GB1580623A - 2-(2-amino-4-thiazolyl)-2-hydroxymino-acetic acid and substituted derivatives thereof useful as intermediates in the manufacture of antibiotic oxime derivatives of 7-aminothiazolyl-acetamido-cehalosporanic acid and processes for preparing them - Google Patents

2-(2-amino-4-thiazolyl)-2-hydroxymino-acetic acid and substituted derivatives thereof useful as intermediates in the manufacture of antibiotic oxime derivatives of 7-aminothiazolyl-acetamido-cehalosporanic acid and processes for preparing them Download PDF

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GB1580623A
GB1580623A GB15561/79A GB1556179A GB1580623A GB 1580623 A GB1580623 A GB 1580623A GB 15561/79 A GB15561/79 A GB 15561/79A GB 1556179 A GB1556179 A GB 1556179A GB 1580623 A GB1580623 A GB 1580623A
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general formula
hydrogenolysis
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acid
alk
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Sanofi Aventis France
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Roussel Uclaf SA
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Priority claimed from FR7601834A external-priority patent/FR2346014A1/en
Priority claimed from FR7617743A external-priority patent/FR2361893A2/en
Priority claimed from FR7625051A external-priority patent/FR2361894A2/en
Application filed by Roussel Uclaf SA filed Critical Roussel Uclaf SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon 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, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Communicable Diseases (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

PATENT SPECIFICATION ( 11) 1 580 623
M ( 21) Application No 15561/79 ( 22) Filed 21 Jan 1977 ( 62) Divided out of No1580621 ( 19 ( 31) Convention Application No 7601834 ( 32) Filed 23 Jan 1976 ( 31) Convention Application No 7617743 ( 32) Filed 11 June 1976 ( 31) Convention Application No 7625051 ( 32) Filed 18 Aug 1976 in ( 33) France (FR) ( 44) Complete Specification published 3 Dec 1980 ( 51) INT CL 3 C 07 D 277/38 ( 52) Index at acceptance C 2 C 1382 200 20 Y 215 220 226 22 Y 247 256 25 Y 30 Y 314 31 Y 321 322 32 Y 339 346 351 355 366 367 368 440 620 670 699 718 AA LY MV ( 54) 2-( 2-AM INO-4-THIAZOLYL)-2-HYDROXYIMINOACETIC ACID AND SUBSTITUTED DERIVATIVES THEREOF USEFUL AS INTERMEDIATES IN THE MANUFACTURE OF ANTIBIOTIC OXIME DERIVATIVES OF 7-AMINOTHIAZOLYLACETAMIDOCEPHALOSPORANIC ACID, AND PROCESSES FOR PREPARING THEM ( 71) We, ROUSSEL-UCLAF, A French Body Corporate, of 35 Boulevard des Invalides, Paris 7 eme, France, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
This invention relates to 2( 2amino 4 thiazolyl)2 hydroxyimino 5 acetic acid and substituted derivatives thereof useful as intermediates in the manufacture of antibiotic oxime derivatives of 7 aminothiazolylacetamido cephalosporanic acid and processes for preparing them In particular, it concerns intermediates useful in the manufacture of certain derivatives of 3 acetoxymethyl 7 l 2 ( 2 amino 4 thiazolyl) 2 imino acetamidol 10 ceph 3 em 4 carboxylic acid.
In our copending Application No 2,640/77 (Serial No 1580621), out of which this Application is divided, there are described and claimed 7 aminothiazolyl acetamido cephalo sporanic acid oxime derivatives of the general formula:
NH-R Sc H S 15 CH 2-O-C CH 3 OR 11 (I) C 02 A 0 wherein R represents a hydrogen atom or a group removable by acid hydrolysis or by hydrogenolysis, R' represents a hydrogen atom, a group removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from I to 4 carbon atoms, and A represents a hydrogen atom, an alkali metal atom, an equivalent of an alkaline-earth metal atom, an equivalent of a 20 magnesium atom or a substituted ammonium group, with the proviso that when R' represents a group removable by acid hydrolysis or by hydrogenolysis R represents the same or a different group removable by acid hydrolysis or by hydrogenolysis, and that when R' represents a hydrogen atom R also represents a hydrogen atom, the compounds being in the form of the syn isomer as indicated in the general formula.
