FI76098B - N-METHYL-11-AZA-10-DEOXY-10-DIHYDROERYTROMYCIN-N-OXIDE DERIVATIVES DIHYDROERYTROMYCIN-A. - Google Patents

Description

χ 76098 N-Methyl-11-aza-10-deoxy-10-dihydroerythromycin N-oxide derivatives, process for their preparation, intermediate used in the process and their use in N-methyl derivatives of 11-aza-10-deoxy-10-dihydroerythromycin A 5 ten

This invention relates to N-methyl-11-aza-10-deoxy-10 10-dihydroerythromycin N-oxide derivatives, to a process for their preparation, to an intermediate used in the process and to their use in 11-aza-10-deoxy-10-dihydroerythromycin. for the preparation of N-methyl derivatives of mycin A.

The N-oxide derivatives of the invention have the formula

O

CH t <0V / 3 / HO., R ”3’2 νΊ ΊΤ | 111; n = 1 20 \ | L'0 I I III-A; n = 0

Η0 '' '·· γ ^ HO 0 ^^ O

HO''Tl 'f / Yr 0> o «OCH3 where n is 0 or 1.

The intermediate of the invention has the formula 76098 2

O

t N (CH 2),

HO -___ _ <'«W X

5? | o I II

HO, XI is' '' ·· / * HO ^ Xpo · '0 ^^ 0 how / i rCf / / 1' (λ, o

i ° y r X

0 xX ^ .OH

The compounds of the invention are used in the preparation of known N-methyl derivatives of 11-aza-10-deoxy-10-dihydroerythromycin A of the formula N (CH 2) -20 I J z

CH, ^. * 2 ° ·., X

3 xνΊο ^ ι ·· Y '^ HO * «, 1 / N., Q Q ^ Ϊ13 H0 V"

25 H ° 7 \ 1S 4sX

χγ ^ γχ 0 vV ···, 'OR, 30 OCH3 wherein R2 is hydrogen, alkanoyl having 2 to 3 carbon atoms or 3-carbethoxypropionyl, and R1 is hydrogen, alkanoyl having 2 to 3 carbon atoms or 3-carbethoxypropionyl .35 in manufacture.

3,76098

Erythromycin A is also a macrolide antibiotic prepared by fermentation and described in U.S. Patent 2,653,899. Numerous derivatives of erythromycin A have been prepared in an attempt to modify its biological and / or pharmacodynamic properties. Esters of erythromycin A and mono- and dicarboxylic acids are described in Antibiotics Annual, 1953-1954, published by Symposium Antibiotics (Washington DC}, pages 500-513 and 514-521. U.S. Patent No. 10,417,077 describes erythromycin. A cyclic carbonate ester of A, the reaction product of erythromycin A and ethylene carbonate, as an effective antibacterial agent U.S. Patent No. 4,328,334 describes 11-aza-10-deoxy-10-dihydroerythromycin A, certain N-acyl and N- (4-substituted benzenesulfonyl) derivatives having antibacterial properties, and a process for their preparation.

Alkylation of the primary and / or secondary amine groups of compounds containing a tertiary amine group is generally difficult. However, it is common practice to protect tertiary amine groups in such compounds by converting them to N-oxides prior to alkylation ^ Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., NY, (1981) pp. 281 ^ · 25 that the N-methyl derivative of 11-aza-10-deoxy-10-dihydroerythromycin A and its 2'-, 4 "and / or 2 ', 4" -acetyl, propionyl and 3-carbethoxypropionyl derivatives are effective antibacterial agents against gram-positive and gram-negative bacteria.

Pharmaceutically acceptable acid addition salts of the compounds can also be used for the same purpose, such as hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, propionate, butyrate, citrate, glycolate, lactate, tartrate, malate, maleate, fumarate, fumarate, , pamoate, benzoate, succinate, lactate, p-toluenesulfonate and aspartate.

4,76098 These compounds of formula I are described in Chemical Abstracts, Vol. 98 (1983), 17006c (BE Patent 892,357).

