EP0000633B1 - Procédé pour la préparation de l'acide thién-3-yl-acétique alpha-substitué et ses dérivés - Google Patents

Procédé pour la préparation de l'acide thién-3-yl-acétique alpha-substitué et ses dérivés Download PDF

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Publication number
EP0000633B1
EP0000633B1 EP78300140A EP78300140A EP0000633B1 EP 0000633 B1 EP0000633 B1 EP 0000633B1 EP 78300140 A EP78300140 A EP 78300140A EP 78300140 A EP78300140 A EP 78300140A EP 0000633 B1 EP0000633 B1 EP 0000633B1
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EP
European Patent Office
Prior art keywords
group
formula
alkyl
carboxylic acid
ester
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EP78300140A
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German (de)
English (en)
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EP0000633A2 (fr
EP0000633A3 (en
Inventor
Angela Wendy Guest
Andrew William Taylor
Robert Ramage
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Beecham Group PLC
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Beecham Group PLC
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Priority to DE8080105285T priority Critical patent/DE2861845D1/de
Publication of EP0000633A2 publication Critical patent/EP0000633A2/fr
Publication of EP0000633A3 publication Critical patent/EP0000633A3/xx
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to a chemical process for the preparation of 3-substituted thiophenes, which are useful as intermediates in the production of penicillins and cephalosporins.
  • This cyclisation process may be carried out in a wide range of solvents subject to the solubility of the source of nucleophilic sulphur. It is often convenient to use a polar solvent, preferably a water-miscible solvent such as, for example, tetrahydrofuran, acetone, dimethylformamide, dimethylsulphoxide, hexamethylphosphoramide, acetonitrile, dimethoxyethane, dioxan, or an alcohol such as methanol, ethanol, propanol, butanol, in particular ethanol.
  • Preferred solvents include tetrahydrofuran and acetone.
  • An organic solvent such as methylene dichloride may also be employed.
  • the reaction may be carried out at ambient to elevated temperature depending on the particular reagents used and the values of X, Y, R 1 and R 2 .
  • suitable temperatures for the process are from -20°C to 100°C, preferably 10° to 50°C.
  • nucleophilic sulphur is for example the bisulphide ion, HS-
  • the bisulphide ion for the process of this invention may be provided by using a salt of this ion, preferably an alkali metal salt for example sodium bisulphide NaSH, which may be prepared, optionally in situ in the reaction, from sodium sulphide Na 2 S and sodium bicarbonate.
  • a salt of this ion preferably an alkali metal salt for example sodium bisulphide NaSH, which may be prepared, optionally in situ in the reaction, from sodium sulphide Na 2 S and sodium bicarbonate.
  • An alternative, and preferred, source of the bisulphide ion comprises hydrogen sulphide and a base, which again produces HS- in situ.
  • This combination of reagents has the advantage that the base employed can be the same as that used for the cyclisation process itself.
  • Suitable bases which may be employed to provide the basic conditions for the process of this invention include inorganic bases, such as alkali metal hydroxides, preferably potassium hydroxide, and alkali metal bicarbonates preferably sodium bicarbonate and organic basis such as substituted amines for example tri(C 1-6 )alkylamines such as trimethylamine or triethylamine.
  • inorganic bases such as alkali metal hydroxides, preferably potassium hydroxide, and alkali metal bicarbonates preferably sodium bicarbonate and organic basis such as substituted amines for example tri(C 1-6 )alkylamines such as trimethylamine or triethylamine.
  • the bisulphide ion may also be generated in situ from sulphurated sodium borohydride, NaBH 2 S 3 .
  • reaction of compound (II) with an alkali metal bisulphide produces an intermediate of formula (IV): Addition of further bisulphide (or presence of excess initially) removes a proton to give structure (III) above which then cyclises.
  • Another way of providing the basic conditions required for the process is to produce the intermediate ion of formula (III) directly which can then act as its own base for cyclisation. This may be achieved for example by treating compound (II) with an alkali metal sulphide, in particular sodium sulphide Na 2 S. Because the sulphur ion in such a compound has a double negative charge, S 2- , the intermediate formed after nucleophilic attack on compound (II), is structure (III) rather than structure (IV). No further base need then be present to complete the cyclisation.
  • the compounds of formula (II) are novel compounds and are the subject matter of copending European Patent Application No. 80105285.3, which is a divisional of the present application.
  • the group X should be readily displaced by nucleophilic attack by sulphide ions.
  • groups include chloride, bromine, hydroxyl, arylsulphonyloxy such as benzenesulphonyloxy, p-toluenesulphonyloxy, or p-nitrosulphonyloxy, alkylsulphonyloxy such as methanesulphonyloxy or C 1-6 alkanoyloxy such as acetoxy, propionoxy or butyroxy.
  • the group Y may be, for example, chlorine, bromine, hydroxy or C 1-6 alkoxy such as methoxy, ethoxy, or propoxy.
  • X and Y are halogen, especially chlorine.
  • the radicals R 1 and R2 in compound (II) are chosen according to the requirements of the compound (I).
  • the group R 1 should be carboxylic acid group or a group which may be converted to a carboxylic acid group or a functional derivative thereof for acylation the amino group of the penicillin or cephalosporin nucleus.
  • the R 2 group is chosen to provide the required a-substituent, or a precursor thereof, for the side chain of a penicillin or cephalosporin.
  • R 1 may be an ester group ⁇ CO 2 R 3 wherein R 3 is an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or heterocyclic group, any of which may be substituted. Suitable such R 3 groups include:
  • Preferred groups for R 3 include C 1-6 alkyl, benzyl, phthalidyl, indanyl, phenyl, mono- di-, and tri-(C 1-6 )-alkyl substituted phenyl such as o-, m or p methylphenyl, ethylphenyl, n- or iso-propylphenyl, n-, sec-, iso- or butylphenyl.
  • Suitable groups R 2 include hydrogen, C 1-6 alkyl, such as methyl, ethyl, propyl, or butyl, benzyl, phenyl, alkyiphenyl, napthyl, a 5- or 6- membered heterocyclic group containing one or more sulphur and/or nitrogen and/or oxygen atoms in the ring and which may be substituted by an alkyl group having from 1 to 3 carbon atoms, for example thienyl, imidazolyl, thiadiazolyl, isoxazolyl, methylisoxazolyl, tetrazolyl, methyltetrazolyl, pyrimidinyl, pyridyl, pyrazinyl, pyrrolidyl, piperidyl, morpholinyl, thiazinyl, furyl, or quinolyl: a carboxylic acid group, a carboxylic ester group -CO Z R 3 as defined above, or a
  • R 1 and R 2 may conveniently both be carboxylic acid or ester radicals. It is convenient to prepare a diester compound of formula (I), i.e. where R 1 and R 2 both represent a group -CO Z R 3 , and then half-saponify in order to produce the compound (I) wherein one of R 1 and R 2 is a carboxylic acid group, suitable for coupling the penicillin or cephalosporin nucleus.
  • the group R 3 may be chosen according to the eventual penicillin or cephalosporin required.
  • the compounds of formula (I) in which one of the groups R 1 and R 2 represents a carboxylic acid function may be converted to a penicillin or cephalosporin by an method known per se, for example as described in British Patent Specification Nos. 1,004,670, 1,125,557, 1,133,886, 1,193,302, W. German OLS No. 2,600,866.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (9)

1. Procédé pour la préparation d'un thiophène de formule (I):
Figure imgb0008
dans laquelle R1 représente un groupe acide carboxylique ou un dérivé ester ou amide de celui-ci ou un groupe nitrile; et R2 représente de l'hydrogène, un groupe hydrocarboné ou hétérocyclique, un groupe acide carboxylique ou un dérivé ester ou amide de celui-ci; ou un groupe acyle, nitrile, isonitrile ou imine éventuellement substitué de formule -CH=NZ ou -N=CHZ, où Z représente de l'hydrogène, un alkyle ou un aryle, ou SO2Ra, -SRa, ―SO.Ra ou -S02Ra, où Ra représente un alkyle en C1-6 ou un aryle, caractérisé en ce qu'on traite un composé de formule (II):
Figure imgb0009
dans laquelle R1 et R2 ont la même signification que dans le cas de la formule (I) ci-dessus; X représente un atome d'halogène, un groupe hydroxy ou un groupe hydroxy fonctionnalisé; Y représente un atome d'halogène, un groupe hydroxy ou un groupe alcoxy avec une source de soufre nucléophile dans ces conditions basiques.
2. Procédé suivant la revendication 1, caractérisé en ce que la source de soufre nucléophileest l'ion bisulfure.
3. Procédé suivant la revendication 1, caractérisé en ce que le composé de formule (II) est traité avec un sulfure de métal alcalin.
4. Procédé suivant la revendication 3, caractérisé en ce que le sulfure de métal alcalin est le sulfure de sodium.
5. Procédé suivant l'une quelconque des revendications 1 à 4, caractérisé en ce que X et Y sont tous deux un halogène.
6. Procédé suivant la revendication 5, caractérisé en ce que X et Y sont tous deux du chlore.
7. Procédé suivant l'une quelconque des revendications 1 à 6, caractérisé en ce que R2 représente de l'hydrogène un groupe acide ou ester carboxylique.
8. Procédé suivant la revendication 7, caractérisé en ce que R2 est un groupe acide carboxylique ou un groupe ester carboxylique de formule -CO2R3, où R3 est un groupe alkyle en C1-6, benzyle, phtalidyle, indanyle, phènyle, mono- di- ou tri- alkyl (C1- 6) phènyle.
9. Procédé suivant l'une quelconque des revendications 1 à 6, caractérisé en ce que R1 et R2 représentent tous deux un groupe acide ou ester carboxylique.
EP78300140A 1977-07-23 1978-07-12 Procédé pour la préparation de l'acide thién-3-yl-acétique alpha-substitué et ses dérivés Expired EP0000633B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE8080105285T DE2861845D1 (en) 1977-07-23 1978-07-12 2,5-disubstituted-3 substituted methyl-penta-2,4-dienoic acid and derivatives and process for their preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB3100877 1977-07-23
GB3100877 1977-07-23

