SE438679B - NEW SET FOR PREPARATION OF 7-AMINO-THIAZOLYL-ACETAMIDO-CEPHALOSPORANIC ACID DERIVATIVES - Google Patents

Description

7906605-6 2 NH-R * \ S N \ === ¿L1r /, C02Ad (II) N “X O\ Rl syn-isomer, wherein R and R1 have the meanings given above, and Ad represents one hydrogen atom or an alkali metal equivalent, or an equivalent of an organic amine base, with a compound of formula A e: ea ÜCH3) zu] 3-12-o-P- [N (C33) 2] 3 (A) Ye Ze wherein Y and Z are such that Y either represents a tosyl ion or mesyl ion and Z represents a halogen ion, or represents Y and Z is each a tosyl ion or Y and Z each represent a mesyl ion, and optionally with a base for the preparation of a compound of the formula III NH-R \\ S N Q (III) K C02? Emma) 213 syn-isomer, with which, in the presence of a base, a formula IV - -> - »« ----.--, -_-_ v ...- V- 7906605-6 (IV) N / CO2R'2 wherein R '2 represents R 2 or an alkali metal equivalent or a equivalent of an organic amine base, and R 3, R 4 and ns have the above given meanings, for preparation, after the addition of an acid, of a compound of formula I. The protecting group for the amino group, which R may represent, can e.g. be an alkyl group having 1 to 6 carbon atoms, as preferred tert-butyl or tert-amyl. R may also represent an ali- phatic acyl group, an aromatic acyl group or a heterocyclic acyl group or carbamoyl group.

Mention may be made of lower alkanoyl groups such as e.g. formyl-, acetyl, propionyl, butynyl, isobutynyl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl group, lower alkoxy or cyclo- alkoxycarbonyl groups such as e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.-butoxycarbonyl, pentyloxycarbonyl, tert.- pentoxycarbonyl, hexyloxycarbonyl, benzoyl, toluyl-, naphthoyl-, phthaloyl, mesyl, phenylacetyl, phenylpropionyl and arylalkoxy the carbonyl groups such as the benzyloxycarbonyl group.

The acyl groups may be substituted e.g. with a chlorine, bromine, iodine or fluorine atoms, such as e.g. chloroacetyl, di- chloroacetyl, trichloroacetyl, trifluoroacetyl or bromoacetyl. The substituent R may also denote a lower aralkyl- group such as benzyl, 4-methoxybenzyl or phenylethyl, trityl, 3,4-dimethoxybenzyl, benzhydryl.

The substituent R may also represent a haloalkyl- group such as trichlorethyl; The substituent R may also represent a chlorobenzoyl-, paranitrobenzoyl, para-tert-butyl-benzoyl-, phenoxyacetyl-, _ caprylyl, n-decanoyl, acryloyl, trichloroethoxycarbonyl group.

The substituent R may also represent a methylcarbamoyl, phenyl- carbamoyl, naphthylcarbamoyl group as the corresponding thiocarbamoyl amoyl groups. 7906605-6 The list above is not a limited list. It is Self- clear that other protecting groups for amines, groups known in especially in peptide chemistry, can also be used.

Among the values of R 1 may be mentioned, among others, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, R 'and R "can represents a methyl, ethyl, propyl or isopropyl group.

Among the values of R5 may be mentioned methyl, ethyl, propyl or isopropyl groups, but especially among the ester groups which can be easily eliminated, can be mentioned: esters, formed with the alkyl groups such as butyl, isobutyl, text.- the butyl, pentyl and hexyl esters. Mention may be made of acetoxymethyl, pionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxy- methyl, 2-acetoxyethyl, 2-propionyloxyethyl and 2-butyryloxyethyl esters. rarna.

Mention may also be made of a 2-mesylethyl-, 2-iodoethyl-, ethyl, vinyl, allyl, ethynyl, propynyl, benzyl, 4-methoxybenzyl, 4-nitro-benzyl-, phenylethyl-, trityl-, diphenyl-methyl-, and 3,4-dimethyl- oxybenzyl ester.

