CS268526B2 - Method of 7 beta(carboxyakenoyl)-3-cefem-4-carboxyl acids production - Google Patents

Abstract

Cephems and analogues of formula (I) are new. R = aryl or heterocyclyl; R1 = H or halogen; R2 = single bond, alkylene, oxa-alkylene or thia-alkylene- R3, R6 = H, salt-forming atom or gp. or ester-forming gp.; R4 = H or MeO; R5 = H or a 3-substituent as found in cephalosporins; X = O, S or SO. Provided that when R2 = thia-alkylene, then R1 = halogen. - Intermediates of formula (II) are new.

Description

The present invention relates to a process for the preparation of antibacterially active 7β- (carboxyalkenoylamino) -3-cephem-47-carboxylic acids of the general formula I

CONH

C

COOR wherein the amino is a thiazolyl group optionally protected by a protecting group selected from formyl, chloroactyl, tert-butoxycarbonyl, benzyloxycarbonyl and tert-butyldlmethyl ethyl and

means a hydrogen atom or a carboxy group which is protected by the same or different groups selected from the group consisting of methyl, tert-butyl, benzyl, methylbenzyl, p-methoxybenzyl and diphenyl.

A closer explanation of the various groups contained in the general formula will now be given

R is an aminothiazolyl group which may be protected by the protecting groups listed above. However, it is also possible for R to be an unprotected aminothiazolyl group. Of these, it is most preferred that R is a protected aminothiazolyl group.

The substituents and R 'are hydrogen or a modified carboxy group, conveniently an ester-forming group. It is particularly advantageous to obtain derivatives suitable for therapeutic purposes.

Protecting groups are not present in the compounds obtainable according to the invention, although this could be the case because their structure has no particular significance if the group can serve well for protection. Such groups could, however, be present and could be a wide variety of equivalent groups.

The substituents R1 and R2, as mentioned above, in particularly preferred cases lead to derivatives suitable for therapeutic purposes. In such cases, pharmaceutically acceptable esters are formed which have an antibacterial effect when administered orally or parenterally and include well-known alkyl esters.

bacterially _effective> antibakterlálně Of these effective compounds which contain R in cis position. The second geometric isomer, i.e., trans-isomer is useful as an intermediate for the preparation of the corresponding cis isomer.

An overview of some representative compounds of Formula I obtainable by the present invention is set forth below. However, these compounds are not to be construed as exhaustive of the compounds within the scope of the present invention.

β - / @ 2- / 2-aminothiazol-4-у 1/4-carboxy-2-enoyl -but-amino _- ^J'-3-Cei> em-4-carboxylic acid, γ д - £ 2/2 -amino-thiazol-4-yl-4-carboxy-2-butenoylamino-4-methyl-4-carboxylic acid,

7β - £ 2- / 2-aminothiazol-4-у 1/4-carboxy-2-butene-1-amino-Хг.уХ -З- ^ ^ Зусе en2-4 kp_rboxylová-acid, β - _j CT2- / 2-Aminothiazol-4-yl-4'-carboxy-2-butenoyl-amino-7-3-trifluoropropenyl-3-cephem-4-carboxylic acid, β-η 2- (2-airlnothiazol-4-yl) -4- carboxy-2-butenoyl-amino-ac _e _7-3 toxymethyl -3.

CS 268 526 B2 cefem-4-carboxylic acid,

7C-2- (2-Aminothiazole-4-71) -4-carboxy-2-butenoylamino-4-carbamoyloxymethyl-3-cephen-4-carboxylic acid,

0- £ ^r 2- / 2-aminothiazol - 4-yl / -4-carboxy-2-butenoylaiiiino -3rmethoxymethyl-3-cephem-4-carboxylic acid,

2- 2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino-7-methyl-thiomethyl-3-oxo-4-carboxylic acid;

O - C 2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino-7,3-cyanomethylthiomethyl-3-cephem-4-carboxylic acid,

0-C 2-aminothiazol-4-yl-carboxy-2-butenoylamino-1,3-pyridinicethyl-3-cephem-4-carboxylate,

