DK160312B - PROCEDURE FOR PREPARING DERIVATIVES OF 7-AMINOTHIAZOLYLACETAMIDOCEPHALOSPORANIC ACID - Google Patents

Description

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DK 160312 B

The invention relates to a novel process for the preparation of derivatives of 7-aminothiazolylacetamidocephalo-sporanoic acid of the general formula I set forth in claim 1, and this method is characterized by the characterizing part of claim 1.

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The protecting group for the amino group, which R may denote, may e.g. be an alkyl group of 1-6 carbon atoms such as preferably tert-butyl or tert.-amyl. R can also represent an aliphatic acyl group, an aromatic or heterocyclic acyl group or a carbamoyl group.

One may mention low molecular weight alkanoyl groups such as e.g. formyl, acetyl, propionyl, butynyl, isobutynyl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, low molecular weight alkoxy or cycloalkoxycarbonyl groups such as e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tert.-pentoxycarbonyl, hexoxyloxyl, benzoyl, toluolyl, naphtoyl, naphtoyl as benzyloxycarbonyl.

The acyl groups may e.g. be substituted by chlorine, bromine, iodine or fluorine such as e.g. chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl or bromoacetyl.

The substituent R may also represent a low molecular weight aralkyl group such as benzyl, 4-methoxybenzyl or phenylethyl, trityl, 3,4-dimethoxybenzyl, benzhydryl.

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The substituent R may also represent a haloalkyl group such as trichloroethyl.

The substituent R may also represent chlorobenzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, phenoxyacetyl, caprylic

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- 2 - lyl, n-decanoyl, acryloyl, trichloroethoxycarbonyl.

The substituent R may also represent methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl and the corresponding thiocarbamoyl groups.

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The above list does not claim to be exhaustive. It will be appreciated that other protecting groups for the amines, which are especially known in the peptide chemistry, may also be used.

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Among the values for are methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert-butyl.

R 1 and R 1 can be methyl, ethyl, propyl or isopropyl.

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Among the values of R 1 may be mentioned methyl, ethyl, propyl or isopropyl, but especially among the easily eliminable ester groups are mentioned: The esters formed with alkyl groups such as butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, 20 hexyl ester. One may mention acetoxymethyl, propionyl, oxy-methyl, butyryloxymethyl, valeryloxymethyl, pivaloyl-oxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl and 2-butyryloxyethyl ester.

Also mentioned are 2-mesylethyl, 2-iodoethyl, beta, beta, beta-trichloroethyl, vinyl, allyl, ethynyl, propynyl, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenylethyl -, trityl, diphenylmethyl and 3,4-dimethoxy-benzyl ester.

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One may also mention the phenyl, 4-chlorophenyl, tolyl-2 or tert-butylphenyl ester. R may denote the same 5 leaving esters as R.

R can represent a phenyl group or 1,2,3-, 1,2,5-, 1,2,4- or 1,3,4-thiadiazolyl, 1-H-tetrazolyl, 1,3-thiazolyl , 1,2,3-, 1,2,4- or 1,3,4-triazolyl, 1,2,3-, 1,2,4-

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- 3 - or 1,2,5- or 1,3,4-oxadiazolyl, these groups being unsubstituted or substituted by one or more groups selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, nitrile, nitro-5 or amino.

16 R can also represent one of the above heterocyclic groups substituted with an alkoxy group having 1-4 carbon atoms such as methoxy, ethoxy, propyloxy, isopropyloxy, butyl, isobutyl or tert-butyloxy. R can represent a zcyl group selected from acetyl, propionyl and butyryl.

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Among the preferred values for R include acetyl, 1-methyltetrazolyl, 2-methyl-1,3,4-thiadiazolyl, 3-methyl-1,2,4-thiadiazolyl-5-yl, 3-methoxy-1 , 2,4-thiadiazolyl, 1,3,4-thiadiazolyl-5-yl, 2-amino-1,3,4-thiadiazol-5-yl, 3-hydroxycarbonylmethyl-1,2,4-thiadiazol-5 -yl, 5-methoxy-1,2,4-thiadiazol-3-yl, 4-methyl-5-hydroxycarbonylmethyl-1,3-thiazol-2-yl, 1-dimethylaminoethyl-1,2,3, 4- tetrazol-5-yl.