The compounds of formula I may be named N-5 methyl-11-aza-4-O- (1-cladinosyl) -6-O- (D-desosaminyl) -15-ethyl-7,13,14-trihydroxy-3 , 5,7,9,12,14-hexa-metyylioksiasyklopentadekan-2-ones. However, for simplicity, they are referred to herein as 11-aza-10-deoxy-10-dihydroerythromycin A as N-methyl derivatives, as designated in U.S. Patent No. 4,328,334.

The compound of formula II (1 * 2 = R 1 = H) is likewise termed the N'-oxide of N-hydroxy-11-aza-10-deoxy-10-dihydroerythromycin A, where the term "N'-oxide" refers to Oxide formation in the dimethylamino group of the desosaminyl moiety.

The structure of formula III (1 * 2 - R 1 = H) is designated N-methyl-11-aza-10-deoxy-10-dihydroerythromycin bis-N-oxide. Space chemistry in the 11-aza-ato-20 miS of formula III is not yet known. However, diastereomers are included in formula III.

As an alternative to the designation used above, the parent compound of the following formula IV may be designated 9-deoxy-9a-aza-9a-homoerythromycin A. Using this system, the compounds of formula I, wherein each R 2 and is hydrogen, are designated 9-deoxy-9a-methyl-9a-aza-9a-homoerythromycin A.

The compounds of formula I and their pharmaceutically acceptable acid addition salts are effective anti-bacterial agents against gram-positive microorganisms, e.g. Staphylococcus aureus and Streptococcus pyogenes, and gram-negative microorganisms, e.g. Pasturella multocida and Neisseria sicca. In addition, they have significant activity against Haemophilus in 35 vitro. The N-methyl derivative (Formula I; R 2 = R 3 = H) is superior to erythromycin A and 11-aza-10-deoxy-10-dihydroerythromycin A in acting against Heamophilus in vitro.

5,76098

The process according to the invention for the preparation of the compounds of the formulas III and III-A is characterized in that i) a compound of the formula 5 N (OH.,),

ho 'I

T 'Tl 10 ΗθΧΧ ° Α

| X

/! 0., / 0

i Vs T X

15 0 '' OH

<och3 is oxidized with hydrogen peroxide or peracid in a reaction-inert solvent; and ii) the obtained compound of formula 0 t n (ch3) 2

25 -X. JL

HO / X

'· ° \ / \ ° ,,, r / 0vY ^

i r Q

X'H

OCH3 is methylated with methyl iodide or bromide or dimethyl sulfate in a reaction-inert solvent in the presence of an acid acceptor.

6 76098

The invention further relates to the use of these compounds for the preparation of compounds of formula I and their pharmaceutically acceptable acid addition salts, wherein a) a compound of formula

O

t CH3 N (CH ^), f_ £ * 'HO ,, 10 ΗΟ'η .....

HO / / 1 15 1 f o

1 I

B) when it is desired to prepare a compound of formula I in which 1 * 2 and are identical and represent other than hydrogen, acylate a compound of formula I in which both R 2 and R ^ represents hydrogen, and is prepared according to step a) with a suitable acylating agent, c) when it is desired to prepare a compound of formula I wherein R 2 is hydrogen and R 1 is other than hydrogen, is carried out on a compound of formula I wherein both R 2 and R 1 is other than hydrogen and prepared according to step b), solvolysis, d) when it is desired to prepare a compound of formula I wherein R 2 and R 2 are different and represent non-hydrogen, acylating a compound of formula I wherein R 2 is is hydrogen and R 3 is other than hydrogen, prepared according to step c) with a suitable acylating agent, and if necessary, a compound of formula I prepared according to one of the steps described above is converted into a pharmaceutically acceptable acid addition salt.

7 76098

Thus, the compounds are prepared from II-aza-10-deoxy-10-dihydroerythromycin A (Formula IV) according to the following reaction scheme: N (CH), HO-

5 “—’X

HN> H ° - .. y

m] -> II

1 CH 2 OH

HO <S

10 'Λ

I% r I I

I II L Alkylating ^ OH substance 'OCH ^

IV

15

The reduction is

I <- III / III-A

The oxidation of 20 II-aza-10-deoxy-10-dihydroerythromycin A is carried out in a reaction-inert solvent mixture (i.e. one which does not react with the starting materials or products to give substances which are not desired under the reaction conditions used) using 25 hydrogen peroxide or peracid as oxidizing agent. , such as peracetic acid, perbenzoic acid, permaleic acid and phthalic acid.

