EP0433425A1 - Process for penems - Google Patents

Process for penems

Info

Publication number
EP0433425A1
EP0433425A1 EP90910622A EP90910622A EP0433425A1 EP 0433425 A1 EP0433425 A1 EP 0433425A1 EP 90910622 A EP90910622 A EP 90910622A EP 90910622 A EP90910622 A EP 90910622A EP 0433425 A1 EP0433425 A1 EP 0433425A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
group
halogen atom
hydroxy group
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP90910622A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ettore Perrone
Marco Alpegiani
Franco Zarini
Giuseppe Mazzini
Giovanni Franceschi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Italia SRL
Original Assignee
Farmitalia Carlo Erba SRL
Carlo Erba SpA
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 Farmitalia Carlo Erba SRL, Carlo Erba SpA filed Critical Farmitalia Carlo Erba SRL
Publication of EP0433425A1 publication Critical patent/EP0433425A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C07D317/40—Vinylene carbonate; Substituted vinylene carbonates
    • 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 process for preparing
  • 2-methoxymethyl penem useful as antibacterial agent and to the preparation of the intermediates useful in the synthesis.
  • R represents a hydrogen atom or a hydroxy protecting group, which process comprises reacting a compound of formula (II)
  • R is as defined above, with an oxalyl halide in an inert solvent; optionally converting the resultant compound of the formula III
  • R is as defined above and X is a halogen atom into a compound of the formula III in which X represents a hydroxy group by hydrolysis; and either (i) treating the compound of formula III in which X is a halogen atom with a compound of the formula IV
  • R is as defined above and optionally deprotecting the resultant compound of the formula I wherein R is a hydroxy protecting group to obtain a compound of the formula I wherein R is a hydrogen atom.
  • the hydroxy protecting group which R may represent include: a) a silyl group -SiR 1 R 2 R 3 wherein R 1 , R 2 , R 3 are each independently C 1 -C 6 alkyl, aryl, C 1 -C 6 alkoxy, aryloxy or halogen atom;
  • R 4 is hydrogen, C 1 -C 6 alkyl or
  • R 5 is an optionally substituted C 1 -C 6 alkyl, aryl or heterocyclyl group or R 4 and R 5 taken together form a part of a C 5 -C 6 ring c) a group wherein R 6 is an optionally substituted
  • alkyl alkenyl, aryl, heterocyclyl or heterocyclylmethyl group
  • R 7 is hydrogen or as defined above under R 6 and W is a bond, a carbonyl
  • Preferred hydroxy protecting R groups are
  • Preferred leaving groups which Y may represent in the formula IV include halogen atom, C 1 -C 4 alkylsulphonyloxy and arylsulphonyloxy groups.
  • halogen atom include bromine, chorine and iodine.
  • a C 1 -C 6 alkyl may be methyl, ethyl, i-propyl, propyl, n-butyl, sec-butyl or ter-butyl groups.
  • Alkenyl may be an allyl, propenyl or butenyl group.
  • Aryl is a benzene ring optionally substituted by one or more methyl, nitro, methoxy, methoxycarbonyl, cyano, hydroxy, acetamido, carbamoyl.
  • Heterocyclyl group is 5-methyl-2-oxo-1,3-dioxolen-4-yl, furyl, thiophenyl, benzothiophenyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl.
  • the present invention also provides a process for preparing a compound of formula (IV) in which Y is hydroxy group, which process comprises treating a compound of the formula
  • the process of the present invention provides penems of formula (I) in good yield and high optical purity.
  • the starting material of formula (II) can be conveniently prepared as described in the above cited EP-A-295,100.
  • the present invention therefore allows the synthesis of compounds of formula (I) as summarized in the following Reaction Scheme.
  • Azetidinones II are reacted in an inert solvent with oxalyl halides, especially oxalyl chloride or oxalyl bromide in the presence of an inorganic or organic base or an acid scavenger affording halooxalyl azetidinones of formula III.
  • Reaction of azetidinones II with oxalyl halides is performed in an aprotic solvent at a temperature ranging from -70°C to + 40°, preferably between -40°C and room temperature.
  • Preferred organic solvents are dichloromethane, chloroform, benzene, toluene, xylenes (as single isomer or a mixture thereof), carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, tetrohydrofuran, dioxane, acetonitrile, diisopropylether, methylethylketone.
  • Said reaction is usually performed in the presence of a tertiary organic base either aliphatic or aromatic or alicyclic such as triethylamine, trimethylamine, disopropyl ethylamine, aniline, pyridine, lutidine, collidine, quinoline, N-methyl morpholine, N-methyl pyrrolidine, N-methylpiperidine, diazobicyclooctane (DABCO).