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

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Ad may represent a hydrogen atom or an alkali metal atom such as sodium or potassium. Ad may also represent an equivalent of aminated organic base, preferably a trialkylamine such as triethylamine. Ad, however, preferably represents a hydrogen atom. In such a case, the effect of compound A on the compound of formula II is followed by the action of a base such as e.g. triethylamine or another trialkylamine.

35 When Ad denotes e.g. an equivalent of aminated organic base, the addition of such base is not necessary.

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2 '2 R can assume the values given above for R

or Ad.

The effect of a compound of formula III on the compound of formula IV is preferably carried out in the presence of a base which may be selected from triethylamine, tributylamine, N-methylmorpholine, pyridine, a picoline or a carbonate or bicarbonate of sodium or potassium. However, another analog organic or inorganic base may be used.

The preferred bases used are triethylamine or sodium bicarbonate.

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

Preferably acetic or hydrochloric acid is used.

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

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Other solvents such as dioxane, acetonitrile, chloroform, dichloroethane or ethyl acetate may also be used. The reaction can also be carried out in excess hexamethylphosphoric triamide.

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This reaction can preferably be carried out at a temperature between 0 and 20 ° C.

The course of the reaction of the compound of formula III with the compound of formula IV can be greatly influenced by the temperature and nature of the solvent used.

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Thus, it has been found that when working in an organic solvent and preferably acetone, methylene chloride, Ν, Ν-dimethylformamide or tetrahydrofuran, the reaction temperature should be below 0 ° C and preferably very much below, i.e. of the order of -90 ° C to -40 ° C.

In contrast, if the acylation reaction of the compounds of formula IV with the compounds of formula III is carried out in an aqueous solvent, the reaction can be carried out at room temperature, i.e. at about. 20 ° C.

By aqueous solvent is meant water or a mixture of water and a miscible solvent 15 such as e.g. acetone, hexamethylphosphoric triamide or dimethylformamide.

The invention also relates to a process for the preparation of the compounds of formula Ia as claimed in claim 2, and this method is characterized by the method of claim 2.

The reagents used and working conditions are identical to the above conditions.

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The invention relates in particular to a process for preparing a compound of formula Ib as set forth in the preamble of claim 3, and this process is characterized by the characterizing part of claim 3.

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The operating conditions are identical to those described above.

Finally, the invention relates in particular to a process for preparing a compound of formula Ic having the general formula Ic as set forth in the preamble of claim 4, and this method is characterized by the knowledge of claim 4.

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drawing part stated.

In particular, the invention relates to the preparation of the compounds of formulas I, Ia, Ib and Ic wherein the protecting groups for the amino group R are selected from formyl, acetyl, ethoxycarbonyl, tert.-pentoxycarbonyl, tert.-butoxycarbonyl, chloroacetyl, trifluoroacetyl, trityl and trichloroethoxy. carbonyl.

The preparation method can be initiated in such a way that the acylation of the compounds of formulas IV, IVa, IVb and IVc is carried out at a temperature below 0 ° C and in a solvent selected from methylene chloride, N, N-dimethylformamide, acetone, tetrahydrofuran or a mixture of these solvents or at a temperature of approx.

20 ° C and in an aqueous solvent and that the base used in the action of the compounds of formulas IV, IVa, IVb and IVc is selected from triethylamine, N-methylmorpholine, pyridine and sodium and potassium carbonate and bicarbonate.

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The compounds of formula II used as starting material in the process of the invention can be prepared as follows: The compounds which denote a saturated alkyl group can be prepared according to the method of Belgian Patent Specification No. 850,662.

The other compounds of formula II may be prepared from a compound of formula K

NH-R

so

CLH (K) 35 2 noh syn-isomer - 7 -

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R 'by the action of a compound of the formula Hal-C-CO-R' - in R 5 'where Hal represents a halogen atom and R', R 'and R have the same meaning as above.

The compounds of formula A are prepared according to the method described in JACS, b. 91, p. 20 (1969). Examples are listed below.

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The compounds of formula IV wherein R represents a hydrogen atom and R represents alkyl are known in the literature or can be readily prepared according to the literature.

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Similarly, the compounds of formula IV wherein R

16 represents CT ^ -S-R, readily prepared by a nucleophilic exchange from 7-ACA.

The following examples illustrate the process of the invention.

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Example 1.

5α-ethoxymethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-metho [g] y-iminoacetamido) -cep] i-3-em-4-carboxylic acid, syn-isomer.

Step At 2- (2-Tritylamino-4-thiazolyl) -2-methoxyiminoacetoxy-5-tris-dimethylaminophosphonium tosyl salt. syn-iso mer.