The aforesaid Application also provides various processes for preparing compounds of general formula I Those compounds of general formula I wherein R represents R, and R' represents R',, R, being a group removable by acid hydrolysis 5 or by hydrogenolysis and R', being a group removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from I to 4 carbon atoms, may be prepared by a process in which 7-aminocephalosporanic acid is reacted with an appropriate acid syn isomer of the general formula:
NH-R 1 C 02 H 10 -.O Rli ( 1) (wherein R, and R', are as defined hereinbefore) or a functional derivative thereof to obtain the desired syn isomer of the general formula:
NH -R SLN O HO NH 11- CH 20 CCH 3 (a 0 R / 1 (a C 02 H wherein R, and R', are as defined hereinbefore.
The compounds of general formula II and related compounds wherein R, 15 and/or R', represent hydrogen are new, and this invention provides these useful intermediates per se.
Accordingly, this invention provides the syn isomer compounds of the general formula:
NH R 2 -CO 2 H 20 OR 2 ( 11 b wherein R 2 represents a hydrogen atom or a group removable by acid hydrolysis or by hydrogenolysis and R'2 represents a hydrogen atom, a group removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, with the proviso that R'2 does not represent a hydrogen atom when R 2 represents a group removable by acid hydrolysis or by 25 hydrogenolysis.
Those compounds of general formula 1 Ib that also fall within general formula II that is, the compounds of general formula lb wherein R 2 and R'2 do not represent hydrogen may be prepared by a process in which an appropriate svn isomer of the general formula: 30 I 1,580,623 NH-R 1 \-,,CO 2 atk N ON \ 111 ' NOR 1 Il (wherein R 1 and R'1 are as defined hereinbefore and alk represents an alkyl radical having from 1 to 4 carbon atoms) is treated first with a base and then with an acid to form the desired product of general formula II This invention extends to such a process 5 The base, which is used to saponify the product of formula III, is preferably sodium hydroxide, but other bases such as potassium or barium hydroxide can also be used.
The acid which is used to isolate the acid of formula II is preferably dilute hydrochloric acid, but other acids such as acetic acid or formic acid can also be 10 used.
The compounds of general formula III are in turn conveniently prepared by protecting the amino groups, and where appropriate the oxime groups as well, of the corresponding syn isomers of the general formula:
NH 2 H SUN CO 02 alk 15 NOR N \ O R 1 (IV)I wherein R' and alk are as defined hereinbefore The appropriate compound of general formula IV is treated with a compound capable of introducing a group removable by acid hydrolysis or by hydrogenolysis to form the corresponding product of general formula III.
Naturally the process employs a compound capable of introducing the 20 appropriate group R 1 (and R'1 when R' in compound IV is hydrogen) into the compound III and the compound most conveniently employed will depend upon the nature of the group However, such protecting groups and their introduction into molecules are well known to those skilled in the art By way of illustration, the trityl group is preferably introduced using trityl chloride, most preferably used in 25 the presence of triethylamine, or another tertiary amine base such as another trialkylamine, N-methylmorpholine or pyridine.
Other compounds capable of introducing groups removable by acid hydrolysis or by hydrogenolysis which may be used include t-butyl chloroformate (conveniently prepared in situ) or t-butyl azidoformate, trichloroethyl or benzyl 30 chloroformate, the mixed formyl-acetic anhydride (prepared in situ), benzyl or dibenzyl halides and particularly the chlorides, phthalic anhydride or Ncarbethoxy-phthalimide.