Mention may also be made of phenyl, 4-chloro-phenyl-, tolyl- or tert.- the butylphenyl esters. R2 can denote the same cleavable esters as sub- stituenten RS.

The heterocyclic group which R 16 may represent may be selected from a phenyl group or a 1,2,3-, 1,2,5-, 1,2,4- or 1,3,4-thiazole diazolyl group, 1-H-tetrazolyl-, 1,3-thiazolyl-, 1,2,3-, 1,2,4- or 1,3,4-triazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl group, which groups may be optionally substituted with one or more groups selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, nitrile, nitro or the amino groups.

R 16 may also represent one of the heterocycles mentioned above, substituted with an alkoxyl group having 1-4 carbon atoms, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyl, isobutyl or tert-butyl oxy, R16 may represent an acyl group selected from acetyl, propionyl- and the butyryl groups.

Among the preferred values of R 10 may be mentioned acetyl-, 1-methyltetrazolyl-, 2-methyl-1,3,4-thiadiazolyl-, 3-methyl-1,2,4- thiadiazol-5-yl-, 3-methoxy-1,2,4-thiadiazolyl-, 1,3,4-thiadiazolyl- 5 * Yl1 2'amiH0 "lf314- filiazol-5-yl-, 3-hydroxycarbonylmethyl-- 1,2,4-thiadiazol-5-yl-, 5-methoxy-1,2,4-thiadiazol-3-yl-, 4-methyl- ..... .a -... fl- we-w-w- 7906605-6 L fl 5-hydroxycarbonylmethyl-1,3-thiazol-2-yl-, 1-dimethylaminoethyl- 1,2,3,4-tetrazol-5-yl groups.

The halogen ion, which Z may represent, is a chlorine, bromine, iodine or fluorine ion. Chlorine ion is preferred.

Ad may denote a hydrogen atom or an alkali metal atom such as sodium or potassium. Ad can also denote an equivalent of an organic amine base, preferably a trialkylamine such as triethylamine. However, Ad preferably denotes a hydrogen atom.

In such a case, the turnover of compound A is monitored with the compound of formula II of reaction with a base such as e.g. tri- ethylamine or another trialkylamine.

When Ad e.g. denotes an equivalent of an organic amine base, no addition of such a base is necessary.

R'2 may have the same meaning as given above for R2 or Ad.

Effect of a compound of formula III on the compound of formula IV is preferably carried out in the presence of a base which can selected from the group consisting of triethylamine, tributylamine, N-methylmorpholine, pyridine, a picoline or a carbonate or a bicarbonate of sodium or potassium. One can, however use another organic base or analogous mineral base.

The preferred bases used are triethylamine or sodium bicarbonate.

The acid used to isolate the compound with formula I, may be selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid or dilute sulfuric acid acid.

Acetic acid or hydrochloric acid is preferably used. acid.

The reaction of the compound of formula A with the compound of formula II can preferably be carried out in an organic solution agents such as acetone, methylene chloride, N, N-dimethylformamide, tetrahydrofuran or a mixture of these solvents.

You can also use other solvents such as dioxane, acetonitrile, chloroform, dichloroethane or ethyl acetate. You can also carry out the reaction in excess of hexamethylphosphorus tri- amid. 7906605-6 This reaction can preferably be carried out at a temperature. temperature between 0 and + 20 ° C.

The development of the turnover of the compound of the formula III with the compound of formula IV can be greatly affected. temperature and the type of solvent used.

It has thus been found that when using one organic solvent, preferably acetone, methylene chloride, N, N-dimethylformamide or tetrahydrofuran should have a reaction temperature. the temperature is below 0 ° C, and preferably much lower, i.e. at a temperature of the order of -90 ° C to -400 ° C.

In contrast, when the acylation reaction of the compounds of formula IV with the compounds of formula III are carried out in an aqueous solvent, the reaction can be carried out at room temperature, i.e. at about 200 ° C.

By aqueous solvent is meant either water or a mixture of water and a miscible solvent such as e.g. acetone, hexamethylphosphoric triamide or dimethylformamide.