Methylene chloride (120 ml) is added under a nitrogen atmosphere and 34 g of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid is added. 30 ml of methylene chloride are distilled at normal pressure. You cool to ea. 0 ° C, and within approx. 5 minutes, the resulting suspension is added to the solution obtained by stirring at 15-20 ° C for 15 minutes of 64.6 g of hexamethylphosphoric triamide in 12.9 g of tosyl chloride. The orange solution obtained is stirred under nitrogen atmosphere at ca. 0GC for another 30 minutes.

Then, with stirring and under a nitrogen atmosphere, at 0 ° C, 12.6 ml of triethylamine are introduced over 5 minutes. Stir under nitrogen atmosphere at 0 ° C for a further 30 minutes.

Step B: 3-aethoxymethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamide o) -ceph-3-em-4-carboxylic acid syn isomer.

The above solution is cooled to -70 ° 0 and introduced with stirring and under nitrogen atmosphere for 15 minutes the following solution, prepared on site under nitrogen atmosphere and at 0 ° C: - 12.27 g of 7-aminocephalosporanoic acid, - 185 ml methylene chloride and 30 - 19 ml of triethylamine.

After completion of the introduction, stir at -70 ° C for an additional 1 hour.

It is then introduced at once, and by raising the temperature, 20 ml of pure acetic acid. Stir under nitrogen atmosphere and bring the internal temperature to 0 ° C. The reaction mixture is then poured into 500 ml - 9 -

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demineralized water. The aqueous phase is stirred, decanted and re-extracted with 100 ml of methylene chloride. The combined methylene chloride phases are washed again with 4 times 250 ml of demineralized water. The organic phase is evaporated to dryness under reduced pressure in a 20-25 ° C bath,

The dry extract, which is in the form of a resin, is taken up in 500 ml of demineralized water. Stir at approx. 20 ° C until conversion of the resin to crystalline suspension. Stir for an additional 30 minutes at about 10 minutes. 20 ° C and sucks. Wash with 5 times 100 ml of demineralized water. Dry under reduced pressure at approx. 30 ° C. The crude product is obtained containing 2-4 # water · Example 2.

3-acetoxymethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido) -ceph-3-em-4-carboxylic acid, syn isomer. lane A: 2- (2-tritylamino-4-thiazolyl) -2-methoxyminoacetoxy-tris-dimethylaminophosphonium tosyl salt.

20 syn isomer.

Under nitrogen atmosphere, 42.1 g of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid are introduced into 100 ml of pure acetone and 18 ml of dimethylformamide. The suspension is brought to 0 ° 0 + 2 ° C with stirring and under nitrogen pressure, and a solution of 76.7 ml of hexamethylphosphoric triamide and 15.75 g of tosyl chloride is added over 15 minutes at 0 ° C + 2 ° C. Then, at 15 ° C, 15 ml of triethylamine are added over 15 minutes at 0 ° 0 + 2 ° C. It is then stirred for 30 minutes at 0 ° C + 2 ° C under a nitrogen atmosphere.

30: 33: 5-Acetoxymethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido) -oeph-3-em-4-oreboxylic acid. syn isomer.

55.5 ml of dimethylformamide, 15 g of 7-aminoeephalosporanoic acid and 23 ml of triethylamine are introduced at a temperature of -70 ° C in the above solution. Stir for 1 hour at -70 ° C + 2 ° C under nitrogen.

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atmosphere and then at -70 ° C crude®G add 24 ml of acetic acid. The mixture is stirred for 15 minutes at> 70 ° G ± 2 ° C and then 30 ml of demineralized water is added. The temperature is allowed to rise to between -12 and -15 ° C and then precipitated in 1800 ml of demineralized water containing 360 g of sodium chloride.

The mixture is stirred at 20 ° C for 30 minutes and then suctioned, washed with water and dried under vacuum. The expected product is obtained. Example 3 5-Acetoxymethylphayl-7- (2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamide o) -ceph-5-em-4-carboxylic acid. syn isomer.

Step A: 2- (2-Tritylamino-4-thiazolyl) -2-methoxyimino-acetoxy-tri-dimethylaminophosphonium tosyl salt.

Syn isomer.

25 # 8 g of tosyl chloride in 126 ml of hexamethylphosphoric triamide is placed under nitrogen pressure.

