WO2006049113A1 - Intermédiaire de synthèse d’un carbapénème et méthode de synthèse dudit intermédiaire - Google Patents

Intermédiaire de synthèse d’un carbapénème et méthode de synthèse dudit intermédiaire Download PDF

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WO2006049113A1
WO2006049113A1 PCT/JP2005/019970 JP2005019970W WO2006049113A1 WO 2006049113 A1 WO2006049113 A1 WO 2006049113A1 JP 2005019970 W JP2005019970 W JP 2005019970W WO 2006049113 A1 WO2006049113 A1 WO 2006049113A1
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compound
group
salt
amine
amine salt
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Japanese (ja)
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Masaaki Uenaka
Yutaka Ide
Masahiko Nagai
Hiromi Yabunaka
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Shionogi & 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
    • C07D477/10—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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D477/02—Preparation
    • C07D477/04—Preparation by forming the ring or condensed ring 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 synthetic intermediate of rubapenem having antibacterial activity and a method for producing the same. Specifically, the present invention relates to the intermediate, its amine salt, its crystal, and a process for producing strong rubapenem using them. Background art
  • Patent Document 1 As a method for producing a synthetic intermediate of 1 alkyl strength rubapenem, Patent Document 1 (Reference Example 1 2) includes the following compound 5 6 as an intermediate for utilizing the Dieckmann condensation reaction. It is disclosed.
  • Patent Document 2 (Example 13) describes a method for producing doripenem from Compound 5 [Chemical Formula 2]
  • Non-Patent Document 1 describes the following reaction as a method for producing the hydroxy-protected form of Compound 5 described above.
  • Patent Document 1 JP-A-1 79180
  • Patent Document 2 JP-A-5-294970
  • Non-patent literature l Synlett, 315-316, 1995
  • Step 1 A step of producing compound (III) by protecting carboxy of compound ( ⁇ ),
  • Step 2 A step of producing Compound (V) by reacting Compound (III) with Compound (IV), and
  • Step 3 The compound (I) or the amine salt thereof according to (1) above, which comprises a step of subjecting the compound (V) to a deprotection reaction and optionally reacting with an amine.
  • COZ represents an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected by a protective group, a substituted aryloxy group, or a heteroaryl carbon group.
  • COZ is an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group for a thiol force propyloxyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group;
  • R 3 comprises preparing a compound (VII) represented by hydroxy protecting group), then treating it with a base, and further treating with a hydroxyl active esterifying agent.
  • (14) is alkylsilyl, 2 is -3 to 11, and Z or L is OP (OXOPh) (Ph
  • the present invention provides a novel synthetic intermediate of force rubapenem derivative, a method for producing the same, and a method for producing force rubapenem derivative using the same.
  • the target strength rubapenem derivative can be synthesized in high yield with high efficiency.
  • Examples of the protecting group for hydroxy include trialkylsilyl (eg, trimethylsilyl, t-butyldimethylsilyl), acyl (eg, acetyl, bivaloyl), lower alkyl (eg, methyl, ethyl), lower alkoxy lower alkyl (eg, methoxymethyl, Methoxyethyl), lower alkyl sulfo (eg methanesulfol), lower alkoxy carbo (eg methoxy carboyl, t-butyloxy carbo), aralkyloxy carbo yl (eg benzyloxy) Noreboninole, o Nitrobenzinore, Xicanoreboninole, p Nitrobenzinore, Xicanorebonyl, p-methoxybenzyloxycarbonyl), substituted methyl (eg, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl) ),
  • Carboxy protecting groups include lower alkyl (eg, methyl, ethyl, n-propoxy, isopropyl, t-butyl), substituted lower alkyl (example of substituent: lower alkoxy (eg, methoxy, ethoxy, n propoxy, Isopropoxy, n-butoxy, isobutoxy, t-butoxy)), substituted or unsubstituted aralkyl (eg benzyl, phenethyl, p-methoxybenzyl, 2, 4 dimethoxybenzyl, o nitrobenzyl, p nitrobenzyl, p— Benzyl)), hetero atoms (eg, 0, S, N) optionally intervening C3-C8 cycloalkyl, alkylsilyl (eg, trimethylsilyl, t-butyldimethylsilyl), lower alkoxymethyl (eg, methoxy) Methyl, e
  • “Lower” preferably means C1-C6, more preferably C1-C4.
