CS261859B2 - Method of aminoglycoside antibiotic's selectively protected n-acylated derivative preparation - Google Patents

Abstract

A method for preparing selectively protected N- -acylated aminoglycoside derivative antibiotics containing 4-O- (aminoglycosyl) -6-O- (3 "-amino) or '3' -methylamino-3 '- -deoxyglycosyl-2-deoxystreptamine in which The N-acylated derivative has a 1-amino group unprotected deoxystreptamine structures however, all other amino groups in the aminoglycoside parts of the molecule are protected identical or different acyl groups, and which N-acylated derivative corresponds to the general formula i, is that it is an alkanoic acid ester of formula VIII allowed to react as an acylating agent partially protected N-acylated aminoglycoside derivative antibiotics in which 1-amino- and 3-amino- or 3-alkylamino are unprotected and all other amino groups they are protected by amino-protective acyl at a temperature of from -30 to + 120 ° C in inert aqueous or anhydrous solvent to achieve selective acylation 3 "-amino- or 3" -methylamino groups partially a protected N-acylated derivative of a thus, the desired 1-N-unprotected a otherwise an N-fully protected aminoglycoside derivative antibiotics of general formula i. The alternative method of preparation is the solution aminoglycoside antibiotic.

Description

The invention relates to a process for the preparation of a selectively protected N-acylated derivative of an aminoglycoside antibiotic comprising 4-0- (aminoglycosyl J -6-0- (3'-amino) or

3'-methylamino-3'-deoxyglycosyl-2-deoxystreptamine in which the N-acylated derivative has the 1-amino group of the deoxystreptamine structure unprotected but all other amino groups in the aminoglycoside molecule are protected with the same or different acyl groups, the N-acylated derivative corresponding to the general Formula I

wherein R 'is hydrogen or ethyl, G is formyl, {C 2 -C 5 alkanoyl or trifluoro- (C 2 -C 5 alkanoyl), or C is (C 1 -C 4 alkyloxycarbonyl or p-methoxyphenyl- (C 1 -C 6 alkyloxycarbonyl), Q ¹ is N- a protected aminoglycosyl group of the formula

wherein G is as defined above, or Q ¹ is an N-protected 3 ', 4'-dideoxy-4'-emo-aminoglycosyl group of formula IVa

(a) wherein R '' is hydrogen or methyl and G is as defined above, Q ² is an N-protected 3'-amino-3'-deoxyglycosyl group of formula Va

w

OH (Va.) Wherein W is hydroxy or N-protected amino -NHG, wherein G is as defined above, X is hydrogen or hydroxy, Y is hydrogen or hydroxy, Z 'is hydrogen, hydroxy or N-protected amino NHG or N-protected methylamino

R "

Z —N \

G wherein R "is methyl and G is as defined above, Z" is hydrogen or methyl, or Q ¹ is an N-protected 3 ', 4'-dideoxy-3'-eno-aminoglycosyl group of formula IIIa wherein M is hydroxy or an atom hydrogen, M 'is hydroxy or hydrogen and G' is an amino-protecting acyl group of formula R ^and CO-, where R ^a is hydrogen, (C 1 -C 6 alkyl or dichloro- or trichloro- (C 1 -C 6 alkyl- or trifluoro- (C 1 -C 6 alkyl)) —C 1-6 alkyl or Q ² is an N-protected 3 "-methylamino-3" -deoxyglycosyl group of formula VIa

(R / -A) wherein R "" is hydrogen or methyl and G ‘is as defined above.

The method according to MS. No. 261,853, sometimes referred to as " zinc complexation ", it is possible to prepare such a selectively but partially protected N-acylated derivative of an aminoglycoside antibiotic in which all amino groups except--amino- and 3'-amino- or 3'-alkylamino aminoglycoside molecules are protected by an acyl group, and only 1-amino- and 3'-amino- or 3'-alkylamino groups remain unprotected. When this partially protected N-acylated aminoglycoside antibiotic derivative is reacted with an α-hydroxy-ω-aminoalkanoic acid or a reactive equivalent thereof to effect acylation, mixed acylation products containing (i) a 1-N-acylated product are obtained, wherein only the 1-amino group of the aminoglycoside molecule was acylated with α-hydroxy-ω-aminoalkanoic acid, (ii) a 3'-N-acylated product wherein only 3'-amino or 3'-alkylamino was acylated, (iii) both 1-amino and 3 The '-amino- or 3'-alkylamino groups were acylated, and (iv) an unreacted substance in which no 1-amino- or 3'-amino- or 3'-alkylamino group was acylated. In order to obtain the desired 1-N-acylation product from the above mixed acylation products, a further reaction is always required in which the 1-N-acylation product is separated from the mixture by chromatography or other isolation method. Since the 1-amino group is fortunately more reactive than the 3'-amino or 3'-alkylamino groups, the actual yield of the desired 1-N-acylation product is usually from 40% to 60% by weight and exceeds the theoretical maximum yield of 25% by weight calculated with the assumption that the reactivity of 1-amino- and 3'-aminoneibo 3'-alkylaminoimino groups is the same. However, while the reaction conditions for 1-N-acylation are best ensured, undesirable N-acylated by-products are inevitably formed, and an additional step is always required to remove undesired N-acylated by-products by subjecting the mixed acylated products to a cliromatographic process. in a column.

To overcome this disadvantage, it is usually desirable to prepare a selectively protected N-acylated aminoglycoside antibiotic derivative in which all amino groups other than the 1-amino group are protected.

To meet this requirement, the present inventors have conducted research in an attempt to provide a process for preparing an aminoglycoside antibiotic derivative as defined above that would allow selective protection of the 3'-amino- or 3'-alkylamino group selectively but partially protected N-acylated aminoglycoside antibiotic derivative containing free. The 1-aminoa 3 '-amino group obtained by said "zinc complexation" process, while the 1-amino group remains unlocked.