Certain of the compounds of general formula III, namely those wherein R'1 represents a saturated or unsaturated hydrocarbyl radical having from I to 4 35 carbon atoms, may be prepared by a process in which an appropriate syn isomer of the general formula:
1,580,623 (wherein alk is as defined hereinbefore) is treated with an equivalent of a compound capable of introducing a group removable by acid hydrolysis or by hydrogenolysis to obtain the corresponding product of general formula:
NH R S<N 5-.CO 2 alk 5 N OH (IV) (wherein R, and alk are as defined hereinbefore) which is then treated with a hydrocarbylating agent to obtain the desired syn isomer product of the general formula:
NHR 1 S N \= 9 O C 02 alk N 01 (lila) (wherein R 1 and alk are as defined hereinbefore, and R"b represents a saturated or 10 unsaturated hydrocarbyl radical having from I to 4 carbon atoms.
The compound capable of introducing a group removable by acid hydrolysis or by hydrogenolysis is chosen to introduce the desired protecting group, as explained above, and again is preferably trityl chloride The formation of the product V using trityl chloride is preferably carried out in the presence of a base 15 such as triethylamine Other bases such as other trialkylamines, N-methylmorpholine or pyridine can also be used.
Other compounds capable of introducing groups removable by acid hydrolysis or hydrogenolysis, such as t-butyl chloroformate or azidoformate, trichloroethyl or dibenzyl chloroformate, the mixed formyl acetic anhydride (prepared in situ), 20 benzyl or dibenzyl halides (preferably the chlorides), phthalic anhydride or Ncarbethoxy-phthalimide can also be used.
The hydrocarbylating agent which is used in the final step of preparing the products of formula lila is preferably an alkyl halide such as an alkyl iodide or an alkyl sulphate 25 The compounds of general formula IV, and thus including the compounds of general formula IV", may be prepared by any of the processes described in our aforementioned Application No 2,640/77 (Serial No 1580621) Thus the compounds of general formula IV may be prepared by reacting thiourea with an appropriate compound of the general formula: 30 1,580,623 XCH 2-C-C-C 02 alk 11 C 11 0 N OR'b (v,,) (wherein X represents a chlorine atom and R'b represents a hydrogen atom, a group removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from I to 4 carbon atoms, or X represents a bromine atom and R'b represents a hydrogen atom or an alkyl radical having from 1 5 to 4 carbon atoms) which process is characterised in that a) the reaction is carried out in an aqueous solvent; or b) the reaction is carried out at ambient temperature in the presence of a substantially stoichiometric amount of thiourea and with a reaction time of from I to 3 hours; or c) the reaction is carried out observing both of conditions a) and b) 10 The compounds of general formula VII' wherein X represents a bromine atom and R'b represents a hydrogen atom may be obtained by treatment of the products of formula:
CH 3 C C-CO -a Lk II II O N OH (V 111) with a brominating agent 15 The brominating agent is preferably bromine itself.
The compounds of formula VII' wherein X represents a chlorine atom which are not known may be prepared from ethyl-y-chloro-a-oximinoacetylacetate (described in J of Medicinal Chemistry 1973, Vol 16, no 9) The compounds of general formula VII' wherein X represents a chlorine atom and R'b represents a 20 group removable by acid hydrolysis or by hydrogenolysis may be obtained by standard protecting reactions using functional derivatives of the removable groups.
The compounds of general formula VII' wherein X represents a chlorine atom and R'b represents a saturated or unsaturated hydrocarbyl radical having from I to 4 carbon atoms may be obtained by reacting ethyl-y-chloro-aoximinoacetylacetate 25 with an appropriate alkyl halide or sulphate.
Naturally, to obtain the desired substituent alk in the compound of general formula VII' appropriate saponification and re-esterification or transesterification -may be used.
The compounds of general formulae III and IV as defined herein are 30 themselves new, and this invention extends to these new intermediates per se.
Those compounds of general formula I Ib wherein R 2 and/or R'2 represent(s) a hydrogen atom may be prepared by subjecting the corresponding compounds of general formula II wherein R 1 and/or R', represent(s) a group removable by acid hydrolysis or by hydrogenolysis to acid hydrolysis or hydrogenolysis, as 35 appropriate, so as to form the desired compound of general formula lib.
The following Examples are now given, though only by way of illustration, to show certain preferred aspects of the invention.