  • Halogen represents F, Cl, Br, or I.
  • Amine salt amines of compound (I) include primary, secondary, and tertiary amines
  • Primary amines include methylamine, ethylamine, isopropylamine, sec-butylamine, tert-butylamine, isoamylamine, n-decylamine, 3-methoxypropylamine, benzylamine, phenethylamine, 4-methoxyphenethylamine, 2,2-dimethoxyethylamine, 3,3-dimethoxypropylamine, p-chloroarine, 2- (p-chlorophenol) ethylamine, (-)- ⁇ -methylbenzylamine, 3 , 4-Dimethoxyphenethylamine, Benzhydrylamine, 2- (4-aminophenol) ethylamine, 2-aminobenzylamine, (+)-dihydroabietylamine, 4-methoxybenzylamine, 3-methoxy Phenethylamine, 4-tert-butylbenzilamine, aniline, 4-bromo-2-fluoroani
  • Secondary amines include dimethylamine, jetylamine, diisopropylamine, dicyclohexylamine, 3,5-dichloro-4,4, -dihydroxydiphenylamine, benzyl-N-methyl. Ethanolamine is exemplified, and diisopropylamine and dicyclohexylamine are preferable.
  • tertiary amines examples include N-methylmorpholine, triethylamine, tributylamine, triarylamine, N-ethyldiisopropylamine, and ⁇ , ⁇ -dimethylbutylamine.
  • the amine salt of compound (I) is preferably a crystal.
  • those having good crystallinity with respect to compound (I) are primary or secondary amines, preferably methylamine, ethylamine, isopropylamine, tert-butylamine, (-)- ⁇ -methylbenzylamine, Diisopropylamine and dicyclohexylamine are preferable, and methylamine and diisopropylamine are more preferable.
  • diisopropylamine is particularly preferred because it has advantages such as low crystallinity, low toxicity, and low reactivity to the ⁇ -ratata ring. It can also be used as a base (acid trapping agent) in the next step condensation.
  • the amine salt or the crystal thereof may be a solvate.
  • the solvent include water and alcohol.
  • R 1 is a hydroxy protecting group
  • R 2 is a carboxy protecting group
  • X is a halogen
  • Compound (III) is obtained by protecting carboxy of compound (II).
  • the reaction may be carried out according to the usual carboxy protection reaction.
  • R 1 is a force exemplified by the above hydroxy protecting group, preferably trialkylsilyl, particularly t-butyldimethylsilyl (TBS).
  • TBS t-butyldimethylsilyl
  • R 2 is a force exemplified by the above-mentioned carboxy protecting group, preferably lower alkyl substituted with lower alkoxy, such as 1-methoxyethyl, 1-ethoxyethyl, 1 isopropoxycetyl, 1 n propoxychetil 1 n-butoxystil, 1-sobutoxyl, 1 t-butoxystil, particularly preferably 1-isobutoxyl.
  • carboxy protecting group preferably lower alkyl substituted with lower alkoxy, such as 1-methoxyethyl, 1-ethoxyethyl, 1 isopropoxycetyl, 1 n propoxychetil 1 n-butoxystil, 1-sobutoxyl, 1 t-butoxystil, particularly preferably 1-isobutoxyl.
  • These protecting groups are less susceptible to side reactions such as rearrangement to the 1-position N atom during the reaction.
  • reaction accelerator such as an acid
  • the acid include methanesulfonic acid, P-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like.
  • Reaction solvents include hydrocarbons (eg, pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), alcohols (eg, : Methanol, ethanol), formic acid, acetic acid, propionic acid, ethyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (eg, tetrahydrofuran, jetyl ether), water and mixed solvents thereof are exemplified. Preferably, it is toluene, acetonitrile, or a mixed solvent thereof.
  • hydrocarbons eg, pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, xylene
  • the reaction temperature is generally 0-100 ° C, preferably 0-50 ° C, more preferably 10-30 ° C.
  • the reaction time is several hours to several tens of hours.
  • the resulting compound (III) may be subjected to the next step without isolation.
  • Compound (V) is produced by reacting compound (III) with compound (IV).
  • the halogen represented by X is preferably C or Br.
  • a reaction accelerator such as a base
  • bases include NaH, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, and sodium bis (trimethylsilyl) amide.
  • an interlayer transfer catalyst may be used in combination.