As a result, we have now found that when a partially protected N-acylated aminoglycoside antibiotic derivative, obtained by the "zinc complexation" process, is reacted with an acylating agent selected from the group consisting of formic acid esters, dihalogenated or trihalogenoalkanoic acid esters, N -formylimidazole, then the 3'-amino or 3'-alkylamino group can preferably be acylated to block without acylation of the 1-amino group. This selective method of 3'-N-protection can be combined with the above-mentioned method of "zinc complexation", i.e. with the method of U.S. Pat. No. 261,853, such that a selectively protected N-acylated aminoglycoside derivative containing an 6-O- (3'-amino- or 3'-alkylamino-3'-deoxyglycosyl) -2-deoxystreptamine structure is produced in an easy and efficient manner. , and in this derivative, all amino groups other than the 1-amino group of the aminoglycoside molecule are selectively protected with the same or different acyl groups. The combination of "zinc complexation" with selective 3 "-N protection affords the advantage that the desired 1-N-unprotected derivative can be prepared from the original aminoglycoside antibiotic in addition to N-fully protected other derivatives in a yield of 70% or more by weight. When this 1-N-unprotected derivative is used, inter alia, an N-fully protected derivative for 1-N-acylation of an aminoglycoside antibiotic, there is the additional advantage that N-acylated products are not undesirably produced, so that extraction and purification of the desired The 1-N-acylated product is greatly facilitated.

The invention therefore provides a process for the preparation of a selectively protected N-acylated aminoglycoside antibiotic derivative comprising 4-O- (aminoglycosyl) -6-O- (3'-amino or 3'-methylamino-3'-deoxyglycosyl) -2-deoxystreptamine in which N- the acylated derivative has the 1-amino group of the deoxystreptamine structure unprotected, but the other amino groups in the aminoglycoside molecule are protected by the same or different acyl groups, and the N-acylated derivative corresponds to the general formula (I) as defined above. of an acid of formula VIII

R a ^— C — R ^b

O (VIII) wherein R ^a is as defined above, i.e., hydrogen, C 1 -C 4 alkyl or C 1 -C 4 dichloroalkyl or C 1 -C 4 trichloroalkyl or C 1 -C 4 trifluoroalkyl, and R ^b is C 1 -C 4 alkoxy or phenoxy, or N-formylimidazole, or

N-acetylimidazole, is reacted as an acylating agent with a partially protected N-acylated aminoglycoside antibiotic derivative in which the 1-amino- and 3'-amino or 3'-alkylamino groups are unprotected and all other amino groups are protected with an amino-protective acyl group and partly the protected N-acylated aminoglycoside antibiotic derivative corresponds to the general formula VII

(VII>

wherein R 'is hydrogen or ethyl and G is as defined above, Q ³ is identical to the above defined Q ¹ , which is an N-protected aminoglycosyl group of formula IIa, N-protected 3', 4'-dideoxy-3'-eno a-aminoglycosyl group of formula IIIa or an N-protected 3 ', 4'-dideoxy-4'-eno-aminoglycosyl group of formula IVa and Q ⁴ is a 3 "-amino-3" -deoxyglycosyl group of formula Vb

OH (Vb) wherein M is as defined above, i.e., hydroxy or OH, and M 'is as defined above, that is, hydroxy or hydrogen, or Q ⁴ is a 3'-methylamino-3'-deoxyglycosyl group of formula

wherein R '' is as defined above, that is, hydrogen or methyl, at a temperature of from -30 ° C to + 120 ° C in an inert organic solvent that is anhydrous or aqueous to form selective acylation of 3'-amino- or 3'- Of the partially protected N-acylated derivative of formula VII with the acyl group R ^and CO of said acylating agent of formula VIII and thus of the desired 1-N-unprotected and otherwise N-fully protected aminoglycoside antibiotic derivative of formula I.

it is preferred that the acylating agent is reacted with the partially protected N-acylated derivative of formula VII at a temperature of from -30 ° C to +120 ° C for from 30 minutes to 24 hours or up to 48 hours in an inert organic solvent selected from the group including dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, sulfolane, dimethylacetamide, chloroform, dichloromethane, methanol, ethanol, n-butanol, t-butanol, benzene, toluene and ethyl ether, the solvent being anhydrous or aqueous.

It is further preferred that the acylating agent of formula VIII is selected from the group consisting of methyl formate, ethyl formate, phenyl formate, methyldichloroacetate, methyltrichloroacetate, methyltrifluoroacetate, ethyltrifluoroacetate, phenyltrifluoroacetate, N-formylimidazole and N-acetylimidazole.

It is further preferred that the partially protected N-acylated derivative of an aminoglycoside antibiotic of formula VII is a partially protected N-acylated derivative of a compound selected from the group consisting of kanamycin A,

6‘-N-alkylcamamycin A,

3‘-deoxycyanamycin A,

6‘-N-methyl-3‘-deoxycyanamycin,

4‘-deoxycyanamycin A,

6‘-N-methyl-4'-deoxycyanamycin A, 3‘, 4‘-dideoxycanamycin A,

6 "-deoxycannamycin A, 4" -6 "-dideoxycanamycin A, kanamycin B,

3-deoxycyanamycim B,

4‘-deoxycyanamycin B,

3‘, 4‘-dideoxycannamycin B, 3‘, 4‘-dideoxy-3‘-eno-kanamycin B, 6‘-N-methyl-3‘, 4‘-dideoxycanamycin B, kanamycin C,

3‘-deoxycyanamycin C,

3 ‘, 4‘-dideoxycycinamycin C, gentamycin A, gentamycin B, gentamycin C, verdamycin, sisomycin and netilmycin.

The aminoglycoside antibiotics that can be used in the method of the invention are the same as the aminoglycoside antibiotics useful in the method of U.S. Pat. No. 261,853.

Embodiments of the method of the invention will now be described in detail.

A partially protected N-acylated aminoglycoside antibiotic derivative to be reacted with an acylating agent of formula VIII of the invention and having all amino groups other than the 1-amino- and 3'-amino- or 3'-alkylamino groups in the aminoglycoside may be protected. be one created by the above-mentioned "zinc complexation" method. The acyl group originally present in the partially protected N-acylated aminoglycoside antibiotic derivative used in the method of the present invention may generally be alkanoyl, aroyl, alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aralkylsulfonyl, or arylsulfonyl protecting group known as a conventional amino group. In addition, the partially protected N-acylated aminoglycoside antibiotic derivative used as starting material may be that prepared by the method of Nagabushan et al. as described in Sp. st. am. No. 4 136 254.