The invention relates in particular to a method, such as it, as described above, for the preparation of the compounds with formula Ia, corresponding to the compounds of formula I wherein R represents a protecting group for the amino group, R1 represents R , wherein R represents 1a 1a a saturated alkyl group having not more than 4 carbon atoms or a group ~ CH 2 -CO R , 1 wherein R 5a represents an ester group which can be easily eliminated, 2 sa RA denotes a hydrogen atom, R 3 represents R 3a, wherein R 3a either represents a methyl group or an acetoxymethyl group or a group ~ CH 2 -S-R 15, wherein R 15 represents a 1-methyltetrazolyl or a 2-methyl-1,3,4-thiadiazol-5-yl group, ns denotes n's, n'S denotes an integer 0 or 1, R 2 represents a hydrogen atom or an ester group which can be easily eliminated. race, characterized by æ fi zman reacting a compound of formula IIa _. wmp-. fl- n-w- »- 7906605-6 7 NH-R s \ * N 4 K 00211 (Ira) N \ O\ Rla wherein R and R1a have the meanings given above, with a compound having formula A $ 9 [man zß fl 3-P-o-P- [N 213 (A) Y9 29 ' wherein Y and Z have the meanings given above, and having a basis for preparation of a compound of formula IIIa NH-R Ä s N e __ e (III) \ __ 4 <\ r, .co2P N (cH3) 2 2 Y a N \ O '\ Rla and the compound of formula IIIa is reacted, in the presence of a base, with a compound of formula IVa ,. Ma ... v ... 7906605-6 2 \ ___ rr (IVa) wherein n's and R3a have the meanings given above, for the preparation, after the addition of an acid, of a compound of formula Ia NH-R S // å§ \ N O sys. . 0 N R 3a la (Ia) COZH The reagents and procedures used are i- identical to those set out above.

In particular, the invention relates to a method for preparation of a compound of formula Ib NH-R s / jš N - coNH S i /> l I (Ib) N \ o N R3b _ o \ COZH Rlb 7906605-6 wherein R represents a protecting group for the amino group, and R 1b represents when a methyl group or a group ~ CH 2 -CO 2 -R 5, wherein R 5 represents a ester group, which can be easily eliminated, and R 3b represents an acetoxy methyl-, 1-methyl-tetrazol-5-yl-thiomethyl- or 2-methyl-1,3,4-thiadi- azol-5-yl-thiomethyl group, which process is characterized in that one reactes a compound of formula IIb L-: SK cozn (Hb) wherein and R and R1b have the meanings given above, with a compound with the formula Ab $$ Üc fi s) zN] 3'P '° "P [ü (m3) 2-13 (Ab) Ybe zbe ~ wherein Yb represents a tosyl ion and Zb represents a tosyl or chlorine ion, and with a base for the preparation of a compound with formula IIIb NH-R / ïs X-: éircoz: [N (g1q3) 2] 3 Y: (IIIb) N \ O \ Rib 7906605-6 10 and the compound of formula IIIb is reacted in the presence of a base with a compound of formula IVb HZN ris ; l :: _ n, / (IVb) 0 Rsb cozn wherein R3b has the meaning given above, for preparation, after addition of an acid, of the compound of formula Ib.

The procedural conditions are identical to those written above.

Finally, the invention particularly relates to the preparation of a compound of formula Ic NH-R Oh At NH N (IC) \ 0 N f / CH occ fl \ 0 2 - 3 C113 || O cozn wherein R represents a protecting group for the amino group, which position is characterized by the sale of an association with meln IIc NH-R SO \ === ¿í1r ,, co2H (Ile) N \ OCH3 7906605-6 11 wherein R is as defined above, with a compound of formula Ab æ e ÜCHB) ZNJ3-P-O-P-EN (C213) 213 (Ab) : m9 zbe wherein Yb and Zb have the meanings given above, and with a base, for preparation of a compound of formula IIIc aa _ / CO 2 P [N (cH 3)] 3 Yb (Inc) and the compound of formula IIIc is reacted, in the presence of a base, with a compound of formula IVc H2 r s I (IVc) N / cH occH 2 o 'à 3 COZH for the preparation, after addition of an acid, of a compound with formula Ic.