The choice of solvent depends in part on the oxidizing agent used. If a water-soluble oxidizing agent such as hydrogen peroxide or peracetic acid is used, a water-miscible solvent should be used. If an oxidizing agent having low water solubility is used, e.g., perbenzoic or m-chloroperbenzoic acid, an aqueous solution of the reaction mixture is generally avoided in order to obtain a single-phase reaction mixture.

8 76098

Suitable solvents for use with the latter oxidizing agents include methylene chloride, chloroform, ethers such as dioxane or tetrahydrofuran.

The oxidation is performed at ambient temperature; i.e.

5 at about 18-25 ° C, with a reaction time of up to 24 hours. Additional oxidizing agent is used to ensure maximum conversion of 11-aza-10-deoxy-10-dihydroerythromycin A, a limiting starting material. Generally, from about 1.0 mole to about 35 moles of oxidant are used per 10 moles of said limiting starting material. In practice, for economic reasons, about 5 to about 15 moles of oxidant are used per mole of limiting starting material. Hydrogen peroxide is preferred as an oxidizing agent because of its easy availability. The amine oxide of formula II is isolated by extraction and then the excess oxidizing agent is removed or decomposed.

The amine oxide of formula II thus prepared is then alkylated by reaction with an appropriate alkylating agent such as methyl iodide or bromide in a reaction-inert solvent in the presence of an acid acceptor. Preferred reaction-inert solvents useful in this step are methylene chloride, chloroform, tetrahydrofuran and toluene. Suitable acid acceptors include inorganic bases such as alkali metal hydroxides and carbonates, and organic amines such as hindered amine bases, e.g. 2-lutidine; and said substances are used in at least a stoichiometric amount based on the alkylating agent used.

Alkylating agents are generally used in amounts based on the amine oxide starting material, ranging from an equimolar amount to an excess of 100%.

The alkylation reaction when methyl iodide is used as the alkylating agent is easily carried out at ambient temperature. Alkylation using methyl bromide is slow at ambient temperature, requiring extended reaction times of several days. When methyl bromide is used, elevated temperatures, e.g., up to about 120 ° C, are preferred to accelerate the reaction.

9 76098

An alternative a lky lint as a scaffold involves the use of dimethyl sulfate in a reaction-inert solvent in the presence of an inorganic base such as those listed above. The reaction conditions using dimethyl sulfate-5 are similar to those mentioned above for methyl halides.

The intermediates formed during the alkylation of a compound of formula II are isolated, if desired, by standard methods, such as evaporation of the reaction mixture, followed by washing with water to remove inorganic salts. The reduction products of said intermediates (formula I) are also isolated by standard methods, such as extraction.

It has been found that alkylation of the crude product from the oxidation of a compound of formula IV affords two products: a compound of formula III as defined herein for bis-N of N-methyl-11-aza-10-deoxy-10-dihydro-erythromycin A. -oxide Ulix; and mono-oxide (III-A), wherein the oxide formation is in desosaminyl types. Said compound is referred to herein as desosaminyl N-oxide of N-methyl-11-20 aza-10-deoxy-10-dihydroerythromycin A.

The intermediates described above do not need to be purified prior to their use in the subsequent steps of the above reaction scheme. They can be used in a coarse form, i.e. as soon as they have been separated from their corresponding reaction mixtures. Due to ease and economy, intermediates are generally not purified before further use in the process.

The third and final step in the reaction scheme, the reduction step, is performed either catalytically or chemically from the crude product of the alkylation reaction or from the purified alkylated mono- or bisoxide (III-A and III). The catalytic reduction is carried out at ambient temperature, e.g. 18-25 ° C, about 1 to about 70 atm of hydrogen-35 in a reaction-inert solvent. Higher temperatures and pressures can be used if desired, but do not provide any benefits.

10 76098

Suitable catalysts are noble metal catalysts, preferably supported, and certain salts thereof, such as oxides. Preferred catalysts are Pd / C, Rh / C, PtO 2 and Raney nickel. The ratio of catalyst to support 5 is not critical, but is generally in the range of 1: 1 to 1: 2.