In carrying out the process of the invention, the partially protected N-acylated aminoglycoside antibiotic derivative having unprotected 1-amino- and 3'-amino- or 3'-alkylamino groups is used as the starting material and dissolved or suspended in any suitable inert inorganic solvent. To the resulting solution or the resulting suspension is added an alkanoic ester of the formula IIIi or N-formylimidazole as an acylating agent in an amount at least equimolar to the amount of the starting material used. The inert organic solvent may preferably be one that has a high dissolution capacity for the starting material, for example dimethylsulfoxide, dimethylformamide and hexamethylphosphoric triamide, but tetrahydrofuran, dioxane, acetonitrile, nitromethane, sulfolane, dimethylacetamide, chloroform, dichloromethane, methanol, ethanol may also be used. , n-butanol and tert-butanol, as well as these solvents in aqueous form. Benzene, toluene and ethyl ether can be used as solvent in the reaction medium, although they are unsuitable and give lower yields of the desired product. In the acylating agent of formula VIII, R ^a may preferably be a dihaloalkyl or trihaloalkyl group, in particular dichloromethyl, trifluoromethyl or trichloromethyl, and R ^b may preferably be an alkoxy group, for example a methoxy or ethoxy group. When R ^b is an aryloxy group, it may be a phenoxy group. Particular examples of the acylating agent of formula VIII are methyl formate, ethyl formate, butyl formate, benzyl formate, phenyl formate, methyldichloroacetate, methyltrichloroacetate, phenyltrichloroacetate, methyltrifluoroacetate, ethyltrifluoroacetate and phenyltrifluoroacetate. Using this series of acylating agents, the 3'-amino group of the starting material may preferably be formyl, dichloroacetyl, trichloroacetylated or trifluoroacetyl. A trifluoroacetic acid ester, especially trifluoroacetate, is most suitable. This class of acyl group is advantageous in that it is very easily removable in the subsequent deprotection by the usual deprotection method. If the alkanoic acid alkyl ester of formula VIII is not used as an acylating agent, but instead using the corresponding alkanoic anhydride or one of its active esters, for example the N-hydroxysuccinimide ester for the acylation process, selective acylation of the 3'-amino group cannot be achieved. however, a side formation of the 1-N-acylated product and / or the formation of mixed acylated products containing predominantly the 1-N-acylated product occurs. It is noteworthy that the desired selective acylation of the 3'-amino group cannot be achieved by using an acid anhydride or active ester of the same alkanoic acid for the acylating agent.

The acylating agents of formula VIII useful in the present invention have different reactivities and have a wide reactivity from "strong" to "weak" reactivity. If an acylating agent with strong reactivity is used, the acylation reaction can be carried out for a shorter time while cooling. In contrast, when an acylating agent with poor reactivity is used, the acylation reaction can be carried out either with heating or over a longer period. In general, however, the acylation reaction is to be carried out at temperatures ranging from -30 ° C to + 120 ° C and the duration of the reaction should be from 30 minutes to 24 hours or 43 hours, respectively.

The desired selectively acylated 3'-N-acylated product thus obtained can be recovered from the reaction mixture in a known manner, for example by evaporation of the solvent or precipitation by addition of water and, if necessary, further purification of the product.

The reaction mechanism by which the selective 3'-acylation is carried out by the method of the invention has not been fully explained. A possible explanation is that the acylating agent of formula VIII first acylates the hydroxy group of the starting material to immediately form the ester and this O-esterification group corresponding to the 3'-amino- or 3'-alkylamino group of this procedure, if this is adjacent esterified hydroxy groups transiently formed to acylate said amino groups. Following this assumption, it is possible to explain why a 1-amino group which has no hydroxy group in the vicinity cannot be acetylated in the process of the invention. Furthermore, it is clear that the intermediate-ester- cannot be obtained when the trifluoroacetylation or formylation is carried out according to the process of the invention. The reason why the ester product cannot be extracted by trifluoroacetylation or formylation is probably because the O-trifluoroacetyl group is unstable and that some of the unstable O-acyl group that has not been converted to an amino group, namely the known ON-acyl migration, is removed from the acylated hydroxy group during extraction and purification of the 3 ' -N-acylation product to recover the free hydroxy group. However, the invention is not limited to the above explanation of the reaction mechanism introduced in the present method. In addition to the compounds which are useful as acylating agents of formula VIII according to the invention, it seems that for the purposes of the invention those compounds having an acyl group which tends to give a less stable ester product when this acyl group is transformed into an O-acyl group by reaction with hydroxy and hence giving the ester product. However, it is very interesting to note that when the process according to the invention is carried out using N-alkanoylimidazole instead of N-formylimidazole, for example N-propionylimidazole and N-butyroylimidazole, then the 3'-amino- or 3'-alkylamino partially protected N The acylated aminoglycoside antibiotic derivative is not acylated, but the hydroxy adjacent to said 3'-amino- or 3'-alkylamino group can be esterified with the alkanoyl group of N-alkanoylimidazole used to form the intermediate O-esterification product. If the O-esterification product or the entire reaction mixture containing the O-esterification product is subsequently reacted with an alkaline agent, for example ammonium hydroxide at room temperature, then the O-esterifying alkanoyl group is forced to move or migrate to the adjacent 3'-amino - or 3 ' -alkylamino resulting in selective acylation and thus protection of the 3 ' -amino- or 3 ' -alkylamino group. Thus, the reaction mixture from the reaction of the partially protected N-acylated aminoglycoside antibiotic derivative with N-alkanoylimidazole does not contain the desired 3'-N-acylated product, but this desired 3'-N-acylated product can only be recovered from this reaction mixture after the reaction. the mixture was basified with some alkaline reagent, for example aqueous ammonia, see Example 39 below.

The invention will be further elucidated by means of non-limiting examples. Example 1

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3 '-N-trifluoroacetylkanamycim A

A solution of 504 mg of 3,6‘-di-N-benzyloxycarbonylcanamycin A in 4 ml of dimethylsulfoxide was mixed with 220 mg of ethyltrifluoroacetate and the mixture thus obtained was allowed to stand at room temperature. A small volume of trifluoroacetic acid was then added to the reaction mixture, and the reaction solution was poured into a large volume of ethyl ether, and the resulting oily residue was washed well with ethyl ether to give a solid. This material was dried thoroughly to give 640 mg of the desired compound as a solid.

Yield 99%; [Α] D ²⁵ = + 98 °, (cl, pyridine). For C36H47N4O16F3. CF3COOH calculated:

C, 47.40; H, 5.02; N, 5.82; found:

H, 5.15; N, 5.79.

Example 2

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3‘-N-trifluoroacetylkanamycin A

A solution of 20 mg of 3,6‘-di-N-benzyloxycarbonylcanamycin A in 0.4 ml of dimethyl sulfoxide was mixed with 6 mg of phenyltrifluoroacetate and the mixture thus obtained was allowed to stand overnight at room temperature. Thereafter, the reaction mixture was worked up as in Example 1 to give 24.8 mg of the desired compound identical to the compound prepared in Example 1.