Example 1
2 ( 2 tritylamino 4 thiazolyl) 2 methoxyimino acetic acid 40 Stage A: Ethyl 2 ( 2 amino 4 thiazolyl) 2 methoxyimino acetate 1 g of ethyl y chloro a methoxyimino acetylacetate, 3 cm 3 of absolute ethanol and 0 42 g of crushed thiourea are placed together, the whole is agitated at ambient temperature for about two hours It is diluted with 60 cm 3 of ether, the hydrochloride obtained crystallises out, the whole is agitated, vacuumfiltered, 45 washed and dried 685 mg of hydrochloride are obtained, and dissolved in 4 cm 3 of water at 50 C Potassium acetate is added until p H 6 is attained, and the amine released crystallises out The whole is cooled and vacuum-filtered, the residue being washed with water and dried, and 270 mg of the desired product are obtained 50 M.Pt= 161 C The product obtained has the syn configuration.
NMR (CDCI 3 60 MHZ) p p m: 4 (N-OCH 3), 6 7 (proton of the thiazole ring).
1,580,623 State B: Ethyl 2 ( 2 tritylamino 4 thiazolyl) 2 methoxyimino acetate 4.6 g of the product prepared according to the previous stage are dissolved at C in 92 cm 3 of methylene chloride The solution is cooled to -10 C, 2 9 cm 3 of triethylamine are added, the whole is cooled to -35 C, 6 1 g of trityl chloride are 5 added over fifteen minutes, and the reaction mixture is left to return to ambient temperature, in all taking two hours thirty-minutes It is washed with water, then with 0 5 N hydrochloric acid and with sodium acetate in water It is dried, concentrated, taken up with ether, concentrated again, then dissolved in methanol; water and ether are added Crystallisation is allowed to take place, and the crystals 10 are vacuum-filtered, then washed with ether 6 15 g of the expected product are obtained M Pt = 120 C.
The product obtained has the syn configuration.
Stage C: 2 ( 2 tritylamino 4 thiazolyl) 2 methoxyimino acetic acid 7 01 g of ester obtained in Stage B are dissolved in 35 cm 3 of dioxane The 15 solution is taken to 110 C in an oil bath and 9 cm 3 of 2 N sodium hydroxide solution are added over five minutes, then the whole is left for thirty minutes at reflux under agitation The sodium salt crystallises out The whole is cooled, vacuumfiltered, washed with dioxane, then with ether, and a first yield of 5 767 g of salt is obtained.
The mother solution is concentrated and a second yield of 1 017 g is obtained to 20 give 6 784 g of salt in all.
3.06 g of salt are placed in 65 cm 3 of methylene chloride and 6 5 cm 3 of 2 N hydrochloric acid, and the whole is washed with water, dried and concentrated to dryness to obtain the free acid quantitatively.
The product obtained has the syn configuration 25 NMR (DMSO, 60 MHZ) p p m: 3 68 (N-OCH 3) 6 6 (proton of the thiazole ring) .
Example 2
2 ( 2 tritylamino 4 thiazolyl) 2 ( 2 propenyl oxyimino) acetic acid Stage A: Ethyl 2 ( 2 amino 4 thiazolyl) 2 ( 2 propenyl oxyimino) acetate 30 a) 9 7 g of ethyl 2 hydroxyimino 4 chloro acetylacetate, 30 cm 3 of acetone and 9 15 cm 3 of 3-iodopropene are cooled in ice and 27 5 cm 3 of 2 N sodium hydroxide solution are added, then the whole is left for an hour-and-ahalf at ambient temperature; b) 3 8 g of thiourea are added to the reaction mixture, then this is maintained 35 at 60 C for 15 minutes and then for 45 minutes at ambient temperature, the acetone is driven off, methylene chloride is added, then water, then potassium carbonate, the whole is agitated, decanted, extracted with methylene chloride, dried and concentrated to dryness, 9 75 g of residue are obtained, which is chromatographed on silica, eluting with ether, 2 7 g of the product are isolated and 40 taken up with isopropyl ether, and the crystals are vacuum-filtered, rinsed and dried 783 mg of the expected product are obtained M Pt= 100 C The product obtained has the syn configuration.