Typical solvents used in the reduction step are C 1-4 alcohols, especially ethanol, ethyl acetate and ethers, e.g. tetrahydrofuran and dioxane.

In addition to the above-mentioned heterogeneous catalytic reaction, homogeneous catalysis using, for example, tris (triphenylphosphine) chlorochlorodium (I), known as Wilkinson's catalyst, is used in the bed. Suitable solvents for said reaction are listed above in connection with the heterogeneous catalyst process and in which the homogeneous catalyst is soluble. The concentration of the homogeneous catalyst is not critical, but for economic reasons it is generally maintained at about 20 0.01 to about 10 mole percent by weight of the substrate.

Hydrogen pressure is not critical, but for convenience it is usually in the range of about 1 to about 70 atm.

In the above presentation, heterogeneous and homogeneous catalysts, although the amounts of catalysts used are not generally considered "catalytic" in the normal use of this term, are considered catalytic herein because there is little or no reaction in their absence.

Heterogeneous or homogeneous, the temperature of the catalytic reduction is not critical, but can range from about 20 ° C to about 100 ° C. The preferred temperature range is 20 to 80 ° C.

The chemical reduction of the alkylated amine oxides (III-A and III) is performed using metal hydrides such as sodium borohydride, sodium cyanoborohydride, pyridine-SO 2 / potassium iodide or zinc / glacial acetic acid.

11 76098

Compounds of formula I in which R 2 and / or are alkanoyls as defined herein are readily prepared by standard acylation methods such as those described by Jones et al .; J. Med. Chem. 15 5 (1972), p. 631, and Banaszek et al., Rocy. Chem. 43 (1969), p. 763. The 2 'and 4 "hydroxy groups are acylated with the appropriate acid anhydride E, e.g. (R2CO) 2 O in pyridine. Solvolysis of the 2', 4" ester with methanol yields the 4 "ester.

The formation of mixed esters, e.g. 2'-acetyl-4 "-propionyl, is readily accomplished by acylation of the 4" ester (R 3 = propionyl) with acetic anhydride in a reaction-inert solvent in the presence of potassium carbonate. Jones et. according to a method suitable for mixed esters described by al. (supra).

The acid addition salts are readily prepared by treating the compounds of formula I with at least an equimolar amount of the appropriate acid in a reaction-inert solvent or, in the case of the hydrochloride salts, with pyridine hydrochloride. Since formula I

more than one basic group is present, the addition of sufficient acid to satisfy all the basic groups allows the formation of polyacid addition salts. When preparing acid addition salts of compounds of formula I wherein R 2 is alkanoyl, isopropanol is used as the solvent to avoid solvolysis of the alkanoyl group. The acid addition salts are collected by filtration if they are insoluble in the reaction-inert solvent, precipitated by adding a solvent in which the acid addition salt is insoluble, or by evaporating the solvent.

The following examples illustrate the method and the products obtained therefrom. In the examples presented, no attempts were made to detect the maximum amount of product produced or to optimize the yield of the product obtained.

12 76098

Example 1 N'-oxide of N-hydroxy-11-aza-10-deoxy-10-dihydroerythromycin A (Formula II)

To a solution of 11-aza-10-deoxy-10-dihydro-5 erythromycin A (10.0 g) in 40 ml of methanol was added a total of 50 ml of 30% aqueous hydrogen peroxide dropwise over 5-10 minutes while mixed.

After stirring overnight at ambient temperature, the reaction mixture was poured into a mass of ice (200 g), ethyl acetate (200 ml) and water (100 ml). Excess hydrogen peroxide was quenched by the careful dropwise addition of saturated aqueous sodium sulfite until a negative starch-iodine test was observed. The layers were separated; and the aqueous layer was washed twice with 200 mL portions of ethyl acetate. The three organic extracts were combined, dried over anhydrous sodium sulfate and evaporated to give coarse N'-hydroxy-11-aza-10-deoxo-10-dihydroerythromycin A N'-oxide as a colorless foam (8.6 g).