Yield 97%.

Example 1 a d 3 ........

Preparation of 3,6-di-N-benzyloxycarbonyl-3'-N-trifluoroacetylkanamycin A

A solution of 10 mg of 3,6‘-di-N-benzyloxycarbonylcanamycin A in 0.3 ml of hexamethylphosphoric triamide was mixed with 7 mg of ethyltrifluoroacetate and the mixture thus obtained was left overnight at room temperature. The reaction solution was then mixed with a small volume of trifluoroacetic acid and then poured into a large volume of ethyl ether. The oily residue was washed thoroughly with ethyl ether and the resulting solid dried to give 11.7 mg, 91% of the desired product as mono-trifluoroacetate as a solid.

Example 4

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3 '-N-trifluoroacetylkanamycin A

A suspension of 10 mg of 3,6‘-di-N-benzyloxycarbonylcanamycin A in 0.3 ml of dimethylformamide was mixed with 7 mg of ethyltrifluoroacetate and the mixture thus obtained was allowed to stand overnight at room temperature. The homogeneous reaction solution thus obtained was mixed with a small volume of trifluoroacetic acid and then poured into a large volume of ethyl ether. The oily residue was washed well with ethyl ether to give a solid, and after drying 11.5 mg, 90% of the desired compound as mono-trifluoroacetate as a solid.

Example 5

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3 '-N-trifluoroacetylkanamycin A

A suspension of 10 mg of 3,6‘-di-N-benzyloxycarbonyl-camamycin A in 0.35 ml of sulfolane was mixed with 7 mg of ethyltrifluoroacetate and stirred overnight at room temperature. The reaction mixture was then worked up as in Example 1 to give 12.0 mg (94%) of the desired compound as mono-trifluoroacetate as a solid.

Example 6

Preparation of 3,0‘-di-N-benzyloxycarbonyl-3'-N-trifluoroacetylkanamycin A

A suspension of 22 mg of 3,6‘-di-N-benzyloxycarbonylkanamycin A in 0.8 ml of tetrahydrofuran was mixed with 10 mg of ethyltrifluoroacetate and stirred for 2 days. The resulting homogeneous reaction solution was mixed with 15 mg ethyltrifluoroacetate and 8 mg anhydrous sodium carbonate and stirred overnight and then left to stand for 2 days. The resulting reaction solution was concentrated to a small volume and the concentrate was washed with water and then dried to give a solid. The solid was suspended in a small volume of tetrahydrofuran along with a small amount of trifluoroacetic acid. The mixture was stirred and then ethyl ether was added. The precipitate was filtered, washed with ether and dried to give 21 mg, 74% of the desired compound as mono-trifluoroacetate as a solid.

[α] ²⁵ D = + 98 °, (cl, pyridine).

Example 7

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3 '-N-trifluoroacetylkanamycin A

A solution of 10 mg of 3,6‘-di-N-benzyloxycarbonylkanaiuycin A in water-tetrahydrofuran 1: 1, in 0.3 ml was mixed with a 5 m solution; ethyl trifluoroacetate in 0.1 ml tetrahydrofuran and the resulting mixture was allowed to stand at ambient temperature for one day. Thereafter, 10 mg of ethyltrifluoroacetate, 4.4 mg of anhydrous sodium carbonate and 0.1 ml of tetrahydrofuran were added to the resulting solution four times at five new intervals to effect 3'-N-trifluoroacetylation. The reaction solution was concentrated and then treated in the same manner as in Example 6 to give 5.5 mg, 43% of the desired compound as mono-trifluoroacetate as a solid.

Example 8

Preparation of 3,6'-di-N-benzyloxycarbonyl-3 ^{L <N-trifluoroacetyl} A

A solution of 10 mg of 3,6'-di-N-benzyloxycarbonyl-kanamycin A in 0.6 ml of water-ethanol 2: 3 was mixed with a solution of 5 mg of ethyltrifluoroacetate in 0.1 ml of tetrahydrofuran and the mixture was allowed to stand at room temperature. one day. The reaction solution was then treated as in Example 6 to give 2.3 mg, 18% of the desired compound as mono-trifluoroacetate as a solid.

Example 1 9

Preparation of 3,6'-di-N-tert-butoxycarbonyl-3 ' ^1- N-trifluoroacetylkanamycin A (a) Preparation of 3,6'-di-N-tert-butoxycarbonylkanamycin A

500 mg i.e. 1.03 mM kanamycin A free base was suspended in 12 ml dimethylsulfoxide and 1 g, i.e. 4.55 mM zinc acetate dihydrate, was added to the suspension. The mixture was stirred at room temperature until a homogeneous solution was formed, to which 370 mg (2.59 mM t-butoxycarbonylazide) was then added. The resulting mixture was left overnight at room temperature and then treated in the same manner as in Example 1 (iij and (iii) B of U.S. Patent 261,853) to give 590 mg, 80% of a colorless solid of the desired compounds.

[.alpha.] D @ ²⁵ = + 89 DEG, (Cl, water-dimethyliformamide, 1: 2).

(b) Preparation of 3,6'-di-N-tert-butoxycarbonyl-3 '' - N-trifluoroacetylkanamycin A mg of 3,6'-di-N-tert-butoxycarbonylcanamycin A was dissolved in 0.5 ml of dimethyl sulfoxide and the resulting solution was mixed with 25 mg ethyltrifluoroacetate and the mixture was allowed to stand overnight at room temperature. The reaction mixture was then worked up as in Example 1 to give 76.8 mg, 98% of the desired compound as the trifluoroacetate as a solid.

(α _D ²⁵ = + 72 °, (Cl, water-dimethylformamide, 1: 2)).

For C 30 H 51 N 11 O 6 F 3. CF3COOH calculated:

H, 5.86; N, 6.26.

found:

H, 5.92; N, 6.38.

Example 10

Preparation of 3,6‘-di-N- (p-methoxybenzyloxycarbonyl) -3'-N-trifluoroacetylkanamycline A

A solution of 40 mg of 3,6'-di-N- (p-methoxybenzyloxycarbonyl) camamycin A according to Example 8 of U.S. Patent 261,853 in 0.4 ml of dimethyl sulfoxide was mixed with 18 mg of ethyltrifluoroacetate and the mixture was allowed to stand overnight at room temperature. The reaction solution was then treated as in Example 1 to give 49.3 mg (98%) of the title compound as a solid.

