HU208020B - Process for producing selective protected sisomycin intermediates - Google Patents

Abstract

The present invention relates to a process for the preparation of a selectively protected novel sulfomycin derivative represented by the general formula (I) wherein X is a group wherein R1, R2 and R3 are independently alkyl, phenyl or phenylalkyl; Y alkanoyl, Y 'hydrogen or alkanoyl; and Z is hydrogen or ethylidene. Compounds of formula (I) are prepared by reacting a compound of formula (Ia) with a silyl group of formula (a) and optionally acetaldehyde. The compounds are useful as intermediates for the synthesis of netilmicin (1-N-ethyl-isomycin). - S1 ■ R1 R2 R3 (a) HU 208,020 Scope of the description: 8 pages (including 2 sheets)

Description

This invention relates to novel selectively protected isomycin derivatives.

Netilmycin (1-N-ethylisosomycin) represented by formula (A) is a well-known aminoglycoside antibiotic.

Produced by, among others, 4002742,

U.S. Patent Nos. 4,230,847 and 4,337,335. It was originally prepared by reacting schizomycin sulfate with acetaldehyde under reducing conditions. However, since schizomycin has five free amino groups, this procedure led to the formation of an unusually high amount of unwanted by-products and the total useful yield was only about 10-11%.

The process described in U.S. Patent No. 4,230,847 showed a significant improvement: the use of copper complexes selectively protected the 3,2 'and 6' amino groups of schizomycin. Alkylation of this intermediate with acetaldehyde in the presence of a reducing agent led to a significant improvement in yield (60% in laboratory, 49% in plant).

However, this improved process also produced a significant percentage of unwanted products which reduced the yield. The largest amount of unwanted by-products was 1-N, N-diethyl-isomycin. Under the reaction conditions used in the above process, i.e. reaction with acetaldehyde in the presence of a reducing agent, the unreacted or excess acetaldehyde appeared to react with the already formed 1-N-ethylated schizomycin to give the N, N-diethylated product. .

Hungarian Patent Publication No. 199498, which has the same priority and filing date as the present application, discloses a method of preparation that results in fewer side reactions and consequently better yields. According to the present invention, a selectively protected schizomycin derivative of formula (I)

X is an organosilyl group of formula (a) wherein R ¹ , R ² and R ³ are each independently lower alkyl, phenyl or phenyl (lower) alkyl;

Y is C2-C7 alkanoyl,

Y 'is hydrogen or C2-C7 alkanoyl, Z is two hydrogen atoms in an inert solvent, is reacted with acetaldehyde and the resulting 1-N-ethylidene derivative is reduced in the same reaction mixture, then deprotected and isolated in the appropriate form.

For the preparation of netilmicin as described above, the selectively protected isomycin derivatives of the formula (I) are required as starting materials or intermediates

X is an organosilyl group of formula (a) wherein R ¹ , R ² and R ³ are each independently lower alkyl, phenyl or phenyl (lower) alkyl;

Y is C2-C7 alkanoyl,

Y 'is hydrogen or C 2 -C 7 alkanoyl; and

Z represents two hydrogen atoms or ethylidene groups.

According to the present invention, these novel intermediates are prepared by treating a schizomicin derivative of formula (Ia), wherein

Y is a C 2 -C 7 alkanoyl group and

Y 'is hydrogen or (C2-C7) alkanoyl is reacted with a compound capable of introducing a silyl group of formula (a) in the presence of a catalyst to give a compound of formula (I) wherein

X, Y and Y 'are as defined above and

H is hydrogen, optionally treated with acetaldehyde, and the unreacted acetaldehyde is decomposed with a metal hydride reducing agent to give a compound wherein Z is ethylidene.

The protected derivative is prepared by reacting the isomycin at the 3,2 ', 6' and optionally 3 'positions with the amino protecting compounds. Preferred amino-protecting substituents are acetyl, formyl and propionyl, with acetyl being particularly preferred. Methods for attaching acetyl and propionyl groups to schizomycin are described in U.S. Patent 4,337,335, which discloses a Formyl substituent by reacting schizomycin with asymmetric formic anhydride.

The preparation of 3,2,6'-tri-N-acetyl-isomycin (compound of formula II) from schizomycin is described in U.S. Patent Nos. 4,230,848 and 4,336,254. Example 16C (1) of each description describes the reaction of part (II) acetate hydrate with schizomycin followed by reaction with acetic anhydride followed by hydrogen sulfide gas. The product is isolated from the ion exchange resin in the hydroxyl ring. The specific example is incorporated herein by reference.