(R) - (2- 2- (2-Einothiazol-4-yl) -4-carboxy-2-butenoylamino) -7-3-triazolylthioethyl-3-cepea-4-carboxylic acid,

7β - [2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -7-3-thiadlazolylthioethyl-3-cephem-4-carboxylic acid,

0- [2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-methyltetrazolylthioaethyl-3-cepea-4-carboxylic acid; 4-yl / -4-carboxy-2-butonoylamino-7,3-methoxy-3-cofem-4-carboxylic acid, β- [2- (2-aminothiazol-4-yl) -4-carboxy-2] -butenoylamino-27-3-chloro-3-ene-4-carboxylic acid,

O- [2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-fluoroethylthio-3-cepha-4-carboxylic acid, β-22 2- / 2-aminothiazole- 4-yl-4-carboxy-2-butenoylamino-4 H -3-trifluoroethylthio-3-cepetine-4-carboxylic acid, β-2- (2-aminothiazol-4-yl) -5-carboxy-2-pentenoyl- amino 27-3-cephem-4-carboxylic acid, β-β-2- (2-arainothiazol-4-yl) -6-carboxy-2-hexenoylamino η 7 * 3-cephem-4-carboxylic acid, β-β * 2- (2-Aminothiazol-4-yl) -4-carboxy-2-pentenoylamino-2,3-cephem-4-carboxylic acid, β-2- (2-aminothiazol-4-yl) -4-carboxy- 4-methyl-2-pentenoylamlno JT-3-cephem-4-carboxylic acid and β - 2T ² '/ ^{2' aninot} thiazol-4-yl / -4-carboxy-3-chloro-2-butenoylanino -З-сеfеи-4kerboxylové acid.

Some of the compounds closely related to the compounds of the invention are disclosed in Japanese Patent Publications Kokoku'10 996/1967 and Kokai 57-93982 and Belgian Patent Nos. 816,408 and 888,389. However, these compounds do not exceed the compounds of Formula I in antibacterial activity, intrinsic or parenteral absorbability, interchangeability, or similar characteristics.

The compounds of the formula I are antibacterially active against aerobic grempositive bacteria (e.g. Bacillus cereus, Bacillus subtilis, Corynebacterium dlphtheriae, Staphyloxoccus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus pyogenes, Streptococcus pyogenes, Streptococcus pyogenes, Streptococcus pyogenes, Streptococcus pyogenes, freundii, Enterobacter aerogena, Enterobacter cloacae, Escharichls coli, Haeaophilus influenzae, Klebsiella pneumoniae, Neiaseria gonorrhoeae, Neieseria meningitidis, Proteus mirabilis, Progous morganii, Proteus vulgaria, Salmonidosa ssp. Shigella sonnei, Yersinia enterocolitiCS 268 526 B2 ca /, including anaerobic bacteria / for example Bacteroides fragilie, Clostridium difficile,

Clostridium pmrfringena, Aubaceterium lentua, Fuaobacterium nucleatua, Propionibacterlum epp, peptostrptococci, Veillonella app.

Especially high antibacterial activity against gram-negative bacteria, high absorption, secretion, distribution and the like are evident · 3 as medicaments for the protection or treatment of bacterial infections and are administered orally, parenferally or topically in a daily dose of 10 mg to 6 g they are desirably administered with the usual additives or coatings, for example other antibacterially active substances.

The compounds are useful as bsctoricidal, bacteriostatic, disinfectant or perishable agents and are useful in the treatment or prevention of human, veterinary or poultry infections caused by sensitive gram-positive or gram-negative bacteria, including anaerobic bacteria. , plant or perishable articles, food additives to promote growth in humans or animals, or as a means of testing the susceptibility of bacteria to antibacterially active compounds of Formula I *.

The protected compounds of formula I are also suitable as starting materials for the synthesis of other antibacterially active compounds of formula I.