The invention relates in particular to the preparation of compounds of formulas I, Ia, Ib, Ic, wherein the protecting groups for the amino group R is selected from the group consisting of formyl, acetyl, ethoxycarbonyl, tert-pentoxycarbonyl, tert-butoxy- carbonyl, chloroacetyl, trifluoroacetyl, trityl and trichloro- the ethoxycarbonyl groups. ' 7906605-6 12 The preparation process can be carried out so that the acylation one of the compounds of formula IV, IVa, IVb and IVc is either carried out at a temperature below 0 DEG C. and in a solvent, selected from the group consisting of methylene chloride, N, N-dimethyl- formamide, acetone, tetrahydrofuran or a mixture thereof solvent or at a temperature close to 20 ° C and in an aqueous solvent and so that the base used during the reaction of the compounds of formula IV, IVa, IVb and Ivc is selected from the group consisting of triethylamine, N-methyl- morpholine, pyridine, sodium carbonate and bicarbonate and potassium carbonate and bicarbonate.

The compounds of formula II used at the beginning of the invention can be prepared as follows: The compounds wherein R 1 represents a saturated alkyl group may manufactured according to Belgian patent 850 662.

The other compounds of formula II can be prepared starting from a compound of formula K NH-R s / gn '_ / cozn (K) N \ OH syn-isomer RI either by reaction with a compound of the formula Hal-ë ~ CO2R5 eel wherein Hal represents a halogen atom, and R ', R "and R5 have the above specified meaning.

The compounds of formula A are prepared by the procedure those described in JACS 91, 20 (1969). Examples are given below in the writing.

The compounds of formula IV wherein R 4 represents a hydrogen atom, and R 3 represents an alkyl group, are known in the literature or can be easily produced on the basis of information in the literature.

In the same manner, the compounds of formula IV wherein R3 CH2-S-R16, is readily prepared by nucleophilic substitution reaction starting from 7-ACA. 7906605-6 13 The following examples describe the invention without border it.

Exemgel l 3-acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- methoxyimino-acetamido] -ceph-3-em-4-carboxylic acid syn-isomer Step A 2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-acetoxy- tris-dimethylaminophosphonium tosylate, syn isomer. 120 ml of methylene chloride are charged under nitrogen and 34 g of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid is added. 30 ml of methylene chloride are distilled off at normal pressure. Thereafter, the to about 0 ° C and for about 5 minutes it is continued to the suspension with a solution prepared by stirring for 15 minutes at 15 DEG-200 DEG C. of 64.6 g of hexamethylphosphorus tri amide in 12.9 g of tosyl chloride. The resulting orange solution is stirred under nitrogen at about 00 ° C for a further 30 minutes.

While stirring and nitrogen gas is then charged at 0 ° C for 5 minutes 12.6 ml of triethylamine. Then stir under nitrogen. gas at 00 C for another 30 minutes.

Step B oxyimino-acetamidoic-cef-3-em-4-carboxylic acid syn isomer 3-acetoxymethyl-7-L2- (2-tritylamino-4-thiazolyl) -2-methyl- The previous solution is cooled to -700 ° C and below stirring and nitrogen atmosphere are charged for 15 minutes the following solution, freshly prepared under nitrogen and at 00 C: 12.27 g of 7-aminocephalosporanic acid 185 ml of methylene chloride 19 ml of triethylamine.

After the addition, stir at -70 ° C for a further time l l hour.

Then bet on a single time and while tem- the temperature must rise to 20 ml of pure acetic acid. Then stir under nitrogen and the internal temperature is brought to 00 C. Then the reaction mixture is poured into 500 ml of deionized water. Therefore The mixture is stirred, decanted and the aqueous phase is re-extracted with 100 ml of methylene chloride. The combined chloromethylene phases are washed on new with 4 x 250 ml deionized water. The organic phase centered to dryness under reduced pressure in a bath at 20-25 ° C, 7906605-6 14 The dry extract, which is in the form of a resin, add 500 ml of deionized water. Then stir at about 20 ° C, until the resin is converted to crystalline lin suspension. Then stir for another 30 minutes at room temperature. at 20 ° C and centrifuged. Wash with 5 x 100 ml deionized rat water. Then dry under reduced pressure at about 300 C and a crude product is obtained, which contains 2 - 4% water.