[.alpha.] D @ ²⁵ = + 78 DEG, (Cl, water / dimethylformamide 1: 2).

For C38H51N4O18F3. CF3COOH calculated:

H, 5.12; N, 5.48.

found:

H, 5.03; N, 5.31.

Example 11

Preparation of 3,6 ‘, 3“-tri-N-trifluoroacetylkanamycin A mg of 3,6‘-dl-N-trifluoroacetylkanamycin A according to Example 10 of Cs. No. 261,853 and 12 mg of triethylamine were mixed with 0.6 ml of dimethylsulfoxide and then with 35 mg of ethyltrifluoroacetate and the mixture was stirred overnight to give 3 &apos; -N-trifluoroacetylation. The reaction solution was then treated as in Example 1 to give 94.2 mg, 96% of the desired compound as a solid.

[ _.alpha. ] _{D @} ²⁵ = + 76 DEG, (Cl, water / dimethylformamide 1: 2).

for C24H33N4O14F9. CF3COOH calculated:

35.22 O / o C, 3.87% H, 6.32 θ / ο N; found:

H, 3.99; N, 6.07.

Example 12

Preparation of 3,6‘-di-N-phenoxycarbonyl-3'-N-trifluoroacetylkanamycin A

A solution of 53 mg of 3,6‘-di-N-phenoxycarbonylcanamycin A according to Example 11 Cs. No. 261,853 and 9 mg of triethylamine in 0.5 ml of dimethylsulfoxide were mixed with 23 mg of methylfrifluoroacetate and the mixture was then treated as in Example 1 to give 65 mg, 95% of the desired compound as a solid. .

[α] D ²⁵ = + 70 °, (c1, water, dimethylformamide 1: 2).

For C34H43N4O16F3. CF3COOH calculated:

H, 4.74; N, 5.99.

n o 1 twpn n ·

H, 4.96; N, 5.77.

Example 13

Preparation of 3,6 ‘, 3'-tri-N-formylkanamycin A

A mixture of 62 mg of 3,6‘-di-N-formylkanamycin A according to Example 13 of Cs. No. 261,853, 90 mg of ethyl formate and 1 ml of dimethylsulfoxide were heated at 100 ° C for 12 hours in a sealed tube to effect 3'-N-formylation. The reaction solution was mixed with a small amount of formic acid and then poured into a large volume of ethyl ether and treated as in Example 1 to give 69 mg (98%) of the desired compound as a ninhydrin positive solid.

[α] ²⁵ D = + 109 °, (cp, water-dimethylformamide 1: 2).

For C21H36N4O14. HCOOH calculated:

% H, 6.23;% N, 9.12;

found:

H, 6.19; N, 9.10.

Example 14

Preparation of 3,6‘-di-N-benzyloxycarbonyl-6‘-N-methyl-3'-N-trifluoroacetylkanamycin A

A mixture of 68 mg of 3,6‘-di-N-benzyloxycarbonyl-6‘-N-methylkanamycin A according to Example 15 of Cs. No. 261,853 11 g of triethylamine, 30 mg of ethyltrifluoroacetate and 0.7 ml of dimethyl sulfoxide were treated as in Example 1 to give 86 mg, 99% of the desired compound as momo-trifluoroacetate as a solid.

[.alpha.] D @ ²⁵ = + 65 DEG, (Cl, water / dimethylformamide 1: 2).

Example 15

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3‘-deoxy-3'-N-trifluoroacetylkanamycin A

A solution of 52 mg of 3,6‘-di-N-benzyloxycarbonyl-3‘-deoxycyanamycin A according to Example 16 of Cs. No. 261,853 and 11 mg of triethylamine in 0.4 ml of dimethyl sulfoxide were mixed with 21 mg of ethyltrifluoroacetate and the mixture was allowed to stand overnight at room temperature. The mixture was then treated as in Example 1 to give 64.8 mg, 97% of the desired compound as a solid.

[.alpha.] D @ ²⁵ = + 70 DEG, (Cl, water-dimethylformamide 1: 2 ').

For C36H47N4O15F3. COOH calculated:

H, 5.11; N, 5.92. found:

H, 5.35; N, 5.77.

Example 16

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3‘-deoxy-3'-N-formylkanamycin A

A solution of 78 mg of 3,6'-di-N-benzyloxycarbonyl-3'-deoxycyanamycin A in 0.7 ml of dimethylsulfoxide was mixed with 65 mg of phenyl formic acid and the mixture was heated overnight at 50 ° C to give 3 "-N- formylation. The reaction solution was mixed with a small amount of formic acid and then treated as in Example 1 to give 83 mg, 97% of the desired compound as the monoformate as a solid.

[ _.alpha. ] _{D @} ²⁵ = + 84 DEG (c, water-dimethylformamide 1: 2).

Example 17

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3'-N-dichloroacetyl-3‘-deoxycyanamycin A

A solution of 35 mg of 3,6‘-di-N-benzyloxycarbonyl-3‘-deoxycyanamycin A in 0.5 ml of dimethyl sulfoxide was mixed with 12 mg of methyldichloroacetate and the mixture was allowed to stand overnight at room temperature. The reaction solution was mixed with a small volume of dichloroacetic acid and then treated as in Example 1 to give 44.5 mg, 96% of the desired compound as a solid.

[Α] D ²⁵ = + 65 °, (cl, water - dimethylformamide 1: 2).

For C36H48N4O15C12. CHCl 2 COOH calculated:

C, 46.73; H, 5.16; N, 5.74; Cl, 14.52; found ·

H, 5.33; N, 5.62; Cl, 14.28.

Example 18

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3'-N-trichloroacetyl-3‘-deoxycyanamycin A

A solution of 58 mg of 3,6‘-di-N-benzyloxycarbonyl-3‘-deoxycyanamycin A in 0.7 ml of dimethyl sulfoxide was mixed with 25 mg of methyl trichloroacetate and the mixture was left overnight at 50 ° C. The reaction solution was mixed with a small volume of trichloroacetic acid and then treated as in Example 1 to give 80.5 mg, 98% of the desired compound as a solid.

[ _.alpha. ] _{D @} ²⁵ = + 65 DEG, (Cl, water / dimethylformamide 1: 2).

