The method of obtaining oleandomycin and oleandomycin

 

(57) Abstract:

Usage: medicine, Antibacterials. The inventive product - oleandomycin formula I listed in the description text. The compounds of formula I exhibit antibacterial activity, while MJC = from 0.2 to 16.0 μg/ml Reagent 1: oleandomycin formula III described in the text descriptions. Reagent 2 : 4 - 6-molar excess chloridrate hydroxylamine. Process conditions: excess pyridine at room temperature, 2 - 40 hours

The invention relates to new Akimov oleandomitsina possessing antibacterial activity, and the way they are received.

Oleandomitsin is a 14-membered macrolide antibiotic with a spectrum similar to the spectrum of erythromycin (1).

The aim of the invention is the creation of new derivatives oleandomycin with high antibacterial activity.

The invention encompasses oleandomycin formula I

in which R1represents CH3, R2hydrogen, or R1and R2together form an epoxy group

R3is a HE and icon ~~ means a single bound is the following compound Ia-Ie

IA R1=R2= O, R3=OH ~~ = single bond

IB R1=R2= O, R3and ~~ = double bond

IC R1= R2= CH2, R3= -OH ~~ = single bond

Id R1= -H, R2= -CH3, R3= -OH ~~ = single bond

Ie R1= -CH3, R2= -H, R3= -OH ~~ = single bond Oleandomycin formula I are new compounds.

These compounds are produced by the interaction of oleandomycin formula (II).

in which R1, R2, R3and ~~ have specified values, with an excess of hydroxylamine hydrochloride.

In particular, the compounds Ia-Ic, as defined above, can be obtained by reaction of compounds IIa-IIc:

IIA R1=R2= O, R3=-OH ~~ = single bond

IIB R1=R2= O, R3and ~~ = double bond

IIc R1= R2= CH2, R3= -OH ~~ = single bond

IId R1= -H, R2= -CH3, R3= -OH ~~ = single bond

IIe R1= -CH3, R2= -H, R3= -OH ~~ = single bond with an excess of hydroxylamine hydrochloride.

This reaction can be carried out with 4-6-molar excess of hydroxylamine hydrochloride in the presence of excess pyridine, SL">

Termination of the reaction is determined by thin layer chromatography (TLC) on silikagelevye plates 60F254in the following system:

A) CHCl3(CH3OH) conc. HN4OH (6:1; 0,1)

B) CH2Cl2(CH3OH) conc. NH4OH (90:0:1,5)

Unloading is carried out by extraction of halogenated solvents such as chloroform or methylene chloride, at pH around 7.0-8.5 and ultimately by evaporation to dryness of the organic extract.

Getting 8-meilleurmobile.com formula Id and Ie carried out using as starting compound 8-methyleneindoline anomers of formula II and IIE, which without pre-separation was directly subjected to the reaction oxymorphine. Was obtained the crude product, consisting of a mixture of anomeric Asimov formulas (Id) and (Ic), which were separated by chromatography in a column of silica gel with elution with a mixture of CH2Cl2CH3OH (85:15).

Antibacterial activity was determined by the number of standard and clinically isolated strains. The results are expressed as the minimum inhibitory concentration (MIC, μg/ml) and presented in table.1 and 2.

P R I m e R 1. In the solution alexanderalexander at room temperature in a stream of nitrogen for 2 hours In the reaction mixture injected water (400 ml), and extracted with dichloromethane by gradient extraction at pH value of 5 and 7. The organic extract (pH 7.0) and evaporated under reduced pressure to dryness and the residual product is evaporated, dried in vacuum at 40aboutWith, the result of 9.1 g (70,0%) of product.

Rf (A) Of 0.51.

(C) 0,32.

M+702.

Ultraviolet spectrum (Meon): the peak at 290 nm disappears ( With = 0). Range NAMR (Dimethylsulfoxide-d6) h/min 2,23 [6H, c (CH3)2N] of 3.33 (3H, s, 3 - core).

10,82 ( = NOH), disappears as a result of ion exchange CD2O.

Range13C-NMR (CDCl3) h/min: 175,8 (s-1, lactone), 159, 6 (-C= N-), The 104.3 (C-1'), 99,3 (C-1'), to 51.1 (C - 8 - CH2), 40,3 [C-3'-N(CH)]

MIC (μg/ml) (clinical isolates)

Strept. pneumoniae 0,5 Strept. serol. group AND 0.5

P R I m m e R 2. Angerielingerie.com Ib.