Example 2 3-acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- methoxyimino-acetamide] -cef-3-em-4-carboxylic acid, syn isomer.

Step A 2- (2-Tritylamino-4-thiazolyl-2-methoxyimino-acetoxy- tris-dimethylaminophosphonium tosylate, syn-isomer: Under nitrogen, 42.1 g of 2- (2-tritylamino-4-thia- zolyl) -2-methoxyiminoacetic acid in 100 ml of pure acetone and 18 ml of di- methylformamide. The suspension is cooled to 0:20 C with stirring and nitrogen and for 15 minutes at 0:20 C a solution is added consisting of 76.7 ml of hexamethylphosphoric triamide and 15.75 g tosyl chloride. Then add for 15 minutes at 0:20 C 15.3 ml of triethylamine. Then stir for 30 minutes at 0:20 C under nitrogen.

Step B 3-Acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2-methyl- oxyimino-acetamide] -ceph-3-em-4-carboxylic acid, syn isomer.

The previous solution is cooled to -700 ° C and below 15 ° C 55.5 ml of dimethylformamide, 15 g of 7-aminocephalosporan acid and 23 ml of triethylamine. Then stir for 1 hour -70: 20 ° C under nitrogen, and then added at -70 ° C 24 ml of acetic acid. Then stir for 15 minutes at -70120 ° C and then 30 ml of deionized water are added. The temperature increases to -12, -150 ° C, after which precipitate in 1800 ml of deionized water. containing 360 g of sodium chloride. The mixture is then stirred for 30 minutes. at 200 ° C, centrifuged, washed with water and dried under vacuum. The desired product is obtained.

Exemgel 3 3-acetoxymethyl-7-E2- (2-tritylamino-4-thiazolyl) -2- methoxyimino-acetamide] -cef-3-em-4-carboxylic acid, syn isomer.

Step A 2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-acetoxy- tris-dimethylaminophosphonium tosylate syn isomer: 7906605-6 15 Under nitrogen pressure, 25.8 g of tosyl chloride in 126 ml are charged hexamethylphosphoric triamide.

Then stir for 30 minutes at 18 DEG-200 DEG C. and cool to 0 ° C and then 61 ml of dimethylformamide and 69 g of 2- (2- tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid is added. Where- after stirring for 15 minutes at 0:20 C and the solution is added for 10 minutes at 12 ° C with 25.2 ml of triethylamine. Then Stir for 30 minutes at 0.20 ° C under nitrogen.

Step B 3-Acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- methoxyimino-acetamido] -cef-3-em-4-carboxylic acid syn isomer: The solution obtained in step A is charged while stirring. at -ss ° C, -70 ° C in a mixture consisting of methylformamide, 24.6 g of 7-aminocephalosporanic acid and 38 ml of tri- ethylamine.

Then stir for 2 hours under nitrogen pressure at -65, -700 ° C, and then added while maintaining this temperature 40 ml of acetic acid are maintained. Then stir for 15 minutes and then 50 ml of deionized water are charged at -650 ° C. The temperature raised to -12, -150 ° C and then precipitated in a mixture consisting of 1.9 liters of deionized water and 390 g of sodium chloride.

Then it is stirred for 30 minutes at 200 DEG C., centrifuged, washed with deionized water and 383 g of a moist product are obtained. duct. This product is stirred into a dough overnight at 200 ° C 664 ml of water containing 30% acetone. Then centrifuge, washed with deionized water, dried under vacuum at 200 ° C in the presence of potassium hydroxide, and the desired the duct.

Exemgel 4 z-aeeteximethyl-v- [z- (z-tritylamina-az-thiazalyi) -2- methoxyimino-acetamide] -cef-3-em-4-carboxylic acid, syn isomer.