Stage B: Ethyl 2 ( 2 tritylamino 4 thiazolyl) 2 ( 2 propenyl oxyimino) acetate 45 511 mg of the product prepared in Stage A, 0 92 cm 3 of dimethylformamide, 1.8 cm 3 of methylene chloride and 0 29 cm 3 of triethylamine are mixed The mixture is cooled to -15 C and 615 mg of trityl chloride are added The whole is left at ambient temperature for an hour-and-a-half, 2 cm 3 of IN hydrochloric acid then 5 cm 3 of water are added, the whole is decanted, dried and concentrated to 50 dryness, and 1 28 g of the crude product are obtained.
The product obtained has the syn configuration.
Stage C: 2 ( 2 tritylamino 4 thiazolyl) 2 ( 2 \propenyl oxyimino) acetic acid 1 28 g of the product obtained in Stage B, 6 2 cm 3 of dioxane and 3 cm 3 of 2 N 55 sodium hydroxide are mixed and heated at 120 C The whole is taken to reflux for one hour, the sodium salt crystallises out and is vacuum-filtered, rinsed with an ether/dioxane mixture, then dried 805 mg of the product are isolated.
1.580,623 This is taken up in 10 cm 3 of methylene chloride and 3 cm 3 of IN hydrochloric acid and agitated to obtain a solution which is decanted, dried, concentrated to dryness, taken up with ether and vacuum-filtered 715 mg of the expected product are obtained M Pt= 1700 C.
The product obtained has the s Yn configuration 5 Example 3
2 ( 2 tritylamino 4 thiazolyl) 2 (ethoxyimino) acetic acid Stage A: Ethyl 2 ( 2 amino 4 thiazolyl) 2 ethoxyimino acetate a) 19 4 g of ethyl p chloro a oxyimino acetoacetate are placed in 60 cm 3 of acetone and 14 3 cm 3 of diethyl sulphate The whole is cooled for 10 minutes in 10 an ice bath and 55 cm 3 of 2 N sodium hydroxide solution are added over 30 minutes, then the whole is agitated for 40 minutes; b) 7 6 g of thiourea are added to the reaction medium, this is heated at 55 WC for 20 minutes, the acetone is driven off, the remainder is taken up with ethyl acetate, 6 9 g of potassium carbonate are added, and the whole is agitated, 15 decanted, extracted with ethyl acetate, dried and concentrated to dryness 17 4 g of residue are isolated and chromatographed on silica, eluting with ether The expected product is recovered, taken up with isopropyl ether, vacuumfiltered, rinsed and dried, and 2 8 g of the expected product are obtained M Pt= 1290 C The product obtained has the syn configuration 20 Stage B: Ethyl 2 ( 2 tritylamino 4 thiazolyl) 2 ethoxyimino acetate 3.16 g of the product obtained in Stage A, 6 cm 3 of dry dimethylformamide, 12 cm 3 of methylene chloride and 1 89 cm 3 of triethylamine are placed under an inert gas The mixture is cooled to -15 C and 3 98 g of trityl chloride are slowly added.
The whole is left to stand for half-an-hour, the temperature is raised to + 100 C, then 25 the whole is maintained for three-and-a-half hours at ambient temperature 13 cm 3 of IN hydrochloric acid are added, and the whole is agitated, decanted, washed with IN hydrochloric acid, then with water It is extracted with methylene chloride, dried and concentrated to dryness, and 7 89 g of crude residue are obtained.
The product obtained has the syn configuration 30 Stage C: 2 ( 2 tritylamino 4 thiazolyl) 2 ethoxyimino acetic acid A mixture of 7 89 g of the product obtained in Stage B, 40 cm 3 of dioxane and 19.5 cm 3 of 2 N sodium hydroxide solution is heated at 1 100 C for one hour The mixture is vacuum-filtered, rinsed with an ether/dioxane mixture, then with ether alone and dried 6 25 g of sodium salt are obtained and taken up in 60 cm 3 of 35 methylene chloride and 20 cm 3 of IN hydrochloric acid, the two phases are agitated, 20 cm 3 of methanol are added, the whole is decanted, washed with water, extracted with a methylene chloride/methanol mixture, dried and concentrated, and 5 85 g of pure 2 ( 2 tritylamino 4 thiazolyl) 2 ethoxyimino acetic acid are isolated 40 The product obtained has the syn configuration.