For C36H47N4Q15Cl3. CCl3CO2H calculated:

% C, 43.65;% H, 4.63;% N, 5.36;

found:

% C, 43.44;% H, 4.77;% N, 5.30. Example 19

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3‘-deoxy-3'-N-trifluoroacetyl-6‘-N-methylkanamycin A

A solution of 72 mg of 3,6‘-di-N-benzyloxycarbonyl-3‘-deoxy-6‘-N-methylcanamycin A in 1 ml of dimethyl sulfoxide was mixed with 30 mg of ethyl trifluoroacetate and the mixture was allowed to stand overnight at room temperature. The reaction solution was then treated as in Example 1 to give 89.5 mg (97%) of the desired compound as mono-trifluoroacetate as a solid.

[α] _D ²⁵ = + 70 °, (cl, water-dimethylformamide 1: 2).

Example 20

Preparation of 3,6‘-di-N-benzyloxycarbonyl-4-deoxy-3'-N-trifluoroacetylkanamycin A

A solution of 71 mg of 3,6‘-di-N-benzyloxycarbonyl-4‘-deoxycyanamycin A according to Example 18 of Cs. No. 261,853, 12 mg of triethylamine and 30 mg of ethyl trifluoroacetate in 1 mL of dimethyl sulfoxide were treated as in Example 1 to give 90 mg, 99% of the desired compound as mono-trifluoroacetate as a solid.

[α] D ²⁵ = + 72 °, (cl, water-dimethylformamide 1: 2).

Example 21

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3‘, 4‘-dideoxy-3'-N-trifluoroacetylkanamycin A

A solution of 75 mg of 3,6'-di-N-benzyloxycarbonyl-3 ', 4'-dideoxycanamycin A and 30 mg of ethyl trifluoroacetate in 1 ml of dimethylsulfoxide was treated as in Example 1 to give 96 mg (99% of the desired). solid compounds.

[α] _D ²⁵ = + 72 °, (cl, water-dimethylsulfoxide

1: 2).

For C36H47N4O14F3. CF3COOH calculated:

C, 49.03; H, 5.20; N, 6.02; found:

H, 5.46; N, 5.87.

Example 22

Preparation of 3,6'-di-N-benzyloxycarbonyl-3 ', 4'-dideoxy-3'-N-formylkanamycin A mg of 3,6'-di-N-benzyloxycarbonyl-3', 4'-dideoxycyanamycin A and 65 mg Phenyl formate was dissolved in 1 ml of dimethylsulfoxide and the resulting solution was treated as in Example 16 to give 80 mg (97%) of the desired compound as the monomate as a solid.

[a] _u = ²⁵ + 80 '(cl, water-dimethylformainid 1: 2).

Example 23

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3‘, 4‘-dideoxy-3'-N-dichloroacetylkanamycim A

A solution of 68 mg of 3,6‘-dl-N-benzyloxycarbonyl-3‘, 4‘-dideoxycarbamycin A in 0.9 ml of dimethyl sulfoxide was mixed with 25 mg of methyl dichloroacetate and the mixture was allowed to stand overnight at room temperature. The reaction solution was mixed with a small amount of dichloroacetic acid and then treated in the same manner as in Example 1 to give 88 mg, 97% of the desired compound as monodichloroacetate as a solid.

[.alpha.] D @ ²⁵ = + 67 DEG, (Cl, water / dimethylformamide 1: 2).

Example 24

Preparation of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-3'-N-trifluoroacetylkanamycin B

A solution of 78 mg of 3,2 ‘, 6‘-tri-N-benzyloxycarbonylcanamycin B according to Example 19 of Cs. No. 261,853 and 11 mg of triethylamine in 1 ml of dimethylsulfoxide were mixed with 35 mg of ethyl trifluoroacetate and treated as in Example 1 to give 92 mg, 95% of the desired compound as monotrifluoroacetate as a solid.

[α] _D ²⁵ = + 60 °, (cl, water-dimethylformamide 1: 2).

Example 25

Preparation of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-3'-N-formyltobramycin

A solution of 82 mg of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyltobramycin according to Example 20 of Cs. No. 261,853 and 12 mg of triethylamine in 1.2 ml of dimethyl sulfoxide were mixed with 60 mg of phenyl formate and treated as in Example 16 to give 86 mg, 97% of the desired compound as a solid.

[α] _D ²⁵ - + 71 °, (cl, water-dimethylformamide 1: 2).

For C43H55N5O16. HCOOH calculated:

% H, 6.09;% N, 7.42; found:

H, 6.22; N, 7.28.

Example 26

Preparation 3.2 ^! 6'-tri-N-benzyloxycarbonyl-6'-N-methyl-3'-N-trifluoroacetyltobramycin

A solution of 80 mg of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-6‘-N-methyltobramycin according to Example 21 of Cs. No. 261,853 and 12 mg of triethylamine in 1.2 ml of dimethyl sulfoxide were mixed with 30 mg of ethyl trifluoroacetate and the mixture was then treated as in Example 1 to give 97 mg, 98% of the desired compound as mono-trifluoroacetate in in the form of a solid.

[Α] _D ²⁵ - -4-60 °, (cl, water-dimethylformamide 1: 2).

Example 27

Preparation of 3,2 ', 6‘-tri-N-benzyloxycarbonyl-3'-N-trifluoroacetyldibecacin

A solution of 82 mg of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyldibecacin according to Example 23 of Cs. No. 261,853 in 1 ml of dimethylsulfoxide was mixed with 30 mg of ethyl trifluoroacetate and treated as in Example 1 to give 100 mg, 98% of the desired compound as a solid.

[ _.alpha. ] _{D @} ²⁵ = + 61 DEG, (Cl, water / dimethylformamide 1: 2).

For C44H54N5O15F3. CF3COOH calculated:

% C, 51.93;% H, 5.21; found:

H, 5.38; N, 6.47.

Example 28

Preparation of 3,2 ‘, 6‘, 3 '-tetra-N-trifluoroacetyldibecacin

A mixture of 71 mg of 3,2 ‘, 6‘-tri-N-trifluoroacetyldibecacin and 30 mg of ethyl trifluoroacetate in 1 ml of dimethylsulfoxide was allowed to stand overnight at 40 ° C. The reaction solution was then treated as in Example 1 to give 90 mg (99%) of the desired compound as a solid.

[α] _D ²⁵ = + 70 °, (cl, water-dimethylformamide 1: 2).

For C26H33N5O12F12. CF3COOH calculated:

% C, 35.42;% H, 3.61;% N, 7.38; found:

35.40% C, 3.89 ° / o H, 7.17% N.