  • a tertiary organic base either aliphatic or aromatic or alicyclic such as triethylamine, trimethylamine, disopropyl ethylamine, aniline, pyridine, lutidine, collidine, quinoline, N-methyl morpholine, N-methyl pyrrolidine, N-methylpiperidine, diazobicyclooctane (DABCO).
  • a tertiary organic base either aliphatic or aromatic or alicyclic such as triethylamine, trimethyl
  • Inorganic base are also effective, preferred ones are alkaline bicarbonates or carbonates such as sodium bicarbonate, calcium carbonate, cesium' carbonate, magnesium carbonate, potassium carbonate.
  • Preferred organic or inorganic bases or acid scavengers are as described above. Preferred range of temperature is -30° to room temperature,
  • the compounds of the formula III wherein X is a hydroxy group thus obtained may be directly treated with alkylating agents IV in which Y is a leaving group or the solvent may be removed and substituted by another aprotic solvent.
  • Suitable organic solvents for the conversion of X in the formula III from halogen to hydroxy group are polar aprotic solvents such as acetonitrile, dimethylformamide, propionitrile, dimethylsulphoxide, hexamethylphosphoramide, sulpholane and acetone.
  • Preferential reaction temperature ranges from -20o to +60°C, preferred organic or inorganic bases or acid scavengers are as described above. Addition of alkaline halides such as sodium iodide is often
  • Preferred leaving groups Y are chloro, bromo or iodo or a mesyloxy, tosyloxy or triflyloxy group.
  • the compound of formula V is typically cyclised in the presence of a trialkylphosphite such as a tri(C 1 -C 4 alkyl) phosphite.
  • a trialkylphosphite such as a tri(C 1 -C 4 alkyl) phosphite.
  • solutions of V are generally dried over a dehydrating agent such as ⁇ odiurp sulphate, magnesium sulphate or calcium sulphate or by azeotropic removal.
  • a dehydrating agent such as ⁇ odiurp sulphate, magnesium sulphate or calcium sulphate or by azeotropic removal.
  • triethylphosphite are heated at a temperature ranging from +60°to +150°C, providing penems I which are isolated by crystallization or silica gel chromatography in high overall yield.
  • the optional final removal of the protecting group R may be carried out by known methods, such as, for instance hydrogenolysis, e.g. in the presence of palladium on charcoal as catalysts or by hydrolysis, either acid hydrolysis, e.g. with acetic acid or oxalic acid, or neutral hydrolysis in the presence of SiO 2 , or basic hydrolysis, or hydrolysis under reductive conditions, for example by the use of Fe/NH 4 Cl, Zn/H + or of Na 2 S 2 O 4 , or by desilylation with fluoride salts, such as KF or (But) 4 NF.3H 2 O.
  • known methods such as, for instance hydrogenolysis, e.g. in the presence of palladium on charcoal as catalysts or by hydrolysis, either acid hydrolysis, e.g. with acetic acid or oxalic acid, or neutral hydrolysis in the presence of SiO 2 , or basic hydrolysis, or hydrolysis under reductive conditions, for example by the use of Fe/NH 4 Cl, Zn/
  • composition also comprises a pharmaceutically acceptable carrier or diluent.
  • the present invention relates also to the preparation of compound of the formula IV in which Y is a hydroxy group by treatment of the compound of the formula IV in which Y is a halogen atom with silver nitrate and subsequent reduction under dissolving metal conditions.
  • a preferred reducing agent is zinc powder in a mixture of acetic acid and an inert organic solvent.
  • the compound of formula IV in which Y is a hydroxy group may be also obtained as described in JP-A-59-212488 (1984) .
  • the starting compounds of the formula IV in which Y is a halogen atom or a leaving group are described in Chem. Pharm. Bull 22 , 2241 (1984), M 394 (1988) and Chemical
  • Example 1 illustrates the invention without limiting it.
  • N,N-diisopropylethylamine (6 ml) in CH 2 Cl 2 (10 ml) was added dropwise at 0°C and the resulting yellow mixture was stirred for 30 minutes.
  • the reaction mixture was stirred at room temperature for 1 h at 45°C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Electric Double-Layer Capacitors Or The Like (AREA)
  • Crystals, And After-Treatments Of Crystals (AREA)
  • Glass Compositions (AREA)
  • Cephalosporin Compounds (AREA)
  • Electrical Discharge Machining, Electrochemical Machining, And Combined Machining (AREA)
  • Medicinal Preparation (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)
  • Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
  • Pens And Brushes (AREA)
EP90910622A 1989-07-05 1990-07-03 Process for penems Pending EP0433425A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB898915392A GB8915392D0 (en) 1989-07-05 1989-07-05 Process for penems
GB8915392 1989-07-05