Example 4
2 ( 2 tritylamino 4 thiazolyl) 2 isopropyl oxyimino acetic acid Stage A: Ethyl 2 acetyl 2 isopropyloxyimino acetate 39 8 g of ethyl 2 acetyl 2 hydroxyimino acetate are placed in 200 cm 3 of 45 pure acetone The whole is cooled in an ice bath and 52 g of potassium carbonate are added then, over half-an-hour, 25 cm 3 of 2-iodopropane The whole is then agitated for 2 hours, 800 cm 3 of water and 500 cm 3 of methylene chloride are added, the whole is agitated, decanted, extracted with methylene chloride, dried, vacuumfiltered and concentrated, and 41 5 g of the expected product are isolated 50 Stage B: Ethyl 4 bromo 2 isopropyloxyimino acetyl acetate The 41 5 g of the product obtained in the previous stage are placed in 190 cm 3 of methylene chloride with traces of para-toluene-sulphonic acid The whole is agitated and a solution of 11 9 cm 3 of bromine in 50 cm 3 of methylene chloride is introduced, over one hour, at ambient temperature The whole is agitated, iced 55 water is added, the whole is decanted, extracted with methylene chloride, washed with iced water, dried and concentrated, and 55 g of the expected derivative are isolated.
I 1,580,623 Stage C: Ethyl 2 ( 2 amino 4 thiazolyl) 2 isopropyloxyimino acetate 14.9 g of thiourea are placed in 55 cm 3 of ethanol and 105 cm 3 of water and a solution of the 55 g of the product prepared in Stage B in 55 cm 3 of ethanol is added over 40 minutes The whole is agitated for two-and-a-half hours at ambient 5 temperature, 220 cm 3 of 10 %,, sodium bicarbonate in water are added, the whole is agitated, vacuum-filtered, rinsed and dried, and 42 15 g of crude product are isolated and chromatographed on silica eluting with ether The fractions rich in the desired product are recovered, then concentrated, the crystals are taken up with isopropyl ether, vacuum-filtered and rinsed 10 75 g of the desired product are 10 obtained.
The product obtained has the syn configuration.
Stage D: Ethyl 2 ( 2 tritylamino 4 thiazolyl) 2 isopropyloxyimino acetate 11 g of the product obtained in Stage C are placed in 20 cm 3 of dry dimethyl 15 formamide, 40 cm 3 of methylene chloride and 6 2 cm 3 of triethylamine The mixture is cooled and 13 2 g of trityl chloride are slowly added, the whole is agitated for two-and-a-half hours, 43 cm 3 of normal hydrochloric acid are added, the whole is agitated, decanted, washed with 40 cm 3 of water, extracted with methylene chloride, dried, vacuum-filtered and concentrated to dryness, and 27 7 g 20 of the expected product are obtained.
The product obtained has the syn configuration.
Stage E: 2 ( 2 tritylamino 4 thiazolyl) 2 isopropyloxyimino acetic acid A mixture of 27 7 g of the product obtained in Stage D, 150 cm 3 of dioxane and 25 cm 3 of 2 N sodium hydroxide are refluxed for two hours The sodium salt crystallises, the mixture is cooled, vacuum-filtered, rinsed with a 1:1 ether/dioxane mixture and dried, and 16 85 g of crude sodium salt are obtained 15 9 g of this sodium salt are dissolved in 15 9 g of dimethyl-formamide, 100 cm 3 of water and about 500 cm 3 of methanol 30 cm 3 of 2 N hydrochloric acid are added and the 30 methanol is driven off The remainder is diluted with water, vacuumfiltered, rinsed and dried The 9 8 g of viscous product obtained are taken up in 220 cm 3 of a 50:50 methylene chloride methanol mixture, concentrated to dryness, taken up with ether and disintegrated The formed crystals are vacuum-filtered, rinsed and dried.