The invention also relates to a method of treating or protecting against human or veterinary bacterial infections, such as abscess, bronchitis, dermatitis, ear infections, inflammation, enteritis, gastroenteritis, naeopharyngitis, osteomyelitis, pneumonitis, pneumonia, pustuitis, respiratory tract, pustuloza, pustuosis. , Rhine, septicemia, tonsillitis, ulceration, Urinary tract infections, soft tissue injury infections caused by susceptible bacteria, when an effective amount of a compound of formula I is administered at a usual daily dose of 10 mg to 1 g externally, 0.2 to 5 g introsvenase or 0.1 to 2 g orally at a time interval of 3 to 12 hours, depending on the infecting bacterium and the patient's conditions and, if desired, treated with the usual ingredients

The carboxylic acid compound of formula I nobo its light metal salt ee can be injected or infused intravenously, intramuscularly or eubcutaneously, for example, as injection or pellets, or administered orally as oral preparations, for example, capsules, dry syrup, emulsion, granules, powder, solution , suspensions, tablets and taps and, if desired, in admixture with an excipient such as an emulsifying agent. The pharmaceutically active eeter can be administered intravenously, intramuscularly, subcutaneously, orally, externally or locally, for example as an ear, nasal or ophthalmic drug. , ointment, inhalant, injection, cough medicine, spray or suppository.

When R is 2-amino-4-thiazolyl and R ³ and R ⁶ are hydrogen, the compound of formula I is absorbed by the oral as well as subcutaneous route. Pharmaceutically acceptable esters of the compounds of formula I are also absorbed by the digestive tract.

The present invention further relates to an antibacterially active pharmaceutical composition comprising a compound of formula I in various enteric and oral dosage forms, alone or in admixture with nobo coating agents. The compositions may contain 0.01 to 99% of a compound of formula I dissolved, dispersed or suspended in solid or liquid pharmaceutical carriers.

The compositions may be solid formulations, for example, capsules, syrup, granules, pellets, pills, powder, suppositories, capsules or tablets, or liquid formulations, for example diepension, elixir, emulsion, inhalant, injection, ointment, suspension, syrup, vial solution or a container containing crystals, lyophilized material or powder. These may be flavored or colored and the capsules, granules and tablets may be coated. These compositions may be in unit dosage form.

The carriers are harmless to both the compound of formula I and the patient. Repre4

Examples of such carriers are, for example, solid binders such as gum arabic, carboxymethylcellulose, gelatin, glucose, polyvinylpyrrolidone, sodium alginet, sorblt, starch, syrup or tragacanth, wetting agents such as bentonite calcium carbonate, calcium phosphate, glycine, kaolin, lactose, polycarboxyaethylan, sodium chloride, aorbitol, starch, sugar or aaatek, diluents such as calcium carbonate, kaolin, lactose, starch or eacharose, deaintegrators such as agar, carbonates, sodium lauryl sulfate or Starch, glidants such as boric acid, coke butter, magnesium stearate, paraffins, polyethylene glycol, silica, sodium bonzoate, stearic acid or talc, and wetting agents such as hydroxypropylcellulose, for solvent solutions such as alcohol, buffer, m-methylol, peanutoil, eeza oil or water, and emulsifying agents, for example, arabic guaa lethicin or eorbitan monooleate, and apapating agents, for example, aluminum stearate gel, carboxymethylcellulose, gelatin, glucose, hydrogenated fats, hydroxyethylcellulose, nethylcellulose, aorbitol or sugar syrup, buffering agents, and, for both types, preservatives, such as methyl p-hydroxybenzoate or ethyl p-hydroxybenzoate or aorbic acid, absorption promoters such as glycine, mono- or dioctanoate, antioxidants, aromatics, analgesics, edible colorants, stabilizers etc*

All of the above-mentioned pharmaceutically active compositions can be prepared by conventional methods.

As mentioned above, the present invention relates to a process for the preparation of compounds of the formula (I). This process is characterized in that the ee 3- (hydroxy, acyloxy or halogen) cepheum compound of the formula (II)

and then the direct amino groups, pothioureas, are lost

R ³ , R ³ and R ⁶ are as defined above and

R ⁷ represents hydroxy, acyloxy or halogen atom, subjected to basic or thermal elimination of the substituent R ^{7 of the} cephem nucleus, the product obtained further deprotects the carboxy protecting group or, if present, hydrogen halide, trihaloacetic acid, acid and Lewis acid selected from the group including aluminum halide, titanium halide and tin halide, if desired in the presence of anisole, and / or converted to a salt by treatment with an aqueous alkali metal bicarbonate solution.