Publications (1)

Publication Number Publication Date
EP0433425A1 true EP0433425A1 (en) 1991-06-26

Family

ID=10659566

Family Applications (2)

Application Number Title Priority Date Filing Date
EP90910622A Pending EP0433425A1 (en) 1989-07-05 1990-07-03 Process for penems
EP90112654A Expired - Lifetime EP0406790B1 (en) 1989-07-05 1990-07-03 Process for penems

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP90112654A Expired - Lifetime EP0406790B1 (en) 1989-07-05 1990-07-03 Process for penems

Country Status (21)

Country Link
EP (2) EP0433425A1 (pt)
JP (1) JPH05500210A (pt)
KR (1) KR920701212A (pt)
AT (1) ATE131483T1 (pt)
AU (1) AU644805B2 (pt)
CA (1) CA2035434A1 (pt)
DD (1) DD299304A5 (pt)
DE (1) DE69024114T2 (pt)
DK (1) DK0406790T3 (pt)
ES (1) ES2083401T3 (pt)
FI (1) FI911081A0 (pt)
GB (1) GB8915392D0 (pt)
HU (1) HU209924B (pt)
IE (1) IE902423A1 (pt)
IL (1) IL94943A (pt)
MY (1) MY105720A (pt)
NZ (1) NZ234329A (pt)
PT (1) PT94589A (pt)
RU (1) RU2049786C1 (pt)
WO (1) WO1991000283A1 (pt)
ZA (1) ZA905198B (pt)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8818789D0 (en) * 1988-08-08 1988-09-07 Erba Carlo Spa Crystalline(5r 6s)-2-carbamoyloxymethyl-6-((1r)-hydroxyethyl)-2-penem-carboxylic acid & pharmaceutical formulation
GB9006114D0 (en) * 1990-03-19 1990-05-16 Erba Carlo Spa Process for preparing penem esters
IT1286558B1 (it) * 1996-02-27 1998-07-15 Menarini Farma Ind Processo per la preparazione di 2-alogenometil-penems e loro uso per la preparazione di penems antibatterici

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5835190A (ja) * 1981-08-25 1983-03-01 Sankyo Co Ltd ペネム−３−カルボン酸誘導体
JPS59212488A (ja) * 1983-05-18 1984-12-01 Kyoto Yakuhin Kogyo Kk ジオキソ−ル誘導体
JPH075463B2 (ja) * 1985-03-09 1995-01-25 サントリー株式会社 抗菌剤
GB8713515D0 (en) * 1987-06-10 1987-07-15 Erba Farmitalia Methoxymethyl compounds
GB8716679D0 (en) * 1987-07-15 1987-08-19 Erba Farmitalia Penem derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9100283A1 *

Also Published As

Publication number Publication date
HUT56374A (en) 1991-08-28
FI911081A7 (fi) 1991-03-04
ZA905198B (en) 1991-04-24
PT94589A (pt) 1991-03-20
DK0406790T3 (da) 1996-01-29
IL94943A (en) 1994-11-11
HU209924B (en) 1994-12-28
ES2083401T3 (es) 1996-04-16
JPH05500210A (ja) 1993-01-21
CA2035434A1 (en) 1991-01-06
AU644805B2 (en) 1993-12-23
MY105720A (en) 1994-11-30
EP0406790A1 (en) 1991-01-09
ATE131483T1 (de) 1995-12-15
IE902423A1 (en) 1991-06-19
KR920701212A (ko) 1992-08-11
DD299304A5 (de) 1992-04-09
DE69024114T2 (de) 1996-05-09
AU6031890A (en) 1991-01-17
HU905471D0 (en) 1991-06-28
FI911081A0 (fi) 1991-03-04
DE69024114D1 (de) 1996-01-25
IL94943A0 (en) 1991-06-10
NZ234329A (en) 1992-03-26
WO1991000283A1 (en) 1991-01-10
GB8915392D0 (en) 1989-08-23
RU2049786C1 (ru) 1995-12-10
EP0406790B1 (en) 1995-12-13

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Legal Events

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PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

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Free format text: VERFAHREN ABGESCHLOSSEN INFOLGE VERBINDUNG MIT 90112654.0/0406790 (EUROPAEISCHE ANMELDENUMMER/VEROEFFENTLICHUNGSNUMMER) VOM 26.11.91.

ITCL It: translation for ep claims filed

Representative=s name: JACOBACCI CASETTA & PERANI S.P.A.