4 9 g of the desired acid are obtainedM Pt _ 170 C 35 An analytical sample is obtained by dissolving 300 mg of crude product in 2 cm 3 of methylene chloride and 1 cm 3 of methanol, diluting this solution with water and methylene chloride This solution is then agitated and the formed crystals are vacuum-filtered off, rinsed with methylene chloride and with water, then dried and 230 mg of pure product are isolated for analysis 40 Analysis:
Calculated: C ' 68 77 H% 5 34 N O 8 91 S% 6 8 Found: C% 68 6 H% 5 5 N% 8 8 S% 6 8 The product obtained has the syn configuration.

Claims (1)

  1. WHAT WE CLAIM IS: 45
    1 A compound of the general formula:
    NH R 2 SXN \=W C 02 H N-O Ri 2 (lb) 1,580,623 wherein R 2 represents a hydrogen atom or a group removable by acid hydrolysis or by hydrogenolysis and R'2 represents a hydrogen atom, a group removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from I to 4 carbon atoms, with the proviso that R'2 does not represent a hydrogen atom when R 2 represents a group removable by acid hydrolysis or by 5 hydrogenolysis, in the form of the syn isomer.
    2 A compound as claimed in claim 1, being a syn isomer of the general formula:
    NH-R 1 S>%N C 02 H 1 r tr aci r 1 a O wherein R 1 represents a group removable by acid hydrolysis or by hydrogenolysis oa and R', represents a group removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from I to 4 carbon atoms.
    3 A process for preparing the compounds of general formula II, as claimed in claim 2, in which process a syn isomer of the general formula:
    NH R 1 Svb N CO 2 alk 15 N \NO Rl I 11111 (wherein R 1 and R'1 are as defined in claim 2 and alk represents an alkyl radical having from 1 to 4 carbon atoms) is reacted first with a base and then with an acid to form a product of general formula II.
    4 A process as claimed in claim 3, in which the base is sodium hydroxide.
    5 A process as claimed in claim 3 or claim 4, in which the acid is dilute 20 hydrochloric acid.
    6 A process as claimed in any of claims 3 to 5, in which the compound of general formula III is prepared by treating the corresponding syn isomer of the general formula:
    NH 2 SUN CO 2 alk 25 0 R 1 (IV) (wherein R' represents a hydrogen atom, a group removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from I to 4 carbon atoms and alk is as defined in claim 3) with a compound capable of introducing a group removable by acid hydrolysis or by hydrogenolysis to form the desired product of general formula III 30 7 A process as claimed in claim 6, in which the compound of general formula 1,580,623 1,5063 i IV is treated with trityl chloride in the presence of trialkylamine, Nmethylmorpholine or pyridine.
    8 A process as claimed in any of claims 3 to 5, in which the compound of general formula III wherein R'1 represents a saturated or unsaturated hydrocarbyl radical having from I to 4 carbon atoms is prepared by a multi-step process in 5 which an appropriate svn isomer of the general formula:
    NH 2 S)+N CO 2 alk N'OH i V( 1) (wherein alk is as defined in claim 3) is treated with an equivalent of a compound capable of introducing a group removable by acid hydrolysis or by hydrogenolysis to obtain the corresponding product of general formula: 10 NH R 1 -C/ CO 2 alk N OH (V {V (wherein R 1 is as defined in claim 2 and alk is as defined in claim 3) which is then treated with a hydrocarbylating agent to obtain the desired syn isomer of the general formula:
    NHR 1 H H R SUN 5\ < CO 2 alk 15 N \OR b {(ila) wherein R 1 is as defined in claim 1, alk is as defined in claim 3 and R"b represents a saturated or unsaturated hydrocarbyl radical having from I to 4 carbon atoms.
    9 A process as claimed in claim 8, in which the compound of general formula IV" is treated with trityl chloride in the presence of a trialkylamine, Nmethylmorpholine or pyridine 20 A process as claimed in claim 8 or claim 9, in which the hydrocarbylating agent is an alkyl halide or an alkyl sulphate.
