CS268513B2 - Method of 7 beta-(carboxyalkanolamino)-3-cefem-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

(57) A process for the preparation of 7- (3-carboxylamino-3-carboxylic acid) -3-ω-4-carboxylic acids α-bacterially active acids of the general formula i.

R represents an aryl or heterocyclic group *

R? means hydrogen or halogen *

R ² represents a single bond alkylene, oxaalkylene or thlaalkylen *

R ^J represents a hydrogen atom or a modified carboxyl group *

R ⁴ is hydrogen or methoxy, R ⁵ * is hydrogen or a substituent at position 3 of a cephalosporin

R ⁶ represents a hydrogen atom or a modified carboxyl group and

X is oxygen, sulfur or sulfinyl, provided that when R is thiaalkylene, R ¹ is halogen * and derivatives thereof, according to the proposed solution is that 7/3 -amino-3-cephem-4- carboxylic acid of formula II wherein

R ⁴ * R ⁵ , R ⁶ and X are as defined above * or a reactive derivative of this chapter, amidating with carboxylic acid of the formula:

R, R * R and R are as hereinbefore defined * or a reactive derivative thereof. The acid obtained is optionally neutralized by the action of a conventional process and optionally protected amino (3-carboxyalkenoylamino) -3-cephem-4-carboxylic acid is removed or carboxy. The compounds obtainable according to the invention are suitable for the treatment of bacterial infections.

(II) (II)

RCCOOH

CR ^{1 -} r2_coOR ³

CS 268513 82

The present invention relates to a process for the preparation of the antibacterially active 4-carboxylic acid-3-carboxylic acid-3-carboxylic acid of the formula I

R-C-CONH

^2- coos ³

(I) where

R represents a phenyl or monocyclic five- or six-membered heteroaryl group having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted by an amino group, optionally protected by an aralkyloxycarbonyl group of 8 to 15 carbon atoms, an alkoxycarbonyl group of 2 to 3 12 carbon atoms, C 1 -C 8 alkanoyl, C 1 -C 8 haloalkanoyl, dimethyl tert -butylsilyl, methoxymethyl or p-nitrobenzal, r ¹ represents a hydrogen atom or a halogen atom,

R represents a single bond, an alkylene group having 1 to 3 carbon atoms, which is optionally branched, or a thlomethylene group;

R ° and R ° are hydrogen, light metal, C 1 -C 8 alkyl, C 2 -C 7 alkenyl optionally substituted by phenyl, C 7 -C 15 aralkyl which is optionally substituted with methyl, methoxy or, nitro, or C 2 -C 12 alkanoyloxyalkyl, hydrogen or methoxy, R ⁵ is hydrogen, hydroxyl, methoxy, methanesulfonyloxy, fluoroethyl, vinylthio, halogen, a methyl group optionally substituted by a pyridyl group, an alkoxy group, an alkanoyloxy group, a carbamoyloxy group, an alkylthio group, an alkylthio group, a haloalkylthio group or a cyanoalkylthio group each having up to 3 carbon atoms or a monocyclic heterothio group having 3 or 4 carbon atoms; sulfur and nitrogen, and optionally contains a substituent selected from the group consisting of. or methyl, amino, C 1 -C 3 alkoxycarbonylamino, aminomethyl, butoxycarbonylaminomethyl and halogen, or a vinyl group optionally substituted by cyano, carboxy or trifluoromethyl, and

X is -S-, -SO- or -O-, provided that when R is a thiaalkylene group, R ¹ is a halogen atom.

CS 268513 82

The individual groups contained in the compound of formula I are now explained.

R as a heterocyclic group denotes an optionally substituted 5- or 6-membered monocyclic ring group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur. Representative rings are pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, thiazinyl and the like. Optionally, said substituents may be substituted by: alkylamino or protected amino. Among the protecting groups in the protected amino group are preferably C 8 -C 15 aralkyloxycarbonyl, wherein the aralkyl moiety is, for example, benzyl, and C 2 -C 12 alkoxycarbonyl in the alkoxy moiety, wherein the alkyl moiety is, for example, methyl, ethyl, propyl, cy Cyclopropyl ethyl, isopropyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, or the like, alkanoyl or haloalkenyl of 1 to 8 carbon atoms, and further dimethyl-tert-butylsilyl, methoxyethoxymethyl or p-nitrobenzyl, and the like.

R is preferably selected from phenyl, furyl, thienyl, oxazolyl, isoxazolyl, optionally protected aminoisoxazolyl, thiazolyl, optionally protected aminothiazolyl, thiadiazolyl, and aminothiadiazolyl. optionally protected aminothiazoles is most preferred.

R ¹ as halogen is fluorine or chlorine, especially chlorine. Preferably R ¹ represents a hydrogen atom.

The alkylene moiety in R is a lower alkylene group, preferably an alkylene group having 1 to 3 carbon atoms, especially methylene.

As the cephalosporin substituent, R 5 may be, but is not limited to, hydroxy, halogen, methoxy, vinylthio, methyl, vinyl, cyanovinyl, substituted methyl, or the like, well-known 3-substituents of cephalosporins. The substituent in the above-mentioned methyl may be pyridinium, C 1 -C 3 alkoxy, asoloxy, for example acetoxy or carbamoyloxy, and alkylthio, haloalkylthio, cyanoalkylthio, monocyclic heterothiazio, thiazolylthio, triazolylthio, triazolylthio, triazolylthio, triazolylthio, triazolylthio, triazolylthio . R ⁵ is preferably hydrogen, vinyl, karbamoyloxymethy1, tetrazolylthiomethy1 or lthiomethy1 thiadiazoles.

R 6 or Κθ as a modified carboxy group is preferably an ester-forming or salt-forming group or any suitable carboxy-protecting group or derivative-forming group suitable for therapeutic purposes.

X is preferably a sulfur atom.

Carboxy protecting groups are known in the field of penicillin and cephalosporins and can be introduced and removed without detrimental effect on another part of the molecule. Representative are inorganic salts, for example lithium, sodium, potassium, magnesium, calcium, aluminum and the like, or organic basic salts.

Preferred R ³ and R ⁶ as carboxy protecting groups are hydrogen, sodium, potassium, methyl, tert-butyl, phenyl, indanyl, benzyl, methylbenzyl, nitrobenzyl or the like.

The protecting group is not present in the compounds of the invention and thus its structure has no particular significance as long as the group is well protected and can thus be replaced by widely diverse equivalent groups.

Particularly suitable carboxy derivatives are medically useful substances, including light metal salts and pharmaceutically acceptable esters. Preferred light metals These are those which form physiologically acceptable ions and belong to Groups 1 to 3 of Period 2 to 4 of the Periodic Table. Lithium, sodium, potassium, magnesium, calcium, aluminum and the like are preferred. Pharmacologically acceptable esters have an antibacterial effect when administered orally or parenterally and include the well-known alkyl esters.

Both geometric isomers at the double bond at position 7 of the side chain are antibacterially active. Of these, compounds having R and R ¹ in the cis position are more antibacterially active. The second geometric isomer (trans) is useful as an intermediate for the production of the corresponding cis isomer.

an overview of some of the representative compounds of Formula (I) of the invention is provided below; these compounds are not to be taken as an exhaustive list of the compounds of the invention:

7β- [2- (2-aminothiazol-4-yl) -4-carboxy-2-butanoylamino] -3-cephem-4-carboxylic acid,

7/3 - [2- (2-aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-methyl-3-cephem-4-carboxylic acid; (aminothiazol-4-yl) -4-carboxy-2-butylamino-3-vinyl-3-cephem-4-carboxylic acid (3 ') 2- (2-aminothiazol-4-yl) -4-carboxy -2-Benethylanino / -3-trifluoropropenes 1-3-cec-4-carboxylic acid,

7 / 3- [2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-acetoxymethyl-3-ethoxy-4-carboxylic acid,

7β- (2- (2-aminothiazol-4-yl) -4-carboxy-2-butenoylamino) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid,

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

7/3 - [2- (2-aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-cyanomethylthiomethyl-3-cephem-4-carboxylic acid, [3- (2-aminothiazole)] (4-yl) -4-carboxy-2-butenoylamino] -3-pyridinylethyl-3-methyl-4-carboxylate,

7 / 3- / 2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino / -3-triazolylthiomethyl-3-cephem-4-carboxylic acid,

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

7H- [2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-methyl-tetrazolylthiomethyl-3-methyl-4-carboxylic acid,

7/3 - [2- (2-aminothiazol-4-yl) -4-carboxy-2-butanoylamino] -3-methoxy-3-cephem-4-carboxylic acid,

7/3 - [(2-aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-chloro-3-cephem-4-carboxylic acid,

N - [2- (2-Aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-fluoroethylthio-3-ene-4-carboxylic acid,

7/3 - [2- (2-aminothiazol-4-yl) -4-carboxy-2-butenoylamino] -3-trifluoroethylthio-3-cephem-4-carboxylic acid,

7/3 - [2- (2-aminothiazol-4-yl) -5-carboxy-2-pentenoylamino] -3-cephem-4-carboxylic acid; 1- (4-yl) -6-carboxy-2-hexenoylamino-3-methyl-4-carboxylic acid, [3- (2- (2-aminothiazol-4-yl) -4-carboxy)] -2-pentenoylamino / -3-cephem-4-carboxylic acid,

7β - [2- (2-Aminothiazol-4-yl) -4-carboxy-4-methyl-2-pentenoylamino] -3-cephem-4-carboxylic acid; and

7/1 - [2- (2-Aminothiazol-4-yl) -4-carboxy-3-chloro-2-butenoylamino] -3-cephem-4-carboxylic acid.

Some of the compounds closely related to the compounds of the invention are disclosed in Japanese Patent Publications Kokok 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, intrinsic or parenteral activity. absorbability, excretion or similar characteristics. *

The compounds of formula I are antibacterially active against aerobic Gram positive bacteria (e.g. Bacillus cereus, 8acillus substilis, Cyrynebacterium diphteriae, Staphyloxoccus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyrobes, Streptococcus bacteria, Streptococcus bacteria, Streptococcus bacteria, , Enterobacter aerogens, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella < / RTI > Shigella sonnei, Yersinia enterocolitica), including anaerobic bacteria (e.g., Bacteroides fragilis, Clostridium difficile, Clostridium perfringens, Eubacterium lentum, Fusobacterium nucleatum, Propionibacterium spp .. peptostreptococc) (Veillonella spp.).

Particularly high antibacterial activity against gram-negative bacteria, high absorption, secretion, distribution and the like are evident. As medicaments for the protection or treatment of bacterial infections, the compounds of the formula I are administered orally, perenterally or locally in a daily dose of from 10 mg to 6 g and, if desired, administered with customary additives or coatings, for example other antibacterially active agents.

The compounds are useful as bacterialidal, 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. In addition, the compounds are useful as inhibitors of bacterial growth on a human, animal, plant or perishable subject, food additives for human or animal growth, 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, purulent inflammation, enterithis, gastroenteritis, nasopharyngitis, osteomyelitis, pneumonitis, pneumonia, pustuloza, pyelonephritis, pyelonephritis, pyelonephritis , rhinitis, septicemia, tonsillitis, ulceration, urinary tract infections, infectious soft tissue injury 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 intravenously or 0.1 to 2 g orally at a time interval of 3 to 12 hours, depending on the infecting bacterium and the conditions of the patient and, if desired, treated with the usual ingredients.

The carboxylic acid compound or light metal salt thereof may be administered by injection or infusion intravenously, intramoscularly or subcutaneously, for example as injections or pallets, or orally as oral preparations, for example capsules, dry syrup, emulsion, granules, powder, solution , suspension,

And, if desired, in admixture with an adjuvant, for example an emulsifying agent. The pharmacologically active ester may be administered intravenously, intramuscularly, subcutaneously, orally, externally or locally, for example, as an ear, nasal or ophthalmic drug, ointment, inhalant, injection, mash, spray or suppository.

When R is 2-amino-4-thiazolyl, R ² is methylene, R ¹ , R ³ R ⁴ and R ⁶ are hydrogen and R ⁵ is hydrogen, methyl, uethoxymethyl, carbamoloxymethyl, methylthiomethyl, cyanomethylthiomethyl, vinyl, fluoropropenyl, methoxy The chlorine, chloro, fluoroethyl or trifluoroethylthio group or the compound of formula I is absorbed orally as well as subcutaneously. Pharmaceutically acceptable esters of the compounds of formula I are also absorbed by the gastrointestinal tract.

The present invention further relates to an anthibacterially effective pharmaceutical composition comprising a compound of formula I in various enteral or parenteral dosage forms alone or in admixture with carriers or coatings. The compositions may contain from 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, dry syrup, granules, pallets, pills, powder, suppositories, capsules or tablets, or liquid formulations, for example, dispersions, elixirs, emulsions, inhalants. injection, ointment, suspension, syrup, ampoule solution, or may be contained in containers containing crystals, lyophilized material or powder. These may be flavored or colored and the capsules, granules and tablets may be coated. The compositions may be in unit dosage form.

Carriers are harmless to both the compound of Formula I and the patient. Representative examples of such carriers include, but are not limited to, solid binders such as acacia, carboxymethyl leeluloza, gelatin, glucose, polyvinylpyrrolidone, sodium alginate, sorbitol, starch, syrup or traction, wetting agents such as bentonite, calcium carbonate , calcium phosphate. glycine, kaolin, lactose, polycarboxymethylene, sodium chloride, sorbitol. Starch, sugar or talc, diluents such as calcium carbonate, kaolin, lactose, starch or sucrose, disintegrators such as agar, carbonates, sodium lauryl sulfate or starch, glidants such as boric acid, cocoa butter, magnesium stearate, paraffin, polyethylene glycol 1 , silica, sodium benoate, stearic acid or talc and wetted agents such as hydroxypropylene cellulose, for solvent solutions such as alcohol, buffer, methyl oleate, peanut oil, sesame oil, or water, emulsifying agents such as acacia, lethicin or sorbitan monooleate, suspending agents, for example, aluminum stearate gel, carboxymethyl cellulose. gelatin, glucose, hydrogenated fats, hydroxyethyl cellulose, methyl cellulose, sorbitol or sugar syrup, buffers, dispersants and solubilizers, and for both types, preservatives such as methyl p-hydroxybenzoate or echyl p-hydroxybenzoate or sorbic acid, absorbent promoters such glyzín mono- or dioctanoate, antioxidants _t flavoring agents, analgesics, edible coloring agents, stabilizing agents and the like.

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

For the general formula I above, examples of suitable R are phenyl, thienyl, thiadiadolyl, aminothiadiazoles 1 and aminothiazoles 1, wherein the amino group may be protected by <

benzyloxycarbonyl, tert-methoxyethoxymethyl, formyl, chloroacetyl, or the like; preferably hydrogen, R ² preferably represents a branched alkelen having 1 to 3 carbon atoms, particularly methylene. Examples of preferred and R 6 are the same or different groups selected from hydrogen, methyl, ethyl, tert-butyl, benzyl, methylbenzyl and the like.

It is an object of the present invention to provide a process for the preparation of compounds of the formula (I), comprising: a 7-amino-4-cephem-4-carboxylic acid derivative of the formula (II)

(П) where

2 3

R ¹ , R ¹ , R 2 and R 2 are as defined above and attenuate with carboxyalkanoic acid or a reactive derivative thereof of formula III

R-C-CO 2

I, CR ¹

I ~ ~

R-COOR (И1) where

R, R ¹ , R ² and R ³ are as defined above and

Z is hydroxy or a leaving group, such as a halogen atom to form a halide, an N-substituted aminooxy group to form a reactive ester, an alkoxy group to form a symmetrical anhydride or a haloalkoxy alkoxy group, .

and then optionally further recovering the carboxy and / or amino protecting group present by treatment with hydrogen halide, trihaloacetic acid, thiourea, zinc, or a Lewis acid selected from aluminum halide, titanium halide and tin halide is required in the presence of anisole, and / or is converted to a salt by treatment with an aqueous alkali metal bicarbonate solution.

CS 268513 82

The amidation according to the invention proceeds according to the following reaction scheme:

RC-CO ¹¹ 1

CR ^X

R ² COOR ³

COOR ⁶ (II)

------------------>

? ⁴

RC-CONH. ·, ¹¹ 1 \ LCR ^X

-----------------> R ² _N.

I 3 У

COOR ^JB .COR (I)

Conventional reaction of an amine of formula II or a reactive derivative thereof with a carboxylic acid of formula III or a reactive derivative thereof provides a compound of formula I or a reactive derivative thereof.

The free acid of formula (III) is reacted in the presence of a condensing agent such as a carbodiimide, for example N, N'-diethylcarbodiimide, N, N-dicycloheyxylcarbodiimide, a carbonyl compound, for example carbonyldiimidazole, isoxazolinium salt, an aminocompound, for example 2-ethoxy-1 -ethoxycarbones of 1-1,2-dihydroquinoline, and the like.

A compound of formula I containing a carboxy group on the cepham nucleus at the 4-position or a substituent at the 7-position can form a light metal salt by reaction with a base or by an exchange reaction with the corresponding light metal salt with another carboxylic acid. The process may be carried out in a conventional manner, for example by neutralizing the free acid with a base such as a light metal hydroxide, carbonate or bicarbonate, and evaporating the solvent, or treating the lower light metal carboxylate in a polar organic solvent such as an alcohol, ketone or ester. a polar solvent to separate the salt. The solvent may be removed by filtration.

A protected carboxy group in a compound of formula I may conveniently be removed, for example, as follows;

a) The highly reactive ester as a carboxy protecting group can be removed by contact in an aqueous solvent and with an acid, a base, a buffer solution or an ion exchange resin. When their reactivity is insufficient, they can be increased in a conventional manner to facilitate their removal, for example by activation with metal and acid, hydrogen and a catalyst such as palladium or nickel, dithionate or metal and acid, or by irradiation.

b) The aralkyl ester can be removed by conventional catalytic reduction with hydrogen in the presence of a catalyst such as platinum, palladium or nickel.

The aralkyl ester, cyclopropylmethyl ester, or the like esters can be removed by solvolysis with a mineral acid, a Lewis acid such as aluminum chloride, tin tetrachloride or titanium tetrachloride, a sulfonic acid such as methanesulfonic acid or trifluoromethanesulfonic acid with a similar carboxylic acid or similar trifluoroacetic acid. , if desired, in the presence of a cation acceptor.

The amino protecting group in the compound of formula (I) may be removed in a conventional manner, for example, as follows:

Substituted alkyl, aralkyl, alkanoyl, for example formyl, trialkylsilyl, or the like may be removed with aqueous or non-aqueous acid. Alkoxyforms 1, for example tert-butoxycarbonyl, aralkoxyforms 1, for example benzyloxycarbonyl, methylbenzyloxycarbonyl, aralkyl, for example trityl or the like, can be removed by treatment with tert-butyric acid in the presence of an acid acceptor. Halogenatedalkanoyl or the like can be removed by reduction. Some groups may be removed by the action of a base.

Removal of other hydroxy protecting groups or similar functional groups of the compound of formula I can be accomplished by methods well known in the art of penicillin and cephalosporin chemistry, as described in various scientific and patent literature.

The amidation is usually carried out at a temperature of -60 to> 120 ° C, preferably at a temperature of -20 to +80 ° C for 10 minutes to 10 hours, in a solvent. Other conventional conditions such as stirring, shaking, inert gas enclosure or drying may also be used.

Examples of typical reaction solvents are hydrocarbons such as pentane, hexane, octane, benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane or chlorobenzene, ethers such as diethyl ether, methyl isobutyl ether, dioxane or tetrahydrofuran, ket , for example acetone, methyl ethyl ketone or cyclohexanone, esters such as ethyl acetate, isobutyl acetate or methyl benzoate, nitrated hydrocarbons such as nitromethane or nitronenzene, nitriles such as acetonitrile or benzonitrile, amides such as formamide, acetamide, dimethylformamide, dimethylacetamide or hexanethylphosphoramide; dimethylsulfoxide, carboxylic acids such as formic acid, acetic acid, propionic acids, organic bases such as diethylamine, triethylamine, pyridine, picoline, collidine or quinoline, alcohols such as methanol, ethanol, propanol, hexa nol, octanol or benzyl alcohol, or water and other industrial solvents and mixtures thereof.

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 processing such as adsorption, elution by distillation, by precipitation, separation or chromatography, or a combination thereof.

Certain compounds of formula I in which the substituents R ² includes methylene, are well absorbed through the digestive tract and are useful as oral cephalosporins. Especially effective are those compounds which contain as R ⁵ hydrogen, vinyl, cyanovinyl, trifluoropropenyl, acetoxymethyl, carbamoyloxymethyl and thiadiazolylthiomethyl-3e, it should be noted that compounds of formula I which contain a single bond, dimethylene and trimethylene as substituent R or such compounds that do not

- side chain, are practically centrally non-absorbable. Compounds containing amino acids such as R may form a salt when mixed with an acid, for example a mineral acid such as hydrochloric acid, or a carboxylic acid such as trifluoroacetic acid.