Step A 2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-acetoxy- tris-dimethylaminophosphonium tosylate, syn isomer. at 20 DEG-2 DEG C., 640 ml of anhydrous hexamethylphoaphore are mixed. triamide and 77 g of tosyl chloride. The mixture is stirred for 30 minutes. there is nitrogen at 18 - 200 C. Then add while the temperature is maintained at 18 DEG-200 DEG C. 206 g of 2- (2-tritylamino-4- thiazolyl) -2-methoxyiminoacetic acid having a purity of 87% in form of finely divided drops. A solution is obtained, which below 10 minutes are kept under stirring and nitrogen at 18 - 200 ° C. ... _._. _. . ...... ...... u, .., ..._ ~.-....-. ~ _..._ 7906605-6 16 after, 56.2 ml of tri- ethylamine, and the resulting solution is allowed to stand for 30 minutes stirring and nitrogen at 18 - 200 ° C. 3-Acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- methoxyimino-acetamidoic-cef-3-em-4-carboxylic acid, syn isomer.

A freshly prepared solution is prepared as follows: looo m1 methylene chloride is cooled to -1 ° C, -1 ° C and 100 g of 7-aminocephalosporanic acid are charged. While the same temperature is maintained, 153 ml of triethylamine are charged. After completion constant solution is cooled to -70, -72 ° C, and the solution, which was prepared in step A, added for another 30 - 40 minutes the above 7-aminocephalosporanic acid while maintaining the temperature kept at -7ø¿2 ° under nitrogen for 1 hour.

C. The mixture is stirred at this temperature At this temperature, 100 ml of acetic acid are added, and the mixture is stirred for 15 minutes. Then bet, while the temperature is allowed to rise to about -60 ° C, 200 ml deionized water. The mixture is then stirred for 15 minutes under nitrogen and the temperature is the puree is brought to -20, -150 ° C, and the mixture is kept in 4000 ml deionized water, kept at a temperature of 18, 200 C. There- after decanting and extracting with 200 ml of methylene chloride and then with water. The methylene chloride is evaporated off under vacuum and man receives the desired product. Example 5 3-acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- methoxyimino-acetamido] -cef-3-em-4-carboxylic acid, syn isomer.

In 1000 ml of deionized water is bubbled at 20 + 2 ° C carbon dioxide for 5 minutes, and 61.7 g of sodium bicarbonate put. After complete dissolution, the bubbling continues of carbon dioxide for 5 minutes at 20 + 2 ° C, and then add 100 g of 7-aminocephalosporanic acid are added in the form of comminuted drops. The mixture is kept for about 15 minutes while stirring. and while bubbling carbon dioxide at 20:20 C, to full resolution. Then add immediately after the end of the carbon dioxide supply and below 30 to 35 minutes at 20:20 C the activated ester solution, which is prepared in step A of Example 4.

Continue stirring at 20 ° C with 16 ° C hours. Thereafter, the suspension is kept under stirring in a solution 7906605-6 17 consisting of 4000 ml of distilled water and 1200 g of sodium chloride. A suspension is thus obtained which is maintained below stirring for 30 minutes at 20:20 ° C. value to 2 by adding 70 ml of hydrochloric acid, which is diluted to half. It is then centrifuged immediately and washed thoroughly. stirring into a dough with 5 x 300 ml deionized water.

The resulting product is charged to a mixture of 1200 ml of deionized water and 400 ml of ethanol. The mixture is kept for 16 hours while stirring at 20:20 C. Then washed by stirring to a dough with 400 ml of 20% ethanol and then with 3 x 400 ml deionized water. The product is dried and obtained 276 g of crude product containing 2.7% of water. The product is purified in the following way.

The 276 g of product are charged in the form of finely divided droplets at 18 DEG-200 DEG C. in 512 ml of pure acetone. A partial distillation takes place as a result of recrystallization. Then get the mixture stand for 5 hours with stirring at 18 - 20 ° C, after which the Centrifuge stirred, stirred into a dough with 2 x 256 ml of acetone, dried at 25 DEG-300 DEG C. under vacuum to give the desired product.

Example 6 3-acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- methoxyimino-acetamido] -cef-3-em-4-carboxylic acid, syn isomer.

