Method of producing tylosine derivatives

专利摘要:
NEW MATERIAL:A compound shown by the formulaI[R1 is amino, mono-, or di-lower alkylamino, a group shown by the formula II (n is 2-20); R2 is H or OH; R3 is aldehyde group which may have a protecting group]. EXAMPLE:23-Deoxy-23-ethylamino mycaminosyl tylonolide shown by the formula III. USE:An antibacterial agent. Having high antibacterial power than tylosin, mycaminosyl tylonolide, etc. A dose of 10-1,000mg/time is medicated orally(parenterally). PROCESS:A compound shown by the formula IV (R3' is an aldehyde group with a protecting group; X is halogen) is reacted with a compound shown by the formula R1-X (e.g., ethylamine, etc.) in an organic solvent such as preferably THF, etc., and, if necessary, the aldehyde-protecting group is eliminated.
公开号:SU1282821A3
申请号:SU833624073
申请日:1983-07-21
公开日:1987-01-07
发明作者:Умезава Хамао；Умезава Сумие；Цутия Цутому；Такеути Томие；Танака Акихиро；Ивамото Хиденори；Сакамото Суити
申请人:Зайдан Ходзин Бисуибутся Кагаку Кенкиу Кай (Фирма)；
IPC主号:

专利说明:


cm
one
The invention relates to methods for producing tylosin derivatives of the general formula
SN: With CHO
 - -about
/he
 ABOUT
R
(Y)
where R is a hydroxyl group or
di-lower alkylamino group}
E „is a hydrogen atom or a hydroxyl group.
The purpose of the invention is to increase new highly effective tylosin antibiotics with antibiotic activity exceeding the known tylosin.
Example 1, Synthesis of 12,13-epo-symicaminosylthilonolide.
I am dissolved in 10 ml of chloroform.
1.08 g of mycaminosylthionol diethyl acetal, and then 8.4 ml of a chloroform solution containing 840 ml of 4-chloropar benzoic acid are added dropwise to the prepared solution while cooling with ice. After the mixture has warmed to room temperature, it is left to stand for 24 hours. The reaction mixture is then washed once with a 0% aqueous solution of sodium sulfate, saturated with an aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate; the solvent is distilled off; and the resulting residue is dissolved in 20 ml of ethyl acetate. After adding 634 m of tripheniophosphine to this solution, the mixture. boil under reflux in a stream of argon for 6 hours. Next, the reaction mixture is washed once with a saturated aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue thus obtained is subjected to chromatography on 50 g of silica gel in a column.
-