CS 268513 82

Examples

In the examples, 'parts' means parts by weight and 'equivalent' means the molar equivalent of the lactam starting material. The symbols 'cis and' trans * denote the relative position of the amide and carboxyl substituents attached to the side chain double bond. The physicochemical constants of the products are summarized in the tables where IR indicates the values in cm @ ¹ , NMR analyzes express the values and Э values denote the constants on the scale given in Hz. Two or more signals are reported in NMR analyzes of mixtures of geometric isomers.

Usually, the reaction mixture is washed, dried and evaporated after addition of a solvent, for example water, acid or dichloromethane, and the product is separated. All evaporations are carried out under reduced pressure.

Abbreviations have this meaning;

AOM acetoxymethy1

QH diphenylmethyl

Du butyl

DOC tert-butyloxycarbonyl

8z1 benzy1

Chz benzyloxycarbonyl ring in the hetero ring of structural formula aromatic ring exo double bond at position 3,4 of the position isomer in the acyl side chain at position 7

Me methyl

MEM methoxyethoxymethyl phenyl

PMB p-methoxybenzyl

PNB p-n 1 trobenzyl1

POM pi va loy loxymethyl.

Example 1

A process for producing sodium salt

1. A solution of 1 g of the carboxylic acid (1) of Table 2 in 6 ml of a 0.5% aqueous sodium bicarbonate solution adjusted to pH 7 with hydrochloric acid is washed with ethyl acetate, desalted and poured into a 10 ml vial. Here, it is freeze-dried in the customary manner to give the corresponding salt. sodium salt (2) in powder form.

2. Similarly, an aqueous sodium carbonate solution was added to a suspension of 1 g of the carboxylic acid of Table 2 in water to obtain a solution of pH 6.5. The solution was desalted and poured into a 10 ml vial where it was lyophilized. The same sodium salt as above was obtained.

3. 1 g of sodium salt produced under sterile conditions is dissolved in 4 ml of sterile water and administered twice daily orally or intravenously to a patient suffering from an infection

Staphy1lococcus. aureus for the treatment of the disease.

4. One of the carboxylic acids listed in Table 2 in each case is dissolved in an aqueous solution of sodium bicarbonate and tested in the form of the sodium salt at the minimum inhibitory concentration (MIC) by the standard method described by the Japanese Chemotherapy Society. The values are determined for 3.1 to 0.2 micrograms per milliliter against Streptococcus pyogenes C-203 and for 0.8 to 0.025 micrograms per milliliter against Escherichia coli II.

Example 2

A method of amidation with the equivalent of a 7β-amine compound (2) is treated with a carboxylic acid corresponding to the 7β-side chain (3) or a reactive derivative thereof, to obtain the amide (1), for example by the method as exemplified below:

R-C-COOII

CR ¹

R ² COOR ³

-

1. stir a mixture of 10 volumes of dichloromethane, 1.1 equivalents of pyridine and 1.1 equivalents of carboxylic acid (3) at a temperature between 0 ° C and room temperature for 1 to 6 hours.

2. A temperature of 10-50 ° C, stirred mixture of 10 parts by volume of ethyl acetate and 1.1 equivalents of di-2-pyridyl-disulfide, and _R L equivalent triphenyl 1fosfinu and 1.1 equivalents of carboxylic acid (3) for 2-6 hours .

3. Stir at a temperature of -10 to +10 ° C a mixture of 3 volumes of dichloromethane, 4 equivalents of 1,3,? -Tripyridinium intrichloride and 1.1 equivalents of carboxylic acid (3) for 1-5 hours. hours.

4. A mixture of 30 parts by volume of carbon tetrachloride, 1.5 equivalents of methylmorpholine, 1.1 equivalents of trisdiethylaminophosphine and 1.1 equivalents of carboxylic acid (3) is maintained at -20 to + 10 ° C for 1 to 5 hours.

5. A mixture of 10 parts by volume of chloroform and 10 parts by volume of dimethoxyethane, 1.5 solar parts of triethylamine and mixed isobutoxy formic anhydride and carboxylic acid (3) is stirred at a temperature between -5 and + 10 ° C for 6.5 hours.

6. A mixture of 10 volumes of ethyl acetate, 10 volumes of dichloroethane, 1.5 equivalents of 4-methylmorpholine and 1.1 equivalents of symmetrical carboxylic anhydride (3) is refluxed for 10 minutes to 2 hours. ‘

7. A mixture of 10 volumes of dichloromethane * 1 * 5 equivalents of pyridine and 1 * 1 equivalents of mixed carboxylic anhydride (3) and methanesulfonic acid is stirred at -70 ° C to room temperature for 1 to 3 hours.

8. A mixture of 10 parts by volume of ethyl acetate * 1.5 equivalents of pyridine and 1.5 equivalents of mixed diethyl hydrogen phosphate anhydride and carboxylic acid (3) is stirred at 0 to 10 ° C for 1 to 5 hours.

9. A mixture of 10 parts by volume of ethyl acetate * 10 parts by volume of dichloromethane, as well as an equivalent of N-ethylmorpholine and 1 * 1 equivalent of mixed carboxylic acid anhydride (3) and dichlorophosphoric acid is stirred at between 0 ° C and room temperature for 1-3 hours.

10. A mixture of 1 * 5 equivalents of lutidine, Ю parts by volume of dichloromethane and 1.1 to 2 equivalents of mixed carboxylic anhydride (3) and monochlorophosphoric dimethylamide is stirred for 1 to 4 hours at 0 to 30 ° C.

11. A mixture of 5 parts by volume of dichloromethane, 1.5 equivalents of trifluoroacetic anhydride, 3 equivalents of pyridine and 1.5 equivalents of carboxylic acid (3) is stirred for up to 5 hours at room temperature.

12. A mixture of 10 parts by volume of dichloromethane, 1.2 equivalents of diethyl hydrogen phosphate bromide, 2.5 equivalents of 4-methylmorpholine and 1.2 equivalents of carboxylic acid (3) is stirred for 1-3 hours at a temperature between 0 ° C and room temperature.

13. Dissolve the amine containing the carboxy group at the 4-position of the geochemical ring in ю volumes of aqueous sodium hydrogen carbonate solution (2.5 equivalents) to the mixture. is added dropwise 1.1 equivalents of carboxylic acid chloride (3). The mixture is maintained at between -5 ° C and room temperature for 30 minutes to 2 hours.

14. The amine containing carboxy group in the 4-position of the cephem ring is treated with 1.2 equivalents of trimethylsilyl chloride and 1.2 equivalents of triethylamine, and then treated with equivalents of pyridine and 1.1 equivalents of carboxylic acid chloride (3) at -30 ° C for 30 minutes to 2 hours and then the resulting silyl ester is hydrolyzed by treatment with acid.

15. A solution of 4 equivalents of picoline and 1.2 equivalents of carboxylic acid chloride (3) in 20 volumes of dichloromethane is stirred at 0 to -30 ° C for minutes and 2 hours.

16. A mixture of 2 parts by volume of dimethylformamide and 10 parts by volume of ethyl acetate is stirred with 1.1 equivalents of triethylamine and 1.1 equivalents of carboxylic acid chloride (3) at a temperature between 0 and 20 ° C for between 30 minutes and 3 hours.

17. A mixture of 30 volumes of dichloromethane, 1.1 equivalents of cyanuroridide, 4 equivalents, pyridine and 1.1 equivalents of carboxylic acid (3) is stirred for 5 minutes to 2 hours at -30 to 10 ° C. .

13. A mixture of 3 volumes of dichloromethane, 1.1 equivalents of phosphorus oxychloride, 1.5 equivalents of triethylamine and 1.1 equivalents of carboxylic acid (3) is stirred for 20 minutes to 2 hours at a temperature between -10 and 10 ° C.

1 <J. The amine (2) is treated with trimethylsilyl chloride and an acid acceptor to give the corresponding N-X-dimethylsilyl compound and this is treated with 1.5 equivalents of phosphorus oxychloride, 1.2 equivalents of carboxylic acid (3) and 4 equivalents of dimethyl. of amine in 5 parts of dichloromethane over 30 minutes to 2 hours at room temperature.

20. A mixture of 8 parts by volume of dichloromethane, 1.5 equivalents of thionyl chloride, 2.5 equivalents of pyridine and 1.1 equivalents of carboxylic acid (3) is stirred for 1 to 5 hours at a temperature of -30 to 0 ° C.

02

21. A mixture of 3 parts by volume of chloroform, 1 part by volume of toluene, 2 equivalents of picoline, 1 equivalent of oxalyl chloride and 1.1 equivalents of carboxylic acid (3) is stirred at -50 to 10 ° C for 10 minutes to 2 hours.

A mixture of 20 volumes of dichloromethane, 3 equivalents of pyridine and 3 equivalents of carboxylic acid benzotriazolyl ester (3) is stirred for 5 to 30 hours at a temperature of 10 to 50 ° C.

23. A mixture of 20 parts by volume of dichloromethane, 2.5 equivalents of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline and 2 equivalents of carboxylic acid (3) is stirred at room temperature for 15 hours.

A mixture of 10 parts by volume of dioxane and 2 equivalents of carboxylic acid phthalimido ester (3) is stirred for 2 and 8 hours at a temperature of Ю to 50 ° C.

25. A mixture of 10 parts by volume of methyl isobutyl ketone and 1.5 equivalents of the carboxylic acid succinimodoester (3) is stirred for 2 to 9 hours at 0 to 40 ° C.

26. A mixture of 1.1 equivalents of carbonyldimidazole, 10 volumes of tetrahydrofuran, volumes of tamid dimethylation and 1.1 equivalents of carboxylic acid (3) is stirred for 1 to 5 hours at a temperature between 0 ° C and room temperature.

27. A mixture of 5 volumes of dimethylformamide, 1.3 equivalents of dimethylaniline, carboxylic acid and Vilsmeyer reagent, made from 1.1 equivalents of dimethylformamide, is stirred at room temperature for 1 to 5 hours.

28. A mixture of 10 parts by volume of dichloromethane, 5 parts by weight of dimethylformamide, 1.1 equivalents of N, N'-dicyclohexylcarbodiimide, 1.2 equivalents of picoline and 1.1 equivalents of carboxylic acid is allowed to react for 2 hours to 24 hours.

29. A solution comprising 7-amino-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid di phenylmethyl ester in 50 parts dichloromethane containing an equivalent of 2- (2-benzyloxycarbonemido-4) acid. -thiazolyl) -4-benzyloxycarbonyl-2-butene, 1 equivalent of N, N &apos; -dicyclohexylcarbodiimide is added. After stirring at room temperature for 2 hours, the mixture was evaporated, the residue was triturated with ethyl acetate, the solids were removed by filtration and chromatographed to afford diphenylmethylester of 7- / 2- (2-benzyloxycarbonylamino-4-thiazoles). 1) -4-benzyloxycarbonyl-2-butylamino-3- [1- (1-methyl-5-tetrazolyl) thiomethyl-3-methoxy-4-carboxy]. The yield was 90%.

30. To a solution of 7-amino-3-pyridinomethyl-3-cephem-4-carboxylic acid chloride hydrochloride in a mixture of 10 parts of water and 15 parts of dioxane are added sodium hydrogen carbonate equivalents, 1.2 equivalents of 2- (2-benzyloxycarbonylamino) at 0C. 4-thiazolyl) -4-benzyloxycarbonyl-2-butane, 1.2 equivalents of 1-hydroxybenzotriazole, 1.2 equivalents of N, N'-dicyclohexylcarbodiimide and 5 parts of dioxane. After stirring at 0 ° C for 3.5 hours, the mixture was acidified with 5 parts of 1N hydrochloric acid and filtered. The filtrate and 50 parts of the washing liquid obtained by washing the solid with acetone are combined, purified by column chromatography and lyophilized. 7- [2- (2-Benzyloxycarbonylamino-4-thiazolyl) -4-benzyloxycarbonyl-2-butenoylamino] -3-pyridinium methyl-3-cephem-4-carboxylate is obtained. the product yield is 50.8 Example 3 *

A method of removing a protecting group from a carboxy group

A solution of tert-butyl ester, p-methoxybenzyl ester or di phenylmethyl ester of Table 1 in a mixture of 0.3 to 3 parts dichloromethane, 0.3 to 3 parts trifluoroacetic acid and 0.5 to 5 parts anisole is stirred for 10 minutes to 3 hours at -10 to 40 ° C. The solution was evaporated to remove solvent and reagents. The residue was washed with benzene or ether to give the corresponding acid in a yield of 70-90

02

2. To a solution of the tert-butyl ester, benzyl ester, p-methylbenzyl ester, p-methoxybenzyl ester or di phenylmethyl ester listed in Table 1 in admixture _with 5-9 parts dichloromethane, and 2 to 8 parts anisole are added 3-12 equivalents of chloride % titanium dioxide at a temperature between -10 ° C to 10 ° C and the mixture is stirred for 1 to 24 hours. The mixture was washed with dilute hydrochloric acid and water, dried and evaporated. The corresponding free acid is obtained in a yield of 80 to 95%. When tert-butoxycarbonylamino, N-tert-butoxycarbonyl-N-methoxyethoxymethylamino or benzyloxycarbonylamino are present, the protecting portion is removed and the amino group is obtained.

3. Add 5 to 6 parts of 90% formic acid and 2 to 3 parts of anisole to the solution of tert-butyl ester, benzyl ester, p-methylbenzyl ester, p-methoxybenzyl ester or di-phenylmethyl ester listed in Table 1. The mixture was stirred at 50-60 ° C for up to 4 hours to give the corresponding carboxylic acid in 40-50% yield.

4. To a solution of the p-nitobenzyl ester of Table 1 in 60 parts of dichloromethane was added 10 parts of acetic acid and 2 parts of zinc dust. After stirring at 0 ° C for 2 h, the mixture was filtered to remove solids, diluted with water, and extracted with dichloromethane. The extract was washed with water and extracted with aqueous sodium bicarbonate solution. The aqueous layer was washed with hydrochloric acid until pH 7 was reached and then extracted with dichloromethane. The obtained organic layer was washed with water, dried and evaporated in vacuo. The corresponding free acid is obtained in a yield of 60 to 80%.

5. The same ester can be deesterified by shaking with hydrogen in the presence of a small amount of 5% palladium on activated carbon in dioxane at room temperature for 2 hours.

6. For a solution of 7- / 2- (2-benzyloxycarbonylamino-4-thiazolyl) -4-benzyloxycarbonyl-2-butenoylamino] -3- (1-methyl-1-5-tetrazolyl) di phenylmethyl ester 9-thiomethyl-3-carboxy-4-carboxylic acid in 12 parts of anisole was added 9 equivalents of aluminum chloride.

After stirring at 0 ° C for four hours, the mixture was neutralized with 5% aqueous sodium bicarbonate solution, the solids were removed by filtration and washed with ethyl acetate. the aqueous layer was acidified with hydrochloric acid, washed with ethyl acetate and passed through a column packed with synthetic HP 20 or SP 207 adsorbent produced by Mitsubishi Chemical K.K. The adsorbed material was eluted with 80% methanol to give 7- [2- (2-amino-4-thiazolyl-4-carboxy-2-butenoylamino) -3- (1-methyl-1-5-tetrazolyl-thiomethyl) acid. 3-Cephem-4-carboxylic acid in 65% yield.

7. To a suspension of 7- [2- (2-benzyloxycarbonyl-amino-4-thiazolyl) -4-benzyloxycarbonyl-2-butenoylamino] -3-pyridiniummethyl-3-cephem-4-carboxylic acid in 2 parts of anisole, add a solution of 9 equivalents of aluminum chloride in 2 parts of anisole at 0 ° C. After stirring for 3.5 hours, the mixture was acidified with 10% hydrochloric acid and washed with ethyl acetate. the aqueous layer is passed through a column filled with Dia ion HP-20. The adsorbed material was eluted with 5% acetone and the eluate was lyophilized. in a yield of 55% 7- (2- (2-amino-4-thiazolyl) -3-carboxymethylacrylamido) -3-pyridinomethyl-3-cephem-4-carboxylic acid is obtained.

8. In the same manner as above 1 to 7, the compounds listed in Table 2 having a free carboxy group are prepared from the corresponding carboxy-protected compounds listed in Table 1.

Example 4

A method for removing an amino protecting group

1. A solution of the tert-butoxycarbonylamino compound listed in Table 1 is mixed with 0.3 to parts dichloromethane, 0.3 to 3 parts trifluoroacetic acid and 0.5 to 5 parts anisole and stirred for 10 minutes to 3 hours at a temperature between - 10 and + 40 ° C. The solution was evaporated to remove solvent and reagents. the residue is washed with benzene and the corresponding amino compound of Table 1 or 2 is obtained in a yield of 70 to 80%.

CS 268513 82

К second solution of tert.-Butoxycarbonyl laminosloučeniny, benzyloxykarbonylaminosloučen ins methylbenzyloxykarbony laminos loučenlny _t methoxyethoxymethylaminosloučeniny or tritylslouČeniny listed in Table 1, the amount of component i in the mixture from 5 to 9 parts of methylene chloride and 2-8 parts of anisole was added 3 to 12 parts NaCl aluminum, tin tetrachloride or titanium tetrachloride at a temperature between -10 and + 10 ° C and the mixture is stirred for 1 to 24 hours. The mixture was then extracted with dilute hydrochloric acid and water, and the aqueous layer was passed through a column packed with N-R-20 adsorbent. The corresponding free amino compound of Table 1 or 2 is obtained in a yield of 60 to 80%. If a tert-butyl ester, a benzyl ester, a p-methylbenzyl ester, a p-methoxybenzyl ester or a di phenylmethyl ester is present, it is removed to give the free carboxy group.

3. Add 4 equivalents of thiourea or N-methyldithiocarbamate and 2 equivalents of sodium acetate to a solution of the chloroacetamide compound of Table 1 in a mixture of 15 parts of tetrahydrofuran and 15 parts of methanol. The mixture was allowed to stand at room temperature overnight, then evaporated, diluted with ethyl acetate, washed with brine, dried and evaporated, the residue chromatographed to give the corresponding amino compound.

4. To a solution of the amide, Schiff base, lylamine or tritylamino compound listed in Table 1 in formic acid or acetic acid or ethanol in an amount of 10 parts, add 0,1 to 3 parts of 1 to 3 normal hydrochloric acid and mix. at room temperature for 1 to 3 hours. The reaction mixture was evaporated, diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and water, dried and evaporated. The residue is purified by conventional means to give the corresponding free amino compound listed in Table 1 or Table 2.

5. To a solution of the benzyloxycarbonylamino compound of Table 1 in 30 parts of a 1: 1 mixture of ethanol and ethyl acetate was added 0.5 parts of 5% palladium on charcoal and shaken under hydrogen until the starting material was consumed. The reaction mixture was filtered to remove the solid and evaporated to give the corresponding amino compound shown in Table 1 or 2.

Example 5

A process for preparing an amine salt

Acetonitrile was added to a solution of the amino compound listed in Table 2 in dilute hydrochloric acid. The precipitated material was collected by filtration to give the corresponding hydrochloride addition salt in good yield.

Preparation A Preparation of Carboxylic Acids Preparation A-1

Process for the preparation of 2- (2-benzyloxycarbonylaminothiazol-4-yl) -4-benzyloxycarbonyl-2-butenoic acid (3)

ω

CbzNH

j> C00CHPh ₂ CH

CH ₂ COOCH ₂ Ph (1)

CbzNH

C-COOCHPh-i

CH ₂ C00CH ₂ Ph

A solution of formyl acetate (1) and 1.3 equivalents of benzyloxycarbonylmethylidentophenylphosphorane in 8 parts of dioxane or toluene is stirred at 80-120 ° C for 1-6 hours. After cooling, the mixture was evaporated and the residue was purified by chromatography on silica gel. Propendicarboxylate (2) is obtained. Yield 87%. This material is a mixture of 34% cis isomer and 53% geometric trans isomer, which can be separated by repeated chromatography.

IR (СНС 1 ₃₎ ч) 3410, 1730 cm ^-1 (trans)

IR (CHC1 _3)>): 3400, 1730 cm ¹ (cis).

2. To a solution of the product (2) in 10 parts of dichloromethane were added 2 parts of anisole and 2 parts of trifluoroacetic acid. After stirring for 2 hours, the reaction mixture was evaporated and the residue was washed with a mixture of ether and hexane. Yield 89% of the dicarboxylic acid monobenzyl ester (3). The mixture of geometric isomers thus obtained can be separated by chromatography.

NMR (CDCl ₃ -CD ₃ -OD) (C: 3.51 (d, J = 7Hz, 2H), 5.13 (s, 2H), 5.26 (s, 2H), 7.06 (s 1 H, 7.0 7.5 (m, 11H) (trans),

NMR (CDCl ₃ -C 0 -C ₃ 0D) Д: 3.73 (d, 3, J = 7 Hz, 2H), 5.13 (s, 2Н) ₄ 7.10 (s, 1H), 7.0 to 7.5 (m, 11H) (cis).

