Method of producing n-methyl-11-aza-10-deoxo-10-dihydroerythromycin a

专利摘要:
11-Methyl-11-aza-4-0-cladinosyl-6-0-desosaminyl-15-ethyl-7,13,14-trihy droxy-3,5,7,9,12,14-hexamethyl-oxacyclopentadecane-2-one and derivatives thereof, such as the 13,14-carbonate and C1-C3-alkanoyl derivatives thereof. The compounds exhibit antibacterial activity.
公开号:SU1287755A3
申请号:SU823402600
申请日:1982-03-05
公开日:1987-01-30
发明作者:Кобрехель Габриела；Дьекич Слободан
申请人:Соур Плива Фармацойтска Кемийска,Прерамбена И Козметичка Индустрия Н.Сол.О. (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of a novel erythromycin A derivative, and specifically K-methyl-11-aza-10-deoxo-10-dihydroerythromycin A, which has antimicrobial deistication.
The purpose of the invention is to obtain a new derivative of erythromycin A, which has improved properties compared with the closest structural analogue.
The method is carried out as follows.
Example 1. To a solution of 0.54 g (0.722 mmol) of 11-aza-10-deoxo-10-dihydropritromycin A in 20 ml of chloroform was added with stirring 0.0589 ml (0.741 mmol) of formaldehyde (approximately 35% w / w ) and 0.0283 g (0.735 mmol) of formic acid (approximately 98-100 weight,% / weight). The reaction mixture is stirred for 8 h at boil
reflux
the mixture is cooled to room temperature, after which 15 ml of water (pH 5) are added. The reaction mixture is acidified with 2N. hydrochloric acid is adjusted to pH 5.0, after which the chloroform layer is separated. 15 ml of chloroform is added to the aqueous portion, the reaction suspension is made alkaline with a 20% w / w solution of NaOH, pH adjusted to 7.5, the layers are separated, and then the aqueous layer is extracted 3 times with 15 ml of chloroform.
The combined chloroform extracts, having a pH of 7.5, are dried over potassium carbonate and evaporated under reduced pressure to yield 0.45 g (82.4%) of M-methyl-11-aza-10-deoxo-10-dihydroeritylumycin A, t. w1.113-115 ° C (chromatographically pure substance, eluted with dimethylformamide: methanol 3: 1).
alpha p -37.0 (1% in chloroform) M 748.
Example2. To a solution of 1.00 g (0.00136 mol) of 11-aza-10-deoxo-10-dihydro-erythroxine A in chlorofor
five
0
five
0

0
five
I (20 ml) is added with stirring 0.238 ml (0.003 mol) of formaldehyde (approximately 35% by weight / weight and 0.128 ml (0.00332 mol) of formic acid (approximately 98-100%). The reaction mixture is stirred and boiled in refluxing vessel for 2 hours, then it is cooled to ambient temperature and the product is isolated as in example 1. Yield: 0.84 g (83.0%).
Example To a solution of 10.8 g (0.0147 mol) of 11-aza-10-deoxo-10-dihydroerythritomy A in carbon tetrachloride (240 ml), 2.57 ml (0.0324 mol) of formaldehyde ( approximately 35% w / w) and 1.38 ml (0.0358 mol) of formic acid (approximately 98-100%). The reaction mixture is stirred for 8 hours at boiling in a reflux vessel, then cooled to ambient temperature the medium, carbon tetrachloride is evaporated under reduced pressure and the remaining precipitate is suspended in water (150 ml) and taken up using a pH-gradient extraction as needed. isano in Example 1.
Yield 8.3 g (75.4%).
Data on biological activity are presented in table.1.

权利要求:
Claims (2)
[1]
1. A method for preparing K-mets1-11-aza-1O-deoxo-10-dihydroerythromycin A, characterized by
in that 11-aza-1O-deoxo-10-dihydro-erythromycin A is reacted with formaldehyde and formic acid at a ratio of 1: (1.02-2.2):: (1.01-2.4), respectively medium chlorinated hydrocarbon at the boiling point of the reaction mixture.
[2]
2. A method according to claim 1, characterized in that chloroform or carbon tetrachloride is used as the chlorinated hydrocarbon.
Streptococcus faecalis ATCC 8043
Staphylococcus epidermidis ATCC 12228
Staphylococcus aureus ATCC 6538-P
Micrococcus flavus ATCC 10240
Sarcina lutea ATCC 9341
Bacillus cereus varmycoide TACC 11778
. Bacillus subtilis TACC 6633
Note
A - 11-aza-10-deoxo-10-dihydroerythromycin A known compound
1 - N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A (the proposed connection), MIC - minimum inhibitory concentrations,
Table 2
Antimicrobial activity outside the body at gram-negative
clinical cultures
T b l and c a 1
0.01
0.5
0.5
0.01
0.05
0.5
0.1
12 63 15
10 41 7
42
Note: R-resistant,
Nri - the number of tested strains
Antimicrobial activity outside the body in gram-negative clinical cultures
Continuation of table 2
Table 3
The number of sensitive strains N "i sensitiNote: Method: two consecutive dilutions
in agar cs.
- T a b l and c a 4
Sensitivity of anaerobic bacteria
A 1
A 1
3 2
13
4 3
Continuation of table. 3
Test organism
Substance
MIC (µg / ml
0.5 T 1, o | 2, oG4, oT7.0 IB. O G32.0 1 64, o | 128.0
A 1
2
Veilonella A 3 SP 1 4

A 1
A 1
2
2
A 16 1 20
58 1
64
Table 5 Acute toxicity (Litchfield-Wilcoxon method on white mice)
280 (141.7) 220
- 10,000 (5060)
825 (421.6)
Intraperitoneal 120 .0 (513.2)
Orally 10,000 (5,100)
Continued that bl.
Number of tested mTaMhJOB
R
N
30 30 30
350
610 1020
1010 1400

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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YU592/81A|YU43006B|1981-03-06|1981-03-06|Process for preparing n-methyl-11-aza-10-deoxo-10-dihydro erythromycin and derivatives thereof|

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