Both basic and thermal elimination are reactions known per se · Basic elimination uses substances of basic character, inorganic or organic origin ·

The thermal elimination is generally carried out at a temperature of -60 to +120 ° C, preferably at a temperature between -20 and * 80 ° C for 10 minutes to 10 hours in a solvent. Other conventional conditions, such as stirring, shaking, inert gas enclosure or drying ·

Examples of typical reaction solvents are hydrocarbons such as pentene, hexane, octane, benzene, toluene, as well as xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane or chlorobenzene, ethers such as diethyl ether, methyliaobutyl ether, dioxane nobo tetrahydrofuran ketones, for example acetone, methyl ethyl ketone or cyclohexanone, ethers, for example ethyl acetate, i-butyl acetate or methyl benzoate, nitrated hydrocarbons, for example

Nitromethane or nitrobenzene, nitriles such as acetonitrile or benzonitrile, amides such as formamide, acetamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric acid, sulfoxides such as dimethyl sulfoxide, carboxylic acids such as formic acid, acetic acid, propionic acid, organic bases such as diethylemine, triethylamine, pyridine, picoline, collidine or quinoline, alcohols such as methanol, ethanol, propanol, hexanol, octanol or benzyl alcohol, or water and other industrial solvents and lards;

The products can be recovered from the reaction mixture by removing impurities such as solvents, unreacted starting materials or by-products by conventional methods such as extraction, evaporation, washing, concentration, precipitation, filtration or drying and isolation of the product by conventional treatment such as adsorbt, elution, distillation, precipitation , separation or chromatography, or a combination of these procedures ·

The compounds of formula I obtainable according to the invention are well absorbed by the gastrointestinal tract and are therefore useful as oral cafalosporins. The compounds of formula I may also form a salt upon contact with an acid, for example a mineral acid such as hydrochloric acid or carboxylic acid. such as trifluoroacetic acid.

The process of the present invention is illustrated by the following examples, which are not intended to limit the invention in any way.

Example 1

6 equivalents of pyridine and 6 equivalents of anhydride are added to a solution of 7-β- [2- (2-benzyloxycarbonylaminothiazol-4-yl) -4-benzyloxycarbonylbut-2-enoylamino] -3-hydroxycepham-4-carboxylic acid, diphenylmethyleatar sulfoxide in 13 parts of dichloromethane. Acetic acid · After stirring for 13 hours at 0 ° C, the mixture is mixed with 3 equivalents of triethylamine and stirred for 24 hours · The reaction mixture is washed with water, aqueous sodium bicarbonate solution and water again, evaporated and evaporated · 7β- diphenylmethyl ester sulfoxide £ 2- (2-benzyloxycarbonylamino-thiazol-4-yl) -4-benzyloxycarbonyl-2-butenoylamino-3-cepham-4-carboxylic acid in a yield of 40 to 60% ·

The term equivalent ”ee mini molar equivalent of β-lactam starting material. Example 2

A solution of 800 mg of 7β-β-trans-2- (2-benzyloxycarbonylamino-4-thiazolyl) -4-tert-butoxycarbonyl-2-butenoylamino-3-hydroxycafaa-4-carboxylic acid diphenylmethyl ester 1-oxide in more than 10 ml of dichloromethane, 0.485 α1 (6 equivalents) pyridine and 0.7 ml (6 equivalents) of acetic anhydride were stirred for 13 hours to partially or completely produce the acetate. The reaction mixture was stirred with 0.418 ml (3 equivalents) of triethylamine for 24 hours under cooling. ice yields 391 mg of 7β-β-trans-2- (benzyloxycarbonylamino-4-thiazolyl) -4-tert-butoxycarbonyl-2-butenoylamino-3-cephem-4-carboxylic acid 1-oxide diphenylmethyl ether

Melting point: 0 DEG C. The yield of the product is 50%.

Examples 3 to 24

In the manner described in the preceding examples, ee produces, using the appropriate starting compounds, the end products described in the attached Table 1.