In a similar manner to that described in Preparation A-1, the diesters of the buccinic acid listed in Table 4 were prepared from the corresponding formyl acetate using the same ratios of reagents and solvents, at the same temperature and for the same reaction time. If desired, the ether obtained is wholly or partially de-esterified using a conventional reagent, for example sodium hydroxide for alkyl esters and tewis acids such as aluminum, titanium or tin (II) halide, for tert-alkyl or aralkyl esters. This gives free acids.

Preparation A-2

2- (2-Benzyloxycarbonylaminothiazol-4-yl) -3-benzyloxycarbonyl-2-propenoic acid (3)

(1)

COCOOCHPh ₂

—C-COOCHPhII ²

CH ÓoOCHgPh

CbzNII (2)

C-COOH

II

CH 2 OOCH 3 Fh

A solution of 2-oxoacetate (1) and 1.25 equivalents of benzyloxycarbonylmethylidentiphenylphosphorane in 10 parts of toluene or dioxane is refluxed for 1-3 hours. The mixture was evaporated and the residue purified by chromatography on silica gel. Diester (2) is obtained. The yield was 95%.

NMR (CDCl ₃ ) δ: 5.12 (s, 4H), 7.00 (s, 1H), 7.07 (s, 1H), 7.1-7.5 (m, 21H).

This product is a mixture of cis / trans isomers at the double bond.

2. The product (2) is dissolved in 7 parts of dichloromethane and mixed with 1 part trifluoroacetic acid and 1 part anisole. After stirring at 0 ° C for 7 hours, the mixture is evaporated and triturated with ether / hexane and then ether / methanol. The trans-isomer of the monoester (3) is obtained in a yield of 83%.

IR (nujol) λ): 1730, 1710, 1695 cm ^-1

MNR (CDCl ₃ - CO ₃ 0D) -1: 5.17 (S, 2H), 5.27 (S, 2H),

7.07 (s, 1H); 7.2-7.5 (m, 1111) ppm.

3. This trans-isomer (3) is dissolved in 10 parts of tetrahydrofuran and mixed with 1.12 equivalents of phosphorus pentachloride. After stirring at 0 ° C for 2 h, the mixture was neutralized with 80 mL of 5% aqueous sodium bicarbonate and stirred at room temperature. The separated crystals were filtered, washed with ethyl acetate and water, suspended in water, acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was crystallized from ether * hexane to give the cis-isomer of the monoester (4), m.p. 144-146 ° C. Yield 47%.

CS 268513 В2

IR (CHC1 ₃₎ 3410, 1720 cm ^'1. .

NMR (CDCl ₃ - CO ₃ 0D): 5.18 (s, 2H), 5.23 (s, 2H),

6.62 (s, 1H), 7.15 (s, 1H), 7.32 (s, 5H), 7.35 (s, 5H), ppm.

Preparation A-3

Process for the preparation of 2- (2-benzyloxycarbonylamino-thiazol-4-yl) -5-benzyloxycarbonyl-2-pentenoic acid

COCH ₉ C1

AND

CH ₉ C00CHPh ₂

----------------------------- =>

CH ₂ CH ₂ CHO

COOCH ₂ Ph (1)

ClCH ₂ C0CC00CHPh

CH ₂ CH _2? CH

COOCI < ₂ Ph (2)

CC00CHH1 II ^{1 2}

------------------------>

CbzNH

CH i

CH,

I ^г

CH ₂ COOCH ₂ Ph ->

CbzNH

C-COOH

II

CH <^ H,

I ²

CH ₂ COOCH ₂ Ph

1 A mixture of benzhydryl ester of 6.95 g of 4-chloro loracetooctové (1), 3 _t 9 g of the aldehyde (2), 35 ml of benzene, 0.79 ml of piperidine and 0.24 mg acetic acid were heated at ° C for 3 hours. The mixture was then washed with water, saturated aqueous sodium bicarbonate, water, 0.5N hydrochloric acid and water, dried over magnesium sulfate and evaporated, the residue was chromatographed on silica gel eluting with benzene to give a 1: 1 mixture of cis and trans isomers. (3) weighing 5,7 g.

2. 1.1 g of thiourea are added to a solution of this product (2) in 30 ml of ethanol. After stirring at 50 ° C for 2 h, the mixture was washed with water and saturated aqueous sodium bicarbonate and evaporated. The residue is dissolved in 20 ml of dichloromethane and mixed at 0 DEG C. with 0.536 ml of pyridine and 0.757 ml of benzyl chloroformate. The mixture is stirred at 0 DEG C. for 1.5 hours, washed with water, dried over MgSO4 and evaporated. . The residue was purified by silica gel chromatography eluting with a mixture of benzene and ethyl acetate in a ratio of 20: 1 to give 467 mg of cis isomer and 600 mg of trans-isomers aminothiazolesteru (4), cis isomer: IR (CHC1 ₃₎ y: 3400, 1720 1540, 1440.

1385, 1280, 1160 cm ^-1 , trans-isomer: IR (CHCl ₃ ) 9: 3400, 1720, 1540,

1440, 1385, 1280, 1160 cm ^-1 .

3. Add 1 part of dichloromethane to the aminothiazolester isomer (4). 1 part anisole and 2 parts trifluoroacetic acid. After stirring at 0 ° C for 2 hours, the mixture gives each isomer of the corresponding dicarboxylic acid monobenzyl ester (5).

Preparation A-4

Process for the preparation of 2- (2-benzyloxycarbonylaminothiazol-4-yl) -6-benzyloxycarbonyl-2-hexenoic acid

COCH ₂ C1 (СНОСНО

COOCHPh COOCH ₂ Ph ₂ (1) (2)

С1СН _о С0СС00СНИ1 _о 2 i 2 N ------ ; | C-COOCHPh? CH : 1 II 1 ---------> ♦! CH (CH ₂ ) ₃ COOCH ₂ Ph \ s / (chJ ₃ 1 ^J / CbzNH COOCH ^ Ph (3) (4)

N and C-COOH II CH A _s / | ^{( JH} 2 ⁾ 3 1 CbzNH COOCH ₂ Ph

(5)

1. A solution of 7 g of ester (1), 4.8 g of aldehyde (2), 0.15 ml of piperidine and 0.3 ml of acetic acid in 40 ml of benzene is heated at 50 ° C for 3 hours. The mixture was then washed with water, saturated aqueous sodium bicarbonate solution, 05N hydrochloric acid and water, dried over magnesium sulfate and evaporated.

2. Dissolve 6.5 g of the resulting residue (3) in 35 ml of ethanol, mix with thiourea and heat at 50 ° C for 2 hours. The mixture was washed with saturated aqueous sodium bicarbonate and evaporated. The residue is dissolved in 20 ml of dichloromethane, mixed with 0.754 ml of pyridine and 1 ml of benzyl chloroformate and stirred at 0 DEG C. for 1.5 hours. The reaction mixture is washed with water, dried and evaporated, and the residue is chromatographed on silica gel, eluting with a 20: 1 mixture of benzene and ethyl acetate, to give a thiazole ester consisting of 470 mg of the trans isomers and 1.17 g of a trans / cis-isomer mixture. 1: 1 ratio.

Trans-isomer of thiazolester (4): IR (CHC1 ₃ ) In: 3400, 3000, 1720, 1540, 1440 1370, 1280, 1150 cm ¹ , cis-isomer of thiazolester (4): IR (CIIC1) ₃ In: 3400, 3000, 1720, 1540, 1440 1370, 1280, 1150 cm ' ¹ .

3. 470 mg of the thiazolester (4) as the product mentioned in 1 above is dissolved in 15 ml of dichloromethane, mixed with 0.611 ml of anisole and 1.22 ml of trifluoroacetic acid and stirred at 0 ° C for 2 hours after evaporation to dryness. The mixture was triturated with ether / hexane (1: 1) to give 336 mg of thiazolecarboxylic acid (5).

Preparation A-5

Process for the preparation of 2- (5-benzyloxycarbonylamino-1,2,4-thiadiazo-3-yl) -4-benzyloxycarbonyl-2-butepic acid

CCOOCHPn. ^

II

CHOH (4)

CC00CHPh _O

II ²

CH --------------->

AND

CHCOOCH ^ Ph

CS 268513 82

CbzNH

C-COOH

II

CHCH ₂ COOCH ₂ Ph

1. 6 g of amino (1) are amidated with 1.2 equivalents of benzyl chloroformate with 120 ml of dichloromethane containing 2.5 equivalents of pyridine at 0 ° C for 2 hours. 11.2 g of carbamate (2), m.p. 157 DEG-158 DEG C., are obtained. The yield was 94.6%.

2. To a solution of 25.2 ml of diisobutylamine in 125 ml of tetrahydrofuran cooled to -30 to -5 ° C was added 112.3 ml of a 1.6N hexane solution of n-butyllithium over 21 minutes. It is then stirred for 1 hour 20 minutes at 0 ° C and then mixed with 11.2 g of a solution of carbamate (2) in 150 ml of tetrahydrofuran at -68 to -64 ° C for 1 hour and 20 minutes. It is then stirred at the same temperature for a further 3 hours. The reaction was quenched by the addition of 200 g dry ice and gradually warmed to -5 ° C. The reaction mixture was diluted with 150 mL of water, washed with ethyl acetate, acidified to pH 2 with 2N hydrochloric acid, and extracted with dichloromethane. The extract solution was washed with water, dried, evaporated and diluted with ether. 6.33 g of the acetic acid derivative (3), m.p. 172 DEG-173 DEG C., are obtained.

3. Add diphenyldiazomethane to a solution of 7 g of the acetic acid derivative (3) in 200 ml of methanol until the acetic acid derivative (3) can be detected. Evaporate the mixture to give the ester (4), mp 144-146 ° C.

4. To a solution of 4.1 g of ester (4) and 3.03 g of diphenylmethyl formate in 41 ml of tetrahydrofuran cooled to 0 ° C is added 1.1 g of 60% sodium hydride. After stirring for 2 hours 20 minutes at 60 ° C, the mixture was diluted with water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give 76.7 g of aldehyde (5) in 63.5% yield.

IR (CHC1 _3): 3140, 1720, 1610, 1540, 128, 1080 cm ^'1.

5. A solution of 781 mg of aldehyde (5) and 985 mg of benzyloxycarbonylmethyldiphosphorane in 17 mg of dioxane is refluxed for 3 hours. The mixture was evaporated to give 63L of acrylic acid (6). Yield: 63.5%. The product is a 4: 6 mixture of cis and trans isomers. '

IR (CHC1 _3): 3150, 1730, 1545, 1280 cm ^1st

6. 0.3 ml of anisole and 0.6 ml of trifluoroacetic acid are added to a solution of 309 mg of acrylate (6) in 4.5 ml of dichloromethane. After stirring at room temperature for 1 hour, the mixture was diluted with hexane to give 171 mg of the semi-ester (7). The yield is

75.7%. The product is a 1: 6.45 mixture of cis and trans isomers. .

IR (CIIC1 ₃ ) \):

1730, 1621, 1540, 1280 cm ¹ preparation A-6

Process for the preparation of 2- (2-benzyloxycarbonylaminothiazol-4-yl) -3-chloro-3-benzyloxycarbonyl-2-propenoic acid

C0C00CHPh ₂

CbzNH ’

C-COOH

II

CCl-COOCH ₂ Ph (2)

1. A solution of 472 mg of the ketone (1) and 467 mg of phenyl benzyloxykarbonylehlormethylentri 1fosforanu in 5 ml of benzene was heated at 60 ^U C for 30 minutes and then evaporated, the residue is crystallized from ether-pentane to give 393 mg of CH lorethylénu (2 ). Yield 61%.

2. A solution of 270 mg of chlorethylene (2) in a mixture of 2 parts of anisole and 1 part of trifluoroacetic acid is allowed to stand for 15 minutes and evaporated to 190 mg of the semi-ester (3). The yield was 95%.

Preparation A-7 ·.

Process for the preparation of 2- (2-benzyloxycarbonylaminothiazol-4-yl) -3-benzyloxycarbonylmethylthio-3-chloro-2-propenoic acid

COCOOCHPh ₂

CbzNH

CbzNH '(1)

CCOOCHPh.

II

CC1

I p

AND

CH ₂ COOCH ₂ Ph (2)

of*

CbzNH (3)

CCOOCHPhII ²

C (C1 ₂ )

C-COOH

II

CCl

I p

CH ₂ COOCH ₂ Ph

1. The ketone (1) and dichloromethylidentiphenylphosphorane are reacted as described in Japanese Patent Application Coca-57-67581 to give dichloroethylene (2).

2. To an ice-cooled solution of 395 mg of dichloroethylene (2) in 3 ml of N, N-dimethylformamide was added 153 mg of triethylamine and 200 mg of benzyl thioglycolate under a nitrogen atmosphere. After stirring for 45 minutes, the mixture was diluted with ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography to give 326 mg of thioether. Yield: 64%.

3. A solution of thioether (3) in a mixture of 2 parts trifluoroacetic acid and 2 parts anisole is allowed to stand for 30 minutes and evaporated. The semi-ester was obtained in 88% yield.

Preparation A-8

Process for preparing 2- (2-benzyloxycarbonylaminothiazol-4-yl) -3-chloro-6-benzyloxycarbonyl-2-hexenoic acid

COCOOCHPh ₂

N

CbzNH

C-COOCHPhI ^г

CC1 (CH _{2) 3} COOH

(2)

C-C00CHPh _o

II ²

CCl (CH ₂ ) ₃ c ^ooc H ₂ p ^h

CbzNH '

N

(4)

C-COOH

II

CC1 (£ k ₂ ) ₃ COOCH ₂ Ph

1. To a suspension of 887 mg of (4-carboxybutyl) triphenylphosphonium bromide in 3.5 ml of tetrahydrofuran is added 4.2 ml of a 1M solution of lithium bistrimethylsilylamide. After stirring at room temperature for 15 minutes, this solution was added dropwise to a suspension of 605 mg of iodobenzene dichloride in tetrahydrofuran at -78 ° C. After stirring at this temperature for 10 minutes, 2.2 ml of lithium bistrimethylsilylamide was added to the mixture. To this solution was added a solution of 378 mg of the ketoester (1) in 2 mL of tetrahydrofuran. The mixture was stirred at -78 ° C for 10 minutes and at room temperature for 1 hour, diluted with dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried and evaporated. The residue is purified by chromatography on silica gel, eluting with dichloromethane / ethyl acetate (1: 1). 250 mg of vinylcarboxylic acid (2) are obtained.

IR (CHC1 _3): 1715, 1540 cm ^-1.

2. Esterification of 353 mg of vinylcarboxylic acid (2) with oxalyl chloride and benzyl alcohol in pyridine is carried out in the usual manner. 305 mg of vinyl ester (3) are obtained.

NMP. (CDCl ₃ ) δ: 1/85 - 3.00 (m, 6H), 5.07 (s, 2H), 5.25 (s, 2H), 6.48 (s, 1H), 7.05 (s) s, 1H), 7.10 7.55 (m, 20H) ppm.

3. Collect 275 mg of vinyl ester (3), 0 * 5 mg of trifluoroacetic acid and 1 ml of anisole for 15 minutes at room temperature. 95 mg of semi-ester (4) are obtained.

NMR (CDCl ₃ - CD ₃ OD): 1.80-3 * 00 (m * 6H), 5 * 09 (s * 2H) *

5 * 26 (s * 2H), 6 * 85 (S * 1H) * 7 * 05-8 * 00 (m,

10H) ppm.

Preparation A-9

Process for preparing 2- / 2- (N-methoxyethoxymethyl-N-benzyloxycarbonylamino) thiazol-4-yl-3-chloro-5-benzyloxycarbonyl-2-pentenoic acid

CbzNH

CH ₂ COOCHPh ₂

CbzN í MEM

CH ₂ COOCHPh ₂

CH-C00CHPh _o ² co (CH ₂ ) ₂ COOH?

СН-С00СНН1 _о

I ² co (CH ₂ ) ₂ COOCH ₂ Ph

C-C00CHPh _o

II cci i (сн ₂ ) ₂ соосн ₂ рь (4)

С-СОШ

II

СС1

I (CH ₂ ) ₂ COOCH ₂ Ph (6)

1. To a solution of 115 mg of aminoester (1) in 1 ml of Ν, Ν-dimethylformamide is added 45 mg of potassium carbonate and 0.043 ml of methoxyethoxymethyl chloride. The mixture was diluted with hydrochloric acid containing ice and extracted with ethyl acetate. The extract was washed with water, dried and evaporated, and the residue was purified by silica gel chromatography to give the methoxyethoxymethylaminoester (2). yield 74

NMR (CDCl ₃ ) δ 3.25 (s, 3H), 3.77 (s, 2H), 5.28 (S, 2H), 5.55 (s, 2H), 6.68 (s, 1H) ) ppm.

2. To 1.4 ml of a 0.3M solution of 1-lithium-bistrimethylsilylamide in tetrahydrofuran, add a solution of 100 mg of methoxyethoxymethylaminoester (2) in 1 ml of tetrahydrofuran at -78 ° C under a nitrogen atmosphere. After stirring for 15 minutes, a solution of 22 mg of succinic anhydride in 0.5 ml of tetrahydrofuran was added to the solution. After stirring for fifty minutes at -78 ° C, the reaction mixture is acidified with 0.5 ml of 4N hydrochloric acid and extracted with dichloromethane. The extract was washed with water, dried and evaporated, and the residue was purified by chromatography on silica gel. 64% yield ketocster (3) and 24% aminoester (1).

. NMR (COC1 _3): 3.27 (s, 3H), 5.32 (s, 2H), 5.50

5.65 (2.times.s, 2H); 9.4 (broad, 1H) ppm.

3- To a solution of 541 mg of the ketoester (3) in 5 ml of benzene was added 1.81 ml of an O.485M solution of sodium methoxide in methanol. After stirring for 5 minutes, the mixture was evaporated. The residue is dissolved in 5 ml of Ν, Ν-dimethylformamide and stirred with 0.149 ml of benzyl bromide with stirring at room temperature for 5.5 hours. The mixture was allowed to stand overnight and then subjected to conventional silica gel chromatography. The ketodiester (4) is obtained. Yield: 33%

NMR (CDCl 3) δ: 3.26 (s, 3H), 5.05 (s, 2H), 5.32 (s,

2H), 5.55.5.63 (2.times.s, 2H) ppm.

4. To a solution of 284 mg of triphenylphosphine in 4 ml of tetrahydrofuran cooled to -15 ° C, add 1.27 ml of a 0.85 M solution of chlorine in carbon tetrachloride, 0.152 ml of triethylamine and a solution of 160 mg of catodiester (4) in 2 ml of tetrahydrofuran. The mixture was allowed to warm to room temperature, stirred for 6.5 hours and then subjected to conventional work-up and chromatographed on silica gel. The chloro ester (5) is obtained in 67% yield.

The product obtained is a 1: 1 mixture of geometric cis and trans isomers.

IR (CIIC1 ₃₎ y: 172 cm ^1st

5. To an ice-cold solution of 109 mg of chlorodiester (5) in 1 ml of anisole is added 0.3 ml of trifluoroacetic acid. After stirring at room temperature for 1 hour, the mixture was evaporated and the residue was purified by silica gel chromatography to give 112 mg of the trifluoracetic acid chloromethyl ester salt (6). This product is a 1: 1 mixture of geometric cis and trans isomers; 1.

IR (CHC1 ₃₎ У: 3350, 1720, 1680 cm ^-1.

preparation A-10

Process for the preparation of 2- (5-benzyloxycarbonylamino-1,2,4-thiadiazol-3-yl) -3-benzyloxycarbonyl-2-propenoic acid (4)

CbzNH

CH ₂ COOCHPh ₂

(1)

P -------------- COCOOCHPhj

AND

CbzNH (1)

CbzNH ^X Λ ¹ C-C00CHPh _o II CH J С00СН ₂ И1 (3)

CbzNH

C-COOH

II

CH i

COOCHiPh (4a, b)

1. To a solution of 1.012 g of ester (1) in 10 ml of dioxane is added 0.66 g of lithium dioxide. After stirring at 100 ° C for 2 hours, the mixture was filtered. The filtrate was evaporated and the residue was dissolved in ether and purified on silica gel by chromatography, eluting with hexane / acetone (3: 2). In a yield of 98.3%, 1.025 g of the ketoester (2) is obtained.

IR (nujol) Q: 330, 1720, 1240, 1085 cm ^-1 .

2. A solution of 1.025 g of ketoester (2) and 1.06 g of triphenylphosphoranilideneacetic acid benzyl ester in 20 ml of dioxane was stirred at 100 ° C for 2 hours and then evaporated. The residue is purified by chromatography on silica gel, eluting with acetone / hexane (3: 1 to 3: 2). In 93% yield, 1.24 g of diester (3) is obtained, m.p. 173-174 ° C.

3. To a solution of 348 mg of diester (3) in 4.7 ml of dichloromethane is added 0.35 ml of anisole and 0.76 ml of trifluoroacetic acid. After stirring at room temperature for 1 hour, the mixture was evaporated and washed with ether. 147 mg of cis-monoester (4a) are obtained in a yield of 58.3%. Mp 201-202 ° C. The wash was evaporated, washed with hexane and crystallized from ether / hexane. 98 mg of trans-monoester (4b), m.p. 155-156 ° C, are obtained. Yield 38.9

Preparation A-11

Process for the preparation of 2- (2-tert-butoxycarbonylaminothiazol-4-yl) -4-methyl-4-benzyloxycarbonyl-2-pentenoic acid (3)

BOCN

CH ₂ COOCHPh ₂

(1)

CC00CHPh _o

II.