Although the crude product proved to be satisfactory for use in the preparation method described below, purification was readily performed by silica gel chromatography, eluting with a methylene chloride: methanol: concentrated ammonium hydroxide system (12: 1: 0.1). Column development was followed by thin layer chromatography on silica gel plates using methylene chloride: methanol: concentrated ammonium hydroxide (9: 1: 0.1). The plates were developed with vanillin spray / ethanol (50 ml): 85% Η ^ Ρ04 (50 ml) with tvanillin (1.0 g) 7 7 indicator with heating. 1 Hnmr (CDCl 3) delta 3.21 / "6H, s, 3.39 (3H, s, cladinose CH 2 O-). MS: main peaks at 30 m / e 576 (ion from desosamine decomposition), 418 (aglycone ion minus both sugars) Both peaks show the -N-OH moiety within the aglycone.

In a similar manner, but substituting an equivalent amount of hydrogen peroxide for peracetic acid, the same compound is prepared.

13 76098

Example 2 Bis-N-oxide of N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A (Formula III)

To a stirred mixture of N'-hydroxy-11-aza-5 10-deoxo-10-dihydroerythromycin A N'-oxide (4.83 g), methylene chloride (100 ml) and solid anhydrous potassium carbonate (69.7 g) , 15.7 ml (35.8 g) of iodomethane were added dropwise under nitrogen over two minutes. The mixture was stirred under nitrogen at ambient temperature for 3.5 hours and the solid formed was collected by filtration. The filter cake was washed with methylene chloride (250 mL), the filtrate and washings were combined, water (300 mL) was added and the pH of the vigorously stirred mixture was adjusted to 11. The organic phase was separated, dried over anhydrous sodium sulfate-15a and concentrated to give the crude product as a colorless foam (4.36 g).

Although the crude product proved to be satisfactory for use in the reduction of the method described later, the purification was easily performed by a method commonly known as "Flash" silica gel chromatography / w. Clark

Still et al., J. Org. Chem. 43 (1978) 2923 J using 230-400 mesh silica gel (silica gel / coarse material about 45/1 by weight), eluting with a "flash technique" with acetone / methanol in a volume ratio of 4/1. The obtained 10 ml fractions which turned out to be pure bis-N-oxide by thin layer chromatography (TLC elution system: methylene chloride: methanol: concentrated ammonium hydroxide = 6: 1: 0.1; vanillin: 85% H 2 O 2: ethanol spray used with heating onto silica gel plates) was combined. 128 mg of pure bis-oxide were obtained from 1 g Λ 30 of coarse product. Hnmr (CDCl 3) delta 3.20 / $ H, broad s, CH 2 N 2 of aglycone and (^ 3) 2 *** "> 0-7 * 3.39 (3H, s, CH 2 Cladinose) MS: m / e 461 and 431, 415 (these two peaks are indicative of aglycone N-oxide), 159 (cladinose-derived moiety), 115 (desosamine-35 N-oxide-derived moiety).

n 76098

The chromatographic method described above also gave another, less polar product from the coarse material: N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A desosaminyl N-oxide. (246 mg).

Δ Hnmr (CDCl 3) delta 2.30 (3H, s, aglycone CH 2 N), 3.18 / 6H, s, (CH 3) 2 -N-> 07.37 (3H, s, cladinose) CH30-); MS: major peaks at m / e 461, 156, 115.

Example 3 N-Methyl-11-aza-10-deoxy-10-dihydroerythromycin A A solution of the crude product of Example 2 containing N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A, desosaminyl-N oxide and N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A bis-N-oxide (4.36 g) in 150 ml of absolute ethanol were hydrogenated on a Parr apparatus (3.52 kg / m 8.0 g of 10% palladium on carbon as catalyst; ambient temperature) for 1 1/4 hours. The catalyst was filtered off and the resulting filtrate was evaporated to dryness to give a colorless foam (4.3 g). The crude product was taken up in methylene chloride (100 mL) and then stirred with water (100 mL) while adjusting the pH of the mixture to 8.8. The organic and aqueous layers were separated. The aqueous layer was then extracted twice with 50 ml portions of methylene chloride. The three organic extracts were combined, dried over anhydrous sodium sulphate and evaporated to give a colorless foam (3.0 g). The whole sample was dissolved in 11 ml of warm ethanol and water was added until the solution became slightly cloudy. Upon standing overnight, 1.6 g of the title product crystallized; mp. 136 ° C, dec. Recrystallization by the same method raised the melting point to 142 ° C, dec. 1 Hnmr (CDCl 3) delta 2.31 / 6H, s, (CH-J-N-J, 2.34 (3H, s, aglycone CH, -N-);