Stir for 30 minutes at 18-20 ° G, bring to 0 ° C + 2 ° C and add 61 ml of dimethylformamide and 69 g of 2- (2-20 -tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid. The mixture is stirred at 0 ° C + 2 ° C for 15 minutes and 25.2 ml of triethylamine are added to the solution at 10 ° C for 10 minutes. Stir for 30 minutes at 0 ° C + 2 ° C under a nitrogen atmosphere.

Step B: 3-aethoxymethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamide o) -ceph-3-em-4-oreboxylic acid. syn isomer.

A solution obtained in step A is introduced with stirring at -65 to -70 ° in a mixture of 86 ml of dimethylformamide, 24.6 g of 7-aminocephalosporanoic acid and 38 ml of triethylamine.

The mixture is stirred for 2 hours at between -65 and -70 ° C under nitrogen pressure and then 40 ml of acetic acid is maintained at this temperature. The mixture is stirred for 15 minutes, then 50 ml of demineralised water is introduced at -65 ° C. It is brought to a temperature between -12 and -15 ° 0 and precipitates in a mixture of 1.9 liters of demineralized water and 390 g of sodium chloride. Stir for 30 minutes at 20 ° G, suction, wash with demineralized water and - 11 -

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gets 383 g of a moist substance. This is effected overnight at 20 ° C with 664 ml of water added with 30 $ acetone. Suction is made, washed with demineralized water, dried under vacuum at 20 ° C in the presence of potassium hydroxide and the expected compound is obtained.

Example 4

3-Acetoxymethyl-7- (2- (2-tritlamino-4-thiazolyl) -2-methoxyiminoaoetamido) -ceph-3-em-4-carboxylic acid syn isomer.

IPrin A: 2- (2-tritylamino-4-thiaolyl) -2-methoxyiminoacetoxy-tris-dimethylaminophosphonium tosyl salt. sewing needle omer.

640 ml of anhydrous hexamethylphosphoric triamide and 77 g of tosyl chloride are mixed at 20 ° 0 + 2 ° C. The mixture is kept under stirring and under a nitrogen atmosphere at 18-20 ° C for 30 minutes. It is added as a rain, maintaining the temperature of 18-20 ° C, 206 g of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid with 87 $ purity.

A solution is obtained which is kept for 10 minutes under stirring and under nitrogen atmosphere at 18-20 ° C. Then, over 15 minutes, add the temperature of 18-20 ° C, 56.2 ml of triethylamine and stir the obtained solution 30 minutes under a nitrogen atmosphere at 18-20 ° 0.

Step B: 3-Ethoxyethylmethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamide o) -ce ph-3-em-4-carboxylic acid. syn isomer.

The following solution is prepared on the spot:

1000 ml of methylene chloride is cooled to between 30 -15 and -10 ° C and 100 g of 7-aminocephalosporanoic acid are introduced.

Maintaining this temperature adds 153 ml of triethylamine. After complete dissolution, cool to between -70 and -72 ° C and pour over 30-40 minutes the solution prepared in step A into the above solution of 7-aminocephalosporanoic acid, keeping the temperature of -70 ° C + 2 ° C. You keep one - 12 -

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hour at this temperature under stirring and under nitrogen atmosphere.

While maintaining this temperature, 100 ml of acetic acid is added and allowed to stir for 15 minutes.

5 It is then introduced, allowing the temperature to rise to approx. -60 ° C, 200 ml demineralized water. It is stirred for 15 minutes under a nitrogen atmosphere, then brought to a temperature between -20 and -15 ° 0 and poured into 4000 ml of demineralized water maintained at 18-20 ° C. Decant and extract with 200 ml of methylene chloride and wash with water. The methylene chloride is evaporated in vacuo to give the expected substance.

Example 5

3-Acetoxylmethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-methoxyminoimethoamido) -ceph-3-em-4-carboxylic acid. syn isomer.

Carbon dioxide is bubbled through 1000 ml of demineralized water at 20 ° C + 2 ° G for 5 minutes and 61.7 g of sodium bicarbonate is added. After complete dissolution, carbon dioxide permeation is continued for 5 minutes at 20 ° C + 2 ° C, then 100 g of 7-aminocephalosporanoic acid is added in the form of a rain. Stir under stirring for approx. 15 minutes while bubbling carbon dioxide at 20 ° C + 2 ° 0 until complete dissolution. 25 is immediately added over 30-35 minutes at 20 ° C + 2 ° C and after quenching of the carbon dioxide stream the activated ester solution prepared in step A of Example 4.