CH i

PhCH ₂ 00CC (CH ₃ ) ₂

C-COOH

II

CH

PhCH ₂ 00CC (CH ₃ ) ₂

CS 268513 82

1. A solution of 628 mg of acetate (1) in 16 ml of tetrahydrofuran is cooled to. -50 θα add 282 mg of potassium tert-butoxide, after stirring for five minutes, the mixture is mixed with 0x32 ml of benzyl (2-form 1-2,2-dimethylacetate), then stirred for 20 minutes, during 5 'inub (warm). to room temperature, neutralized with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried and evaporated. The residue is dissolved in 10 ml of benzene, mixed with 0.36 ml of DBU, stirred at room temperature for 4 hours, neutralized with 10% hydrochloric acid, washed with water, dried, evaporated, dissolved in 10 ml of benzene, mixed with 10 ml of an aqueous solution containing 250 ml. ml of sodium sulfite and stirred for 24 hours. The benzene layer was washed with water, dried, evaporated and purified by silica gel chromatography to give the diester (2). Fabric make up

431 mg of the cis -isomer (59% yield) and 158 mg of the trans -isomers (22% yield).

IR (CHCl?): 3410, 1725 cm ¹ (cis isomer).

IR (CHC1 _3): 3400, 1720 cm ^-1 (trans isomer).

2. A mixture of 1.2 ml of anisole with 1.2 ml of trifluoroacetic acid is added to a solution of 431 mg of the cis isomers of the ether (2) in 8 ml of dichloromethane. After stirring at 0 ° C for 3 h, the mixture was evaporated and purified by silica gel chromatography. in 77% yield

242 mg of monoester (3), m.p. 158 DEG-160 DEG C. (dec.), After recrystallization from benzene.

3. 0.6 ml of anisole and 0.6 ml of trifluoroacetic acid are added to a solution of 237 mg of the diester trans-isomers (2) in 4 ml of dichloromethane. Stir at 0 ° C for 3.5 hours, concentrate and purify on silica gel by chromatography. in 57% yield, 98 mg of the monoester (3) trans isomer, m.p. 175-177 ° C (dec.), was obtained after crystallization from benzene.

Preparation A-12

Process for the preparation of 2- (2-tert-butoxycarbonylaminothiazol-4-yl) -3-tert-butoxycarbonylmethoxy-2-propanoic acid (7)

CH ₂ COOH

BocNH

CH ₂ C00TCE

C-CCOTCE

II choh (2)

Ν -------- rr / О

BocNH (4)

СН-СООТСЕ

AND

CHSPh

AND

OCH ₂ C00Bu-t

С-СООТСЕ • II

CHOCH ₂ COOBu-t cis (6) cis / trans ------->

N

BocNH

C-COOH

II

CH

0CH ₂ C00Bu-t

1. To a suspension of 11 g of acetic acid (1) in 120 ml of dichloromethane is added 90 ml of triethylamine. The mixture was cooled to -78 ° C, mixed with 4.87 mL of 2,2,2-trichloroethyl (chloroformate) and 432 mg of Ν, Ν-dimethylaminopyridine, stirred at 0 ° C for 10 minutes and at room temperature for 2 hours, diluted ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on silica gel, eluting with a 9: 1 mixture of benzene and ethyl acetate. In a yield of 66%, 9.10 g of trichloroethyl ester (2) is obtained.

IR (CHCl) 0 3400, 1760, 1720, 1150. ^1st

2. A solution of 9.10 g of trichloroethyl ester (2) and 6.21 g of 2,2,2-trichloroethyl formate in 34 ml of tetrahydrofuran is added dropwise to a suspension of 2.88 g of sodium hydride in 80 ml of tetrahydrofuran. After stirring at room temperature for 2 hours, the mixture is diluted with ethyl acetate, acidified with 5.3 ml of acetic acid, washed with water, dried and evaporated. The residue was crystallized from petroleum ether to give 4.49 g of the formyl ester (3). Yield: 46%.

IR (CHC1 _3): 3420, 1735, 1620 cm ^1st

3. To an ice-cooled solution of 4.49 g of the formyl ester (3) in 40 ml of Ν, Ν-dimethylformamide is added 426 mg of 60% sodium hydride. The mixture was stirred until gas evolution ceased and then mixed with 3.15 g of tert-butyl bromoacetate, kept at room temperature overnight, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried, concentrated, and purified by silica gel chromatography eluting with mixtures benzene and ethyl acetate in a ratio of 19: 1 to 2: 1. 3.03 g of diester (4) are obtained in a yield of 53%.

IR (CHC1 ₃₎ У: 34.00, 1723, 1630, 1150, 1120 cm ^-1.

4. To a solution of 3.03 g of diester (4) in 30 ml of tetrahydrofuran is added 0.70 ml of benzenethiol and 0.79 ml of triethylamine. The mixture was stirred at room temperature for 3.5 hours, concentrated and purified on silica gel using 9: 1 to 8: 2 benzene-ethyl acetate as eluent. 3.36 g of phenylthiopropionate (5) were obtained in 92% yield.

The product obtained is a 7: 3 mixture of two geometric isomers.

IR (CHC1 _3): 3400, 1750, 1725, 1155, 1120 cm ^-1.

5. To a solution of 3.15 g of phenyl thiopropionate in 35 ml of dichloromethane cooled to -40 ° C was added 1.07 g of 80% m-chloroperoxybenzoic acid. The mixture was stirred at -40 ° C for 10 minutes and at room temperature again for 10 minutes, diluted with ethyl acetate, mixed with a 2% aqueous solution of sodium bisulfite and stirred at room temperature for 5 minutes. The organic layer was collected, washed with 5% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried, evaporated and dissolved in 150 ml of benzene and refluxed for 15 minutes. The mixture was then washed with 5% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried, concentrated and purified by silica gel chromatography eluting with benzene / ethyl acetate 9: 1 to 1: 1. The diester (6%) was obtained in 45% yield. ) weighing 1.13 g.

IR (CHC1 _3): 3420, 1730, 1620, 1540, 1153, 1140 cm ^-1.

6. To a solution of 0.80 g of diester (6) in 8 ml of acetic acid, add 2.0 g of zinc dust. After stirring at room temperature for 1 hour, dilute the reaction mixture with dichloromethane, mix with 2N hydrochloric acid, stir for 10 min. at room temperature, filtered to remove solids and the organic layer was removed. This layer was washed with water, dried and evaporated. There was thus obtained 605 mg of the Z-isomer of the monoester (7). Yield 100%.

IR (CHC1 ₃₎ * 3400, 3550-2500, 1725, 1620, 1150. ^1st

The E-isomer is obtained from the mother liquors. 750 mg of the E-isomer of the monoester (7) is obtained in 30% yield.

IR (KBr) \)

3420, 1742, 1710, 1610, 1130 cm

CS 268513 02 preparation А- ^ з

Process for preparing 2- (2-benzyloxycarbonylaminothiazol-4-yl) -4-benzyloxycarbonylpentenoic acid

CbzNH

C-COOCHPh ₉

CHOH

(1)

C-COOCHPh_

C00CH ₂ Ph

C ---- COOH

ΙΓ- h

OH - C_____

AND

C00CH ₂ Ph ^CH 3

1. A solution of 1.46 g of hydroxymethylene of 2.5 g of benzyloxycarbonylethyl 1 ident.phenyl phosphorus in 20 ml of toluene was stirred at 80 ° C for 19 hours and at 110 ° C for 4 hours. hours and then evaporated, the residue is purified by chromatography on silica gel. Yield 0.808 g of diester (2) in 43% yield.

NMR (CDC1 _3): 1.15 (d, J = 7 Hz. 1.5H), 1.71 (s,

1.511), 4.90 (d, 3 = 9 Hz, 0.5H), ppm.

2. To a solution of the diester (2) in 20 ml of dichloromethane is added 3 ml of anisole and 3 ml of trifluoroacetic acid. After stirring at room temperature for 3 hours, the mixture was evaporated and triturated with hexane / ether to give 508 mg of nonoester (3) in 85% yield.

IR (CHC1 _3): 3400, 1725 cm ^-1.

Preparation A-14

Process for the preparation of 2- (thiazol-4-yl) -4-benzyloxycarbonyl-2-butenoic acid (3)

C-COOCHPh ₉ II

CHOH (2)

N ------- - C-C00CHPh _of 11 ^Z N ------ -------- C-COOH · II - - * II 11 CH pcs / ' CH CH ₂ C00CH ₂ Ph 1н ₂ соосн ₂ рь (2) (3)

1. To a solution of 11.5 g of the formyl ester (1) in 220 ml of benzene is added 19.5 g of benzyloxycarbonylmethylidenephosphorane. The mixture is refluxed for 7-10 hours, evaporated to half to one third the volume and purified by chromatography on silica gel eluting with 30: 1 benzene: ethyl acetate. 97% yield of diester (2), which is a mixture of geometric cis isomers and trans.

IR (CHC1 ₃₎ \ J>: 1720 cm ^-1.

2. To a solution of 15.0 g of diester (2) in 150 ml of dichloromethane is added 32 ml of trifluoroacetic acid at 0 ° C. Stir at room temperature for 1.5 h and evaporate. The residue was stirred in hexane, diluted with ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The extract was acidified to pH 3-4 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried, evaporated and triturated with 1: 1 ether: hexane to give the monoester (3) in 55% yield. This product is a 1: 1 mixture of geometric cis and trans isomers.

NMR (COC1 ₃ - CD ₃ 0D): 3.53, 3.76 (d, □ = 8 Hz,

2H), 5.13, 5.15 (2x s, 2H), 7.23, 7.38 (2x t, J = 8 MHz, 1H), 7.35 (s, 5H), 7.57,

7.61 (d, J = 2 Hz, 1H), 8.79, 8.82 (d, J = 2 Hz, 1H), ppm.

02

Preparation A-15

A process for the preparation of 2- (3-tert-butoxycarbonylamino-5-isoxazolyl) -4-benzyloxycarbonyl-2-butenoic acid (7).

HOOC

PhCH ₂ OOCCH ₂ CH

NHBOC (6)

1. A solution of 56 g of 3-amino-5-methylisoxazole (1) in di-tert-butylpyrocarbonate is stirred at 105-110 ° C for 17 hours. The mixture was evaporated and diluted with ether and water. The organic layer was separated, washed with water, dilute hydrochloric acid, water and saturated brine, dried and evaporated. The residue was washed with petroleum ether to give 75 g of tert-butylcarbonylamine (2), m.p. 108-109 ° C.

2. To a solution of 23.4 ml of diisopropylamine in 90 ml of tetrahydrofuran cooled to -20 ° C and kept under a nitrogen atmosphere was added 25 ml of a 1.6 N hexane solution of n-butyllithium. After stirring for 15 minutes, the mixture is cooled to -78 ° C and mixed with 8.3 g of a solution of tert-butoxycarbonylamine in 40 ml of telrahydrofuran over 2 minutes. Stir for 1 hour and quench the reaction by adding 20 g dry ice. The mixture was evaporated, the residue was dissolved in water, washed with ether, acidified with hydrochloric acid under cooling, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was washed with ether to give 4.35 g of the acetic acid derivative (3), m.p. 173-174 ° C (dec.).

3. To a solution of the acetic acid derivative (3) in 200 ml of dichloromethane add 8.63 ml of triethylamine at 0. The solution is cooled to -78 ° C and mixed with 13.1 g of trichloroethyl (chloroformate) and 0.76 g. 4-dimethylaminopyridine and stirred for 15 minutes. The mixture was warmed to room temperature, left overnight, evaporated, diluted with water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution, water and saturated sodium chloride solution, evaporated and purified by silica gel chromatography, eluting with benzene / ethyl acetate (3: 1). 19 g of trichloroethyl ester (4), m.p. 147 ° C.

4. To a suspension of 6.72 g of 60% sodium hydride in 220 ml of tetrahydrofuran at -30 to -10 ° C, add a solution of trichloroethyl ester (4) and 14.4 ml of trichloroethyl (formate) in 100 ml of tetrahydrofuran over 40 minutes. minutes. After stirring for 1.5 hours, the mixture was poured onto ice-cold hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, saturated sodium chloride solution, evaporated, washed with petroleum ether to give 17.45 g of hydroxymethylidene compound (5), m.p. &gt; 210 ° C.

5. A solution of 8.06 of hydroxymethylidene compound (5) and 11.1 g of benzyloxycarbonylmethyl identifenyl phosphorane in 350 ml of dioxane is stirred at 55 ° C for 9 hours. The mixture was evaporated, dissolved in water and ethyl acetate, washed with dilute hydrochloric acid, aqueous sodium bicarbonate, water and saturated sodium chloride solution, dried, evaporated and purified by chromatography on silica gel, eluting with benzene / ethyl acetate 1: 0 to 15: 1 yielding 6.35 g of diester (6)

3410, 2950, 1735, 1607, 1585 cm

6. To a solution of 1.85 g of diester (6) in 20 ml of dichloromethane add 5 g of zinc and 20 ml of acetic acid at 0 ° C. After stirring for 40 minutes, the mixture was poured into dichloromethane and dilute hydrochloric acid, filtered to remove solids and extracted with dichloromethane. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried, evaporated and purified by chromatography on silica gel, eluting with a 3: 1 mixture of benzene and ethyl acetate. 0.25 g of monocarboxylic acid (7) was obtained.

IR (KBr) \): 3400, 3250, 2960, 1736, 1618 cm ^1st

preparation A-16

Process for preparing 2-phenyl-4-benzyloxycarbonyl-2-butenoic acid (3)

Ph-C-C00CHPh _2. Ph-C-C00CHPh ₂

CHOH

(1)

Ph-C-OOH

WHOSE

II

CH nywCH ₂ C00CH ₂ Ph

1. To a solution of 1.94 g of 2-formyl-phenylacetic acid di-phenylmethyl-ester in 20 ml of dioxane at room temperature was added 3.16 g of benzyloxycarbonylmethyl-tridentophenylphosphine. After stirring for 50 minutes at 60-65 ° C, the mixture is concentrated and purified on silica gel by chromatography eluting with dichloromethane. Yield 1.81 g of diester (2) in 61% yield.

NMR (CDCl ₃ ) (δ: 3.18, 3.58 (2 xs, J = 8 Hz, 2H),

5.12, 5.24 (2x s, 2H), 6.93 (s, 1H), ppm.

2. To a solution of 1.79 g of diester (2) in 40 ml of dichloromethane was added 4 ml of anisole and 4 ml of trifluoroacetic acid at 0 ° C. After stirring for 2.5 hours, the mixture was evaporated and triturated with hexane. Yield 0.84 g of monoester (3) in 73% yield. This product is a 17: 83 mixture of geometric cis and trans isomers.

IR (CHC1 _3): 1730, 1690 Honor ^'first

Preparation A-17

Process for the preparation of 2- (2-thionyl) -4-benzyloxycarbonyl-2-butenoic acid (2)

(1)

II

CH r \ J CH ₂ C00CH ₂ Ph (2)

3.3 g of the diester (1) produced in the same manner as in Preparation A-16 are dissolved in 60 ml of dichloromethane and mixed with 7 ml of anisole and 7 ml of trifluoroacetic acid at room temperature. Míchá / stirred for 2.5 hours, evaporated and triturated with hexane. The resulting solid was purified using hexane-ether. Yield 1.19 g of monoester (2) in 56% yield.

Oiester (1): IR (CIICl) 0: 1730, fold, 1722, 1165 cm ^-1 . Monoester (2): IR (ClICl) J: 1730, 1695 cm ^-1 .

Preparation в

Method for introducing substituents at the 3-position

Preparation B-1

7-Amino-3- (2,2,2-trifluoroethylthio) -3-cephem-4-carboxylic acid p-nitrobenzyl ester (3)

COOPNB (2)

PhCH2 CONH

CF

COOPNB (2)

1 * 0.96 g of sodium iodide is added to a suspension of 1.86 g of silver mercaptide in 45 ml of phosphoric acid hexamethylamide. After stirring for 50 minutes at room temperature under a nitrogen atmosphere, the mixture is mixed with 2.95 g of trifluoroacetate. The reaction mixture was then stirred at room temperature for 1 hour, poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was purified by chromatography on silica gel, eluting with benzene / ethyl acetate 2: 1. 3.0 g of sulfide (2), m.p. 159-160 ° C.

A ice-cold solution of 690 mg of sulfide (2) in 22 ml of dichloromethane is added

675 mg of phosphorus pentachloride and 0.288 ml of pyridine. After stirring at room temperature for 2 hours, the mixture was cooled to -40 ° C, diluted with 22 mL of methanol, stirred at room temperature.

CS 268513 D2

0 ° C for 2 hours, mixed with 0.5 ml of water and evaporated, the residue was triturated with ether to separate the solid, which was suspended in dichloromethane, washed with aqueous sodium bicarbonate solution and water and evaporated. 562 mg of amine (3) is obtained.

IR (CHC1 ₃₎ \): 3300 br, 1775, 1735 cm ^-1.

Preparation B-2

7-Amino-3- (2-fluoroethylthio) -3-cephem-4-carboxylic acid p-nitrobenzyl ester (4)

COOPNB (2)

COOPNB (2) h ₂ n

COOPNB (3)

CS 268513 82

1. To a suspension of 2 g of silver mercaptide (1) in 60 ml of phosphoric acid hexamethylamide, add 2.95 g of p-toluenesulfonic acid 2-fluoroethyl ester and 2.02 g of sodium iodide. The whole was kept at room temperature for 4.5 hours and then poured onto 100 ml of ice-water and extracted with ethyl acetate. The extract was washed with water, dried, evaporated, dissolved in dichloromethane and diluted with ether. The thioether (2), m.p. 144 DEG-149 DEG C., is obtained in a yield of 87.8%.

IR (CH ₃₎ 3400, 1780, 1720, 1680, 1630 cm ^-1.

2. To a solution of 1.54 g of thioether (2) in 38.5 ml of dichloromethane add 0.52 ml of pyridine and 1.207 g of phosphorus pentachloride. The mixture was kept at room temperature for 2.5 hours, cooled to -40 ° C, diluted with 38.5 ml of isobutanol, kept at 0 ° C for 3 hours, and filtered. The amine hydrochloride crystals (3) are collected in a yield of 91%.

IR (nujol): 3140, 2645, 2585, 1773, 1604, 1500, 1512.

1492, 1460 cm ^-1 .

3. A mixture of 1.186 g of the amine hydrochloride (3), 50 ml of ethyl acetate, 1.107 g of sodium bicarbonate and 30 ml of water is stirred at 0 ° C. The organic layer was washed with aqueous sodium bicarbonate solution and water, dried and evaporated to give amine (4) in 94.2% yield.

IR (CHC1 ₃₎ 9: 3400, 1772, 1726, 1602, 1513 cm ^-1.

Preparation V - 3

Method for the preparation of 7β-amino-3-vinyl-thio-3-cephem-4-carboxylic acid p-nitrobenzyl ester (4)

PhCH ₂ COH

'cOOPNB (2)

COOPNB (1)

COOPNB (2)

1. To a solution of 9.38 g of 3-enol (1) in 120 l of acetonitrile is added 6.57 g of diphenylphosphoric phosphate and 2.97 g of diisopropylaminoethane. After stirring for 2 hours, this mixture was mixed with 3.16 g of 2- (benzenesulfinyl) ethanethiol, 2.19 g of diisopropylaminoethane and 6 ml of acetonitrile and stirred at -40 to -25 ° C for 2.5 hours. The mixture was poured onto ice-cold hydrochloric acid and extracted with dichloromethane. The extract was washed with water, dried and evaporated. The residue was recrystallized from a mixture of ethyl acetate and ether. There were obtained 6.84 g of sulfoxide (2), m.p. 174-175 ° C.

2. A solution of 2 g of sulfoxide (2) in 40 ml of 1,1,2-trichloroethane is refluxed for 11 hours under a nitrogen atmosphere. The reaction mixture was concentrated and crystallized from ether. 1.38 g of vinylthioether (3), m.p. 193-194 ° C, are obtained.

3. To a stirred, ice cold solution of 440 mg of vinylthioether (3) In 15 ml of dichloromethane, 358 mg of phosphorus pentachloride and 149 mg of pyridine are added under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was cooled to -40 ° C, diluted with 15 mL of methanol and stirred at 0 ° C for 2 hours. The mixture is mixed with 1 ml of water, evaporated, washed with ether, suspended in dichloromethane, washed with 10% aqueous sodium bicarbonate solution and water, dried and evaporated. The residue was recrystallized from dichloromethane / ether. 152 mg of amine (4), m.p. 152-154 ° C, are obtained.

