Method of producing carbapenem derivatives or their 4-nitrobenzyl esters

专利摘要:
Compounds of formula (I): wherein: one or both of R' and R2 are selected from a variety of organic groups; R3 is an optionally substituted heterocycle; and R4 is hydrogen or optionally substituted alkyl or alkoxy. and salts and esters thereof have valuable antibiotic activity.
公开号:SU1501922A3
申请号:SU853878791
申请日:1985-03-26
公开日:1989-08-15
发明作者:Сугимура Юкио；Хасимото Тосихико；Танака Теруо；Иино Кимио；Сибата Томоюки；Ивата Масаюки
申请人:Санкио Компани Лимитед (Фирма)；
IPC主号:

专利说明:


s
This invention relates to a process for the preparation of new carbapenem derivatives of the general formula
R, Yag
.
m -i
- r-rK-SRs
(I)
3150
where R. is hydrogen, fluorine, methyl or
methoxy group,. Rj is hydrogen or methyl, and R (and R are not hydrogen at the same time,
RJ - heterocyclic) radical of formula
.
Y
where X is hydrogen or a group -
Y is hydrogen, 4-nitrobenzyloxycarbonyl
or group) NR, where Rp is hydrogen, C-C6-alkyl or
C, -C-alkoxy-C, -C-alkyl,
Rg is hydrogen or 4-nitrobenzyl oxycaronyl,
R. - 1-hydroxyethyl, which can be protected by trimethylsilyl, or their 4-nitrobenzyl; esters, which are characterized by metabolic stability, easy digestibility, high activity against a wide range of pathogenic microorganisms, which allows their use in medicine in the treatment of diseases caused by these microorganisms or used as intermediates for syn.tesa biologically active compounds.
The purpose of the invention is to develop a method for producing new carbapenem derivatives with useful properties based on known methods.
Example 1. lS, 5R, 1 (R) -ooxyethylJ-1-methyl-2-OR) - (N-para-nitrobenzyloxycarbon-1 acetimidoyl) pyrrolidine-3-yl-tyr} carbopen-2-p p-nitrobenzyl ester em-2-carboxylic acid.
0.174 ml of diisopropyl (ethyl) amine and 0.245 ml of diphenylphosphoryl chloride are added under nitrogen and under ice-cooling to 5 ml of ateto nitrile solution containing 363 mg of p-nitro benzyl ester, 5R, l (R) -oxyethyl-1 -methyl-2-oxocarbapenam-3-carboxylic acid. This mixture is stirred for 2 hours at the same temperature, after which another 0.2 NP of diisopropyl (ethyl) amine and 330 ml of 3 (R) -MepKanTo--1- (L-p-nitrobenzyloxycarbonyl acetate) are added to this mixture.
9224
amidoyl) pyrrolidine and stirring is continued for another 1 hour. The reaction mixture is then diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off. The residue obtained is subjected to a chromatographic separation using a short column filled with silica gel to remove contaminants, resulting in 450 mg of the indicated compound in 1-1 ovine, which has been partially crystallized. NMR spectrum (60 MHz, CDC1, + CD ,, OD in an amount sufficient to dissolve the test compound), 20 S, part on W: 1.3 (G, d), 1.4 (G, d) 1.8-2.4 (ZN, m), 2.3 (ZN, s), 3.0-4.3 (8H, m), 5.15 (2H, s), 5.32 (2H, AB), 7.3, 8.1 (A, jB), 7.5, 8.1 ().
25 PRI mme R 2. lS, 5R, (3R) - -1-Acetimidoylpyrrolidin-3-ylthio - -6- (R) -oxo-ethylJ -1 -methylcarbapen-2-em-3-carboxylic acid.
