Classifications

• • 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
  • C07D277/32—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 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
  • C07D277/38—Nitrogen atoms
  • C07D277/40—Unsubstituted amino or imino radicals
• • 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

Definitions

• the present invention relates to a process for the preparation of salts of organic nitrogen bases with carboxylic acids of formula (I)
• - Q is nitrogen, a hydrocarbyl (CH) or chlorocarbyl (CC1) residue;
• the salts of acids of formula (I) with organic nitrogen bases can be easily transformed into the corresponding free acids (I) or into solvates thereof, or into compounds of general formula (III), which can either be isolated or used in situ, for the preparation of third and fourth generation cephalosporanic antibiotics, such as Cefdinir and Cefdaloxime
• Q and R are as defined above, and Z is a carboxy-activating group conventionally used in the synthesis of cephalosporanic antibiotics, such as an anhydride, an ester or an acyl halide.
• Carboxylic acids of formula (I) are important syntons for the preparation of third and fourth generation cephalosporins having wide spectrum activity and high potency against Gram-positive and Gram-negative microorganisms .
• Said salts can be advantageously used for the preparation of intermediates, which can be isolated or used in situ, for the preparation of third and fourth generation cephalosporins.
• these salts allow faster reaction rates with advantages in terms of both yield and purity of the obtained products.
• the present invention relates to a process for the preparation of salts of organic nitrogen bases with carboxylic acids of general formula (I)
• - Q is nitrogen, a hydrocarbyl (CH) or chlorocarbyl (CC1) residue, preferably nitrogen;
• - R is trityl, benzhydryl or para-methoxy benzyl, preferably trityl; which process comprises reacting a carboxylic acid of general formula
• halide of formula (V) (V) RX wherein R has the meaning defined above and X is a halogen selected from chlorine, bromine and iodine, in the presence of a nitrogen organic base and of an organic inert solvent.
• the nitrogen organic base can be selected from tertiary amines, preferably triethylamine, tributylamine, N-ethyl diisopropylamine, N-methyl morpholine, N-methyl pyrrolidine, N-methyl piperidine, trioctylamine; amidines, preferably diazabicyclononene (DBN) and diazabicycloundecene
• the organic inert solvent can be selected from: halogenated hydrocarbons, preferably methylene chloride and dichloroethane; carboxylic acid esters, preferably ethyl acetate and butyl acetate; ketones, preferably acetone, diethyl ketone and methyl ethyl ketone; amides, for example N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone; aromatic hydrocarbons, preferably benzene, toluene and xylene; ethers, preferably tetrahydrofuran, dioxane or ethylene glycol dimethyl ether; sulfoxides or sulfones, preferably dimethylsulfoxide, dimethyl sulfone and sulfolane; or mixtures thereof.
• halogenated hydrocarbons preferably methylene chloride and dichloroethane
• carboxylic acid esters preferably ethy
• the reaction can be carried out at temperatures ranging from -50° to 200°C, preferably from 0° to 100°C.
• the halide (N) is used typically in stoichiometric amounts to compound of formula (II) or in a slight molar excess, whereas the organic base can be present in a ratio ranging from 1 : 1 to 1 :10, preferably from 1 :2 to 1 :5.
• the halide which is usually added to a mixture consisting of compound of formula (II), base and organic inert solvent, can be added directly in a single or more portions, or it can be dissolved in a suitable organic solvent, for example methylene chloride, dichloroethane, toluene or xylene, and then added to the reaction mixture in a time ranging from a few minutes to some hours.
• a suitable organic solvent for example methylene chloride, dichloroethane, toluene or xylene
• the reaction is usually considered complete when the residual compound (II) is lower than 3% (HPLC analysis).
• the salts which will hereinafter be referred to as compounds (IA), usually crystallize during the reaction or upon cooling the mixture and can therefore be filtered off easily.
• salts (IA) can be further purified from traces of the starting compound (II) and any water-soluble amines hydrochlorides present by treatment with water or an aqueous solvent.
• Drying of salts (IA) does not require particular procedures and can be carried out, for example, under vacuum or by ventilation at temperatures from 30° to 100°C.
• Salts (IA) can be used for the preparation of the corresponding free acids of formula (I) and the solvates thereof, for example with formamide, dimethylformamide, dimethylacetamide or N-methylpyrrolidone, according to conventional methods reported in literature (Liebigs Ann. 1996, 1743 - 1749).
• salts (IA) can be used for the preparation of reactive derivatives of general formula (III), which can be isolated or used in situ in the acylation reactions to obtain cephalosporanic antibiotics, such as Cefdinir, Cefdaloxime and other third and fourth generation cephalosporins, according to the procedures described in literature (US 6,093,814, Organic Process Research & Development 1997, 1 121-123).
• thioester of formula -C(0)-S-R 3 wherein R 3 is a heterocyclic residue selected from 2-pyridyl, benzothiazol-2-yl, benzoxazol-2-yl, benzimidazol-2-yl; preferred is the thioester with 2- mercaptobenzothiazole (EP 0037380, EP 0849269);
• NR 3 R 1 is the residue of a nitrogen heterocycle selected from imidazolyl, 1,2,4- triazolyl, tetrazolyl, benzotriazolyl; preferred is the amide with benzotriazol-3-oxide-l-yl (The Journal of Antibiotics , 1993, 46(2), 359 - 361);
• salts (IA) are usually more soluble in the organic solvents traditionally used for the activation reactions, such as methylene chloride, ethyl acetate and tetrahydrofuran, and the reactions are usually faster, give higher yields and yield compounds of formula (III) having higher purity.
• Salts (IA) allow therefore to carry out a process for the preparation of cephalosporins of general formula (IX),
• Q is as defined above and A is a typical residue of cephalosporins chemistry, preferably vinyl, (-CH ⁇ CH ⁇ or methoxymethylene (-CH 2 -0-CH 3 ).
• Example 1 Preparation of (Z)-2-(2-aminothiazoI-4-yI)-2- trityloxyimino acetic acid triethylammonium salt.
• the suspension was heated to 50°C and a further 1100 ml of ethanol was added in 30 minutes.
• the mixture was gradually cooled to 10°C in an hour, acidified to pH 4.0 by addition of 20% hydrochloric acid, then kept for an hour at 10°C and filtered.
• the solid was washed with water and dried to obtain 366 g of (Z)-2-(2-aminothiazol-4-yl)-2-trityloxyimino acetic acid.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Cephalosporin Compounds (AREA)
• Thiazole And Isothizaole Compounds (AREA)

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• 2001
  • 2001-11-09 IT IT2001MI002363A patent/ITMI20012363A1/it unknown
• 2002
  • 2002-11-05 WO PCT/EP2002/012328 patent/WO2003040116A1/en active Application Filing
  • 2002-11-05 EP EP02802646A patent/EP1442029A1/de not_active Withdrawn
  • 2002-11-05 CN CNB028222148A patent/CN1309713C/zh not_active Expired - Fee Related
  • 2002-11-05 JP JP2003542162A patent/JP2005508385A/ja active Pending
  • 2002-11-05 KR KR10-2004-7006840A patent/KR20040064270A/ko not_active Application Discontinuation

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