Preparation B-4

Method for the preparation of 7- [2- (2-aminothiazol-4-yl) -4-carboxy-2-butenamido] -3-cyanomethylthiomethyl-3-cam-4-carboxylic acid (5)

(1)

(2)

(3)

CbzNH

C-CONH

II CH

AND

CH, 1

COOBu-t

(4)

C-CONH

COOH

(5)

CS 268513 B2 41

1. To a solution of 340 mg of the bromomethyl compound (2), which was produced by amidation of the amine (1) in a manner similar to that described in Example 2, in 3 ml of NN-dimethylformamide is added at -70 ° C an ethanol solution of sodium cyanomethylmercaptide. was made from 71 mg of cyanomethyl (thioacetate) and sodium ethoxide in ethanol. after stirring for 2 hours at -65 to -70 ° C, the mixture is poured into ethyl acetate, washed with water, dried and evaporated. The residue is purified by chromatography on silica gel, eluting with a 3: 1 mixture of benzene and ethyl acetate. Yield: 57.2% (3).

2. To a solution of 690 mg of oxide (3) in 10 ml of ecetone is added 883 mg of potassium iodide and 0.339 ml of acetyl chloride at -35 ° C. After stirring for 90 minutes at -20 to -25 ° C, the mixture is diluted with ethyl acetate, washed with dilute sodium thiosulfate solution and aqueous sodium bicarbonate solution, dried and evaporated to give the sulfide (4) in a yield of 85.6%.

3. To a solution of 550 mg of sulphide (4) in 10 ml of anisole, add a solution of 1.24 g of aluminum chloride in 5 ml of anisole at -30 ° C. After stirring for 3 hours, the mixture was diluted with hydrochloric acid and washed with ethyl acetate. The aqueous sc layer was purified on HP 20 synthetic adsorbent (Mitsubishi Chemical К.K.) and eluted to obtain the aminocarboxylic acid (5) in 74.4 yield.

Preparation B-5

7-Amino-3- (3,3,3-trifluoro-1-propenyl) -3-cephem-4-carboxylic acid diphenylmethyl ester (3)

CH = CHCl ₃

C00CHPh ₂

(3)

1. To 4 ml of trifluoroacetaldehyde ethyl-hemiketal was added dropwise phosphoric acid while heating to 165 ° C, the released trifluoroacetaldehyde condensed at -78 ° C and dissolved in 6 ml of ethyl acetate.

2. To a suspension of 1.38 9 of phosphorous acid (1) in a 60: 1 mixture of dichloromethane and ethyl acetate (5: 1) cooled to -70 ° C is added a solution prepared as described. ad 1) above. After stirring for 10 minutes at -70 ° C and stirring for 30 minutes at room temperature, the mixture is concentrated, the residue is purified by chromatography on silica gel, eluting with a 9: 1 mixture of benzene and ethyl acetate. gives trifluoropropene (2).

IR (CHC1 _3): 3380, 1787, 1722, 1682 cm ^-1.

3. To a solution of 292 mg of trifluoropropene (2), in 5 ml of benzene, add 89 microliters of pyridine and 208 mg of phosphorus pentachloride. After stirring at room temperature for 2 hours, the mixture was diluted with 5 mL of methanol. After stirring for 15 minutes, the reaction mixture was diluted with ice-water, neutralized and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to give the amine (3) in 65% yield.

Preparation D - 6 гризоЬ production

-carboxylic

rmethylthio-3-cephen-д-

(1)

C00CHPh ₂

(6)

1. To a suspension of 22.8 g of glycolate (1) in 300 ml of dichloromethane, 4.63 ml of pyridine and 4 ml of thionyl chloride are added at -20 to -23 ° C over 24 minutes. After stirring for 10 minutes from -20 ° C and stirring for 30 minutes at 0 ° C, the reaction mixture was washed with ice water and dried over magnesium sulfate. 4.63 ml of pyridine and 13 g of triphenylphosphine are added to the solution. After stirring at room temperature for 2 hours and at reflux for 2 hours, the mixture was washed with water and purified by chromatography on silica gel, eluting with 2: benzene / ethyl acetate; 1. 20.13 g of phosphoranilidene ester (2) are obtained.

2. To a solution of 16.65 g of phosphoranian ester 1 (2) in 80 ml of dioxane, add a 99% solution of 5.87 g of silver perchlorate monohydrate in 19 ml of water and 7.96 ml of a 60% aqueous solution of perchloric acid at room temperature. . After stirring for 1 hour, the mixture was diluted with dichloromethane and ice water. The organic layer was removed, washed with water, dried and evaporated to give silver mercaptide (3).

3. Add 3,95 g of 1- (difluoromethylthio) -3-chloroacetone (4) and 3,55 g of sodium iodide to a solution of cierkaptide silver (3) in 100 ml of phosphoric acid hexamethylamide. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and water. The organic layer is taken up, washed with water, dried and evaporated, and the residue is purified by chromatography on silica gel, eluting with a 1: 1 mixture of benzene and ethyl acetate. The ketone (5) is obtained.

The above 1- (difluoromethylthio) -3-chloroacetone (4) can be prepared as follows;

_{CHF2 SCH2} COC1 -----------> CHF ₂ COCH ₂ SCH ₂ C 1 (4).

A solution of 10 g of difluoromethylthioacetyl chloride in 20 ml of ether was added dropwise to the solution of diazomethane in 200 ml of ether made of 20.6 g of N-nitrosemethylurea over a period of minutes while cooling with ice. After stirring for 20 minutes at 0 ° C and stirring for two hours at room temperature, the mixture was saturated with hydrogen chloride under ice-cooling for 30 minutes. The reaction mixture was diluted with water, the ether layer was removed, washed with water, dried, concentrated and distilled. A colorless liquid is obtained from the reactions above at a boiling point of 52-5 ° C at 1 mmHg.

4. 180 mg of hydroquinone are added to a solution of 8.388 g of ketone (5) in 200 ml of toluene and refluxed for 14 hours. After evaporation of the toluene, the mixture is purified by chromatography on silica gel, eluting with a 2: 1 mixture of benzene and ethyl acetate. 4.42 g of cephem (6) are obtained.

NMR (COC1 _3): 3.58 (s, 3H), 3.73 (s, 2H).

5. To an ice-cold solution of 4.42 g of cephem (6) in 80 ml of dichloromethane and add 1.35 pyridine and 3.17 g of phosphorus pentachloride. After stirring for 10 minutes at 0 and 90 minutes at room temperature, the mixture was cooled to -45 to -55 ° C, mixed with 110 mL of cold methanol, stirred at 0 ° C for 30 minutes, diluted with ice water and neutralized. The organic layer was removed, washed with water, dried and concentrated. The residue is purified on silica gel by chromatography, eluting with a 2: 1 mixture of benzene and ethyl acetate. 2.86 g of amine (7) are obtained.

Г: 1.73 (broad, 2П) ppm

NMR (COC1 ₃₎

CS 268513 82

Table 1 (1)

A process for preparing esters, i.e., compounds of formula (i)

(AND)

Abbreviations:

Starting substances: '

Q * NH ₂ = cephalosporin amine core containing Q ⁵ CO * 7-side chain of acyl residue

Structure:

Ac = acety.1

Et = ethyl

MEM x methoxyethoxymethyl

Ms = methanesulfonyl

The reactant;

EEDQ = 2-ethoxy-1-ethyl-1,2-dihydroquinone

DCC = dicyclohexylcarbodiimide

TFA = trifluoroacetic acid

Time:

h = hour min x minute

An explanation of the other abbreviations is given before

Dissolve the bodies:

R ⁵ , R ⁶ , etc. chf = chloroform

DcM = dichloromethane

Di = dioxane

DMD = dimethylacetamide

DMF = dimethyl formamide

EtAc = ethyl acetate

MIK = 4-methylpentan-2-one py = pyridine

THF = tetrahydrofuran

Auxiliary Folder:

eq. = equivalent

Temperature _:

t. m. = room temperature by the example part

Ref. c is: trans R ° R ³ R ⁵ R ⁶ Starting substance ( ^m 9) Solvent Lo (Kml) The reactant Auxiliary s / s Time Temperature (° C) Yield (%) Yield ( ^m 9) 1 H ме D H ^R6 = BH 500 mg 2 OCH TFA 0.5 ml anisol 500 / U1 5 h t. m. 94 340 2 c is H Me H BH R ° = SiMe ₃ HOAc EN-HCl 3h t. m. 70 442

704 mg (aq) ml (excess)

Table j (1) - continued

Ref. cis: trans R ° R ³ R ⁵ R ⁶ Starting substance (mg) Solvent (Kml) The reactant Auxiliary folder Time Temperature (° C) Yield (%) Yield (rng) 3 trance H Me H BH R ° = SiMe ₃ HOAc En-HCl (aq) 2 h t. m. 66 413 704 mg excess 1 ml 4 c is H-TFA 9 ml H H R ° = B0C DCH TFA anisol 2 h 0 84 R ⁶ = BH 0.5 150 / U1 300 / U1 153 mg 5 trance H.TFA Bzl H H R ° = B0C DCH TFA an iso 1 2h 0 76 93 R ⁶ = BH 0.5 150 / lil 300 / lil 153 mg 6 c is H Bzl II BH R ° = TIIF MeNHCSSMe NaOAc over t. m. 22nd 147 C1CH CO 11 484 mg 162 mg, night 742 (4 eq) (2 eq .; ) меон 11 ml 7 trance H Bzl II OH 36 269 8 c is Cbz at H BH R ³ = allyl DCH Pd (PPh _{3) 4} ; ^pph 3 1 h 25 94 3340 3750 30 125 mg 655 mg

(0.5 eq)

To 2-ethylhexanoate

1/0 g (1.5 eq)

9 trance Cbz t-Bu H 2H QNH ₂ DCH. C 6 -C 10 picoline 1 h 0 86 439 244 5 320 mg 307 yUl (1.1 eq.) (5 eq.) 9 trance Cbz t-Bu H OH R ⁶ = H DCH Ph ₂ CN ₂ MeOH 3 ml 1 h t.m. 81 310 300 6 190 mg

(surplus)

^R6 = 0ms 430 DCH 6 for 1.1 g HOAC 4.3 5 h 50 (excess) ml 51 195 ^R6 = 0H 800 DCH 10 Ac ₂ 0 0.7 mL (6 eq) Py 485 / U1 24 H (6 eq.) For 13 H, then mixing with NEt ₃ 418 / U1 (3 equiv.) 50 391 S— 0

CS 268513 82

Table 1 (1) - continued

Ref. cis R ° R ³ R ⁵ R ⁶ Starting substance ( ^m 9) Solvent (ml) Reaction Auxiliary Time Temperature (° C) Yield (Ж) Yield (mg) trance folder folder 10 15:85 Cbz CH ₂ -CH = CH ₂ H BH q * nh ₂₂₄₄ DCH 7.3 0‘COOH cyanurchlorid 295 mg 135 mg 1 hr (1.1 eq.) (1.1 eq.) Py 300 / U1 (6 eq) 0 79 394 11 1 - 1 Cbz CHMe.CH = CH ₂ H BH Q-NH ₂ 367 DCM 7 40 QC00ll POC1 ₃ (1.1 equiv.) Min 169 mg 457 mg (1.1 eq.) Of NEt ₃ 200 / ul (1.5 equiv). 0 83 6 39 12 Cbz -CMe = CH _of CH? Z. II BH Q'NH ₂₃₆₇ Chf • 6 0 * C00H (COC1) ₂ 30,457 mg 0.19 mg min (1.1 eq) (1.5 eq) To 350 / U1, picolin 200 / U1 (2 eq) -10 73 55 8 13 2 - 3 Cbz сн ^ снвснме H BH Q "nh ₂₃₆₇ DCM 6 СГС00Н POC1 ₃ 1h 458mg 168mg (1.1eq) (1.1eq) Py 230 / U1 (4eq) 0 86 657 14 trance Cbz CMe ₂ - CH ₂ Cl ₂ H BH QNH ₂₃₆₇ DCM 6 О'СООП poc1 ₃ 1 h 437 mg 168 mg (1.1 eq.) (1.1 eq.) Py 330 / U1 (4 eq.) 0 88 698 15 Dec trance Cbz CH ₂ -CH ₂ CMe ₂ H .BH q'nii ₂₃₆₇ DCM 6 Q'COOH SOCl ₂ 3 h 473 mg 295 mg (1.1 eq) (2.5 eq) Py 200y.ul (2.5 eq) -10 79 617 16 mixture Cbz CH ₂ -CH = CHph H BH q --NH ₂₃₆₇ DCM 11 Q * COOH cyanuric chloride 526 mg 203 mg 2 hrs (1.1 eq.) (1.1 eq.) Py 320 / Ul (4 eq) -20 85 703 17 1: 4 Cbz Bzl H H Q'NII ₂₂₀₀ DCM 2 Q * C00MS Py 121 mg 1 hr 583 mg (1.5 eq) -50 89 564

(1.1 eq.)

CS 268513 82

Table 1 (1) - continued

Cis R ° trance R ³ R ⁵ R ⁶ Starting substance ( ^m 9) Solvent (ml) The reactant Auxiliary folder Time Temperature (° C) Yield (%) Yield (mg) Q'NH ₂₂₀₀ Chf 2 QCOC1 520 mg Me2 SiCl 130 mg 2 h -30 51 323

(1.1 eq) (1.2 eq),

NEt ₃ 167 / ul (1.2 equiv.), Py 324 / U1 (4 eq). R ⁶ = BH 400 DCM 1/2 TFA 0.4 ml anisole 1 h 1.2 ml 0 86 273 18 Cbz Bzl H H Q'NH ₂ DCM Q’COOMS Py 121 mg lh -50 87 551 200 2 595 mg (1.5 eq)

(1.1 eq.)

Qnh ₂ Chf Q'COCl Me ₃ SiCl 2 h -30 54 34 200 2 520 mg 130 mg (1.1 eq.) (1.2 eq.)

NEt ₃

167 / Ul (1.2 eq.)

Py 324 / U1 (4 eq)

R ⁶ = BH 400 DCM 1/2 TFA 0.4 ml an isol 1 ml 1 h 0 88 227 19 Dec 1: 4 Cbz Bzl H BH QNH ₂ DCM Q’COOH EEDQ 6 h t. m. 65 520 367 3.6 498 mg 271 mg

(1.1 eq.) (1.1 eq.)

DCC 226 mg (1.1 eq.) Py 110 / U1 (1.1 eq.)

Q'nh ₂₃₆₇ DCM 7.3 Q'C0Cl picoline 30542 380 mg / Ul min (1.15 eq _f) (4.1 eq.) 0 86 690 Qnh ₂ Chf QCOOH (COCl) ₂ 2 h 10 91 732 367 1/1 498 mg 140 mg

(1.1 eq.) (1.1 eq.), Polinoline 190 / uL (2.15 eq.) Toluene 400 / uL

Table 1 (1) - continued

Ref. cis R 0 R ³ trans

Default Dissolve- Reaction Pomocná Tep- Výě- Výě- substance body component with bed lota žek žek (mg) (ml) (° C) (%) ( ^m 9)

1: 4 Cbz Bzl Η BH R ^{6 0} 0Ms DCH Zn 302 mg AcOH 1.2 5 h 50 63 69

121 ml, isopropanol

1.2 ml trans Cbz Bzl H BH QNH ₂ Chf Q'C00000-Bu Et ^ N 6 h O 59 478

366 3.7 825 mg 21O / U1 (1.5 eq) (1.5 eq) (MeOCH ₂ ) ₂

3.6 ml

20 May trans Cbz BZ 1 H BH QNH ₂₃₆₆ Ch f 4 Q’C00H 477 mg (1.05 (COC1) ₂ 30 90 / µl min (1 eq) -30 82 6o5 eq. ) toluene, 5 ml, icolin 188 / ul (2 eq)

20 May trans Cbz Bzl H BH R ⁶ = C1 357 DCM 4.6 Zn HOAc 3.6 895 mg ml, iPrOH 1.4 ml 5 h 50 54 184 S — 0 acetone K1 AcCl 340 1.5 h -20 87 589 690 10 883 mg of µl (5.5 (5 eq.) Eq.) 21 Cbz MeBz 1 H BH q-nh ₂ DCM QCOOMS Py 121 mg 1 h -50 83 676 366 3.7 599 mg (1.5 eq) (1.1 eq.) 22nd Cbz PMB H BH Q'NH ₂ DCM Q’COC1 picolin 30 0 95 526 244 7.3 400 mg 300 ml (1.2 eq.) (5 eq.) min Q ₂ NH ₂ DCM Q 'C00H POCl ₃ 30 -10 92 765 366 3.0 531 mg 170 mg min (1.1 eq.) (1.1 eq. )

Et ₃ N 210 / U1 (1.5 eq)

Table 1 (1) - continued

ČÍS. c is: trans R ° R ³ R ⁵ R ⁶ Starting substance (mg) Solvent (ml) Reactive auxiliary component Time Temperature (° C) Yield (%) Yield (mg) 23 trance BOC Bzl H BH q * nh ₂₃₆₆ DCM 7.3 Q * COOH EEDQ 833 mg 618 mg (2 eq.) (2 eq.) 14 h t.m. 40 306 24 c is BOC Bzl H BH 33 253 25 HCO H H H R @ ³ = tBu, R @ ⁶ = BH, 330 DCM 1.3 IFA 0.3 anisole ml 0.3 ml 30 min t.m. 82 180 R ³ = R ⁶ = 3 H 102 DCM 0.5 AlCl ₃ anisole 70 mg 0.5 ml (4 eq) 5 h 0 96 55 R ³ = tBu; R ⁶ = BII, 230 90% IICOOH anisole 1.4 ml 0.7 ml 2 h 50 68 103 26 trance HCO t-Bu H BH · 0. \ Ή ₂₃₆₇ DCM 1.1 Q'COOH POCl 342 mg 168 mg (1/1 eq), (1.1 eq) NEt ₃ 209 / U1 (1.5 eq) 20 May min г -10 91 600 27 Mar: 1: 2 HCO BH H BH R ³ = R ⁶ = H 88 DCM 0.7 PhCl ₂ MeOH (2 eq.) 1.7 mL 1 h t.m. 72 111 28 1: 2 c1ch ₂ 00 BH II II R ³ = Bz 1, R ⁶ = H 235 DCM 2.1 SnCl anisol 424 mg 1.9 ml (1 eq) 1 h 10 89 176 29 0 1CH ₂ CD Bz 1 H II R ³ = Bzl, R ⁶ = 530 BH DCM 0.16 TFA anisol 1.6 m1 2.65 m 1 10 min 10 87 358 30 5: 6 C1CH ₂ WHAT H BH q ^r \ H ₂₃₆₇ DCM 1.1 QCOOII Р0С1 (1.1 eq) 168 mg 434 mg (1.1 eq) Et ₃ 209 mg (1.5 eq) 2h 10 90 669 31 trance tBuSiMe ₂ Bzl II BH nh ₂ - 132 ng DCM t-BuSiMe ,, Cl NEt ₃ 70 2 h 75 mg (3.5 eq) (2.5 eq) t.m. 2 5 39

Table 1 (1) - continued

Ref. cis: R ° R ³ R ⁵ R ⁶ Starting substance (mg) Solvent (ml) The reactant Auxiliary folder Time Temperature (° C) Yield (%) Yield (»> g) trance 32 c is tBuSiMe H BH NH ₂ - OCM t-BuSiMe ₂ cl NEt ₃ 70 2 h t · m. 24 38 Bzl 132 mg 2 75 mg 70 .ul

(2.5 eq) (2.5 eq)

33 1: 3 Cbz Bzl Me BH QNH ₂₆₉₆ Chf 64 Q * C00000iBu NEt ₃ 3h 1111 mg 380 / UL (1.1 eq) (1.5 eq) меосн ₂ ) ₂ 6.4 ml 10 69 1028 34 1: 2 Cbz Bzl CH = CH ₂ BH Q * _NH2 ¹¹⁷⁷ DCM 23 Q * COC1 picoline 30 1691 mg 13 ml min -10 88 2180

(1.2 eq.) (4 eq.)

35 2 - 1 Cbz Bzl CH = CHCN DCM 1 Λ Q * COOH 183 mg (1.1 eq. 2,4,6- -trioxy. ) -1,3,5- -tr iaz in 1,3,5-tri-pyridinium trichloride 622 mg (4 eq) 4 h 0 89 280 BH • Q \ H ₂₁₅₄ 36 2 - 1 Cbz Bzl CH = CHCN R ⁶ = BH OCM IFA 0.4 anisol 10 0 86 147 H 213 0.60 ml 0.4 ml min 37 Cbz Bzl CH = CHOOOt-Bu < ₂ DCH CTCOOMS Py 80 / Ul 3 h 0 82 512 (E) BH 332 3.3 405 mg (1.5 eq) (1.1 eq. ) 38 Cbz Bzl CH = CH00t-Bu R ⁶ = CH DCH TFA anisol 40 0 80 197 (E) II 300 10 0.3 ml 0.6 ml min 39 Cbz Bzl CH = CHCl ₃ Q * nh ₂ EtAC 0COC1 NEt ₃ 30 0 52 647 (SE-ZZ) BH 640 6.5 720 mg 213 / U1 min

(1.1 eq.) (1.1 eq.)