13 3 * J I

Cnmr fCDCl3, (CH2 ^ Si internal standard ^ ppm 178.3 (lac-Toni, C = O), 102.9 and 94.8 (C-3, C-5), 41.6 (aglycone CH .. MS: m / e 590, 432, 158.

3 I

, 5 76098

Example 4

N-methyl-11-aza-10-deoxy-l0-dihydroerythromycin

The pure N-methyl-11-aza-10-deoxy-10-dihydroerytrorazine A bis-N-oxide (20 mg) of Example 2 was hydrogenated according to the procedure of Example 3. Thin layer chromatography with methylene chloride: methanol: concentrated ammonium hydroxide (9: 1: 0.1) and the use of vanillin spray as an indicator (see Example 2) heating on silica gel plates showed a single, uniform product. Its 1 Hnmr and TLC-10 R 1 values were identical to the product values of Example 3. Yield: 60%.

Example 5

N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A

A solution of the crude product of Example 2 containing desosaminyl N-oxide of N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A and N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A: n bis-N-oxide (10.0 g) in 150 ml of absolute ethanol, hydrogenated in a Parr apparatus at 3.52 kg / m 2; 15 g Raney nickel catalyst (water-wet slurry); 20 ambient temperature ^ 1 1/2 hours. The development as described in Example 3 gave 8.5 g of the title product with TLC Rf values identical to those of Example 3.

Example 6

N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A

A solution of N-raethyl-11-aza-10-deoxy-10-dihydroerythromycin A desosaminyl N-oxide (15 mg) in ethanol (5 mL) was hydrogenated at 2 psi using 5 mg of 5% Pd-C lythe for three hours. Filtration of the catalyst and removal of the solvent in vacuo gave the title compound (98% yield) as a colorless foam. Its Hnmr and TLC Rf values were identical to those of the product of Example 3.

Example 7 N-Methyl-11-aza-10-deoxy-10-dihydroerythromycin A 35 hydrochloride in a solution of N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A (0.2 g, 0.27 mmol) In 50 ml of ethanol 16,76098 (absolute), an equimolar amount of hydrogen chloride was added and the reaction mixture was stirred at room temperature for one hour. Removal of the solvent by evaporation under reduced pressure gave the mono-hydrochloride salt.

In a similar manner, hydrobromic, acetate, sulfate, butyrate, citrate, glycolate, stearate, pamoate, p-toluenesulfonate of N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A was prepared. , benzoate and aspartate salts.

Repetition of this method, but using twice the amount of acid, gave the diacid salt of said N-methyl derivative.

Example 8 N-Methyl-11-aza-10-deoxy-10-dihydroerythromycin 15A bis-hydrochloride

To a solution of 2.00 g of N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A in 50 ml of methylene chloride was added dropwise a solution of 308 mg of pyridine hydrochloride in 25 ml of methylene chloride. , over several 20 minutes. The mixture was concentrated to a brittle foam (2.35 g), triturated throughout with 125 mL of water. The clear aqueous solution was decanted from the water-insoluble residue and lyophilized to give the 25-bis-hydrochloride salt of N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A as a colorless amorphous foam (1.21 g).

Analysis for C 18 H 18 N 2 O 2 • HCl

Calculated: 8.65% Cl

Found: 8.89% Cl.

Treatment of a small portion of the water-soluble product with aqueous sodium bicarbonate gave a water-insoluble product having an identical TLC-R 2 value compared to those given above for the free base of N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A.