Example 29

Preparation of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-3 '-N-formyldlbekacin

A mixture of 79 mg of 3,2 ', 6'-tri-N-benzyloxycarbonyldibecacin and 60 mg of phenyl formate in 1.1 ml of dimethylsulfoxide was treated as in Example 16 to give 84 mg, 98% of the desired compound as the monomerate in in the form of a solid.

[α] ²⁵ D + 70 °, (cl, water-dimethylformamide 1: 2).

Example 30

Preparation of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-3 '-N-dichloroacetyldibecacin

A solution of 84 mg of 3,2 ', 6'-tri-N-benzyloxycarbonyl-dibecacin in 1.2 ml of dimethylsulfoxide was reacted as in Example 17 to give 104 mg, i.e. 97% of the desired compound as mono-dichloroacetate in in the form of a solid.

[ _.alpha. ] _{D @} ²⁵ = + 59 DEG, (Cl, water / dimethylformamide 1: 2).

Example 31

Preparation of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-6‘-N-methyl-3 '-N-trifluoroacetyldibecacin

A solution of 85 mg of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-6‘-N-methyldibecacin according to Example 24 of Cs. No. 261,853 in 1 ml of dimethylsulfoxide was mixed with 30 mg of ethyl trifluoroacetate and treated as in Example 1 to give 103.5 mg, 98% of the desired compound as mono-trifluoroacetate as a solid.

[α] _D ²⁵ = + 60 °, (cl, water-dimethylformamide 1: 2).

Example 32

Preparation 3.2 ^! -di-N-benzyloxycarbonyl-3'-N-formylkanamycin C

A solution of 81 mg of 3,2‘-di-N-benzyloxycarbonylcanamycin C according to Example 25 of Cs. No. 261,853 and 14 mg of triethylamine in 1.5 ml of dimethylsulfoxide were mixed with 90 mg of ethyl formate and the mixture was worked up as in Example 16 to give 85.5 mg, i.e. 96% of the desired compound as monomerate. in the form of a solid.

[.Alpha.] D @ ²⁵ = + 81 DEG (cp, water-dimethylformamide 1: 2).

Example 33

Preparation of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-3'-N-trifluoroacetyl sisomycin

A solution of 82 mg of 3,2 ‘, 6‘-tri-N-benzyloxycarbonylsisomycin according to Example 29 of Cs. No. 261,853 in 1.5 ml of dimethylsulfoxide was mixed with 30 mg of ethyl trifluoroacetate and treated as in Example 1 to give 99 mg, 97% of the desired compound as mono-trifluoroacetate as a solid.

[.alpha.] D @ ²⁵ = + 151 DEG (Cl, water / dimethylformamide 1: 2).

Example 34

Preparation of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-3 '-N-trifluoroacetyl netilmycin

A solution of 85 mg of 3,2 ', 6'-tri-N-benzyloxycarbonylnetilmycin in 1.3 ml of dimethylsulfoxide was mixed with 30 mg of ethyl trifluoroacetate and treated as in Example 1 to give 103 mg (98% of the desired). compounds such as monotrifluoroacetate as a solid.

[ _.alpha. ] _{D @} ²⁵ = + 145 DEG, (Cl, water / dimethylformamide 1: 2).

Example 35

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3 '-N-trifluoroacetylgentamycin B

A solution of 72 mg of 3,6'-di-N-benzyloxycarbonylgentamycin B in 1.2 ml of dimethylsulfoxide was mixed with 30 mg of ethyl trifluoroacetate and treated as in Example 1 to give 91 mg, 99% of the desired compound as monotrifluoroacetate as a solid.

[ _.alpha. ] _{D @} ²⁵ = + 92 DEG, (Cl, water / dimethylformamide 1: 2).

Example 36

Preparation of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-3'-N-trifluoroacetylgentamycin

Cl and in a mixture

A solution of 84 mg of 3,2 ', 6'-tri-N-benzyloxykarbonylgentamycinu Cl and _L and C in the mixture in 1.5 ml of dimethylsulfoxide was treated with 30 mg of ethyl trifluoroacetate, and the resulting mixture was processed as in Example 1 to afford 101 mg of the desired compound as mono-trifluoroacetate as a solid.

[ _.alpha. ] _{D @} ²⁵ = + 97 DEG, (Cl, water / dimethylformamide 1: 2).

Example 37

Preparation of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-3‘, 4‘-dideoxy-3‘-eno-3 -N -N-trifluoroacetylkanamycin B

A mixture of 83 mg of 3,2 ‘, 6‘-tri-N-benzyloxycarbonyl-3‘, 4‘-dideoxy-3‘-eno-kanamycin B according to Example 28 of Cs. No. 261,853 and 35 mg of ethyl trifluoroacetate in 1.2 mL of dimethyl sulfoxide were allowed to stand overnight at room temperature. The reaction mixture was then worked up as in Example 1 to give 99.5 mg, 96% of the desired compound as monotrifluoroacetate as a solid.

[Α] D ²⁵ - + 26 ', (cl, water-dimethylformamide 1: 2).

Example 38

Preparation of 3,6‘-di-N-benzyloxycarbonyl-3‘-deoxy-3'-N-formyamamycin A

A solution of 90 mg of 3,6‘-di-N-benzyloxycarbonyl-3'-deoxy-kanamycin A in 0.8 ml of dimethyl sulfoxide was mixed with 13 mg of N-formylimidazole and the mixture was allowed to stand overnight at room temperature. The reaction solution was mixed with a small amount of formic acid and then treated with ethyl ether as in Example 1 to give 94 mg, i.e. 95% of the desired compound as a formate as a solid.

Example 39

Preparation of 3,6 ‘, 3'-tri-N-acetylcanamycin A

A mixture of 100 mg of 3,6'-di-N-acetylkanamycin A and 20 mg, which is 1.03 M relative to one mole of starting material, N-acetylimidazole in 1 ml of dimethylsulfoxide, was stirred under ice-cooling for 3 hours and then left to stand over night. The reaction solution was made basic by the addition of 0.3 ml of 28% aqueous ammonia and then left to stand at room temperature for 3 days. The resulting reaction mixture was treated with ethyl ether to give an ether-insoluble syrup which was dissolved in water and chromatographed on a CM-Sephadex C-25 column in NH 4 ⁺ form, manufactured by Pharmacia Fine Chemicals Co., Sweden. The column was developed with a 0.05 N aqueous ammonia solution. The eluted fractions containing the desired product were combined and concentrated to dryness. The concentrate was dissolved in water, the aqueous solution neutralized with acetic acid, and concentrated to dryness to give 109 mg, 90% of the desired compound as a solid.