Another way to make 3,2 ', 6'-tri-N-acetylisomycin from schizomycin is as follows:

Copper (III) acetate is suspended in a mixture of dimethylformamide / water (about 6: 2) and isomycin concentrate is added. The pH was adjusted to 8.5-10.5 by addition of triethylamine. The slurry was cooled to about 5 ° C and a solution of acetic anhydride in dimethylformamide was added slowly at 0-10 ° C with vigorous stirring. The pH of the reaction mixture is maintained between 8.5 and 10.5 with the additional addition of triethylamine, if necessary. Alternatively, first add about 90% of the dimethylformamide acetic anhydride solution as above, then dilute the remaining 10% with about six volumes of dimethylformamide and then add. The reaction was monitored by thin layer chromatography. If the reaction is incomplete, additional dimethylformamide acetic anhydride solution is added to the reaction mixture to complete the reaction. When the reaction is complete, the mixture is concentrated under reduced pressure. The concentrate was diluted with water, cooled to 0-10 ° C for about four hours, and the solid precipitated by filtration.

HU 208 020 Β junk. The product was isolated with an ion exchange resin in a partial ammonium cycle.

Whatever method is used, the 3,2 ', 6'-tri-N-acetylisomycin is prepared and then spray dried to remove water.

For example, the first step in the preparation of the compounds of the present invention is the silylation of 3,2 ', 6'-tri-N-acetyl isomycin of formula (H). Silylating agents are organosilyl compounds which, when reacted with hydroxyl sites, yield an organosilyl substituent of formula (a) wherein R 1, R ² and R ^{3 are} lower alkyl, phenyl or phenyl lower alkyl. Preferred substituents are tri (lower alkyl) -syl], of which the (trimethylsilyl) substituent is particularly preferred.

The three hydroxyl groups can be silylated, i.e. the 5, 2 "and 4" positions. However, it is within the scope of the invention to silylate only two sites, the 5 and 2 "sites. This can be accomplished by appropriately selecting the silylating agent, the conditions for the silylation reaction and controlling the amount of silylating agent introduced. The degree of silylation of the schizomycin derivative can be monitored by NMR. Preferably, all three hydroxyl groups are silylated to simplify the silylation process and improve solubility. In a preferred method described below, 3,2,6'-thyr-N-acetylisomycin is converted into 3,2 ', 6'-tri-N-acetyl-5,2,', 4 '- (trimethylsilyl) isomycin. [Compound (III)] is silylated according to Scheme [A].

The reaction shown in Scheme [A] is carried out under reflux under anhydrous conditions, preferably in the presence of a catalyst such as a sulfate salt or an ammonium salt such as ammonium chloride or ammonium sulfate, sulfuric acid or trimethylsilyl chloride. A preferred catalyst is the sulfate salt of the compound of formula (II), i.e., 3,2 ', 6'-tri-N-acetylisomycin sulfate. The compound of formula (Π) (mixed with a very small amount of its sulfate salt) and a silylating agent such as a trimethylsilylating agent such as hexamethyldisilazane, bis (trimethylsilyl) acetamide (BSA), mono (trimethylsilyl) acetamide (MSA). ), trimethylchlorosilane (TMCS) or other equivalent silylating agent is carried out in an inert organic solvent, i.e. the reaction conditions in an organic solvent such as acetonitrile, toluene, 1,2-dimethoxyethane or the like. The preferred solvent is 1,2-dimethoxyethane (DME). The course of silylation is monitored by the 'HNMR spectrum. The reaction is complete within 5 hours. The silyl substituent is used to block alkylation at the 3 "amino group by spherical inhibition of the trimethylsilylated 2" and optionally 4 "positions.

The free amino group of the triacetyl tris (trimethylsilyl) compound of formula (III) is then converted to the ethylideneimino group according to Scheme [B], preferably under anhydrous conditions. The presence of water in the imine formation may result in an imperfect reaction. The imine formation reaction is one of the key reactions of a series of reactions. The reaction of the compound of formula (III) with acetoaldehyde is carried out at a temperature in the range of about 10 ° C to room temperature (about 25 ° C), preferably about 15 ° C, in an organic aprotic solvent which is inert to the reaction conditions. Examples of such solvents include 1,2-dimethoxyethane, acetonitrile, toluene, hexane, dichloromethane, tetrahydrofuran and the like. A preferred solvent is methylene chloride. The reaction takes about 30 minutes. The metal hydride reducing agent is then added to the reaction mixture, preferably under anhydrous conditions, so that any excess acetaldehyde is completely reacted to prevent unwanted side reactions. Preferred reducing agents are sodium borohydride, amine boranes and lithium aluminum hydride, with sodium borohydride being particularly preferred. Sodium borohydride is added to the reaction mixture, warmed to about room temperature and reacted for about 10-15 minutes. Imine formation is monitored by 'HNMR spectrum. The first step of the reaction is completed in about 30 minutes. Sodium borohydride reduces unreacted acetaldehyde, thus preventing unwanted side reactions.