CS 268 525 B2

Table 1: Esters of general formula

R ° NH

C --- I

CH

CH _O

I \

COOÍT

Cis · cis: t rans R ° R ³ R ⁵ R ⁶ iC (i want) Y NMR (CDCl 3) (?: Ppa 3 H Me H H not specified 3.70-4.30 (m, 4H), 4.13, 4.16 (2xs, 3H), 5.56, 5.62 (2xd, 3 = 5 Hz, 1H), 6.20, 6.26 ( 2xd, 3 · 5 Hz, 1H), 6.66 6.83 (π ·, 1H), 6.90, 7.26 (2xt, 3 = 9 Hz, 1H), 7.06, 7.13 (2χβ, 1H) £ 0 ₂ 0? 4 C8 H Me H BH 1787 1731 1680, 1280 3.35-3.47 (m, 2H), 3.58 (d, 3 = 8 Hz, 2H), 3.70 (s, 3H), 4.98 (d, 3-5 Hz, 1H); 5.44 (broad s, 2H), 5.95, 6.04 (dd, ₁ 5 3 Hz, ₂ 3 »9 Hz, IH), 6.47 (s, IH), 6.61 (t, 3 -8 Hz, 1H), 6.56 -6.66 (m, 1H), 6.95 (8, 1H), 7.24-7.48 (a), 8.56 (d, 3-9 Hz, 1H)

trans H

Me H

BH

1785, 1730, 3.40 (d, J = 8 Hz, 2H),

1678; 1280 3.35-3.47 (и, 2H), 3.68 (β, ЗН), 4.92 (d, 3-5)

Hz, 1H), 5.59 (broad s, 2H), 5.94, 6.03 (dd, D 5 - 5 Hz, □ ₂ - 9 Hz, 1H), 6.48 (a,

IH), 6.53 -6.63 (m, IH), 6.90 (with, 1H), 7.14 (t, 3-8 Hz, IH), 7.23-7.45 (m, 10H), 8.65 (d, □ 9 Hz, IH)

CS 268 525 B2

δίο. cis: trans R ° R ³ R ⁵ R ⁶ ID (CHCip ·) j cm '’· *’ NMR (CDCl 3) δ ppm 6 ais H Bzl H BH 1782, 1722, 1278 1670, 3.32-3.46 (m, 2H), 3.62 (d, J = 8 Hz, 2H), 4.95 (d, J = 5 Hz, 1H), 5.13 (in, 2H), 5.31 (wide in, 2H), 5.92, 6.02 tdd, 5 Hz, Jg 8 Hz, 1H), 6.46 (δ, IH), 6.53-6.61 (m, IH), 6.63 (t, J = 8 Hz, IH), 6.94 (β, IH) , 7.21-7.47 (m), 8.67 (d J = 8Hz, 1H) 7 trance H Bzl H BH 1780 1721 1280 1670, 3.30-3.45 (m, 4H), 4.88 (d, J = 5 Hz, IH), 5.11 (β, 2H), 5.52 (wide β, 2H), 5.92, 6.02 (dd, »5 Hz, Jg => 8 Hz, IH), 6.41 (δ, IH), 6.50-6.65 (m, IH), 6.88 (β, IH), 7.15 (t, J = 7.5Hz, IH), 7.16-7.48 (a), 8.61 (d, □ Hz, IH) 8 1: 4 Chz Bzl H H not specified 3.00-3.90 (m, 4H), 4.96, 5.00 (2xd, J = 5Hz, 1H), 5.13 (in, 2H), 5.23 (in, 2H), 5 , 73-5.88 (m, 1H), 5.76, 5.86 (dd, -5 Hz, Jg = 9 Hz, 1H), 6.50-6.60 (.m, 1H), 6, 93 (δ, IH), 7.11 (t, J = 8 Hz, IH), 7.33 (δ, 5 Hz),. 7.36 (в, 5H) [CDC1 ₃ - CD-dep 9 Chs Bzl H H 3160 1775 1670, 1630 1720, 3.34-3.50 (m, 4H), 4.95 (d, J = 5 Hz, 1H), 5.13 (in, 2H), 5.23 (in, 2H), 5.80 (d, J-5) Hz, 1H), 6.48-6.60 (δ, IH), 6.94 (e, 1H), 7.03-7.40 (a, 11H) 10 trance Chz t-Bu H BH 3330 1775 1670 1630 162-164 ° l 1725, 1.34 (t, 9H), 2.58-3.26 (m, 4H), tt: 4.70 (d, J = 5 Hz, 1H), 5.07, 7 5.51 (ABq) J = 13 Hz, 2H), 5.68, 5.76 (dd, J _× 5 Hz, J g = 8 Hz, 1H), 6.30-6.39 (m, 1H), 6.61 ( δ, IH ;, 6.75 (δ, IH), 7.10 -7.57 (m, 15H), 7.67 (d, J = 8 Hz, IH) 11 1: 4 Chz Bzl H BH 3340 1775 1725, 3.04 (in, 2H), 3.6-4.1 (m, 2H)

1670 4.58 (d, J = 5Hz, 1H), 4.85.6 (m, 4H), 5.68 (d, J = 5)

Hz, 1H), 6.25 (m, 1H), 6.59,

6.67 (2χβ, IH), 6.63 (e, IH),

7.0-7.9 (m. 22H)

CS 268 525 B2

^R6 IR (CHCl?) NMR (CDCl-j): ppm t cm ^"3 · No. cist R 0 R ³ R ⁵ trans trans

Chz Bzl H

BH 3830, 1780, 1725, 1675, 1630, mp: 131-133 ° C

2.68-3.36 (m, 4H), 4.69 (d, J = 5 Hz, 1H), 4.98 (s, 2H), 5.03, 5.46 (ABq, J - 12 Hz) 2H), 5.65, 5.74 (dd, J _x - 5 Hz, J ₂ »8 Hz, 1H), 6.29 to 6.40 (m, 1H), 6.60 (β, 1H) 6.64 (α, 1H), 7.10 -7.47 (m, 15H), 7.63 (d, J = 8 Hz, 1H)

Chz MeBzl H

BH 3340 1775

1770, 1670,

1630, 1560

2.30 (s, 3H), 2.70-3.37 (n >, 4H), 4.71 (d, J = 5 Hz, 1H),

4.95 (d, 2H), 5.04, 5.49 (ABq,

J = 12 Hz, 2H), 5.67, 5.76 (dd, < 5 Hz, J < ₂ > 8 Hz, 1H), 6.30-6.40 (m, 1H), 6.62 (в, 1H), 6.69 (e, 1H), 7.05-7.47 (m, 20H), 7.66 (d, J = 8Hz, 1H)

14 Chz PMB H BH 3325 »1771, 2.60-3.65 (m, 4H); 3.74 (s. 1720, 1665, 3H), 4.67, 4.75 (2xd, J = 5 Hz, 1625, 1605, 1H), 4.86-5.53 (m, 4H), 5.65, 1505, 1400 5.73, 5.82 (2xdd, J _x -5 Hz,

J ₂ = 7Hz, 1H), 6.25-6.50 (m, 1H), 6.59-6.95 (m, 4.5H), 7.057.50 (m, 18.5H), 7, 65, 7.90 (2xd, J = 7Hz, 1H)

15 Dec trance BOC Bzl H BH 3400 1.50 (s, 9H); 3.16 (d, J = 4.5) 1773 1720 Hz, 2H), 3.29 (d, J = 8 Hz, 2H), 1668, 1278 4.73 (d, J = 5Hz, 1H), 5.04 1152 (s, 2H), 5.68, 5.77 (dd, J = _x

Hz, J ₂ - 7.5 Hz, 1H), 6.35 (t, J = 4.5 Hz, 1H), 6.64 (s, 1H), 6.71 (s, 1H), 7.17 -7.48 (m), 7.79 (d, J = 7.5 Hz, 1H) cis

BOC Bzl

34Ю, 3340, 1.53 (t, 9H), 3.15-3.37 (m, 2H), 1780 1725 3.86 (d, J = 7Hz, 2H), 4.85 1682, 1282, (d, J = 5 Hz, 1 H), 5.17 (s, 2 H), 1154 5.82, 5.91 (dd, 5 Hz, J ₂ = 8 Hz, 1H), 6.43-6.54 (m, 1H), 6.70 (t, J = 7 Hz, 1H), 6.79

(s, 1H); 6.83 (s, 1H); 7.15-7.49 (m); 8.14 (d, 1H);

HCO H

Η H not determined

5.02 (d, J = 5Hz, 1H), 5.86 (d, J = 5Hz, 1H), 6.54-6.64

CS 268 525 B2

^R6 IR (CHCl?) NMR (CDCl-j) (f: ppm x cm ^"3.

Ref.

cis: R ° R ³ R ⁵ trans (m, 1H), 7.04 (t, J = 1 Hz, 1H), 7.16 (in, 1H), 8.51 (a, 1H). - CDjODj

IS trans HCO t-Bu Η BH

3420,1770,

1715, 1665, 1625

1.39 (α, 9H), 3.12 (broad β, 2H), 3.27 (d, 3-7 Hz, 2H), 4.67 (d, 35 Hz, 1H), 5.74, 5.83 (dd, 3 J - 5 Hz, □ _2-8 Hz, 1H), 6.29 to 6.38 (β, 1H), 6.62 (β, 1H), 6.83 _(8, 1H) 7.20-7.47 (m, 11H), 7.68 (d, 3-8 Hz, 1H), 8.51 (s, 1H)

1x2

HCO BH

H BH 1775, 1772,

1672 1280

1152

3.60-3.16 (in, 2H), 3.46, 3.87 (2xd, 3-8 Hz, 2H), 4.65, 4.70 (2xd, 3-5 Hz, 1H), 5 , 72, 5.81x5.77, 5.86 (2xdd, 3 _χ - 5 Hz, 3 ₂ - 8 Hz, 1H), 6.26-6.45 (а, 1H), 6.61, 6.76 (2xs, 1H), 6.66 (3, 1H), 6.87, 6.95 (2xs, 1H), 7.10-7.47 (-), 7.64, 7.86 (2xd, 3) - 2 Hz, 1H), 8.40, 8.43 (2X8, 1H), 11.27, 11.51 (2x 51-y in 1H)

1: 2

Cl H H H

AND

CH ₂ CO

1761.1720, 4.61, 4.75 (2xa, 2H), 5.45, 5.51

1700, £ nujolj (2x d, 3-5 Hz, 1H), 6.08, 6.19 '(2xdd, _χ 3 - 5 Hz, 3 _2-8 Hz. 1H), 7.01, 7.30 ( 2XT, 3-8 Hz,

1H), 7.60, 7.72 (2X8, 1H), 8.26, 8.74 (2xd, 3-8 Hz, 1H)

C CO ₃ S0CD ₃ ]

21 Cl 1 CH ₂ CO Bzl H H 3150,1770, 1718.1680, 1278.1152 [jw j of] 3.38-3.70 (4H), 4.38 (β, 2H), 5.06 (d, 3-5 Hz 1H), 5.13 (a, 2H), 5.73, 5, 82 (dd, _χ 3 - 5 Hz, 3 _2-8 Hz, 1H), 6.41-6.52 (s, 1H), 6.62 (t, 3 - 7.5 Hz, 1H), 7, 24 ( ₉ , 1H), 7.38 (β, 5H), 9.00 (d, 3-8 Hz, 1H), 12.57 (Wide, 1 H) δ cd ₃ socd ₃ J 22nd 5: 6 Cl CH ₂ CO Bzl H BH 3320 1780 1732 1727 1680 3.13, (2xd, 4.69: 3.26 (d, 2H), 3.36.3.76 □ - 8 Hz, 2H), 3.87, 4.16, 4.32 (2xA8q, 3-17

Hz, 2H), 4.70, 4.79 (2xd, 3 5.0 Hz, 1H), 5.06, 5.17 (2xs, 2H), 5.69, 5.78x5.87 (2xdd, 3) _χ 5.0 Hz, 3 ₂ - 9.0 Hz, 1H), 6.3110

CS 268 526 B2 Art.

cis: trans

R ° R ³ R ⁵

R ⁶ L6 (, CHC1 ₃₎ BMR (CDCl) ppm ζ t "cm" ^3.