- DMF 1.2 ml. 40 Cbz Bzl CH = CHCl ₃ BH 36 44 8

Table 1 (1) - continued

Č3. cis: trans R ° R ³ R ⁵ R ⁶ Starting substance (<ng) Solvent (ml) The reactant Auxiliary folder • Time Temperature (° C) Yield Yield (mg) 41 1: 2 cbz Bzl ch ₂ Ng ₅ ^h ₅ : Q “nh ₂ ^H 2 ° Q * COOH NaHCO ₃ 3,5 h 0 51 389 Cl 327 3 (1.1 eq. 168 mg H 497 mg (2 eq)

ОСС 247 mg (1.2 eq.), 1-hydroxybenzotriazole

162 mg (1.2 eq.) Dioxane 3 mL

42 c is Cbz Bzl _CH2 0Me BH ₍₂ ΓΝΗ 1030 DCM 10 Q'C000P0Cl ₂ N-methyl- 1 h 1.68 g morpholine tm (1.1 eq) 253 / U1 (1 eq) EtOAc 10 mL 29 614 43 trance Cbz Bz) _CH2 0Me BH 53 1123 44 Cbz Bzl CH ₂ OC Me Me BH QNH ₂ 3510 DCM 40 0'COOH (F ₃ COO) ₂ O 4h tm 3985 mg 2.52 ml (1.1 eq) (1.5 eq) Py 1.94 ml (3 eq) 69 4820 45 1:10 Cbz Bzl OCONH ₂ CH ₂ BH q'nh ₂ 2640 DCM 25 QCOOII DCC 1.36 g 4 hr. 2988 mg (1.1 eq) 69 3620

(1.1 eq) Py 729 / U1 (1.5 eq)

EEDQ 1.63 g (1.1 eq)

46 Cbz Bzl CH ₂ SMe BH Q'NH ₂₂₈₂ DCM 10 Q * ^p COOH 0Cl ₃ 30 mg 328 mg 112 min (1.1 eq.) Of (l, l eq.) Of NEt ₃ 138 / L (1.5 eq.) 10 87 4 95 47 Cbz Bzl CH ₂ SCH ₂ CN R ⁶ ®Cl ₂ Br DMF ASSCH ₂ CN EtOH 3 mL, 2 h -70 57 194 BH 640 3 (1.6 eq.) NaH 15 mg * 71 mg (1.6 eq) 48 Cbz Bzl CH ₂ SCHF ₂ q-nh ₂ DMF О'СООН Me ₂ NPh 5 h t.m. 71 510 8I < 371 1.9 398 mg of 132 / U1

(1.1 eq.) (1.3 eq.) СГме ^ СП 82 mg (1.1 eq.)

02

Table 1 (1) - continued

Ref. cis: R ° R ³ R ⁵ R ⁶ Default Dissolve- Reaction Pomocná Tep- Výě- Výě- trance substance body component component lota žek žek (mg) (ml) (° c) (mg)

Q * nh ₂

1160

DCM

Q * COOMs Py 293 ml 3 h 0 1 * 41 g (1 * 5 eq.) (1.1 eq.)

1503

3: 5

MeBb MeBzl BH

O'nh ₂

1050

DCM

Q'C00P0ClNMe ₂

1 * 34 g lutidine 4 hr. 60,1216 (1 * 1 eq.)

295 / U1 (1 * 5 eq)

1 - 1

Cbz Oz 1 BH q'nh ₂ EtAC 750 7.5 N N

Py 250 / U 1 h 0 53 745

QCOCO (OEt) *

1 * 33 g (1.5 eq) (1 * 5 eq)

3000 20

Q * COOH РОСЦ

3 * 00 g 1.018 g (1.1 eq) (1.1 eq)

NEt 1264 / U1 (1.5 eq)

5230

52 Cbz Bzl NN ЛЛ CH ₂ S Me Q '\ H ₂₇₇₀ DCM 7.7 Q * COOH 749 mg (1.1 eq. DCC 342 mg 2 hr. 57 (1.1 eq.) * ,) Example 1 in 180 µl (1.2 eq) DMF 3.9 ml 812 0 · \ Ή ₂ DCM o * coon P0Ci ₃ 1 h 0 96 5507 3100 20 May 3,014 g 1,018 g

(1.1 eq.), NEt ₃ (1.1 eq.)

1264 / U1 (1.5 eq)

53 1: 1 Cbz Bzl BOC QNH ₂ MIK QCOON (COCH ₂ ) ₂ 5 hrs 51 1252 i hI ^{1423 15} 1 * 41 g (1 * 1 eq)

CH 2 S * BH

54 1: 1 Cbz Dzl BH Q'NH ₂ DCM Q‘COC1 pikolin 2 h 0 96 1252 N N 612 12 564 mg 0.39 ml NHBOC \ 1 (1.2 eq) (4 eq) CH ₂ S \ CH ₂

Table 1 (1) - continued

Ref. cis: R ° R ³ R ⁵ R ⁶ Starting substance (mg) Solvent (ml) The reactant Auxiliary with bed Time Temperature (° C) Yield (%) Yield ( ^ro 9) trance 55 cis Cbz Bzl BH Q * NH ₂ OCM QC00H DCC 330 mg 2 h t.m. 38 565 . MeN | i N -if 793 40 726 mg (1 eq) л N (1 eq) л ^CH 2 ^S 56 trance Cbz Bzl 56 834 57 Cbz -> • Bzl OMe BH q'nh ₂ · OCM QCDC1 picoline 200 / µl -10 95 418 210 4.2 300 mg (4 eq) 30 (1.2 eq. ) min 58 Cbz Bzl 0S0 ₂ No. q'nh ₂ DCM QC00H (Et0) ₂ P0Br 1 h t · m. 75 232 BII 159 1.6 187 mg 90 mg

(1.2 eq) (1.2 eq) 1-methylmorpholine

88 / U1 (2.5 eq) 59 1: 2 Cbz Bzl cl BH Q &apos; NH ₂ 802 OCM 8 QCOOH OCC via 993 mg 454 mg night (1.1 eq.) t.m. 67 1120

(1.1 eq.), P icoline

250 / U1 (1.2 eq) DMF 4 ml 60 BOC Bzl Cl PNB q-nh ₂ Di ’ Q’C00NSt 8 hrs.m. 50 58 2-cefemový isomer 56 0.5 94 mg (1.1 eq.) 61 MeCbz sch ₂ ch ₂ f 0’NH DCM О'СООН cyanurchloride 10 97 361 MeBzl PNB 176 5.3 224 mg 86 mg (1.1 eq.) Min (1.1 eq.) Py 134 ^ υ1 (4 eq) 62 MeCbz sch ₂ ch ₂ f q-nh ₂ Chf Q’C00000iBu 5 h 0 80 725 MeBzl BH 445 4,5 638 mg _NEt3 209 / l (1.1 eq.) (1.5 eq.), (MeOCl ₂ ) ₂ 4.5 mL 63 1: 1 Cbz Bzl SCH ₂ CF ₂ QNH ₂ DCM Q’COO-1- Py 120 / U1 over t.m. -benzotria- night. 64 283 PNB 225 4,5

zolyl (3 eq)

855 mg (3 eq)

Table 1 (1) - continued

Ref. cis: R ° R ³ R ⁵ R ⁶ Default Dissolve- Reaction Help Time Pulse- Výě- Výě- trance substance body component component lo ta žek žek ( ^m 9) (ml) (° C) (%) ( ^m 9) 64 Cbz DZ1 SCH ₂ CF ₂ R ⁶ = PN0 DCM Zn H0Ac 2.5 ml 2 h 0 59 127 H 254 15 Dec 508 mg 65 Cbz Ozl SCH-CH ₂ Q'nh ₂ DCM Q * C00H cyanurichloride 0 90 385 BH 210 6.3 249 mg 94 mg 30

(1.1 eq) min (1.1 eq) py 150 / U1 (4 eq)

66. Cbz Bzl SCH = CH ₂ Q'NH ₂ DCM О’СООП kyanurchlor id 0 48 1515 PNB 1500 22nd 1898 mg 387 mg 30 (1.1 eq. ►) min (1.1 eq.) Py 615, ul (4 eq)

Table 1 (2)

A process for preparing esters, i.e., compounds of formula (i)

C-CONH

R 'COOR ³

(AND)

Ref. cis: R R ¹ R ² R ³ R ⁵ R ^{6 characterized cho2Í} trans ^letka (mg) of cis Cbz II

Bzl Me BII QNI < ₂

1900

R0Solvent (ml) The reactant Auxiliary folder Time Temperature (° C) Yield (%) Yield (mg) DCM QCOOH DCC 1015 mg over t.m. 76 3047 19 Dec 2415 mg (1.1 eq.) night

(1.1 eq) picoline 578 / U1 (1.2 eq), DMF 950 / U1 cis Cbz II

Bzl CH = CH ₂ 0ΊΝΗ ₂ ³⁹¹

DCM

QCOOH

877 mg (2 eq)

EEDQ 618 mg (2.5 eq) via rt. 51 night

415

3 c is Cbz H - Bzl CH осоме BII QNH ₂ 2640 DCM 78 Q (0011 cyanurchlor id 1 h 2910 mg 224 mg (1.1 eq) (1.1 eq.) 1952 / U1 (4 eq.) 0 6 318 4 trance Cbz H - Bzl CH OCOMe BH 54 2799 5 c is Cbz II CH ₂ CH ₂ Bzl H BH Q "NH DCM Q COOH SOC1 ₂₁₀₇ / ul 3 h 0 23 188 367 3 514 mg (1.5 eq), py (1.1 eq.) 203 µl (2.5 'eq.) 6 trance Cbz H CH ₂ CH ₂ Bzl H BII 50 408 7 Cbz H xCHMe Bzl H BH Q * NH Chf Q * COOH picoline 484 / µl 1 h -10 56 457 367 lei 514 mg (2 eq.) (COCl) ₂

cxo Cbz H x CHMe Bzl H bh (1.1 eq) 85 / U1 (1 eq),

To 360 / Ul

02

Table 1 (2) - continued

no. c i3: trance R ° R ¹ R ² R ³ R ⁵ R ⁶ Starting substance (mg) Solvent (ml) Reactant Auxiliary Do- component ba Temperature (° C) Yield (%) Yield ( ^m 9) 9 cis Cbz H (b ₂ ) ₃ Bzl H BH QNH ₂₃₆₆ Cbf 1Д QCOOH 528 mg (1.1 eq) picolin 1 h 193 µl (2eq.), (COCl) ₂ 127 mg (1 eq.) -10 21 174 10 trance Cbz H < ^CH 2> 3 33 273 Bzl H BH TO 37 / Ul 11 c is В0С H x2Me ₂ Bzl H BH Q * nh ₂₃₆₆ EtAC 3.7 (<Tco) ₂ o 961 mg (1.1 eq. N-methylmorphine ¹⁵¹ / ^µl 30) (1.5 eq) _min (ClCH ₂ ) ₀ 3.7 mL re f 1. 28 222 12 trance DOC H х2ме ₂ BH 42 334 Bzl H 13 3 - 2 Cbz Cl - Bzl II BH Q'NH ₂₃₆₆ OCM 3.7 Q “COOH 520 mg (1.1 eq. EEDQ 272 mg, (1.1 eq.) DOC 228 mg, (1.1 5 h 0) equiv, py 121 / U1 (1.5 eq) 72 591 14 1 - 1 Cbz Cl CH ₂ CH ₂ M-MEM Bzl H BH N-Q-MEM * NIH ₉₃₆₆ EtAC 3.7 Q * CDC1 610 mg MEt ₃ 153 / U1 (1.1 2 eq.) ONF 730 / U1 h 0 83 740 15 Dec Cbz Cl (C ₂ ) ₃ Bzl H BH Q'nh ₂₃₆₆ Chf 1Д Q’C00H 566 mg picoline 202 / U1 1 h (2 eq), (COCl) ₂ -10 61 527 (1.1 eq. 85 µg (1 eq), To 370 / U1 16 Cbz Cl scn ₂ Oz H BH Q'NH ₂₃₆₆ Chf 1Д QC00H 570 mg (1.1 eq. picoline 202 / h 2 h (2 eq.), (CO ₂ ) ₂ ) 85 / UL, (1 eq.), To 370 / UL -10 68 589

Table 1 (3)

Method of making esters,

C-CONH

R ² COOBzl

(AND)

no. cis: X R ¹ R ² R ⁴ R ⁵ Default ROZ- Reaction assistant To- Pulse- Výě- Výě- trance substance pouš- folder folder ba lo- žek žek (mg) now- the (%) ( ^m 9) lo (° O (ml) 1 c is scw. H CH _O <_ H H QNH ₂ DCM 0'COOH S0C.l ₂₂₁₃ / U1 1 h 0 91 1485 751 6 996 mg (1.5 eq) (1.1 eq.) 2 trance so ^ H CH ₂ H H qnh ₂ DCM Q'COOH SOC1 ₂₂₁₃ / U1 996 mg (1.5 eq.) 1 h 0 88 1436 751 6 (1.1 eq.) 3 trance sop H CH ₂ H H Q'nh ₂ DCM Q'COOH SOC1 ₂₂₁₃ / Ul 1 h 0 87 1409 751 6 996 mg (1.5 eq) (1.1 eq.) 4 Sat II ^CH 2 H CII ₂ SCH ₂ CN Q'nh ₂ DCM Q COOH (C00 ₃ F) ₂ 0315 mg t.m. 78 699 462 2.3 678 mg (1.5 eq), (1.5 eq) Py 245 / U1 2 h (3 eq)

4 SO H CH ₂ H CH ₂ SCH ₂ CN R ⁵ = CH ₂ DMF acsch ₂ cn EtOII 5 ml, 3 h -70 53 237 ВГ 455 5 99 mg NaH 21 mg (1.5 eq. ) (1.5 eq.)

Qnh ₂

507

DCM Q'C0011 (F ₃ C00) ₂ 0 3 hrs 70 658

2.5 679 mg 315 mg (1.5 eq) (1.5 eq), Py 245 µl (3 eq)

sop> h CH ₂ H OH Q'NH ₂ DCM Q’COOPONMe Cl 130 1.3 113 mg lutidine 49 µl 1 hr rt. 61 167 (2 eq.) (1.5 eq.)

7 1 - 1 0 H CH ₂ OMe CH = CH ₂ Q'NH ₂₄₀₈ DCM 8.2 Q’CDC1 565 mg picolin 377 ml 1 h -10 94 (4 eq) 791 (1.2 eq. )

Table 1 (3) - continued

Ref. cis; XR ¹ trans R ² R ⁴ R ⁵ Starting material ( ^m 9) Halve * body (ml) The reactant Pomocná 3 bed Do- Tepba lo- (° C) Yield (%) Yield ( ^m 9) 8 0: 1 0 H CH ₂ оме Q'nh ₂ DCM Q’COC1 picolin 621 ml 2 hr -10 93 1446 MeN N 1 11 840 16 1115 mg (4 eq) / AJ (1.2 eq. ) CH ₂ S

CS 268513 D2

Table 1 (4)

A process for preparing esters, i.e., compounds of formula (I)

no. c is: trans R R ² R ⁵ Starting substance (mg) Dissolved (ml) Reaction Auxiliary folder folder Time Temperature (° C) Yield (%) Yield (mg) 1 1: 3 Ph ^CH 2 H QNH ₂ THF QCOOH carbonyldiimidazole t.m. 68 439 367 3.7 326 mg 132 mg (1.1 eq.) (1.1 eq.) 3 h . DMA 1.8 ml 2 trance th ieny1 ch ₂ H q'nh ₂ DCH Q’COOH DCC 227mg over t.m. 74 4 82 367 3.7 333 mg picoline night (1.1 eq.) Of an ^IL-1 mg ^kV '^

(1.2 eq.), DMF 1.9 mL

3 1: 4 thienyl CH- ^from MeN-N Q-NH ₂ 494 DCH 46 Q’COOH 333 mg DCC 227 mg via tm 79 (1.1 eq.) ^ПСС 616 (1.1 eq. Jpikolin 117 / Ul _r CH ₂ S ™ (1.2 eq.), DMF 1.9 mL

cn ₂ H

Q ^r NH ₂ DCM Q'C00PO ₄ Me ₂ Cl

367 3.7 630 mg lutidine 169 / U1 (1.5 eq.) (1.1 eq.) 3 hr. 73 549

1: 1 thiazole-4-γ1

CH ₂ H

Q ₂ NH ₂ DCM Q’C00Ms Py 122 / U1 (1.5 eq) 367 3.7 584 mg 1 b 0 84 548 (1.5 eq. )

Table 1 (4) - continued

no. cis: R R ² R ⁵ Default ROZ- Reaction Pomocná To. Pulse- Výě- Výě- trance substance pouš- component component ba lo- žek žek (ng) now- the (%) (rag) lo (° C)

(ml) tr ₂ NO ₂ -p

AND

PbCH = N

H CH ₂ NH ₂ 222 DCM p -NO ₂ C ₆ N ₄ cho

61 mg p-MeC ₆ N ₄ SO ₂ H 5.7 mg (1.2 eq.) (0.1 eq.) 7 h refl. 30 80 cis _N

N0 ₂ -p

I PbCH = N

CH ₂ H NH ₂ - 300 DCM 12 p -NO ₂ ^C 6 ^H 4 ^CH DEG 82 mg of p-MeCJLSO ^ 5.7 mg (1.2 eq.) (0.1 eq.) _{7 h refb 3} _ 126

1 - 1

CbzNH

CH ₂ H 0‘мц DCM Q’COOII DCC 228 mg (1.1 eq), 367 3.7 500 mg EEDQ 272 mg _{3 h} 602 (1.1 eq.) i (1.1 eq). Py 120 / U1 (1.1 eq)

Q'NH ₂ DCM Q * COOII DCC 228mg (1.1eq)

367 3.7 184 mg EEDQ 272 mg ₃ ht (1.1 eq) (1.1 eq)

120 / UL (1.1 eq.)

CS 268513 82

Table 2 (1)

Process for preparing carboxylic acids

Abbreviations;

Na-salt = the product was neutralized with aqueous NaHCO 3, (2 eq) and the resulting solution was passed through an adsorbent column and lyophilized to a solid sodium salt.

MIC = minimum inhibitory concentration against E. еоФт ^ ЕС — 14 in µg / ml

R ³ R ³ _R 6 Starting material Dissolve- Reaction Pomocná To- Pulse- Výě- Výě- (mg) body with bed component ba lo- žek žek (ml) the (%) (mg) (° O

1 1 - 1 H II H Rc = Cbz, R ³ = tBu, R ⁶ = DCM BH 766 10 AlCl 2 anisole 10 ml 1.2 g (9 eq) 30 min t. m. 79 BALL 328 0.1 2 c is clay HCl H II R = H 2500 GN-IIC1 7.5 ml (surplus) 1 h 10 72 1800 3 cis H (1 H R 0 = BOC, R ³ = Bz 1, aniso 1 R ⁶ = BH 766 13 А1СЦ 1.6 g (12 eq) 2 h 0 82 338

R 0 = Cbz, R ³ = CH ₂ CH = CH ₂

R ⁶ = BH 375 toluene 4 А1СЦ anisol 800 mg (12 eq) 2 ml 6 h t. m. 61 140 R ° = Cbz to luen А1СЦ anisol n ml 3 h 20 May 80 164 R ³ = CH ₂ CHMeCH = 4 ' 800 mg R ⁶ = BH 382 (12 eq) R ° = Cbz anisol ^A1C1 3 8 h t. m. 67 145 R ³ = CH "CMe = CH _{in the} (- 2 4th 8 800 mg Rf = BH 382 (12 eq.

R 0 = Cbz, R ³ = CH ₂ CH = CHMe,

R ⁶ = 230 BH toluene А1СЦ anisole 1,2 ml 5 h t.m. 60 83 2.4 360 mg (9 eq)

CS 268513 82

Table 2 (1)

ČÍS. Cis R ^J R R ° Starting material Solvent-Reaction Pomocná To- Pulse- Výě- Výě- trance (“9) dough ingredient component ba lo- žek žek (ml) the (° C) (X) (mg)

R 0 = Cbz, anisole AlCl 4 4 hr. 85 348

R ³ · CMe ₂ CH = CH ₂ 10 800 mg

R ⁶ = BH 779 (6 eq.)