  • quaternary ammonium salt eg, tetra n-butyl ammonium chloride, tetra n-butyl ammonium chloride
  • Reaction solvents include hydrocarbons (eg, pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), alcohols (eg, : Methanol, ethanol), formic acid, acetic acid, propionic acid, ethyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (eg, tetrahydrofuran, jetyl ether), water and mixed solvents thereof are preferable, , Toluene, acetonitrile, tetrahydrofuran or a mixed solvent thereof.
  • the reaction temperature is usually 70 to 0 ° C, preferably 50 to 30 ° C.
  • the reaction time is several hours to several tens of hours.
  • the resulting compound (V) may be subjected to the next step without isolation.
  • Compound (V) is subjected to a deprotection reaction and then optionally reacted with amine to give compound (I) or an amine salt thereof.
  • the deprotection reaction may be carried out in accordance with the conditions for a normal carboxy deprotection reaction.
  • compound (V) may be treated with an acid.
  • Acids include hydrochloric acid, sulfuric acid, potassium hydrogen sulfate Examples are sodium hydrogen sulfate, nitric acid, phosphoric acid, sodium dihydrogen phosphate, and potassium dihydrogen phosphate.
  • the reaction time is usually several minutes to several tens of hours.
  • the reaction with amine is usually carried out under ice cooling to room temperature.
  • a seed crystal may be added if desired.
  • Solvents used for crystallization include hydrocarbons (eg, pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride).
  • Alcohol eg methanol, ethanol
  • formic acid acetic acid, propionic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (eg tetrahydrofuran, jetyl ether), Examples thereof include water and mixed solvents thereof.
  • ether eg tetrahydrofuran, jetyl ether
  • examples thereof include water and mixed solvents thereof.
  • heat treatment, ultrasonic treatment, stirring, etc. may be performed.
  • compound (I) or an amine salt thereof is in the 4-position according to the method described in JP-A-6-316559.
  • COZ represents an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected by a protective group, a substituted aryloxy group, or a heteroaryl carbon group.
  • the Z group may be a halogen atom such as chlorine, bromine or iodine; for example, ethoxycarboxoxy, isopropyloxycarboxoxy, sec- Lower alkyloxycarboxoxy groups having 1 to 5 carbon atoms such as butyroxycarbonyloxy; A lower alkanesulfo-loxy group having 1 to 4 carbon atoms such as ruoxy; for example, an arylsulfo-loxy group such as p-toluenesulfo-loxy; for example, di (carbon number 1) such as dimethylphosphoryloxy and jetylphosphoryloxy -4 lower alkyl) phosphoryloxy groups; diarylphosphoryloxy groups such as di (phenol) phosphoryloxy; cyclic imidooxy groups such as N-succinimidoxy, N-phthalimidoxy Groups; heteroaryl groups such as imidazole and triazole;
  • a halogen atom such as chlorine, bromine or iodine
  • Suitable examples of the protective group for the carboxyl group and the protective group for the thiol carboxyl group used when COZ is a protected carboxyl group or a thiol carboxyl group are the same as those described above.
  • preferred examples of the substituted aryloxy group include P--trophenyloxy, o--trophenyloxy, 2,4,5-trichlorophenyloxy, etc.
  • the heteroaryloxy group includes o —Pyridyloxy, p-pyridyloxy and the like can be mentioned.
  • the conversion from the above compound (I) to (VI) is preferably carried out in the presence of a condensing agent. More preferably, compound (VI) in which COZ is COSPh (Ph is a phenol) can be produced by subjecting the carboxy moiety of compound (I) or its amine salt to a thioester in the presence of a condensing agent.
  • the above reaction is preferably performed in a high yield of 70% or more, more preferably 80% or more, and even more preferably 90% or more.
  • reaction may be used in combination with an acid scavenger if desired.
  • the above-mentioned amine can be used as the acid scavenger.
  • coz is an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group for a thiol force lpoxyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group; R (3 ) is a hydroxy protecting group), after the production of compound (VII), it is treated with a base according to the method described in JP-A-6-316559, and further treated with an active esterifying agent for a hydroxyl group.
  • R 3 is a force exemplified by the above hydroxy protecting group, preferably trialkylsilyl, especially trimethylsilyl (TMS).
  • TMS trimethylsilyl
  • TMS is preferably used in terms of deprotection.
