP2005179336A (en) MANUFACTURING METHOD FOR 1-OXACEPHALOSPORIN-7alpha-METHOXY-3-CHLOROMETHYL DERIVATIVE
JP3479720B2 (en) Method for producing carbapenems
WO2007020960A1 (en) Process for producing carbapenem derivatives through reactions without isolating intermediates
KR20020068518A (en) Penicillin crystal and process for producing the same
JP2011057602A (en) Method for removing remaining palladium
JP5019389B2 (en) Preparation of carbapenem derivatives and their intermediate crystals
CH628900A5 (en) PROCESS FOR THE PREPARATION OF THIO-OXIMES DERIVED FROM CEPHALOSPORINS AND PENICILLINS.
WO2007116728A1 (en) Process for production of intermediate for meropenem
WO2010098332A1 (en) Method for producing polycyclic compound and intermediate for same
KR101299162B1 (en) Method for preparing intermediates of imipenem
JP4481829B2 (en) Novel synthetic intermediate of carbapenem compound for oral administration and process for producing the same
JPWO2004043961A1 (en) Method for producing carbapenem compounds for oral administration
EP2906561A1 (en) Preparation of ertapenem intermediates
US7157574B2 (en) Process for preparing crystalline 3-chloromethyl-3-cephem derivatives
JP3467265B2 (en) Crystals of azetidinone compounds
ES2283781T3 (en) PROCEDURE TO PRODUCE A COMPOSITE OF 1,2,3-TRIAZOL.
US7932381B2 (en) Process for producing carbapenem derivative and intermediate crystal therefor
JP2003128674A (en) NEW PRODUCTION METHOD OF CARBAPENEM ANTIBIOTIC BY OnePot REACTION AND RECRYSTALLIZATION
KR100848752B1 (en) Thienamycin solvate and its process
KR101028689B1 (en) Process for production of 3-mercapto-1-acetimidoylpyrrolidine derivative and crystalline intermediate therefor
TW202311275A (en) Method for producing alkylsilyloxy substituted benzyl compound

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06796497

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP