Classifications

• • 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.
• a-Carboxy-3-thienylmethylcephalosporin is disclosed as an antibacterial agent in U.K. Patent No. 1,193,302.
• 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, NaBH2S3.
• 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 constitute a further aspect of this invention.
• the group X should be readily displaced by nucleophilic attack by sulphide ions.
• groups include chlorine, bromine, hydroxyl, arylsul- phonyloxy such as benzenesulphonyloxy, p-toluenesulphonyl- oxy, 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 and R 2 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 - C0 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 -C 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, alkylphenyl, 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,methylisoxa- zolyl, tetrazolyl, methyltetrazolyl, pyrimidinyl, pyridyl, pyrazinyl, pyrrolidyl, piperidyl, morpholinyl, thiazinyl, furyl, or quinolyl; a carboxylic acid group, a carboxylic ester group -C0 2 R 3 as defined above,
• R 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 -C0 2 R 3 , and then half-saponify in order to produce the compound (I) wherein one of R and R 2 is a carboxylic acid group, suitable for coupling to the penicillin or cephalosporin nucleus.
• the group R 3 may be chosen according to the eventual penicillin or cephalosporin required.
• the compound of formula (II) above may be prepared by a process which comprises condensing a compound of formula (V): wherein X and Y are as defined above with respect to formula (II); with a compound of formula (VI): wherein R 1 and R 2 are as defined above with respect to formula (I); under mild condensation conditions; and subsequently, if required, converting one group X or Y to a different such group.
• the conditions used for this condensation reaction should be sufficiently mild to prevent or minimise selfcondensation or other unwanted reaction of the compound (II), and the conditions and reagents employed for the 2 reaction depend on the nature of the groups R and R . In general, the more electron-withdrawing are the groups R 1 and R 2 then the more activated is the methylene group in compound (VI) and milder conditions may be employed.
• both the groups R and R 2 are selected from a carboxylic acid group, a carboxylic ester group or an activated acyl group (for example in the form of a silyl enol ether), then the condensation of compound (V) with compound (VI) may conveniently be carried out in the presence of titanium tetrachloride and an organic nitrogen - containing base containing no acidic proton, for example pyridine.
• Suitable solvents for such a reaction are chlorinated hydrocarbon solvents, preferably carbon tetrachloride, optionally in the presence of a co-solvent such as tetrahydrofuran, dioxan or a polar aprotic solvent.
• the condensation is conveniently carried out at low to ambient temperature, preferably from 0°C to 25°C.
• This reaction may be carried out using conventional conditions known in the literature, for example as described by Naito et al, J. Antibiot (Tokyo) Ser A 20 (2), 77-86 (1967) or by Benson and Pohland, J. Org. Chem 29. 385.
• 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.
• Aluminium chloride (79.8g, 0.6 mol) in methylene dichloride (300ml) was treated with stirring with chloroacetyl chloride (44.6ml, 0.56 mol). Acetylene (ca 1.2 mol) was passed throught the reaction mixture with stirring for three hours at a flow rate of 150ml/min.
• the reaction solution was slowly treated with ice-water (200ml), and the mixture extracted with methylene dichloride (200ml, 2 x 100ml). The combined extracts are washed with brine (2 x 50ml) and saturated sodium bicarbonate (50ml), dried (Na 2 SO 4 ) and evaporated to give the title product in 74% yield, b.p. 71-74°/10mm.
• Titanium tetrachloride (10ml., 0.1 mol) in CC1 4 (10ml) was added to tetrahydrofuran (25ml) at 0°.
• a premix of trans 1,4-dichlorobut-3-en-2-one (5.6g, 0 04 mol) and diethyl malonate (6.45g., 0.04 mol) was added in tetrahydrofuran (20ml).
• pyridine 13.0ml ., 0.16 mol
• tetrahydrofuran (10ml) was added.
• the reaction mixture was stirred for three hours at room temperature, diluted with water (100ml) and extracted with MDC (50ml., 2 x 25ml).
• Titanium tetrachloride (10ml., 0.1 mol) in carbon tetrachloride (25ml) was added to tetrahydrofuran (THF) (250ml) at 0°C.
• THF tetrahydrofuran
• Pyridine (13.0g., 0.16 mol) in THF (80ml) was added over 20 mins. The reaction mixture was stirred at room temperature for 16 hours, diluted with water, and extracted with ether.
• Titanium tetrachloride (0.5ml, 5.0 mol) in carbon tetrachloride (1.5ml) was added to THF (10ml) at 0°C.
• pyridine (0.32ml., 4.0 mol) in THF (4ml) was added.
• Calcium carbonate (0.4g., 4.0 mol) was added and the reaction mixture stirred at room temperature for 3 hours, diluted with water and extracted with ether. The ether extracts were washed with brine, sodium bicarbonate solution, brine; dried, treated with charcoal and evaporated to give the title compound in 69% yield, purified as in Example 6 (Spectroscopic data as in Example 6).
• Titanium tetrachloride 2.5ml., 25 mmol in carbon tetrachloride (7.5ml) was added to THF (60ml) at 0°C.
• Malonic acid 1.0g., 10mmol
• trans 1,4-dichlorobut-3-en -2-one 1.g., 10mmol
• Pyridine 3.3ml., 40 mmol
• THF 10ml
• Titanium tetrachloride (0.25 ml, 2.5 mmol) in CC1 4 (1.5 ml) was added to THF (10 ml) at 0°C.
• Trans-1,4-dichlorobut -3-en-2-one (0.28 g, 2.0 mmol) and ethyl cyanoacetate (0.21 g, 1.9 mmol) in THF (2 ml) were added.
• Pyridine (0.32 ml, 4.0 mmol) in THF (5 ml) was added over 5 minutes, and the mixture stirred for eighteen hours at room temperature. Work up as in example 6 gave the title compound (0.04 g, 8%).
• Cis-1,4-dichlorobut-3-en-2-one (0.28 g, 2.0 mmol) in toluene (5 ml) was heated at 90° with carbomethoxymethylene triphenylphosphorane (0.66 g, 2.0 mmol) for 15 hours. Water was added, and extracted with ether.

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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)

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• 1978
  • 1978-07-12 EP EP80105285A patent/EP0023726B1/de not_active Expired
  • 1978-07-12 EP EP78300140A patent/EP0000633B1/de not_active Expired
  • 1978-07-14 IL IL55144A patent/IL55144A0/xx unknown
  • 1978-07-19 DK DK323978A patent/DK323978A/da not_active Application Discontinuation
  • 1978-07-19 ZA ZA00784101A patent/ZA784101B/xx unknown
  • 1978-07-20 FI FI782300A patent/FI782300A/fi not_active Application Discontinuation
  • 1978-07-21 ES ES471964A patent/ES471964A1/es not_active Expired
  • 1978-07-21 US US05/926,727 patent/US4252976A/en not_active Expired - Lifetime
  • 1978-07-21 IE IE1469/78A patent/IE47135B1/en unknown
  • 1978-07-21 IT IT50415/78A patent/IT1105934B/it active
  • 1978-07-24 JP JP9032178A patent/JPS5424867A/ja active Pending
• 1979
  • 1979-05-07 US US06/036,407 patent/US4282373A/en not_active Expired - Lifetime

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