[ _.alpha. ] _{D @} ²⁵ = + 98 DEG (cl, water: dimethylformamide 1: 2).

For C24H42N4O14. CH3COOH. H2O calculated:

% C, 45.34;% H, 7.02; found:

H, 7.20; N, 8.11.

Claims (3)

A process for the preparation of a selectively protected N-acylated aminoglycoside antibiotic derivative comprising 4-O- (aminoglycosyl) -6-O- (3'-amino- or 3'-methylamino-3'-deoxyglycosyl) -2-deoxystreptamine, wherein N the acylated derivative has the 1-amino group of the deoxystreptamine structure unprotected, but all other amino groups in the aminoglycoside molecule are protected by the same or different acyl groups, and the N-acylated derivative corresponds to the general formula I wherein R 'is hydrogen or ethyl, C 2 -C 5 alkanoyl or tri- (C 2 -C 5 alkanoyl), or G is (C 1 -C 4) alkyloxycarbonyl or p-methoxyphenyl- (C 1 -C 4) alkyloxycarbonyl, Q ¹ is an N-protected aminoglycosyl group of the formula wherein W is hydroxy or N- protected amino group of formula -NHG, wherein G is as defined above, X is hydrogen or hydroxy, Y is hydrogen or hydroxy, Z 'is hydrogen, hydroxy or N-chr NHG Néna amino or N-protected methylaminoiskupina R "/ —N \ G wherein R "is methyl and G is as defined above, Z" is hydrogen or methyl, or Q ¹ is an N-protected 3 ', 4'-dideoxy-3'-eno-aminoglycosyl group of formula IIIa OF THE INVENTION wherein G is as defined above, or Q ¹ is an N-protected 3 ', 4'-dideoxy-4'-eno-aminoglycosyl group of formula IVa Rc = CH-NHG NHG (IV-a) wherein R "'is hydrogen or methyl and G is as defined above, Q ² is an N-protected 3" -amino-3 "deoxyglycosyl group of formula Va OH (v-aO where M is hydroxy or hydrogen, M 'is hydroxy or hydrogen and G' is amino-protecting acyl of the formula R _and CO-, where Ra is hydrogen, (C1-C4) alkyl or dichloro- or trichloro- (C 1 -C 4) alkyl- or trifluoro- (C 1 -C 4) alkyl or Q ² is an N-protected 3 "-methylamino-3" -deoxyglycosyl group of the formula Via 7Π 281859 wherein R "" is a hydrogen atom or a methyl group and G 'is as defined above, characterized in that the alkanoic acid ester of the formula R _a —C — R _b II o (VIII) wherein R a is as defined above, i.e., hydrogen, C 1 -C 4 alkyl or dichloroalkyl or C 1 -C 4 trichloroalkyl or C 1 -C 4 trifluoroalkyl, and R _b is C 1 -C 4 alkoxy; up to 4 carbon atoms or a phenoxy group, or N-formylimidazole or N-acetylimidazole, is reacted as an acylating agent with a partial N-rolled derivative of an aminoglycoside antibiotic in which the 1-amino and 3'-amino- or 3'-alkylamino groups are unprotected and all the other amino groups are protected with an amino-protecting acyl group, and the partially protected N-acylated derivative of the aminoglycoside antibiotic corresponds to the general formula VII ^NHG nhr 'and ³ o oo (vti> wherein R 'is hydrogen or ethyl and G is as defined above, Q ³ is identical to the above defined Q ¹ , which is an N-protected aminoglycosyl group of formula IIIa, N-protected 3', 4'-dideoxy-3'-eno an aminoglycosyl group of formula IIIa or an N-protected 3 ', 4'-dideoxy-4'-eno-aminoglycosyl group of formula IVa and Q ⁴ is a 3 "-amino-3" -deoxyglycosyl group of formula Vb OH (Vb) wherein M is as defined above, i.e., hydroxy or hydrogen and M 'is as defined above, i.e., hydroxy or hydrogen, or Q ⁴ is a 3'-methylamino-3''-deoxyglycosyl group of formula VI- b wherein R "" is as defined above, that is, a hydrogen atom or a methyl group, at a temperature of from -30 ° C to + 120 ° C in an inert organic solvent, which is anhydrous or aqueous, to form selective 3ylamino-acylation; The 3'-methylamino group of the partially protected N-acylated derivative of formula VII with the acyl group R _and CO- of said acylating agent of formula VIII and hence the desired 1-N-unprotected and otherwise N-fully protected aminoglycoside antibiotic derivative of formula I. 2. The process of claim 1, wherein the acylating agent is reacted with a partially protected N-acylated derivative of formula VII at a temperature of from -30 [deg.] C to + 120 [deg.] C for 30 minutes to 48 hours in an inert organic a solvent selected from the group consisting of dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, sulfolane, dimethylacetamide, chloroform, dichloromethane, methanol, ethanol, n-butanol, t-butanol, benzene, toluene and ethyl ether, the solvent being anhydrous or aqueous. 3. The method of claim 1 wherein the acylating agent of formula (VIII) is selected from the group consisting of methyl formate, ethyl formate, phenyl formate, methyldichloroacetate, methyltrichloroacetate, methyltrifluoroacetate, ethyltrifluoroacetate, phenyltrifluoroacetate, N-formylimidazole a N-acetylimidazole. 4. The method of claim 1, wherein the partially protected N-acylated aminoglycoside antibiotic derivative of formula VII is a partially protected N-acylated aminoglycoside antibiotic derivative of formula VII is a partially protected N-acylated derivative of a compound selected from the group consisting of kanamycim A, 6‘-N-alkylkanamycin A, 3‘-deoxycyanamycin A, 6‘-N-methyl-3‘-deoxycannamycin A, 4‘-deoxycannamycin A, 6‘-N-methyl-4‘-deoxycannamycin A, 3‘, 4‘-dideoxycannamycin A, b “-deoxycannamycin A, 4 ", 6" -dideoxycycloamycin A, kanamycin B 3'-deoxycannamycin B, 4'-deoxycannamycin B, 3 ', 4'-dideoxycanamycin B, 3', 4'-dideoxy-3'-eno-kanamycin B, 6'-N-methyl-3 ', 4'- dideoxycanamycin B, kanamycin C, 3‘-deoxycyanamycin C, 3β, 4β-dideoxycycinamycin C, gentamycin A, gentamycin B, gentamycin C, verdamycin, sisomycin and netilmycin.