  • the active ester of a hydroxyl group represented by L is, for example, a substituted or unsubstituted aryl sulfonic acid ester group (substituted or unsubstituted aryl sulfonic sulfo-oxy group), a lower alkane sulfonic acid ester group (lower alkane sulfo-oxy group), a halogeno lower alkanthol. It represents a phosphonic acid ester group (norogeno-lower alkanesulfo-oxyloxy group) or a dialyl phosphoric acid ester group (diarylphosphoryloxy group) or a halogenated metal atom that is an ester with a hydrogen halide.
  • the active esterifying agent for a hydroxyl group is a reagent that produces an active ester as described above.
  • the substituted or unsubstituted aryl sulfonic acid ester include benzene sulfonic acid ester, p toluene sulfonic acid ester, p-trobenzene sulfonic acid ester, and p bromobenzene sulfonic acid ester.
  • the acid ester include methanesulfonic acid ester and ethanesulfonic acid ester.
  • the halogeno lower alkanesulfonic acid ester include trifluoromethanesulfonic acid ester.
  • dialyl phosphoric acid ester examples include Examples of the diphenyl phosphoric acid ester and the halogenated compounds include chlorine, bromine, and iodide.
  • these active esters of alcohol p-toluenesulfonic acid ester, methanesulfonic acid ester and diphenylphosphoric acid ester can be mentioned, and diphenylphosphoric acid ester is preferable.
  • diphenyl phosphoric acid chloride eg, diphenyl phosphoric acid chloride
  • the active esterifying agent is preferable as the active esterifying agent.
  • Bases for treating compound (VII) in an inert solvent include metal salts of amines such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, and sodium amide, metal salts of alcohols such as potassium tert-butoxide, Examples thereof include alkali metal hydrides such as sodium hydride and lithium hydride, and sodium methylsulfinylmethide.
  • the amount of base used is usually 1.5 to 3 equivalents.
  • the preferred reaction temperature is -75 ° C to 50 ° C.
  • R 3 is alkylsilyl
  • Z is SPh
  • Z or L is OP (OXOPh) (Ph is full).
  • the compound (ring) has the formula: R 4 — SH (R 4 is the same as the method described in JP-A-1-79180, JP-A-6-316559, JP-A-5-294970, USP 5,317,016, etc.
  • Examples of pharmaceutically acceptable salts include basic salts such as alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; trimethylamine salts. , Triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, medalamine salt, diethanolamine salt or aliphatic amine amine salt such as ethylenediamine salt; ⁇ , ⁇ -dibenzyl ethylenediamine, Aralkylamine salts; Heterocyclic aromatic amine amines such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltrie Tiluamum salt, benzyltri Examples include quaternary ammonium salts
  • the acid salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate, and ascorbate; sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate, and ⁇ ⁇ ⁇ ⁇ -toluenesulfonate Salt: aspartate, glutamate And acidic amino acids such as Examples of solvates include hydrates and alcohol solvates.
  • Compound (X) includes: (1) cenamycin, (2) imipenem, (3) meropenem, (4) beer penem, (5) panipenem, (6) BQ-2727, (7 ) S-4661 (Doripenem) is an example (each “SR 4 " is shown below).
  • TBS t butyldimethylsilyl
  • TMS trimethylsilyl tBu: t butyl
  • the ethyl acetate layer was washed twice with 389 ml of water, the aqueous layer was extracted with 311 ml of ethyl acetate, the ethyl acetate layers were combined, concentrated under reduced pressure, 200 ml of toluene was added, and the solution was concentrated under reduced pressure to give a 6-like residue 108.16 g (quantitative value: 85.0 g, yield: 94%) was obtained.
  • the toluene layer was washed sequentially with 270 ml of water and 270 ml of saturated saline, the aqueous layer was extracted with 160 ml of toluene, the toluene layers were combined, concentrated under reduced pressure, and 92.70 g (quantitative value: 53.36 g, yield) of 7 Rate: 87%).
  • Example 13 of JP-A-5-294970 compound 7 obtained in Example 3 was subjected to a condensation reaction for forming a 2-position side chain to synthesize compound 8, and further deprotection By subjecting to reaction, compound 9 (doripenem) is obtained.
  • the corresponding amine salt was obtained by reacting the above-mentioned various amines other than diisopropylamine with the free form of Compound 4.