76098

Example 9

2 ', 411-Diacetyl-N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A

A solution of N-methyl-11-aza-10-deoxy-5-10-dihydroerythromycin A (1.5 g, 2 g) in pyridine (50 mL) and acetic anhydride (30 mL) was allowed to stand at room temperature. at 3 days. It was then poured onto ice and the pH was adjusted to 9 with 20% NaOH (w / w) solution. Extraction of the mixture with chloroform (3 x 50 ml) followed by drying of the combined extracts (CO 2) and evaporation of the solvent under reduced pressure gave the title compound.

Repetition of this procedure, but using propionic anhydride or 3-carbethoxypropionic anhydride as the acylating agent, gave the corresponding 2 ', 4 "-diacyl derivatives.

Example 10

411-Acetyl-N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A

21.4 "-Diacetyl-N-methyl-10-deoxy-10-dihydro-erythromycin A (1.0 g) was dissolved in 100 ml of ethanol and allowed to stand for 3 days at room temperature. Evaporation of methanol under reduced pressure gave the title product.

Solvolysis of the 21,4 "-dipropionyl and 2 ', 4" -3-carbethoxypropionyl derivatives of Example 9 gave the corresponding 4 "-propionyl and 4" - (3-carbethoxypropionyl) derivatives.

Claims (11)

A compound of formula 0 Process for the preparation of a compound according to claim 1, characterized in that i) a compound of formula N (CH 2) 25 HN ^ S I χ „0χχ ° Λ H0 / ^ | fX i ° / r x ° Xc "" ° h och3 35 is oxidized with hydrogen peroxide or peracid in a reaction-inert solvent; and is 76098 ii) the compound obtained by the formula O t N «CH3» 2 5 jOl HO / / 1 10 / / o ° * · ✓O ✓ i / r Y * '· 0H *' och3 is methylated with methyl iodide or - bromide or dimethyl sulfate in a reaction-inert solvent in the presence of an acid acceptor. Process according to Claim 2, characterized in that the oxidation of step i) is carried out using hydrogen peroxide or a peracid selected from the group consisting of peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, permaleic acid and phthalic acid. Process according to Claim 2, characterized in that the alkylation of step ii) is carried out using methyl iodide and an inorganic base or an organic amine in at least stoichiometric amounts, based on methyl iodide. 5 HO. »'Jv N> Hq' ->„ oX ..... θλλ 10 ΗΟ ^ ί / Ι 1 * 0 'i Y ° T 0 OCH3 15 Process according to Claim 2, characterized in that the oxidation of step i) is carried out using hydrogen peroxide and the alkylation of step ii) is carried out using methyl iodide. 20 7 6 0 9 8 5 CH t (0) / 3. N (CH) XL— / ho-, n 1 r 1 \ i L "'II Η0' · 'γ ^ HO ^ muo / ^ ON 10 no''1 7 | ('” / Y ° T 15 0 / ¾ '' 'OH OCHj where n is 0 or 1. 6. A compound of formula O t N (CH-.) „ Use of a compound according to claim 1 of formula N (CH 3) 2 CH 3 For the preparation of a compound of formula or a pharmaceutically acceptable acid addition salt thereof, wherein R 2 and R 3 are independently hydrogen, alkanoyl having 2 to 3 carbon atoms, or 3. -karbetoksipropionyyli; wherein 21 76098 a) reducing a compound of formula 0 t CH 3 N (CH 2), 5 (O) / J 3 3 H <> ^ | ..... 0 ^ 10 ho '' ^ 0 skt · - · B) when n is 0 or 1, b) when it is desired to prepare a compound of formula I in which 1 * 2 and are identical and denote non-hydrogen, acylating a compound of formula I in which both R 2 and R 2 denote hydrogen, and prepared according to step a) with a suitable acylating agent, c) when it is desired to prepare a compound of formula I in which R 2 is hydrogen and R 3 is other than hydrogen, is carried out on a compound of formula I in which both R 2 and R 3 represent non-hydrogen , and prepared according to step b), solvolysis, d) when it is desired to prepare a compound of formula I wherein R 2 and R 3 are different and represent other than hydrogen, acylating a compound of formula I wherein R 2 is hydrogen and R 3 is other than hydrogen hydrogen, prepared according to step 30 (c), with a suitable acylating agent, and, if necessary, one of the above The compound of formula I prepared according to the above step is converted into a pharmaceutically acceptable acid addition salt. 22 7 6098