Keep at 20 ° + 2 ° C and with stirring for 16 hours. The suspension is then poured with stirring into a solution of 4000 ml of distilled water and 1200 g of sodium chloride. Thus, one suspension is obtained which is kept for 30 minutes with stirring at 20 ° C + 2 ° G. The pH value of 2 is adjusted by the addition of 70 ml of semi-dilute hydrochloric acid. Immediately the suction is washed, washed by rinsing with 5 times 300 ml of demineralized water and introducing the obtained compound into a mixture of 1200 ml demineralised water.

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and 400 ml of ethanol · Stir for 16 hours with stirring at 20 ° C + 2 ° C. Wash by rinsing with 400 ml of water added with 20 $ ethanol and then with 3x 400 ml of demineralized water. The product is dried and 276 g of crude product containing 2.7 $ water are obtained. You cleanse as follows:

Said 276 g is introduced as a rain at 18-20 ° C in 512 ml of pure acetone. Partial distillation is followed by recrystallization. It is allowed to stand for 5 hours, with stirring at 18-20 ° C, suctioned, sprayed with 10 times 256 ml of acetone, dried at 25-30 ° C in vacuo and obtained the expected compound.

Example 6, 5-Acetoxymethyl-7- (2- (2-triamino-4-thiazoly 1) -2-methoxy-15-iminoacetamido) -oeph-3-em-4-oreboxylic acid, syn-isomer .

Step A: 2- (2-Tritylamino-4-thiazolyl) -2-methoxyimiaoacetoxy-tris-dimethylaminophosphonium tosyl salt. sight - isomer.

1600 ml of anhydrous hexa-20 methylphosphoric triamide is introduced at 20 ° C + 2 ° C and 228 g of tosyl chloride over 2-3 minutes.

This solution is cooled to a temperature between 0 and 2 ° C under a nitrogen atmosphere and, as a rain and while maintaining this temperature, 595 g of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid with 89% purity are added. . Stir at between 0 and 2 ° C until complete dissolution. It is then added over 20--25 minutes while maintaining a temperature of 0 ° 0 165 ml of triethylamine. A solution is obtained which is kept under stirring under a nitrogen atmosphere at this temperature.

Step B: 3-Acetoxymethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido) -ceph-3-em-4-carboxylic acid. syn isomer.

As in step B of Example 4, one is operated from a solution of 250 g of 7-aminocephalosporanoic acid in 2500 ml of methylene chloride.

Claims (8)