2828212
using a solvent system, chloroform - methanol - 28% aqueous ammonia solution in a ratio of 15: 1: 0.1, as a result of which
5, 820 mg of 12,13-epoxy-amino-zylthilone di-ethyl acetate are obtained,
In 4, .1 ml of acetonitrile, the indicated product is dissolved and after adding 24 ml of 0.1 K hydrochloric acid to the solution
 The acidic mixture was allowed to stand for 60 minutes. Then, 240 mg of sodium bicarbonate is added to the reaction mixture, and this mixture is subjected to a threefold extraction treatment with
 5 using chloroform each time. The chloroform layers are combined, washed with a saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate, the solvent is distilled off, and the resulting
thus, the residue is purified by chromatographic treatment in a column of 40 g of silica gel using a solvent system chloroform – methanol — 28% ammonia solution
in the ratio of 10: 1: 0.1, as a result of which 617 mg (yield: 63%) of 12,13-epoxymicamosostilonylonolide are obtained as a colorless solid. 30
wah
NMR spectrum (CDCIg) at 5 Hz:
 $ 1.45 m, d, 3N, S, Me (22); b 2.50 ppm, - 6H, S, S 4.30 m, d, 1H,,; 5.26 m, d, 1H, t, H, S; S 6,44m, d ,,
10,11,16 11,10
, 6 6.64 m, d ,, 9.72 m, d ,, W,
W, d W, d
S -. . Mass spectrogram, m / z: 613 (M),
IR spectrum (potassium bromide), cm: 2970-СНз 2940 1720-СОО-, СНО; 1620 -CO,,
Calculated,%: C 60.67; H 8.38; N 2.28.
five
,., NO ,,
0
Found,%: C 60,32; H 8.24; N 2.26,
Example 2, Synthesis of 12,13-β-zpoxy-4-dioxymicamososylthylolonide,
572 mg (61% yield) of 12,13-epoxy-4-dioxyimicomisosylthilonolide are obtained using 1.03 g of 4-deoxymycamosylthylononidione diacetal in accordance with the procedure similar to Example 1, using 1.03 g.
NMR spectrum (CDCIj) at, 5 gi 5 1.45 m, d., 3N, S, Me (22); &
 2.28 MD, 6H, s, NMe; (4.26 ppm,
IH, d
15-.
H.
27
Ih,
m
H
 s
ppm
s 6.41 M.D. , IH,) 4 H.oJ 2G 6.64 MD, IH, d, S 9.75 MD, IH, s, H,.,.
Mass spectrogram, m / Z: 597 (M), IR spectrum (potassium bromide), 2970 - CH3; 2940 1720-СОО-, -СНО; 1620-C- ,. t
ABOUT
Calculated,%; N 2.34.
C3iH5, NO ,,
C 62.29; H 8.60;
thirty
Found,%: C 61.98; H 8.32; N 2.16,
Example 3. Synthesis of 23-deoxy-23-dimethylamino-12,13-epoxymiconosylthylonolide.
18 ml of chloroform solution yut20
1.83 g of 23-deoxy-23-dimethylamino-aminosylthionone-diethyl acetal, and after adding a dropwise chloroform solution of m-chloroperboxylic acid containing 20 ml of chloroform and 2.04 g of acid to the solution while cooling with ice, the mixture is left stand for 24 hours at room temperature. The solvent was distilled off, and the residue thus obtained was dissolved in 17.6 ml of ethyl acetate. After adding 3.09 g of triphenylphosphine to the solution, the mixture is refluxed for 2 hours in a stream of nitrogen. The solvent was distilled off, and the residue thus obtained was dissolved in a small amount of methanol. A large amount is added to the prepared solution.
a precipitate is formed which is filtered off. The filtrate is concentrated, and the resulting residue is dissolved in water. The solution is washed with toluene, and after adding 0% of sodium carbonate solution to the aqueous layer, the mixture is subjected to triple extraction treatment each one. Once chloroform, the chloroform layers are combined with each other, washed with a saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue thus obtained is subjected to column chromatography with 50 g of silica gel using the system. solvent chloroform - methanol 28% aqueous solution of ammonia in
a ratio of 15: 1: 0.1, resulting in a gain of 225 mg of 23-deoxy-23-dimethylamino-12,13-epoxymicamino zylthylolidine diethyl acetal.
5This product is dissolved in 2 ml.
acetonitrile, and after adding 9.5 ml of 0.1 N to it. hydrochloric acid mixture is left to stand for 60 minutes. 0.1 M sodium carbonate solution is added to the reaction mixture, a white precipitate forms (pH 9), the product is extracted three times with chloroform each time. Chloroform layers
 5 are combined with each other, washed with a saturated aqueous solution of sodium sulphate and then dried over anhydrous sodium sulphate. The solvent is distilled off and the residue thus obtained is subjected to column chromatography on 20 g of silica gel using chloroform-methanol solvent system — 28% aqueous solution.
2 ammonia in a ratio of 10: 1: 0.1, resulting in a gain of 185 mg (yield 11%) of 23-deoxy-23-dimethylamino-12,13-epoxymykamosylthyl thiolonolide.
NMR spectrum (CDCIj) at 5 Hz: - B 1.46 m, d, ZN, S, Me (22); S 2.24 ppm, 6H, S, 23-NMe, j; 5 2.50 ppm, 6H, S, Z-KMe; 6 3.30 ppm, 1H,, Well, OZm.d.,
35 1H,
d d
m,
10,11,16
H
iS
1,1O
S 6.41 MD, IH, H ,; S 6.60 MD, IH, 5 9.72 ppm, IH, s, H .. Mass spectrogram, m / Z: 640 (), IR spectrum (potassium bromide), cm;
water, resulting in 40 2970 2940-CH -; 1720-СОО-,
- SNO; 1620 -CO, Calculated,%: C, 61.85; H, 8.81; iN 4.37,
.O ,,
45 Found: C 61.58; H 8.62; N 4.38.
Example 4. In accordance with the procedure analogous to Example 3, using 2.0 g of 23.4-dimethyl hydroxy-23-dimethylamino aminosinosylthiolonyl diethyl acetal, 140 mg are obtained (yield 7.6%) of 23.4-dideoxy-23- di-methylamino-12,13-epoxy-amycosynosyl-tilonolide,
55 NQR spectrum (CDCI) at 5 Hz: & 1.41 ppm, 3N, S, Me (22); /five
 2.20 MD, 6H, S, 23-NMe
2
five
2.24 ppm, 6H, S, 3 —She; S 4.22 ppm, 1H, d. , 2
2 N
0
0
a ratio of 15: 1: 0.1, resulting in a gain of 225 mg of 23-deoxy-23-dimethylamino-12,13-epoxymicamino zylthylolidine diethyl acetal.
5This product is dissolved in 2 ml.
acetonitrile, and after adding 9.5 ml of 0.1 N to it. hydrochloric acid mixture is left to stand for 60 minutes. 0.1 M sodium carbonate solution is added to the reaction mixture, a white precipitate forms (pH 9), the product is extracted three times with chloroform each time. Chloroform layers
5 are combined with each other, washed with a saturated aqueous solution of sodium sulphate and then dried over anhydrous sodium sulphate. The solvent is distilled off and the residue thus obtained is subjected to column chromatography on 20 g of silica gel using chloroform-methanol solvent system — 28% aqueous solution.
 ammonia in a ratio of 10: 1: 0.1, resulting in a gain of 185 mg (yield 11%) of 23-deoxy-23-dimethylamino-12,13-epoxymykamosylthylthillonolide.
NMR spectrum (CDCIj) at 5 Hz: - B 1.46 m, d, ZN, S, Me (22); S 2.24 ppm, 6H, S, 23-NMe, j; 5 2.50 ppm, 6H, S, Z-KMe; 6 3.30 ppm, 1H,, Well, OZm.d.,
S 6.41 MD, IH, H ,; S 6.60 MD, IH, 5 9.72 ppm, IH, s, H .. Mass spectrogram, m / Z: 640 (), IR spectrum (potassium bromide), cm;
5 1H,
d d
m,
10,11,16
H
iS
1,1O
Mass service IR Spectrum
 NQR spectrum (CDCI) at 5 G & 1.41 ppm, 3N, S, Me (22); /five
 2.20 MD, 6H, S, 23-NMe
2
five
2.24 ppm, 6H, S, 3 —She; S 4.22 ppm, 1H, d. , 2
2 N
51282821 6
NMR spectrum (CDCl1) at Hz: Calculated: С 64.44; H 9.03;
S 4.99 MD, IH, m, H; 6, 36 m, d., N 4,48. W, d ,,,,, H ,; 1) -6.58-ppm, W,, o) iJ 9.71 ppm, 1H, S, Hjo Mass spectrogram, m / Z: 624 (M). five
Large mass, m / z; 624,401 () (calculated: 624,398).
IR spectrum (potassium bromide), 2970 —CH ,; 2940, 1720 -COO, -CHO; 1620 -CO,
C.
Found,%: C 64.23; H 9.04;
N 4.37.
fO
Antimicrobial activity (MI of tylosin derivatives is illustrated in the table.
N 4.48.
C.
Found,%: C 64.23; H 9.04;
N 4.37.
fO
The antimicrobial activity (MIC) of tylosin derivatives is illustrated in the table.
Invention Form
The method of obtaining tylosin derivatives of general formula
JV it
2
R; - hydro to strong group
di (lower alkyl) amino group;
R j is a hydrogen atom or a hydroxyl group.
characterized in that the compound of the general formula
ЖСН5) 2 О / -i.
- ,. d,
where R and R g have the indicated meanings, react with methacperperbenzoic acid in chloroform at, treat the resulting product with triphenylphosphine in boiling ethyl acetate in an inert stream and remove the diethyl acetal protection from the aldehyde group.