The following examples illustrate the process of the invention.

Example 1

Trisilylated Tri-N-Acetyl-Isomycin (Compound III)

15.0 g (26.2 mmol, 83% purity by high performance liquid chromatography) in a 500 ml 3-necked round bottom flask equipped with a mechanical stirrer, a reflux condenser with a drying tube and a purity of 3.2%, 6'- tri-N-acetylisomycin, 0.75 g (1.12 mmol) of 3,2'6'-tri-N-acetylisomycin sulfate, 150 mL of 1,2-dimethoxyethane and 25 mL (118, Hexamethyldisilazane (5 mmol) was added. The reaction mixture was heated in an oil bath (external oil bath temperature 105 ° C) for 5 hours under reflux, and the progress of silylation was monitored by 1 H NMR. The silylation reaction at the 5, 2 "and 4" sites is complete in about 3 to 8 hours.

Example 2

Trisylated 1-N-ethylidene-3,2 ', 6'-tri-N-acetyl-isomycin [Compound (IV)]

To the anhydrous reaction mixture of Example 1 was added methylene chloride (150 mL) at room temperature. The mixture was cooled to about 15 ° C and cold acetaldehyde (3.0 mL, 53.6 mmol) was added. After stirring for 30 minutes, powdered sodium borohydride (1.9 g, 50.2 mmol) was added, warmed to room temperature, and stirred for 10-15 minutes until excess acetaldehyde was completely eliminated.

Example 3

Preparation of 3,2 ', 6', 3 "-Tetra-N-acetyl-1-N-ethylidene-5,2", 4 "-trisilylisomycin Pure 3,2 ', 6', 3" -tetra- N-acetylisomycin a

3,2 ', 6' -tri-N-acetyl-isomycin-3 '-amino

HU 208 020 Β

It is prepared by acetylation with N-acetylimidazole and purification on a silica gel column.

Such lyophilized tetra-N-acetylisomycin (g) is suspended in 40 ml of 1,2-dimethoxyethane and 4.4 ml of hexamethyldisilazane is added. The reaction mixture was refluxed for 7 hours. The 1 H-NMR spectrum showed that the silylation reaction was complete.

Imine formation was carried out as described in Example 2.

3,2 ', 6'-tri-N-acetyl-5,2', 4 '- (trimethylsilyl) isomycin (Example 1) and 3,2', 6'-tri-N-acetyl The HNMR data of -5.2 ", 4" - (trimethylsilyl) -1N-ethylideneisomycin (Example 2) is shown in Table 1.

Table I

A) Trislylated tri-N-acetylisomycin:

1 H-NMR (CD ₂ Cl ₂ ) δ = 0.118 [S, 9H, Si (CH ₃ ) ₃ ], 0.124 [S, 9H, Si (CH ₃ ) ₃ ], 0.165 [S, 9H, Si - ( CH3) _3], 1.38 (S, 3H, CH ₃ C-4 "-en), 1.93 [s, 3H, CH ₃ C (O) -N]

1.96 [S, 3H, CH ₃ C (O) -N), 1.98 [S, 3H, CH ₃ C (O) -N], 2.45 (S, 3H, CH ₃ -N 3 "), 4.69 (dd,

1H, J = 3.29 and 4.02 Hz, CH on C-4'), 5.01 (d, 1H,

J = 2.19 Hz, CH at C -1 '), 5.08 (d, 1H, J = 1.82 Hz,

CH at C-1'en), 8.03 [d, 1H, J = 6.99 Hz, NH-C (O) -],

6.47 [dd, IH, J = 5.11 and 6.96 Hz, _CH2 NH-C (O) -] and 7.1 ppm [d, H, J = 9.13 Hz, NH-C (SHE)-).