Step A 2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-ethoxy- tris-dimethylaminophosphonium tosylate, syn isomer.

At 20 ° C, 1600 ml of anhydrous hexamethylphosphorus are charged. triamide and for 2 to 3 minutes 228 g of tosyl chloride.

This solution is cooled to 0, +20 C under nitrogen and maintaining this temperature is invested in the form of distributed drops 595 g of 2- (2-tritylamino-4-thiazolyl) -2-methoxy- iminoacetic acid with a purity of 89%. Then stir at 0.20 C to complete dissolution. Finally, un- 20 to 25 minutes and while maintaining a temperature trip of 00 C 165 ml triethylamine. You get a solution that kept under stirring under nitrogen at this temperature.

Step B 3-Acetoxymethyl-7-E2- (2-tritylamino-4-thiazolyl) -2- methoxyimino-acetamidel-cef-3-em-4-carboxylic acid, syn isomer.

Proceed as indicated in step B of Example 4 starting from a solution of 250 g of 7-aminocephalosporanic acid in 2500 ml of methylene chloride.

Claims (8)

10 15 20 25 30 35 18 7906605-6 Patent claims A method of preparing compounds having the general formula N1-IR AS \ _ N (ä (Q) n 'å x TEH xs 24' (I) Ng 0 NR \ R10 3 co zRz syn-isomer wherein R represents a protecting group for the amino group, ns represents an integer 0 - 2 R 1 represents a saturated alkyl group having 1 to 4 carbon atoms or R 1 represents a group -é-CO 2 R 5 wherein R 5 represents 13. R 1 and R "each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, - R 2 represents a hydrogen atom or an ester group which can be easily eliminated, R 3 represents an alkyl group having not more than 5 atoms, or a group -CH 2 - S-R16, wherein R16 represents a heterocyclic group containing nitrogen or R3 represents an acetoxymethyl group, R4 represents hydrogen, characterized in that a compound of the formula II is reacted,. (II) syn-isomer wherein R and R 1 have the meanings given above, and Ad represents a hydrogen atom or an equivalent of an a alkali metal or of an organic amine base, with a product of formula A e ø. ['° “3f_2"] 3 “P' ° 'P f" (c flfl zls W a Ye Ze Vari Y and & Z are such that Y represents a tosyl or mesyl ion and Z represents a halogen ion or Y and Z each represent a tosyl ion, or Y and Z each represent a mesyl ion, and optionally with a base for the preparation of a compound of formula III NH-R su ° Ye Lä l / co21 = [u (cr13) 2] 3 N (0) (III) "in the syb isomer with which, in the presence of a base, a compound of the formula IV (O) -r" is reacted as: [: T * N ff " CO 2 R '2 nzu (IV) wherein R' 2 represents R 2 or an equivalent of an alkali metal or even organic amine base, and R 3, R 4 and ns are as defined above. meanings, for the preparation, after addition of an acid, of a compound of formula 1. A process according to claim 1 for the preparation of compounds of formula Ia, corresponding compounds of formula I wherein R represents a protecting group for the amino group, R1 represents R1a, R1a represents a saturated alkyl group having not more than 4 carbon atoms or a group -CH2-CO3R5a, wherein R 5a represents an ester group which can be easily eliminated, R 4 represents a hydrogen atom, 3a 'R represents a methyl group or R 3 represents R a represents either an acetoxymethyl group or a group -CH 2 -S-R 15, wherein R 15 represents a 1-methyltetrazolyl- or 2-methyl-1,3,4-thiadiazol-5-yl group, NS represents n'S, n'S represents 0 or 1, R 2 represents a hydrogen atom or an ester group, which can be easily eliated by reacting a mined, characterized compound with the formula IIa NH-R Ä SN "_" f /, C023 (ïïa) N \ 0 \ R la wherein R and R1a have the meaning given above, with a compound of the formula A es æ [way zl fl 3-voP-ß: (C113) 2] 3 (A, Ye 29 wherein Y and Z have the meaning given in claim 1, and with a base for the preparation of a compound of formula n IIIa _....