    11 A process as claimed in claim 3 and substantially as described herein with reference to any one of the Examples.
    12 A process for preparing a compound of general formula llb, as claimed in 25 claim 1, wherein R 2 and/or R'2 represent(s) a hydrogen atom, comprising subjecting a compound of general formula II claimed in claim 2 wherein R 1 and/or R', represent(s) a group removable by acid hydrolysis or by hydrogenolysis to acid hydrolysis or hydrogenolysis, as appropriate, so as to form the corresponding compound of general formula lib 30 13 A process as claimed in claim 12 substantially as described herein with reference to any one of the Examples.
    1,580,623 1 n 11 1,580,623 1 1 14 A compound of general formula Ib as claimed in claim 1, whenever prepared by a process as claimed in any of claims 3 to 13.
    2 ( 2 Tritylamine 4 thiazolyl) 2 methoxyimino acetic acid, svn isomer.
    16 A syn isomer of general formula III as defined in claim 3 5 17 A syn isomer of general formula IV as defined in claim 6.
    For the Applicants, SANDERSON & CO.
    Chartered Patent Agents, 97, High Street, Colchester Essex.
    Reference has been directed in pursuance of section 9, subsection ( 1) of the Patents Act 1949, to patent No 1,536,282.
    Printed for Her Majesty's Stationery Office by the Courier Press Leamington Spa 1980 Published by The Patent Office, 25 Southampton Buildings, London WC 2 A l AY, from which copies may be obtained.
GB15561/79A 1976-01-23 1977-01-21 2-(2-amino-4-thiazolyl)-2-hydroxymino-acetic acid and substituted derivatives thereof useful as intermediates in the manufacture of antibiotic oxime derivatives of 7-aminothiazolyl-acetamido-cehalosporanic acid and processes for preparing them Expired GB1580623A (en)

Applications Claiming Priority (3)

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FR7601834A FR2346014A1 (en) 1976-01-23 1976-01-23 Amino-thiazolyl-hydroxyimino-acetamido-cephalosporanic acids - with antibacterial activity
FR7617743A FR2361893A2 (en) 1976-01-23 1976-06-11 Amino-thiazolyl-hydroxyimino-acetamido-cephalosporanic acids - with antibacterial activity
FR7625051A FR2361894A2 (en) 1976-01-23 1976-08-18 Amino-thiazolyl-hydroxyimino-acetamido-cephalosporanic acids - with antibacterial activity

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GB15561/79A Expired GB1580623A (en) 1976-01-23 1977-01-21 2-(2-amino-4-thiazolyl)-2-hydroxymino-acetic acid and substituted derivatives thereof useful as intermediates in the manufacture of antibiotic oxime derivatives of 7-aminothiazolyl-acetamido-cehalosporanic acid and processes for preparing them

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JPS5444695A (en) * 1977-09-13 1979-04-09 Fujisawa Pharmaceut Co Ltd 3,7-disubstituted-3-cephem-4-carboxylic acid and its salt and their preparation
FR2410655A1 (en) * 1977-12-05 1979-06-29 Roussel Uclaf NEW OXIMES DERIVED FROM 3-SUBSTITUTE 7-AMINO THIAZOLYL ACETAMIDO CEPHALOSPORANIC, THEIR METHOD OF PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS
JPS5498795A (en) * 1978-01-13 1979-08-03 Takeda Chem Ind Ltd Cephalosporin derivative and its preparation
FR2387235A1 (en) * 1978-01-23 1978-11-10 Fujisawa Pharmaceutical Co PROCESS FOR THE PREPARATION OF COMPOUNDS OF 3,7-DISUBSTITUE-3-CEPHEM-4-CARBOXYLIC ACID AND NEW PRODUCTS THUS OBTAINED, HAVING A STRONG ANTIBACTERIAL ACTIVITY
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Date Code Title Description
PS Patent sealed [section 19, patents act 1949]
704A Declaration that licence is not available as of right for an excepted use (par. 4a/1977)
PE20 Patent expired after termination of 20 years

Effective date: 19970120