B) Silylated-1N-ethylidene-3,2 ', 6'-tri-N-acetylisomycin:

1 H-NMR (CD ₃ CN) δ = 0.08 [S, 9H, Si (CH ₃ ) ₃ ], 0.102 [S, 9H, Si (CH ₃ ) ₃ ], 0.140 [S, 9H, Si (CH ₃ ) ₃ ], 1.5 (S,

3H, CH ₃ C-4 "), 1.83 [S, 3H, CH ₃ C (O) -N], 1.86 [S, 3H, CH ₃ C (O) -N], 1, 89 [d, 3H, J = 4.76 Hz,

CH ₃ CH = N], 1.93 [S, 3H, CH ₃ C (O) -N], 2.36 (S,

3H, CH ₃ -N on C-3 '), 4.71 (bm, 2H, CH on C-4 and 0-1'), 5.19 (d, 1H, J = 1, 46 Hz, CH 0-1), 6.37 [d, 1H, J = 8.04 NH-C (O) -], 6.77 [d, 1H, J = 8.4 Hz, NH- C (O) -], 6.99 [t, 1H, J = 5.48 Hz, CH ₂ -NH-C (O) -] and 7.69 ppm (q, 1H, J = 4.76 Hz CH). ₃ CH = N).

CMMR (CD ₃ CN) δ = 162.04 (N = CHCH ₃ ) and 22.46 ppm (N = CH-CH ₃ ).

Claims (16)

PATENT CLAIMS A process for the preparation of selectively protected isomycin derivatives of the formula I wherein X is an organosilyl group of the formula wherein R ', R ² and R ³ are independently lower alkyl, phenyl or phenyl (lower) alkyl; Y is C2-C7 alkanoyl, Y 'is hydrogen or C 2 -C 7 alkanoyl; and Z is for the preparation of two hydrogen atoms or ethylidene groups, characterized in that one of the isomycin derivatives of the formula Ia Y is C 2 -C 7 alkanoyl; Y is hydrogen or C2-C7 alkanoyl is reacted with a compound capable of introducing a silyl group of formula (a) in the presence of a catalyst, preferably a sulfate salt, to give a compound of formula I wherein X, Y and Y 'are as defined herein. ; and Z is hydrogen, optionally reacted with acetaldehyde, and the unreacted aldehyde is decomposed with a metal hydride reducing agent to give a compound of formula (I): X, Y and Y 'are as defined herein; and Z is ethylidene. 2. A process according to claim 1 for the preparation of a compound of formula I wherein: X, Y and Y are as defined in the preamble of claim 1; and Z represents two hydrogen atoms, characterized in that the appropriately substituted starting compounds are used. 3. A process according to claim 2 for the preparation of compounds of formula I wherein X is a trimethylsilyl group, wherein the starting compounds are suitably substituted. A process according to claim 2 or 3 for the preparation of a compound of formula (I) wherein: Y is an acetyl group, wherein the appropriately substituted starting compounds are used. 5. A process according to any one of claims 1 to 6 for the preparation of a compound of formula (I) wherein Y 'is hydrogen, wherein the appropriately substituted starting materials are used. 6. A process according to claim 1 for the preparation of selectively protected schizomycin derivatives of formula (I): X, Y and Y'are as defined in the preamble of claim 1; and Z is ethylidene, characterized in that the appropriately substituted starting materials are used. A process for the preparation of a compound of formula (I) according to claim 6 wherein X is a trimethylsilyl group, wherein the appropriately substituted starting compounds are used. A process according to claim 6 or 7 for the preparation of a compound of formula (I) wherein: Y is an acetyl group, wherein the appropriately substituted starting compounds are used. 9. A 6-8. A process according to any one of claims 1 to 6 for the preparation of a compound of formula (I) wherein X is trimethylsilyl, EN 208 020 Β characterized in that the appropriately substituted starting compounds are used. 10. A 6-9. A process according to any one of claims 1 to 6 for the preparation of a compound of formula (I) wherein Y 'is hydrogen, wherein the appropriately substituted starting materials are used. 11. A process according to claim 1 for the preparation of selectively protected schizomycin derivatives of formula (I): X, Y and Y are as defined in the preamble of claim 1; Y 'is C2-C7 alkanoyl; Z is two hydrogen atoms, wherein the appropriately substituted starting materials are used. A process according to claim 11 for the preparation of a compound of formula (I) wherein: Y and Y 'are acetyl; characterized in that the appropriately substituted starting compounds are used. A process according to claim 11 or 12 for the preparation of a compound of formula (I) wherein: X is a trimethylsilyl group, wherein the appropriately substituted starting compounds are used. A process according to claim 13 for the preparation of a compound of formula (I) wherein: Z is ethylidene, characterized in that the appropriately substituted starting materials are used. A process according to claim 13 or 14 for the preparation of a compound of formula (I) wherein: X is a trimethylsilyl group, wherein the appropriately substituted starting compounds are used. 16. A process according to any one of claims 1 to 6 for the preparation of a compound of formula (I) wherein Y is an acetyl group, wherein the appropriately substituted starting compounds are used.