-- .. ~ ._-... ~> .. ._. NH 7 (6a) in which a compound of formula IIIa is reacted, in the presence of a NH-R A. ° e _- _ Y r /, - cozr [n (cn3) ¿] 3 _ (IIIa) base, with a compound of formula IVa (0) n. HNT 8 2 \\ s 15 I / I (xva), [: N 1 * R 0 3a cozn 20 wherein n's and R3a have the meanings given above, for the preparation, after addition of an acid, of a compound of formula Ia NH-R * \ 25 SN, / fi \\ H NH SH (Ia) \ o / R 30 \ 0 3a Ria C028 A process according to claim 1 for the preparation of a compound of the formula Ib 5 7906605-6 in 22 NH-R S // èb \ nl \ c :: ¿:] f / I CONH SN: E wherein R represents a protecting group for the amino group and R 1b represents a methyl group or a group -CH 2 -CO 2 R 5, wherein R 5 represents represents an ester group which can be easily eliminated, and R 3b represents an acetoxymethyl-, 1-methyl-tetrazol-5-yl-thiomethyl- or known- (rxb) 2-methyl-1,3,4-thiadiazole-5 -yl-thiomethyl group, characterized by reacting a compound of the formula IIb NH ~ RS \\ N * III r /, CO2H N \ O \ nn »wherein R and R1b have the meanings given above, with a compound of the formula Ab eo [ way 214] avo-Pfn (C113) 213: the: he (Ab) wherein Yb represents a tosyl ion, and Zb represents a tosyl or chlorine ion, and with a base for the preparation of a compound of formula IIIIb 10 15 20 25 30 35 23 79Û66Ü5-5: an-n ii A * (en, ..._ cozv [u (ca3) 213 vbe "m" m \ O x and the compound of formula IIIb is reacted in the presence of a base, with a compound of formula IVb H 2 N S I / (IVb) 0 N I / R 3b CO 28 wherein R 3b has the meaning given above, for the preparation, after addition of an acid, of the compound of formula Ib. A process according to claim 1 for the preparation of a compound of formula Ic NH ~ R Å s N ° K IH N S m) N _ \. 0 n / cn2occn3 - \ CH Q u - 3 O _ C023 k ä n - of reacting a compound with for- wherein R denotes a protecting group for the amino group, not designated mel IIC '7906605-6 21 »Ef fi l / cozn (ne) Wherein R has the meaning given above, with a compound of the formula Ab oe BCHB, 2 "] 3'P '°' P“ EN (C537 2] 3 mb) 15: m9 zbe wherein Yb and Zb have it in claim 3, and with a base for the preparation of a compound of formula IIIc NH-R 8 \\ NG (IIIC) \ -_- S | / coz Pfxucnahh: fbe 20 which compound of formula IIIc is reacted in the presence of a base having a compound of formula IVc 35 in H / I l (IVC) Û CHZOCCE3 II 10 15 20 25 25 79Û66Û5-6 for the preparation, after addition of an acid, of a compound of formula Ic. Process according to one or more of Claims 1 to 4, characterized in that the protecting group R for the amino group is selected from the group consisting of formyl, acetyl, ethoxycarbonyl, tert-pentoxycarbonyl, tert .-butoxycarbonyl, chloroacetyl, trifluoroacetyl, trityl and trichloroethoxycarbonyl groups. Process according to one or more of Claims 1 to 4, characterized in that the acylation of the compounds of the formulas IV, IVa IVb and IVc is carried out at a temperature below 0 DEG C. and in a solvent selected from the group consisting of methylene chloride, N, N-dimethylformamide, acetone, tetrahydrofuran or a mixture of these solvents. 7. A process according to any one of claims 1 to 4, characterized in that the acylation of the compounds of formulas IV, IVa, IVb and IVc is carried out at a temperature in the vicinity of 20 ° C in an aqueous solvent. that the base used in the acyl- A process according to one or more of claims 1 to 4, wherein the ring of the compounds of formulas IV, IVa, IVb and IVc is selected from the group consisting of triethylamine, N-methylmorpholine, pyridine, sodium and potassium carbonate and sodium and potassium bicarbonate.