  • Dicyclohexylamine salt, methylamine salt, ethylamine salt, isopropylamine salt, t-butylamine salt, and (1) -a-methylbenzylamine salt were obtained as crystals.
  • dicyclohexylamine, methylamine, t-butylamine, and (1) a methylbenzylamine showed good crystallinity.
  • the powder X-ray diffraction patterns are shown in Figures 2 to 5, and the diffraction angles of the main peaks are shown below.
  • Example 9 Using the various amine salts obtained in Example 5 as raw materials, Compound 9 is obtained according to the methods of Examples 2-4.
  • the obtained SPL / methanol solution was cooled to 18 ° C., and 10% aqueous sodium hydroxide solution (130.5 g) was added to adjust the pH to 2.4.
  • ethyl acetate (357 ml) and brine (113 ml) were added, liquid separation was performed, and SPL was extracted into the organic layer.
  • the organic layer was washed successively with water (357 ml) and 2% brine (119 mix x 2).
  • the resulting four aqueous layers were back extracted with ethyl acetate (102 ml) to recover SPL lost to the aqueous layer.
  • FIG. 1 is a powder X-ray diffraction pattern and peak value of diisopropylamine salt crystals obtained in Example 1.
  • the vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2 ⁇ , unit: degree).
  • FIG. 2 is a powder X-ray diffraction pattern and peak value of dicyclohexylamine salt crystals obtained in Example 5.
  • FIG. 3 shows a powder X-ray diffraction pattern and peak value of methylamine salt crystals in Example 5.
  • FIG. 4 shows a powder X-ray diffraction pattern and peak value of t-ptylamine salt crystal in Example 5.
  • FIG. 5 shows the powder X-ray diffraction pattern and peak value of (1) -a-methylbenzylamine salt crystals in Example 5.
  • FIG. 6 is a powder X-ray diffraction pattern of SPL hemihydrate crystals obtained in Reference Example 1.
  • the vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2 ⁇ , unit: degree).
  • FIG. 7 is a powder X-ray diffraction pattern of anhydrous SPL crystals obtained in Reference Example 1.
  • the vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2 ⁇ , unit: degree).

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  • Health & Medical Sciences (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention a pour objet un composé (I) obtenu via le schéma réactionnel suivant (où R1 et R2 représentent respectivement un groupement protecteur de fonction hydroxy et un groupement protecteur de fonction carboxy, et X représente un atome d’halogène), ainsi qu’un sel d’ammonium dudit composé. La présente invention a également pour objet une méthode de synthèse d'un dérivé de carbapénème impliquant le composé (I) et un sel d'ammonium dudit composé.
PCT/JP2005/019970 2004-11-01 2005-10-31 Intermédiaire de synthèse d’un carbapénème et méthode de synthèse dudit intermédiaire WO2006049113A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2401278A1 (fr) * 2009-02-26 2012-01-04 Orchid Chemicals&Pharmaceuticals Limited Procédé amélioré pour la préparation d'antibiotique à base de carbapenème

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05294970A (ja) * 1991-08-20 1993-11-09 Shionogi & Co Ltd ピロリジルチオカルバペネム誘導体
JPH0656836A (ja) * 1992-08-06 1994-03-01 Tanabe Seiyaku Co Ltd カルバペネム誘導体の製法
WO2003089432A1 (fr) * 2002-04-22 2003-10-30 Sumitomo Pharmaceuticals Co., Ltd. Procede de production de derives de carbapenem

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05294970A (ja) * 1991-08-20 1993-11-09 Shionogi & Co Ltd ピロリジルチオカルバペネム誘導体
JPH0656836A (ja) * 1992-08-06 1994-03-01 Tanabe Seiyaku Co Ltd カルバペネム誘導体の製法
WO2003089432A1 (fr) * 2002-04-22 2003-10-30 Sumitomo Pharmaceuticals Co., Ltd. Procede de production de derives de carbapenem

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2401278A1 (fr) * 2009-02-26 2012-01-04 Orchid Chemicals&Pharmaceuticals Limited Procédé amélioré pour la préparation d'antibiotique à base de carbapenème
EP2401278A4 (fr) * 2009-02-26 2012-07-04 Orchid Chemicals & Pharm Ltd Procédé amélioré pour la préparation d'antibiotique à base de carbapenème

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