权利要求:
Claims (1)
[1]
Claim
A method of obtaining tylosin derivatives of the General formula
5) 2 Wsh, characterized in that the compound of the general formula where R and R _g have the indicated meanings, are reacted with meta R. · - hydroxyl group, di (lower alkyl) amino group;
Rj is a hydrogen atom or a hydroxyl group, chloroperbenzoic acid in chloroform at 0-20 ° С, the resulting product is treated with triphenylphosphine in boiling ethyl acetate in an inert stream and the diethylacetyl protection is removed from the aldehyde group.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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RU2173689C2|1995-08-14|2001-09-20|ПЛИВА фармацойтска, кемичска, прерамбена и козметичка индустрия, д.д.|12,13-epoxytilosing derivatives and methods of preparation thereof|

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US4454314A|1982-08-02|1984-06-12|Pfizer Inc.|Antibacterial mycaminosyl tylonolide and related macrolide derivatives|

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JPH039918B2|1982-08-19|1991-02-12|Microbial Chem Res Found|

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JPH0534360B2|1984-08-17|1993-05-21|Microbial Chem Res Found|

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US4604380A|1985-01-18|1986-08-05|Eli Lilly And Company|C-23-substituted mycaminosyltylonolide compounds, pharmaceutical compositions and methods of use|

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US8053418B2|2005-01-24|2011-11-08|Microbial Chemistry Research Foundation|Anti-penicillin resistant pneumococci agent and novel 16-membered macrolide derivative|

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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JP56107485A|JPS6242919B2|1981-07-09|1981-07-09|

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