6.48 (m, 1H), 6.66, 6.75 (2xs, 1H), 6.72, 6.83 (2xs,

1H), 6.67 (t, 3-8 Hz, 5H / 11), 7.18-7.49 (.), 7.73, 7.94 (2xd, J = 9 Hz, 1H) trans tBuSi- Bzl H

N

Me ₂

BH 3400, 1785, 0.28 (,, 6H), 0.93 (,, 9H),

1725, 1670, 3.18-3.78 (·, 2H), 3.47 (d, 3 »

1630 7.5 Hz, 2H), 4.79, (β, 1H),

4.98 (d, H - 5 Hz, 1H), 5.16 (β, 2H), 6.00 (dd, _χ 3 - 5 Hz, 3 _2-9 Hz, 1H), 6.48 (а, 1H), 6.57-6.67 (·, 1H), 6.98 (α, 1H), 7.17 (t, 3 - 7.5 Hz, 1H), 7.27.6 (·, 15H) 8.65 (d, 3-9 Hz, 1H)

Me ₂

BH

3390.1780, 0.28 (а, 6H), 0.94 (а, 9H),

1720.1670, 3.17-3.75 (·, 2H), 3.66 (d, □ 1630 7.5 Hz, 2H), 4.68 (а, 1H), 4.99 (d, 3 - 5 Hz, 1H), 5.16 (β, 2H),

6.00 (dd, 3 _χ - 5 Hz, 3 ₂ - 9

Hz, 1H), 6.50 (α, 1H), 6.576.65 (>, 1H), 6.68 (t, 3 - 7.5)

Hz, 1H), 6.97) and, 1H), 7.17.6 (·, 15H, 8.35 (d, 3-9 Hz,

1H)

In the above table, the cis and trans symbols indicate the relative position of the amide and carboxyl substituents attached to the double bond of the side chain,

Abbreviations used in the tabooe have this meaning »

BH diphenylmethyl Bu butyl BOC tert-butoxycarbonyl Bzl benzyl Chz benzoxycarbonyl Me methyl POM pivaloyloxymethyl t tertiary PMB p-methoxybenzyl

CS 268 525 B2

Claims (5)

SUBJECT OF THE INVENTION A process for the preparation of 7β- (carboxyalkenoyl) -3-cephem-4-carboxylic acid of the formula I wherein R is an aminothiazolyl group optionally protected with a protecting group selected from formyl, chloroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl and tert-butyldimethylsilyl; and R ³ and R ⁵ represent a hydrogen atom or a carboxy group which is protected by the same or different groups selected from the group consisting of methyl, tert-butyl, benzyl methylbenzyl, p-methoxybenzyl and diphenyl, characterized in that it is 3- (hydroxy, acyloxy) or a halogen / cephem compound of formula II R— - c --- II ch 1 Г ² CONH 0- ^ with ] - ^R? where COOR ⁰ COOR ⁶ R, R 6 and R 6 are as defined above and R? represents hydroxy, acyloxy or halogen atom, (II) undergoes basic or thermal elimination of the substituent R? cephem core and then optionally further obtaining a deprotected carboxylic acid or amino group, if present, by treatment with trihaloacetic acid, thiourea, zinc and acid or Lewis acid hydrogen halide selected from the group consisting of aluminum halide, titanium halide and tin halide, if needed in the presence of anisole, a / nobo is converted to a salt by treatment with an aqueous alkali metal bicarbonate solution * 2. A process according to claim 1, wherein a compound of formula (I) is prepared using the appropriate starting materials, wherein the 7-acylamide double bond has an amide compound and a carboxy substituent at the cis position. 3. A process according to claim 1, wherein the compound of formula I is prepared using the appropriate starting materials, wherein R is a protected aminothiazolyl group and the other substituents are as defined in point 1. 4. A process according to claim 1, wherein R @ 1 and / or R @ 1 is hydrogen or a pharmaceutically acceptable ester group as defined in point 1 and the remaining substituent is as defined in point 1 * 5. A process according to claim 1, wherein a compound of formula (I) is prepared using the appropriate starting materials in which and / or R1 is a alkyl or aralkyl group falling within the scope of item 1 and the remaining substituent is as defined in point 1 *