R 0 = Cbz, R ³ = CH ₂ CH = CMe ₂ R ⁶ = BH 779 toluene 8 AlCl ₃ anisole 8 ml 800 mg 3 h t.m. 90 370 R 0 = Cbz, R ³ = CH ₂ CH = CHPh, R ⁶ = BH 238 toluene 2.3 AlCl ₃ anisole 1.2 ml 350 mg (9 eq) 4 h t.m. 59 78 R ° = Cbz aniso1 Alcl, 3 h 5 71 291 R ³ = t-Bu. R ⁶ = H 10 500 mg 300 (9 eq) R 0 = TFA-H, R ³ = Bzl, an isol 7 AlCl ₃ 400 mg 2 h 0 56 115 R ⁶ = H 364 (3 eq) R 0 = H, R ³ = Dzl, R ⁶ = BII 222 anisol 5 Ald ₃₄₀₀ mg (eq. 9) 4 h 0 75 101 Rc = Cbz, R ³ = H, R ⁶ = IJH, 355 aniso1 10.5 A1C1 ₃₅₀₀ mg (eq. 9) 2 h 30 85 174 R 0 = Cbz, R ³ = 0zl R ⁶ = 1117 , anisol 15 Dec А1C1 ₃₅₀₀ mg (eq. 9) 4 h t.m. 80 165 - R ° = Cbz, R ³ = steBzl Rf = BH 2030 anisol 30 TiCl ₄ 4.12 mL (15 eq .) 3 h 10 54 549 R ° = Cbz, R ³ = PM0 R ⁶ = OH 3000 aniso1 30 AlCl ₃ 4330 mg (9 eq. ) 3 h 3 92 1360 R ° = IICO, R ³ = 11, HOAC 1N4IC1 over t.m. 73 623 R ⁶ = 911 l 2.5 10 «1 (excess) night R 0 = C ¹ CH ³ CO ₄ , R ³ = H, R = H TUP 5 thiomo-EtOII 5 ml, IL.O china 2 ml, NaOAc, over night t.m. 46 95 155 mg 240 mg (3 eq)

Table 2 (1) - continued

Starting material Solvent-Reactive Auxiliary (mg) body component component (ml) ta (%) ( ^m 9)

Ref. cis: R 0 R ³ trans

Heat timeYield

Yield cis-H

HR ° = p-NO ₂ -benzyl anisole AlCl ₃ for 3H at 5 ° C 8 hr t 25 R ³ = Bzl, R ⁶ = BH 10 400 mg R = p-O ₂ N400 (6 eq) - benzal R ³ = H,

R ⁶ = H 207 mg (76

%), then treated with 20% HCl (2 mL) in acetone (2.Ш1)

Rc = Cbz, acetone

R ³ = Bzl, R ⁶ = BH 1.5 ml

2-cefem

Zn

392 mg (excess)

HOAc 1.5 mL, 5.h 50 The product was deprotected with 3-cephem as above

R 0 = H

MIC = 0.05

1: 1 И ме

II R ° = cbz

R ³ = Bzl, R ⁶ = 7 BH

364 an isol ^Alcl 3

770 mg (13 eq)

410 = 1.6

1: 1 H CH = CH,

H R ° = Cbz

R ³ = BZ1, ^R6 = BII 70

3213 anisol

А1СЦ

9/4 g (18 eq)

2,5 h

O

836

MIC = 0.8

1: 1 H CH = CHCN (Z) H R 0 = Cbz,

R ³ = Bzl, R ⁶ = H

234 anisol

SnCl.

500 / U1 (13 eq) h O

MIC = 0.2

1: 1 H CH = CIIC0011 (E)

II

R ° = Cbz

R ³ = Bzl, R ⁶ = BH 3.5

246 aniso1

SnCl _A

875 / U1 (18 eq) h O

MIC = 1.6

1: 1 H CH = CHCl 3, (IZ; 2E) '

II R 0 = Cbz, R ³ = Bzl, R ⁶ = BH

150 anisole A1C1 ₃

336 mg (15 eq) h 0 24 20

MIC = 0.8

Table 2 (1) - continued

Ref. c is: trans R ³ R ⁵ R ⁶ Default (<ng) substance 1 Solvent-Reaction Auxiliary Time Temperature (° O Yields (Nig) tcdlo (ml) folder folder 9 1 - 1 H CH = CHCF ₃ (Z) H R 0 = Cbz, R ³ = Bzl, R ⁶ = BH anisol 3 AlCl ₃ 290 mg 3 h 0 43 31 130 (15 eq) MIC = 0.8 10 112 H ch ₂ Ng ₆ h ₆ ® Θ · R 0 = Cbz, R ³ = Bzl, R ⁶ = BH anisol 1/5 AlCl ₃ 150 mg 3, , 5 h t.m. 55 137 381 (9 eq) MIC = 0.1 11 2 - 3 H СЩОме II R ° = Cbz R ³ = Bzl R ⁶ = BH ме \ 0 ₂ 1.5 AlCl 2 anisole 6 460 mg m 1 4 h 0 72 65 170 (17 eq) = II 12 3: 5 H СЩОСОме II R 0 = Cbz, R ³ = Bzl, R ⁶ = BII anisol 12 A1C1 1.13 g 3 h 0 68 155 410 (18 eq) MIC = 0.1 13 2 - 3 H сщосомщ H R 0 = Cbz, R ³ = Bzl, R ⁶ = BII Me ₂ 1.5 AlClg anisole 1 137 mg ml over 5 h 60 20 60 (15 eq) MIC = 0.05 14 1 - 1 N3 CH ₂ SMe On R 0 = Cbz, R ³ = Bzl, R ⁶ = BII anisol 8 SnCl. Na-salt 4 0.84 ml 24 h 0 74 158 393 (15 eq) MTC = 3.1 15 Dec H CH ₂ SCH ₂ CM H R ³ = cbz, R ³ = Bzl, R ⁶ = BII anisol 15 Dec A1C1- 1.2Д 3 h 0 74 228 * 550 (15 eq) AND MIC = 1.6

Cil SCHF II _{0 0}

II R ° = Cbz

R ³ = Bzl, R ⁶ = BII 7

678

DCM

SnCK anisole 7 ml 4

1.34 ml меМО _э 1 ml (15 eq)

146

MIC = 3.1

Table 2 (1> - continued)

Ref. cis: R ³ R ⁵ trans

2000

R ⁶

Default lá tka Dissolve- Reaction aids To- Pulse- Výě- Výě- (mg) body folder folders ba lota žek žek (ml) (° C) (%) (mg) R ° = Cbz anisol A1C1 _O Na-salt 4 h 0 59 91 R ³ = Bzl _/ R ⁶ = BH 7 667 mg 270 (17 eq)

MIC = 0.2 R @ ³ = MeCl2, R @ ³ = MeBzl, R @ ⁶ = BII 312 DCM 4 SnCl ₄₅₇₂ / l (15 eq anisole 177 / U1, 7 h мемо ₂ 1 ml Na-salt.) 0 47 82 MIC = 0.2 R ° = MeCbz acetone AcC 1 KI 432 mg (4 eq) R ³ = MeBz1 5 78 mg product with 2 h 0 87 371 R ⁶ = BH (2 eq. ) gets rid of protective sul foxide 470 groups as above R 0 = Cbz, R ³ = Bzl, R ⁶ = BH an iso1 35 SnC 1 3.8 ml 21 h 0 4 S 554

(15 eq)

R @ ³ = Cbz, R @ ³ = Bzl, R @ ⁶ = BH 1755 anisol 29 SnCl ₄ 3.26 ml (15 eq) 9 h 0 43 442 MIC = 0.2 R 0 = Cbz, R ³ = Bzl, R ⁶ = BH anisol 7.5 SnCl ₄ 813 .mu.l 20 h 0 47 122

(15 eq)

438

Μ10 = 0.2

22 1: 1 II H N --- N АЛЛ CH ₂ S CH ₂ R 0 = cbz, R ³ = Bzl, R ⁶ = B 11 460 DCM 4 SnCl ₄ MeNO ₂ 4 ml, 23 h 0 840 / Ul anisole 7.6 ml (15 eq) 53 145 MIC = (), 1 23 1-1 11 H R 0 = Cbz _t anisol AlCl 3 4 h 0 55 110 - MoN-- N R ³ = B 1, R ⁶ = BH 6.5 650 mg i ¹¹ 340 (13 eq) /

ЛУ ”

MIC = 0.1

Table 2 (1) - continued

Ref. c is: trans R ³ R ⁵ R ⁶ Starting substance (mg) Solvent- Reaction Auxiliary Oo- Temperature (° C) Yield (Й) Yield ( ^m 9) body (ml) folder - folder ba 24 3: 5 H About me H R ° = Cbz anisol AlCL · 3.5 h R ³ = Bzl, R ⁶ = BH 12 1,55 g 5 58 185 598 (16 eq) MIC = 1 ₍ , 6 25 3: 5 H Cl H R ° = Cbz anisol A1C1, 3h 5 58 120 R ³ = Bzl, R ⁶ = BH 11 bl 9 386 (18 eq. MIC = O ₍ , 8 26 1: 2 H SCH ₂ CH ₂ F H R ° = MCCbz Zn (1.15 g) (excess) and HOAc 64 69 R ³ = MeBz1 (8.6 ml in DCM (8.6 mL) for 4 h at 0 ° c,

then excess di phenyldiazomethane (203 mg)] product (R = Mecbz, R ³ = MeDzl, R ⁶ = OH 317 mg) was treated with $ SnCl ₄ , 0.26 mL (10 eq.) in DCM (1 mL) and Me (1 mL) in anisole (0.24 mL) at 5 h at -30

^R6 = PNB 574 ° C

MIC = 1.6

3: 7 To SCH ₂ CF ₃

On

R ° = Cbz

R ³ = Bzl, R ⁶ = P 1 'B

670

Zn 1.3 g (excess) and HOAC 7 mL 45,163 in DCM 35 mL for 2.5 h at 0 ° C. 530 mg of product (R ° = Cbz, R ³ = Bzl, R 4 = H 536 mg) is treated with MIC = 3.1 with А11, 1.38 g (10 eq.) In anisole 10 ml of 2, 5 b at 0 ° C. Na-sul

4: H 5 SCH ₂ CH =

H R ° = Cbz

R ³ = Bzl, 'R ⁶ = PNP'

750

Zn 1.5 g (excess and HOAc 7 mL in DCM 60 130 mL for 2 h at 0 ° C, then with an excess of - phenyldiazoraethane. 400 mg of MIC = 25 (R = Cbz, R ³ = Bzl, R ⁶ = BH 516 mg) was treated with SnCl, 1.82 g (9 eq.) In anisole, overnight at 0 ° C.

Table 2 (2)

Process for preparing carboxylic acids

Ref. c is: R ¹ R ² R ³ R ⁵ R ⁶ starting material (mg) Solvent (ml) Reaction Auxiliary folder folder Do- Tep- Výě- Vytě- ba lo- the Item (*) ( ^m 9) 1 c is H - H ме II R 0 = Cbz R ³ = Bz 1 anisol 4,5 ^AlCl 3 500 mg 4 h 0 39 42 R R ⁶ = BH (14 eq) 213 MIC = 1.6 2 c is II - H CH = CH ₂ II R 0 = Cbz, R ³ = Bz 1 anisol AlCl ₃ 400 mg 4 h 0 32 31 r ⁴ = bh (13 eq) 190 MIC = 0.4 3 c is H - II CH ₂ 0C0Me II R ° = Cbz anisol A1 _C 1 ₃ 4 h O 52 32 R = Bzl, O 240 mg R ⁶ = BH (14 eq) MIC = 0.1 4 trance H - H CH ₂ OCOMe Η R ° = Cbz DCM A1C1 ₃ anisol 3.5 h R = Bzl, 2 530 mg 4 ml 0 36 66 R ⁶ = BH (10 eq _f ) 336 MIC = 1.6 5, c is H CH ₂ CH ₂ On Η On R ° = Cbz O anisol A1C1 ₃ Na-sal 3 h 0 40 50 R = Bzl, R ⁶ = BH 5 473 mg MIC = 0.2 243 6 trance H CH ₂ CH ₂ On Η On R ° = Cbz O anisol AlCl ₃ Na-salt 3 h 0 54 65 R = Bz 1 5 497 mg R ⁶ = BH (13 eq. MIC = 0.4 231

Table 2 (2) - continued

Ref. c is: trans R ¹ R ² R ^{3 4} R ⁵ R ⁶ Starting material Italy (9) Solvent (ml) Reaction bed Auxiliary with bed Time Temperature (° C) Yield yield (%) (mg 7 * 1 - 1 H> снме Na H On R ° = Cbz, R ³ = Bzl, R ⁶ = 0H anisol 10 SnCl. 4,650 / U1 (15 eq) Na-soul 18 h 0 65 103 305 MIC = 0.1 8 exo H> CHMe Na H On R 0 = Cbz, R ³ = SO 2, R ⁶ = BH anisol 10 SnCl. 4 650 / UL (15 eq) Na-sú1 20 May h 0 48 75 300 MIC = 0.1

trans H ( ^н 2 ^ з ^H

Na R ° Cbz, R ³ = Bzl, anisol 7 AlCl ₃ Na-salt 831 mg 4 h 0 60 130 R ⁶ = OH (13 eq) 413 MIC = 0.8

cis H (? ^ 2? 3 Na H

Na R ° = Cbz, R ³ sBzl, anisol 5 AlCl ₃ Na-salt 612 mg 4 h o 35 70 R ⁶ = BH (12 eq. 304 MIC = 0.2

cis H > CMe ₂

Na H

Na R ° = BOC, anisol A1C1 ₃ Na-sal 4 h 0 44 93 R ³ = Bzl 11 850 mg R ⁶ = BH (13 eq) 384 MIC = 0.8

12 trance II > CMe ₂ Na H On R 0 = BOC, R ³ = BZ 1, R ⁶ = 8H 120 13 cis II CO ₂ Na ll On R o «H, R ³ = H, R ⁶ = H 300

anisole БпСц Na-sul via

270 / Ul night 0 47 31 (15 eq.) __________

MTC = 25

200 20% DC 1 Na-salt 24 h rt. 38 115

1 ml

1: 1 Cl - H 11

HR ° sCbz _f anisole SnCl ₄

R ³ ^ Bzl, 3 320 / Ul

R ⁶ = BH (15 eq)

145 through 5 42 31 night

MIC = 0.2

1: 1 Cl (CH ₂ ) ₂ Η II

HR ° = Cbz, anisole SnCl ₄

R ³ = Bzl, 1.2 181 / U1

R ⁶ * BH (N-MUM) 78 over 5 41 16 night

MIC = 1.6

CS 268513 D2

Table 2 (2) - continued

Ref. c is R ¹ íT R ³ R ⁵ R ⁶ Default Dissolve- Reaction Pomocná To- Pulse- Yield trance substance body component with bed ba lo- English Translation: (mg) (<nl) the (X) (mg) (° C) 16 10: 1 cl (CH ₂ ) ₃ On H On R ° = Cbz an isol SnCl ₄ Na-soul over t.m. 62 47 R ³ = Bzl R ⁶ = BH 2.5 28O / U1 (15 eq) night 137 MIC * 3 ₍ 1 17 cl SCH ₂ H 11 H R ° = Cbz anisol SnCl, over t. m · 69 41 R ³ = Bzl, 3 230 / UL (15 eq) night R ⁶ = BH MIC = 0.8 3 - 2 H (CH ₂ ) ₃ H H R ° = Cbz DCM TFA anisol 1 h t. m. 80 386 R ³ = BZ1, 5 3 ml 0.5 ml R ⁶ = BH (surplus) MIC = 0.2 725 MICeO, 8

Table 2 (3)

Process for preparing carboxylic acids

Ref. c is: trans X R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ Starting material ( ⁿ 9) Solvent (ml) The reactant Auxiliary with bed Time Temp lo- the (° C) žek (%) that '( ^m 18 1: 2 50Л H ^{C ,,} 2 On H Η On R ° = Cbz O anisol A1C1 ₃ Na-salt 4 h 0 66 72 R = Bz1, 6 600 mg R ⁶ = Bh (18 eq) MIC = 0 * 8 210 19 Dec 1 - 1 50 |! , H CH ₂ On H Η On R ° = Cbz anisol Л1С1 ₃ Na-salt 4 h 0 45 63 R = Bz 1 10 750 mg R ⁶ = BII (17 eq) 269 20 May 2 - 3 0 H Objective ₂ On About me CH = CH ₂ On R ° = Bzl O anisol А1СЦ Na-salt 3 h 0 63 12I R = Bzl 11 904 mg R ⁶ = BH (15 eq) MIC = 50 380 21 1 - 1 0 H CH ₂ H About me MeN ---- N H || R ° = Cbz O anisol A1C13 5 h 0 55 10C L and R = Bzl, 8 570 mg л R ⁶ = BH (13 eq) сн ₂ with 309

MIC = 6 * 3

22nd 1 - 1 0 H CH _O Na OMe MeN ---- N Na 1 J R 0 = 11 R ³ = H, H ₂ 0 1 NallC0 _? (2 eq) then lyof111- 5 h f.m. 99 103 R ⁶ = H zace CH ₂ S 100 ALIGN!

Table 2 (4)

Process for preparing carboxylic acids

No. 1 a * cis; trance R R ² R ³ R ⁵ R ⁶ Starting materials (mg) Dissolved lo (ml) The reactant Auxiliary with bed Do- Tep- výtě- Výě.- ba lo- the (° C) English Translation: % (mg) 1 trance Ph CH ₂ On H On R ³ = Bzl, R ⁶ = BH anisol 6 SnCl. 4800 / U1 (10 eq. Na-salt 4 h 0 49 136 462 MIC = 100 2 trance 2-thienyl ^CH 2 On H N3 R ³ = R ⁴ = Bzl dii 540 anisol 6.5 SnCl, 4,970 / Ul (10 eq.) Na-salt 4 h 0 66 215 MIC = 25 ' 3 2: 8 2-thienyl ch ₂ On MsN__ r On N R ³ = Bzl, R ⁶ = BI 1 anisol 6 SnCl, 4 730 / Ul Na-salt 24 h 0 67 217 4 85 (1Oeq) C1C = 12.5

CH ₂ S

Na R ³ = Bzl, R ⁶ = BII, 237 anisole AlCl 3 Na-salt

500 mg (10 eq)

MIC = 1.6

Bzl = HR ^3, R ⁶ = BH

500 anisole SnCl,

1.5 <nl (18 equiv.) H 5 38 100

V.IC = 6 _Z 3

CIL, Na H Na

N7 Cbz, anisole

R ³ = Bzl, 0.5

R ⁶ = BH

228

SnCl Na-salt

ЗОО / Ul (15 eq.) H 43 51

1-2 ___________

MIC = 0.2 h ₂ n

II II Ν-Cbz, anisole SnCl ₄

R ³ = Bz 1, 1,1 138 / U1

R ⁶ = BII (15 eq) h 0 90

CS 268513 82

Table 3

Pharmaceutically acceptable esters

COOR ⁶

ČÍS. C is: R 0 R ³ trans R ⁶ Starting material Solvent- Reaction Auxiliary component To- ba Temperature (° c) Výč- Výč (° g) body (ml) žek (λ.) žek (mg) 1 cis 11 II POM R ° = cbz anisol A1C1 ₃ 1 h 0 47 109 R ³ = BZ1, * 8.5 0.6 g ^R6 = POM (10 eq)

330 mg

R 0 = H, R ³ = H, DMF

R ^{6 -} 11 410 mg 10

POM-iodine X 'and ₂ CO ₃ 318 mg

252 / U1 (3 eq) (1.5 eq) h -5,221,123

1: 1 Η H

POM R 0 = Cbz, DCM SnCl ⁴

R-Bzl 13 585 µl

^R6 = POM (10 equiv.)

375 mg h 5 63,165

1: 1 Η H

POM R 0 = 11, R ³ = H, DMF

R ⁶ = H 205 mg 5

POM iodide K _o CO ₃ 200 mg 1 h -5 44 115

190 / UL (3 eq) (1.5 eq)

3 1 - 1 H POM POM R 0 = 11, R ³ = 11, R ® = H 205 mg DMF 5 POM iodide 317 / U1 (2.5 eq) K ₂ CO ₃ 200 mg (3 eq) Ího 11 35 4 1 - 1 H AOM лом R 0 = 11, R ³ = 11, л DMF AOM iodide K ₂ CO ₃ 200 mg 1 h -5 8 23 R-205 mg 3 167 / U1 (3 eq) (2.5 eq) 5 1 - 1 Cbz Bzl POM R ° = Cbz DMF POM iodide К Ct-hexanoate 2 h R ³ = D 2, R ⁶ = H 4 152 / Ul 138 mg -10 87 565 476 mg (1.2 eq) (1.1 eq.)

Reaction conditions used in the attached tables

Amidace

7-Aminocephamic derivatives are amidated by treatment with the corresponding carboxylic acid (1-2 equivalents) in the presence of a condensing agent such as sodium bicarbonate, pyridine, picoline, dimethylaniniline, N-methylmorpholine, triethylamine, trifluoroacetanhydride, 2-ethoxy-1-ethoxycarbones. - dihydroquinoline, Ν, Ν-dicyclohexylcarbodiimide, carbonyldiimidazole, 1-hydroxybenzotriazole, phosphorus oxychloride, thionyl chloride, oxalyl chloride, Ν, Ν-dimethylformamide, enol chloride, 2,4,6-trihydroxy-1,3,5-tripyridine 3,5-triazine trichloride, diethylphosphoryl bromide or cyanuric chloride (1 to 6 equivalents) in a solvent (for example toluene, chloroform, dichloromethane, dioxane, tetrahydrofuran, diaethylformamide, dimethylacetauid or water) for 10 minutes to 15 hours (or overnight) at - 30 ° C to room temperature *

Alternatively, the starting material is treated with an acid chloride, symmetric or asymmetric anhydride, for example derived from methanesulfonic acid, isobutoxymeric acid, diethoxyphosphonic acid, dichlorophosphonic acid or dimethylaminochlorophosphonic acid, (1.1 to 1.5 equivalents) or an ester (e.g. -hydroxybenzotriazole, N-hydroxysuccinimide or N-hydroxyphthalimide (1.1-3 equivalents) in the presence of a base such as triethylamine, pyridine, picoline, lutidine or N-methylmorpholine (1.5-5 equivalents) in a solvent such as chloroform, dichloromethane, dichloroethane, dioxane, methyl isobutyl ketone, ethyl acetate, dimethylformamide, or dimethoxyethane for 30 minutes to overnight at -50 ° C to the reflux temperature of dichloroethane.