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP80105285.3 Division-Into 1978-07-12

Publications (3)

Publication Number Publication Date
EP0000633A2 EP0000633A2 (fr) 1979-02-07
EP0000633A3 EP0000633A3 (en) 1979-06-13
EP0000633B1 true EP0000633B1 (fr) 1981-11-04

Family

ID=10316543

Family Applications (2)

Application Number Title Priority Date Filing Date
EP78300140A Expired EP0000633B1 (fr) 1977-07-23 1978-07-12 Procédé pour la préparation de l'acide thién-3-yl-acétique alpha-substitué et ses dérivés
EP80105285A Expired EP0023726B1 (fr) 1977-07-23 1978-07-12 Acides méthyl penta-2,4-diénoiques-2,5 disubstitués,3-substitués, leurs dérivés, et procédé pour leur préparation

Family Applications After (1)

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EP80105285A Expired EP0023726B1 (fr) 1977-07-23 1978-07-12 Acides méthyl penta-2,4-diénoiques-2,5 disubstitués,3-substitués, leurs dérivés, et procédé pour leur préparation

Country Status (10)

Country Link
US (2) US4252976A (fr)
EP (2) EP0000633B1 (fr)
JP (1) JPS5424867A (fr)
DK (1) DK323978A (fr)
ES (1) ES471964A1 (fr)
FI (1) FI782300A (fr)
IE (1) IE47135B1 (fr)
IL (1) IL55144A0 (fr)
IT (1) IT1105934B (fr)
ZA (1) ZA784101B (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0038121B1 (fr) * 1980-04-11 1984-05-02 Beecham Group Plc Procédé de préparation de thiophènes 3-substitués
ES504690A0 (es) * 1981-08-11 1982-05-16 Madaus Cerafarm Lab Procedimiento para la preparacion de acidos de 2-(3'-tienil)propionicos 5'-sustituidos
DE3544079C2 (de) * 1985-12-13 1998-07-30 Bosch Gmbh Robert Verfahren zur Verarbeitung von Interrupt-Signalen
AT392497B (de) 1989-06-02 1991-04-10 Voest Alpine Maschinenbau Gleitstuhl, gleitplatte bzw. rippenplatte fuer schienenweichen oder -kreuzungen
DE3919029A1 (de) * 1989-06-10 1990-12-13 Hoechst Ag Verfahren zur enzymatischen spaltung von 2-arylpropionsaeure-vinylester
WO1993009112A1 (fr) * 1991-11-06 1993-05-13 Ciba-Geigy Ag Procede de production de sels de sulfonium cycliques
DE202008004595U1 (de) 2008-04-02 2008-07-17 Wastec B.V. Müllbehälter mit einer elektronischen Dateneinrichtung

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2381882A (en) * 1945-08-14 Ester
US2183929A (en) * 1939-12-19 Chx c ch
US2093519A (en) * 1935-04-25 1937-09-21 Ig Farbenindustrie Ag Process for the manufacture of condensation products of crotonaldehyde
FR990943A (fr) * 1948-07-20 1951-09-27 Bataafsche Petroleum Procédé de préparation des acides 2, 4-pentadiénoiques
US2540071A (en) * 1949-01-21 1951-01-30 Rohm & Haas Allylic rearrangement
US2662914A (en) * 1950-04-22 1953-12-15 Eastman Kodak Co Alpha, alpha-vitamin a diacid and synthesis of isoprenic polyenes
US3360527A (en) * 1966-05-03 1967-12-26 Bristol Banyu Res Inst Ltd Vinylpenicillins
DE1667997A1 (de) * 1967-01-13 1971-07-22 Tenneco Chem Fungicide Mittel und diese enthaltendes Saatgut
US3801608A (en) * 1972-07-17 1974-04-02 Zoecon Corp Novel 2,4-diolefinic 2,2-diesters and cyanoesters
SU527431A1 (ru) * 1974-10-22 1976-09-05 Иркутский институт органической химии СО АН СССР Способ получени тиофена и тиоацетальдегида
JPS51122061A (en) * 1975-03-20 1976-10-25 Seitetsu Kagaku Co Ltd Process for preparation of thiophene and its derivatives

Also Published As

Publication number Publication date
EP0023726B1 (fr) 1982-05-19
IL55144A0 (en) 1978-09-29
EP0023726A1 (fr) 1981-02-11
JPS5424867A (en) 1979-02-24
ZA784101B (en) 1979-07-25
IT7850415A0 (it) 1978-07-21
IE781469L (en) 1979-01-23
DK323978A (da) 1979-01-24
ES471964A1 (es) 1980-01-16
US4252976A (en) 1981-02-24
FI782300A (fi) 1979-01-24
EP0000633A2 (fr) 1979-02-07
IE47135B1 (en) 1983-12-28
US4282373A (en) 1981-08-04
IT1105934B (it) 1985-11-11
EP0000633A3 (en) 1979-06-13

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