Anhydroerythromycin (IIb) (2.2 g 0,0033 mol) was dissolved in dry pyridine (4 ml), was injected NH2OH HCl (1.2 g of 0.017 mol) and the reaction mixture stirred at room temperature in a stream of nitrogen for 18 hours, the Pyridine was removed by evaporation under reduced pressure and by entering water. Water was added to a suspension of chloroform, the pH value was brought to 8.3 by UB>) and evaporated to dryness, and the resulting received 21 g (93,0%) of a white solid.

Rf (A) 0,52

(C) 0,37

M+68.

Range 'H-NMR (Dimethylsulfoxide-d6) ppm: 2,21 [6H, c (CH3)2N-], 3,34 (SN, s, 3"-och3), 10,97 (1H, s, =NOH), disappears as a result of exchange with D2O.

Range13C-NMR (CDCl3) ppm: 174,8 (S-I, lactone) 157,3 (-C = N-), 104,6 (I'), of 99.5 (C-I), to 130.1 (C-II), 135,0 (C-10), A 51.2 (C-8-CH2), 40,3 [C-3'-N(CH3)2]

MIC (μg/ml) (clinical isolates)

Strept. pneumoniae 2,0; Strept.serol. group And 1.0.

P R I m e R 3. 8-Methylene-Oleandomycin IC.

8-Methylenedianiline (IIc) (2,7 with 0,004 mol) dissolved in dry pyridine (19 ml) and injected hydroxylamine hydrochloride (1.35 g 0,019 mol). The reaction mixture was stirred at room temperature in a stream of nitrogen for 2 hours After extraction with dichloromethane at pH of 5 and 7, the product is recovered by evaporation of the extract (pH 7.0) dry (2.0 g 73,0%).

Rf (A) 0,58

(C) 0,35

M+686

Range 'H-NMR (Dimethylsulfoxide-d6) ppm: 2,29 [6H, c (CH3)2N-], 3,34 (CH, c., 3" - OCH3) 10,28 (1H, s, =NOH), disappears as a result of exchange with D2O.

Range13C-NMR (CDCl3) ppm: 176,6 (s-1 lactone) 163,4 (-C=N-t. serol. group AND 1.0

P R I m e R 4. 8-Methyl-oleandomycin Id and Ie.

8-Methyl-oleandomitsin (mixture of anomers IId and IIE).

(1.2 g 0,0018 mole) is dissolved in dry pyridine (4 ml) and injected NH2OH HCl (0.6 g, 0,0086 mol) and the reaction mixture stirred at room temperature in a stream of nitrogen. Thin layer chromatography indicates complete conversion of compound IId (Rf(A) is (0.67) after 5 h product Id (Rf(A) = 0,48), while the original compound IIe (Rf(A) = 0,63) gives the product Ie (Rf(A) = 0,57) after 40 hours Performing gradient extraction with methylene chloride at pH = 7.5 to receive the product as a mixture of isomers (0.7 g 57%), which may be divided into a column of silica gel with elution CH2Cl/CH3OH (85:15).

These isomers have the following physicochemical properties:

Id

____< / BR>
Rf (A)0; 48

(C) 0,34

M+688.

Range 'H-NMR (Dimethylsulfoxide-d6) ppm; 2,42 [6H, c (CH3)2N] of 3.43 (3H, c., 3"-OCH3), the 10.40 (1H, c., =NOH), disappears as a result of exchange with D2O.

Range13C-NMR (CDCl3) ppm: 176,8 (C-1, lactone), 165,5 (-C=N-), 104,7 (C-I'), of 99.5 (C-I), 40,4 [C-3"-N(CH3)2].

Ie

Rf (A) 0,57

M+688,

Range H-NMR (Dimethylsulfoxide-d6) ppm;

Spectrum 13 C-NMR (CDCl3) ppm: 176,2 (S-I, lactone), 168,6 (-C=N-), 104,2 (C-1'), to 98.5 (C-1') 40,4 [C-3'-N(CH3)2]. Activity: 657 u/mg Sarcinalutea ADS.

1. The method of obtaining oleandomycin General formula

< / BR>
where R1is hydrogen or methyl;

R2is methyl or hydrogen, or R1and R2together form an epoxy group, or = CH2;

R3the hydroxy - group;

~ ~ simple or double bond,

characterized in that conduct the reaction oleandomycin derivatives of General formula

< / BR>
where R1, R2, R3and ~~ have specified values, with 4 - 6-molar excess of hydroxylamine hydrochloride in the presence of excess pyridine in a stream of nitrogen at room temperature for 2 to 40 hours, followed by separation of the target product.

2. Oleandomycin General formula

< / BR>
where R1is methyl;

R2is hydrogen or R1and R2together form an epoxy ring;

R3the hydroxy - group;

~~ - a simple link, or R3and ~~ together form a double bond.

 

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