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WO2007020960A1 - Procédé servant à produire des dérivés de carbapénème via des réactions sans isoler d'intermédiaires - Google Patents

Procédé servant à produire des dérivés de carbapénème via des réactions sans isoler d'intermédiaires Download PDF

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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
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Prior art keywords
compound
solvate
protecting group
reaction
solvent
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Japanese (ja)
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Kenji Kanamoto
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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    • 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.

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

Abstract

Procédé industriellement avantageux pour la production de dérivés de carbapénème, à savoir procédé pour la production de composés (V), de solvates de ceux-ci ou de cristaux des solvates, caractérisé en ce qu'il comprend la première étape consistant à faire réagir un composé (I) avec un catalyseur métallique dans un solvant pour former un composé (II), la deuxième étape consistant à mélanger le composé (II) ainsi que le fluide réactionnel obtenu dans la première étape avec du phosphorochloridate de diphényle et une base pour former un composé (III) et la troisième étape consistant à mélanger le composé (III) ainsi que le fluide réactionnel obtenu dans la deuxième étape avec un composé (IV) ou un sel de celui-ci pour former un composé (V) : (I) (II) (III) (IV) (V) où R1 est un groupe protecteur de carboxyle ; R2 est un hydrogène ou un groupe protecteur d'hydroxyle ; et R3 est un hydrogène ou un groupe protecteur d'amino, à condition de n'isoler ni le composé (II) ni le composé (III).
PCT/JP2006/316140 2005-08-19 2006-08-17 Procédé servant à produire des dérivés de carbapénème via des réactions sans isoler d'intermédiaires Ceased WO2007020960A1 (fr)

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CN101613351B (zh) * 2008-06-24 2011-10-19 上海医药工业研究院 多尼培南中间体的甲醇溶剂合物及其制备方法

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US7932381B2 (en) * 2005-02-15 2011-04-26 Shionogi & Co., Ltd. Process for producing carbapenem derivative and intermediate crystal therefor

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