1-1H-R - 18 - (ib) co 2h 10 where R represents a protecting group for the amino group and R 1 -k represents a methyl group or a group -CE R 2 represents acetoxymethyl, 1-methyltetrazol-5-ylthiomethyl or 2-methyl-1,3,4-thiadiazol-5-ylthiomethyl, characterized by treating a compound of formula IIb NH- R Λ 20. NV = / ^ CO 2 H (Ilb) R1b wherein R and R ^ have the same meaning as above, with a compound of formula Ab Θ Θ ((CH 3) 2 N) 3-P-O-P (N (CH 3) 2 (3) Yb® Zb® where represents a tosyl ion and Z, represents a tosyl or chlorine ion and with a base to give a compound of formula Hib 35 NH-R DK 160312 B - 19 - A process for the preparation of 7-aminothiazolyl-acetamidocephalosporanic acid derivatives of the general formula I 5 mR (o) - U JL t “(I) 10 'n-r-r'S-R o * - co2r2 syn isomer, where R a protecting group for the amino group, n 1. represents an integer from 0 to 2, R represents a saturated alkyl group of 1-4 carbon atoms, or a group 20 R 'I 5 -C-CC ^ R 2, where R represents an alkyl group of 1 -3 carbon R1 represents atoms or an easily eliminable ester group, and R1 and R11 each represent a hydrogen atom or an alkyl group having 1-3 carbon atoms, R represents a hydrogen atom or a light, 3 eliminable ester group, R represents an alkyl group of 16 16 represents at most 5 carbon atoms or a group -CH 2 -SR wherein R 30 represents a heterocyclic group containing nitrogen, or. R 2 represents acetoxymethyl and R 2 represents hydrogen, characterized by treating a compound of formula II NH-R DK 160312 B - 15 - Λ s N (II) A process according to claim 1 for the preparation of the compounds of formula Ia corresponding to the compounds of formula I, wherein R represents a protecting group for the amino group, R represents R ^a, wherein R aa represents a saturated alkyl group having a maximum of 4 carbon atoms or a group -CH ^ CC ^ R c; , where R 1 represents a readily eliminable ester group, R represents a hydrogen atom, R 1 represents R 3a, with R 2 having the following meaning: either a methyl group or Yes 15 aeetoxymethyl or a group -CH 2 -SR wherein R represents 15 1 -methyltetrazolyl or 2-methyl-1,3,4-thiadiazol-5-yl, n 2 s represents n ', where n 1 is equal to 0 or 1, and R represents an S s hydrogen atom or an easily eliminable ester group, characterized by treating a compound of formula Ila Wherein NH and R 2a have the same meaning as above, with a compound of formula A0 0 ((ch3) 2n) 3- pop (n (ch 3) 2) 3 (A) wherein Y and Z have the meaning set forth in claim 1, and having a base to give a compound of formula IIla DK-160312 B - 17 - NH-R S ^ 11 5 \ = <CO ^ / WCB,) ^ Ιβ (IIIa) k ° ^ • a 10 with which a compound of formula IIa is treated in the presence of a base a compound of formula IVa (0) a, ts H2K__X 15 1 1 I (IVa) O ^ YSa co 2h 20 where n 'and having the same meaning as above, to give - after addition of an acid - of a compound of formula Ia NH-R' 0 5 'in A _A, Ia, S) Π Aa c / —N ^ A-R3a C0 * H 30 ^ A process according to claim 1 for the preparation of a compound of formula Ib 35 A process according to claim 1 for the preparation of a compound of formula Ic NH-R Wherein R represents a protecting group for the amino group, characterized by treating a compound of formula Ile 35 - 20 - DK 160312 B NH-R WN "OCH3 wherein R has the same meaning as above, with a compound 10 of the formula Ab © © ((CH3) 2N) 3-P-O-P (N (CH3) 2) 3 (Ab) Yb® Zb® where Yj 3 and Z 2 have the meaning set forth in claim 3, and having a base to give a compound of formula IIIc NH-R S '' N © 20 \ - / CO2 P / N (CH3y3 Yb0 duc) ° 'ch3 which compound of Formula IIIc is treated - in the presence of a base - with a compound of Formula IVc H2N - S> N 30 oJ - <IVC) CO 2 H 0 to obtain - after addition of an acid - of a compound of Formula Ic. Process according to claims 1-4, characterized in that the protecting group for the amino group R is selected from formyl, acetyl, ethoxycarbonyl, tert.-pentoxy- carbonyl, tert.butoxycarbonyl, chloroacetyl, trifluoroacetyl, trityl and trichloroethoxycarbonyl. COgP / N (CH3) 273 τβ (mb) IL ° vo R1b which compound of formula Hib is treated in the near room of a base having a compound of formula IVb (IVb) o CO H where the same meaning as above is obtained to obtain - after the addition of an acid - of the compound of formula Ib. 20 10 is syn-isomer, where R and have the same meaning as above, and Ad represents a hydrogen atom or equivalent of alkali metal or of an aminated organic base, with a compound A 15 φ φ ((ch3) 2n) 3-pop (n (ch 3) 2) 3 (A) x where Y and Z are such that either 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 to give a compound of formula III • NH-R 25 (III) S g W. co2p / m (ch3) 2/3 VrI 30 syn isomer, thereby treating - optionally in the presence of a base - a compound of formula IV (?) ns H2N - ^ _ ^ Sv. -R 4 Wherein R represents R or an equivalent of alkali metal 3 4 or of an aminated organic base and R, R and n have S the same meaning as above, to obtain - after the addition of an acid - of a compound of formula I. 5 Process according to claims 1-4, characterized in that the acylation of the compounds of formulas IV, IVa, IVb and IVc is carried out at a temperature below 0 ° C and in a solvent selected from methylene chloride, Ν, Ν-dimethylformamide, acetone, tetrahydrofuran or a mixture of these solvents. 10 Process according to claims 1-4, characterized in that the acylation of the compounds of formulas IV, IVa, IVb and IVc is carried out at a temperature close to 20 ° C and in an aqueous solvent. 15 Process according to claims 1-4, characterized in that the base used for the acylation of the compounds of formulas IV, IVa, IVb and IVc is selected from triethylamine, N-methylmorpholine, pyridine and sodium and potassium carbonate and bicarbonate. . 25 30 35