Making of vellos

The carboxylic acid is treated with a dilute aqueous solution of sodium bicarbonate (1 to 1.1 equivalents) in water at room temperature each time.

Removal of a protecting group

The protected compound is deprotected by treatment with palladium triphenylphosphine, optionally in the presence of 2-ethyl-hexanoate, with Lewis acid (e.g., aluminum chloride, tin tetrachloride, titanium tetrachloride), with carboxylic acid (e.g., formic acid or trifluoroacetic acid) or 8 reducing agent. metal (e.g. zinc) in a solvent (e.g. toluene, dichloromethane, anisole, nitromethane or acetic acid) for 10 minutes to 24 hours at 0 to 50 ° C, or with thiourea, methyl- (N-methylxanthate) (3 to 4) equivalents) or 8 with hydrochloric acid in a solvent (e.g. tetrahydrofuran, ethanol, methanol, water, acetone or acetic acid) for 8 hours to overnight at room temperature.

The following table illustrates a process for preparing other compounds of the invention.

CS 268513 82

Table 4

Side-chain acids and their derivatives of the general formula

Ref. R R ¹ R ² IR (nujol): сю “ ¹ NMR: pp · m.p. 1 BOC (ci) H H 3120, 1700, 1675 m.p. 153-154 ° C (decomposition) 1.50 (a, 9H), 3.45 (d, 0-7.5 Hz, 2H), 7.00 (t, 0-7.5 Hz) 1H), 7.13 (a, 1H), 7.13 (a, 1H) / CDgSOCDy 2 BOC H H 3150, 1700, 1630 1600, m.p. 165 to 167 ° C (decomposition) 1.49 (a, 9H), 3.41 (d, 0-7.5 Hz, 2H), 6.89 (t, 0-7.5 Hz, 1H), 7.08 (α, 1H) / CO-jSOCDg / 3 Chz H H 3200. 1738. 1715 1690 m.p. 169 až 172 ° C (decomposition) 3.44. 3.50. (2xd, 0-8 Hz, 2H), 5.25 (Å, 2H), 7.07, 7.35 (2xt, δ = 8 Hz, 1H), 7.12 (Å, 1H), 7.38 (wide, 5H), / С0С1 ₃ -С0 ₃ 00 / 4 HCC H H 3400, 1718, 1690, 1630/1550, m.p. 168 ° C (decomposition) 3.45, 3.63 (2xd, 0-7.5 Hz, 2H), 7.14, 7.32 (2x, 07.5 Hz, 1H), 7.23, 7.25 (2xa, 1H) , 8.51 (а, 1H) / сос1 ₃ -со ₃ оо / 5 C1CH ₂ CO H H 3100. 1720, 1685, 1620, m.p. 153 ež 155 ° C (decomposition) 3.45 (d, 0-8 Hz, 2 H). 4.37 (β, 2H), 6.97, 7.05 (2XT, 0-8 Hz, 1H), 7.23, 7.27 (2xa, 1H) / CD 2 SOCDs 6 BOC H Bzl 3160 1740 1724 1700, 1678/1255, 1168 3.95 (d, 0-7.5 Hz, 2H), 5.50 (s, 2H), 7.26 (t, 0-7.5 Hz, 1H), 7.30 (broad, 1H), 7, 49 (β, 1H), 7.75 (e, 5H), 11.86 (broad, 1H) / CD ^ OCO ^ 7 HCO (2 cis: 1 trans) H target. -Bii - 3150, 3100, 1720, 1690, 1635 m.p. Mp 185-188 ° C 1.40 (α, 9H), 3.43 (d, 0-7 Hz, 2H), 6.89, 7.00 (2Xt, 0-7 Hz, 1H), 7.20, 7.26 (2-inch) (1H), 8.48 (.alpha., 1H) .alpha 8 <· - HCO- «·· H Bzl 1735 1680 1620 m.p. 153-155 ° C (dec 3.69 (d, 0-7 Hz, 2H), 5.12 (α, 2H), 7.17 (t, 0-7 Hz, 1H). 7.21 (,, 1H), 7.32 (,, 5H), 8.46 (,, 1H) / CO ₃ S0CD ₃ / 9 C1CH ₂ CO H Me not specified 3.39 (d, 0-7.5 Hz, 2H), 3.70 (α, 3H), 4.24 (α, 2H), 7.11 (a, 1H), 7.23 (t, 0) -7.5 Hz, 1H), 9.37 (broad, 2H) (CDCl3) 10 C1CH ₂ CO H Bzl 1726, 1685, 1160, m.p. 155 ° C (decomposition) 3.95, 4.01 (2xd, 0-7.5 Hz, 2H), 4.71 (α, 2H), 5.45, 5.47 (2X3, 2H), 7.28, 7.40 ( 2xt, 0-7.5 Hz, 1H), 7.58, 7.65 (2xa, 1H), 7.70 (α, 5H), 12.9 (broad, 1H) / CD 2 CO 2 11 Chz H Me 3400 to 2300, 1740, 1550 3.58 to 3.73 (β, 2H), 3.63 (a, 3H), 5.27 (a, 2H), 7.03 to 7.46 (δ, 7H) / СОдвОСОд /

Table 4 - continued

ČÍS. R R ¹ R ² IR (nujol); from ¹ tt NMR: ppn 12 Chz H target. -Bu - 3160 to 2200, 1720, 1680, 1635 m.p. Mp 169-171 ° C 1.42 (β, 9H), 3.53 (d, 3-7 Hz, 2H), 5.29 (β, ΙΗ), 7.27 (t, 3 = 7 Hz, δ), 7.35 (a, 1H), 7.30 to 7.50 (a, 5H), (COgCOCOg) 13 Chz (cis) H target.- -Bu not specified 1.44 (β, 9H), 3.53 (d, 3-7 Hz, 2H), 5.27 (a, 2H), 7.13 (t, 3-7 Hz, 1H), 7.24 ( 8, 1H), 7.30 to 7.47 (and SH) / С0С1 ₃ / 14 Chz H Me- 3150 to 2050, 1720, 2.33 (α, 3H), 2.53, 2.70 (2xd, 3-8 Hz, 2H), 5.11 (a, (2 cis: 1 trans) Bzl 1670, 1620, 157X1 m.p. Mp 160-163 ° C 2H>, 5.26 (α, 2H), 6.99 to 7.40 (α, 10H), (CDCl ₃ - - - CD ₃ CD) 15 Dec Chz (2 cis: 2 trans) H Bzl 1725 1675 1620 .1575 m.p. Mp 164-166 ° C 3.51, 3.73 (2xd, 3 = 7 Hz, 2H), 5.13 (8, 2H), 5.26 (a, 2H), 7.06, 7.10 (2χβ, 1H), 7 , 0 to 7.5 (в, 11H) / СОСl ₃ -CD ₃ 0D / 16 H (HCl-salt) Me H 3330-2450, 1720 1680, 1630 3.39 (d, 3 = 7Hz, 2H), 3.73 (a, 3H), 6.88 (α, 1H), 7.25 (t, 3 = 7 Hz, 1H) (CDCl 3 SO 3) 17 Chz H PMB 1720, 1575, 1515 m.p. Mp 145-148 ° C 3.80 (d, 3 = 8 Hz, 2H), 3.90 (s, 3H), 5.20 (α, 2H), 5.33 (α, 2H), 7.00 (8, 1H), 6.85 to 7.60 (m, 10H) / СОС1 ₃ -С0 ₃ 00 / 18 H (HCl-salt) Me Me 3200 1720 1625 1605 / CHCl 3 3.44 (d, 3 = 7 Hz, 2H), 3.75 (a, 3H), 3.85, 3.88 (2xs, 3H), 6.70, 6.75 (2X3, 1H), 6 , 97, 7.43 (2xt, 3 = 7 Hz, η) / coci ₃ -co ₃ oo / 19 Dec BOC Me ме 3415 1720 1541 1155 (CHCl3) 1.52 (s, 9H), 3.54 (d, 3 = 6.5 Hz, 2H), 3.64 (8, 3H), 3.76 (β, 3H), 7.11 (β, 1H ), 7.18 (t, 3 = 6.5 Hz, 1H), 9.12 (broad, 1H) / CDC1 ₃ / 20 May BOC (customs duties) Me Me 3410, 1720, 1541, 1150 / СНС1 ₃ / 1.51 (β, 9H), 3.54 (d, 3 = 6.5 Hz, 2H), 3.69 (β, 3H), 3.83 (a, 3H), 7.03 (α, 1H ), 7.08 (t, 3 = 6.5 Hz, 1H), 9.12 (broad, 1H) / CDC1 ₃ / 21 Chz Me Me 3390, 1720, 1540 / с _{3 3} / 3.41, 3.48 (2xd, 3-8 Hz, 2H), 3.65, 3.73, 3.69, 3.83 (4xa, 6H), 5.24 (b, 2H), 7, 00 to 7.37 (α, 7H), / coci ₃ / 22nd Chz Et Et 3395, 1720 / СНС1 ^ / 1.19, 1.20, 1.22, 1.30 (4X, 3-8 Hz, 6H), 3.34, 3.42 (2x D, 3-8 Hz, 2H), 4.08, 4, 12, 4.15, 4.24 (4xq, 3-8 Hz, 4H), 5.21, 5.22, 5.24 (3xe, 2H), 7.03, 7.13 (2xt, 3 = 8) HZ, 1H), 7.03 (Å, 1H), 7.31 (Å, 5H), 10.15 (W, 1H), (CDCl ₃ ) 23 Chz Bzl Bzl 3400, 1725 / с _{3 3} / 3.31, 3.42 (2xd, 3-7 Hz, 2H), 5.01, 5.03, 5.11, 5.17 (4X8, 6H), 6.96-7.30 (η, 17H) ), 10.19 (broad, 1H), (COCl 8)

Table 4 - continued

ČÍS. R R ¹ R ² IR (nujol): cm -1 ¹ mp NMR: ppm 24 Chz PMB Bzl not specified 3.40 (d, 0-7 Hz, 2H), 3.75 (α, 2H), 5.10 (s, 2H), 5.15 (s, 2H), 5.20 (α, 2H), 6.8 to 7.4 (·, 16H) / CDCl 3 25 Chz BH Bzl 3490, 1725- / COClj / 3.43, 3.40 (2xd, O = 7 Hz, 2H), 5.02, 5.05, 5.09, 5.17 (4X8, 4H), 6.8-7.4 (·, 23H) ), 9.90 (broad, 1H) / CDCl 3 26 HCO Me Me 3380, 3140, 1722, 1705, 1695 (CM1 ₃ ), mp 100 ° C 3.46 (d, 0-7.5 Hz, 2H), 3.66 (s, 3H), 3.78 (s, 3H), 7.05 (s, 1H), 7.24 (t, 0) -7.5 Hz, 1H), 8.49 (β, 1H), (CDCl 3) 27 Mar: HCO Me Me 3390, 3150, 1715, 1700, 1535 (CHCl3) 3.56 (d, O = 7.0 Hz, 2H), 3.73 (s, 3H), 3.84 (α, 3H), 7.02 (t, 0-7 Hz, 1H), 7, 12 (β, 1 H), 8.55 (з, 1 H), / CDCl 3 28 HCO (Cis) Me target -Bu 3380, 1710, 1540 / CHCl-j / m.p. Mp 101-104 ° C 1.47 (s, 9H), 3.50 (d, 0-7 Hz, 2H), 3.86 (s, 3H), 7.07 (t, O = 7 Hz, 1H), 7.13 ( s, 1H), 8.60 (s, 1H) / сос1 ₃ / 29 HCO Me target. -Bu - not specified 1.44 (s, 9H), 3.27 (d, O = 7 Hz, 2H), 3.80 (β, 3H), 7.05 (s, 1H), 7.31 (t, 0 = 7 Hz, 1H), 8.52 (β, 1H), (COCl./) 30 ClCH ₂ C0 Me Me not specified 3.50 (d, 0-6.5 Hz, 2H), 3.68 (a, 3H), 3.79 (3, 3H), 4.25 (3, 2H), 7.24 (β, 1H 7.24 (t, O = 6.5 Hz, 1H) (CDCl3) 31 C1CH, CO (cis) Me Me 3470, 1725, 1715, 1680, 1535 / снс1 ₃ / 3.60 (d, O = 7 Hz, 2H), 3.75 (a, 3H), 3.87 (a, 3H), 4.27 (a, 2H), 7.18 (a, 1H), 7.18 (t, O = 7 Hz, 1H) / CDClg / 32 ^Ph 3 ^C (3 cis: 2 trans) Me Me 3380, 1720, 1703, 1500, 1480, 1425 / снс1 ₃ / 3.43 (d, O = 6.5 Hz, 2H), 3.26, 3.64 (2xa, 3H), 3.70, 3.75 (2X8, 3H), 6.44, 6.63 ( 2xs, 1H), 6.54, 6.70 2X3, 1H), 7.01 (t, 0 = 6.5 Hz, 1H), 7.25 (в, 15H) / CDC1 ₃ /

SUBJECT OF THE INVENTION

Process for preparing 7- (carboxyalkenoylamino) -3-cephem-4-carboxylic acid

Claims (11)

SUBJECT OF THE INVENTION Process for the preparation of 7- (carboxyalkenoylamino) -3-cephem-4-carboxylic acid of the formula I CS 268513 82 (I) where R represents a phenyl group or a monocyclic 5- or 6-membered hetero group of 8 to 3 heteroatoms selected from nitrogen, oxygen and sulfur and an optionally substituted amino group optionally protected by an aralkyloxycarbonyl group of 8 to 15 carbon atoms in the aralkyl moiety, alkoxycarbonyl (C 2 -C 12) alkoxy, (C 1 -C 8) alkanoyl, (C 1 -C 8) haloalkanoyl, dimethyl-tert-butylsilyl, methoxyethoxymethyl or p-nitrobenzal group, R ¹ represents a hydrogen atom or a halogen atom, R ² represents a single bond, an alkylene group having 1 to 3 carbon atoms which is optionally branched or thiomethylenovou group, R ³ and R ⁶ are hydrogen, light metal, C 1 -C 8 alkyl, C 2 -C 7 alkenyl optionally substituted by phenyl, C 7 -C 15 aralkyl which is optionally substituted substituted with methyl, methoxy or nitro, or an alkanoyloxyalkyl of 2 to 12 carbon atoms, R ⁴ is hydrogen or methoxy, R ³ is hydrogen, hydroxyl, methoxy, methanesulfonyloxy, fluoroethylthio, vinylthio, halogen, methyl optionally substituted by pyridinium, alkoxy, alkanoyloxy, carbamoyloxy, alkylthio, haloalkylthio to 3-cyanoalkylthio, cyanoalkylthio to 3-cyanoalkylthio carbon atoms, a monocyclic heterothio group having 3 or 4 heteroatoms selected from the group consisting of sulfur and nitrogen, optionally substituted with a substituent selected from methyl, amino, alkoxycarbonylamino, C 1 -C 3, aminomethyl, butoxycarbonylaminomethyl or a halogen atom, or is a vinyl group optionally substituted by a substituent selected from the group consisting of cyano, carboxy, butoxycarbonyl, and trifluoromethyl, and X is -S-, -SO-, or -O-, with the proviso that when R is a thiaalkylene group, R ¹ is a halogen atom. CS 268513 82 79 characterized in that the 7-amino-3-cep-4-carboxylic acid derivative of the general formula II (II) X, R ⁴ , R ⁵ and R ⁶ have the meanings given above, amidating with carboxyalkenoic acid or a reactive derivative thereof of the general formula III R-C-COZ , 2. 2. The method of claim 1, wherein a compound of formula I is prepared using the appropriate starting materials, wherein the 7-acylaid double bond has an amido substituent and a carboxy substituent at the cis position. 2 3 R -COOR where R, R ^1, R ² and R ³ have the meaning mentioned above and Z is hydroxy or a leaving group such as a halogen atom to form a halide, an N-substituted aninoxy group to form a reactive ester, an acyloxy group to form a symmetrical anhydride or a haloalkanoyloxy group, an alkoxyformyloxy group, an alkanesulfonyloxy group or an optionally anhydrous deprotects the carboxy and / or aaino group, if present, with hydrogen halide, trihaloacetic acid, thiourea, zinc and an acid or Lewis acid selected from aluminum halide, titanium halide and tin halide, if necessary in the presence of anisole, and or is converted to salt by treatment with an aqueous alkali metal bicarbonate solution. 3. A process according to claim 1, wherein R is phenyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl or thiadiazolyl, or in particular R is aminoisoxazolyl or aminothiazolyl. a group or an optionally protected group as defined in 1 and the other substituents have the meaning given in 1. 4. A process according to claim 1, wherein the compound of formula I is prepared using the appropriate starting materials, wherein R is an anothiothiazolyl group optionally protected by the group depicted in item 1 and the other substituents are as defined in item 1. 5. A process according to claim 1, characterized in that a compound of the formula (I) is prepared using the appropriate starting materials, wherein R @ ¹ , which has been depleted of hydrogen or chlorine and the other substituents have the meaning given in item 1. 6. The method of claim 1, wherein said method is:. using the appropriate starting materials, it produces a compound of formula (I) wherein R ^{2 is} an optionally branched alkylene group and 1 to 3 carbon atoms and the other substituents are as defined in 1. 7. A process according to claim 1, wherein a compound of formula (I) wherein R ^{@ 4 is a} hydrogen atom and the other substituents are as defined in item 1 using the appropriate starting materials. 8 · method according to claim 1, wherein TiN that by using appropriate starting materials, produces a compound of formula I wherein R ⁵ znanená Aton hydrogen, vinyl, kyanovinylovou, acetoxynethylovou, karbamoloxynethylovou, triazolylthiomethy salicylic, methyltetrazoly1thiooethylovou or thiadiazolyIthionethylovou group optionally substituted aninoskupinou, aninonethylene or ethy ethylene group, and the other substituents have the meaning given in point 1. 9. The method of claim 1, wherein said starting material is used О Ж? ‘The substances are manufactured by a compound of formula I, wherein R and / or R is a hydrogen atom, an alkali metal atom or a pharmaceutically acceptable ester group as defined in 1 and the other substituents have the meanings given in 1. 10. A process according to claim 1, wherein the compound of formula (I) is prepared using the appropriate starting materials, wherein R and / or R is a alkyl or aralkyl ester group as defined in item 1 and the other substituents are as defined in item 1. 1. 11. A process according to claim 1, wherein the compound of formula I is prepared using the appropriate starting materials, wherein X is a sulfur atom and the other substituents have the meaning given in point 1. Process for the preparation of 7beta .- (carboxyalkenoylamino) -3-cephem-4-carboxylic acids A process for the preparation of 7 (b - (carboxyalkenoylamino) -3-cephem-4-carboxylic acids of the formula I) wherein r is phenyl or a non-cyclic hetero group having 1-3 nitrogen, oxygen or sulfur atoms and is optionally substituted with an amino group optionally protected -15 / aralkyloxycarbonyl С / 2-12 / -alkoxycarbonyl, С / 1-8 / alkanoyl, С / 1-8 / haloalkanoyl, dimethyl-t-butyl-silyl, methoxyethoxymethyl or p · nitrobenzalea, R ¹ represents hydrogen or halogen, r ² represents a single bond, C (1-3) alkylene or thiomethylene, R ³ and r ^{6 are} hydrogen, light metal, C (1-8) alkyl, C (2-7) alkenyl, optionally substituted with phenyl or optionally substituted C (7-15) aralkyl, r ⁴ is hydrogen or non-methoxy, r ⁵ is hydrogen , hydroxy, methoxy, methanesulfonyloxy, fluorothio, vinylthio, halogen, optionally substituted methyl, or optionally substituted vinyl, and X is -S-, -SO- or -O-, characterized in that the 7-amino-3-cephem-4-carboxylic acid derivative of the general formula II wherein: X, R ⁴ , R ⁵ and R ⁶ are as defined above, amidating with a carboxyalkenoic acid or a reactive derivative thereof, of the general formula (III): R 1, R ¹ , R ² and R ³ are as defined above and Z is hydroxy or a leaving group, and the resulting acid is optionally neutralized by treatment with a base, and optionally the amino or carboxy protecting group is removed from the protected acid. The compounds of the present invention are useful in the treatment of bacterial infections. CS 288512 B2