80 MP of water and 1.6 g of palladium-30 carbon with a 10% weight ratio are added to 50 MP of tetrahydrofuran solution containing 450 mg of p-nitrobenzyl ester 1S, 5R, (R) -oxyethyl -1 -methyl-2- (ZR) -1- 25 (N-p-nitrobenzyl-oxycarbonylacet-imidoyl) pyrroline-3-ylthio} carbapen-2-em-3-carboxylic acid (prepared as described in example 1), after which the mixture is stirred for 40 hours in a hydrogen atmosphere. The catalyst is filtered off, the tetrahydrofuran is distilled off under reduced pressure, and the residue is washed with ethyl acetate. The aqueous layer is condensed by evaporation under reduced pressure to a volume of approximately 50 mp, and then subjected to chromatographic separation on columns using Diyona CHP-20P (the trade name of the product manufactured by Mitsubishi Chemical Industry). 62 mg of the desired compound are obtained from the fraction eluted with an aqueous solution of acetone with a 5% volume ratio.
Nuclear Magnetic Resonance Spectrum (90 MHz, D / jO), 5 h. No.: N: 1.02 (d); 1.06 (MN, d); 2.03 (ЗН, s); 1.8-2.3 (2H, m); 3.0-4.2 (9H, m).
50
NK spectrum (KVg),. cm-: MQ to s
3400, 1760, 1675.
Example 3. lS, 5R, fl (K) -oxyethyl -1- -methyl-2- (3S) -1- (N-p-nitrobenzyl-hydroxycarbonyl-acetymidoyl) pyrrolidine-3-ylthio-carbapen-2- p-p-nitrobenzyl ester EM-3-carboxylic acid.
The procedure described in Example 1 is repeated, but using 365 mg of 1S, 5R p-nitrobenzyl ester, (K) -oxyethyl} -1-methyl-2-oxocarbapenam-3-carboxylic acid and 390 mg 3 (5) -mercapto-1- (L-p-nitrobenzyloxycarbonylacetimidoyl) pyrrolidine, resulting in 360 mg of the title compound.
Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl1), h on mpn: 1.3 (3N, d); 1.4 (3N, d); 2.29 (ЗН, s); 1.6-2.5 (ZN, m)} 2.9- 4.5 (8H, m), 5.21 (2H, s); 5.28, 5.44 (2H, AB); 7.59, 8.20 (4H, A, 7.67, 8.24 (4H, A.B-d).
ten
Bj);
-oxocarbapenam-3-carboxylic acid and 430 mg of 3 (K) -merk pto-1- (Mn-benzylroxycarbot ilacetamide strength) pyridine, resulting in a yield of 430 mg of the title compound.
NMR spectrum (60 MHz, CDC1, 4 CD in an amount sufficient to dissolve this compound), S, ppm: 1.3 (G, d), 1.4 (G, d), 1 2, 4 (3N, M) i 2.3 (3N, s); 3.0-4.3 (8H, m); 5.20 (2H, s); 5.35 (2H, A 7.5; 8.2 (4H,); 7.7, -. 8.2 (4H A B).
EXAMPLE 6 lR, 5R, (3 -1-Acetimidoyl pyrrolidin-3-ylthio-p (K) -oxyethyl -1-methylcarbapen-2-em-3-carboxylic acid.
The catalytic 20 hydrogenation process described in Example 2 is repeated, but 430 m p-nitrobenzyl ether 1R, 5R, 6s (K) -oxyethyl -1-methyl-2- (CK) -1 -1 (N-p -nitrobenzyloxycarbonyl
15
P
Sample 4. 1S, 5R, 6SJ-2- (3S) - 25 imidoyl) pyrrolidin-3-ylthio carba-1-acetimidoyl-pyrolidin-3-ylthioJ-6- - fl (R) -oxy-JET-1 methylcarben-2-em-3-carboxylic acid.
The catalytic hydrogenation process described in Example 2 is repeated, but 360 mg of flS, 5R, -6-l (R) -oxi-ethyl -1-methyl-2- (3S) - (N-p -nitrobenzyloxycarbonylacetimidoyl-pyrrolidin-3-ylthio} -carbap--2-em-3-carboxylic acid (prepared as described in Example 3), which allows to obtain 60 ml of the said compound.
NMR spectrum (400 MHz, D., 0), (9, ppm: 1.09 (ZN, d, J, 6.4 Hz); 1.16 (ZN, d, J 6.8 Hz ); 1.7-2.0 (1H, m); 2.07; 2.08 (every 1.5 N, - s) 2.1-2.3 (1H, m); 3.1-3 , 95 (8H, m)) 4.0-4.2 (1H, m).
UV spectrum (), A d, nm (5): 289 (4790).
IR spectrum (KBG), ox 3400, 1760, 1675.
Example 5. 1R, 5R, 6Sj-6-l (R) -oxo-ethyl-1-methyl-2-G (3R) -1- (N-p-nitrobenzyl-oxycarbonylacetimidoyl) pyrrolidine-3-yl p-nitrobenzyl ester tyr carbapen-2-em-3-carboxylic acid.
The procedure described in Example 1 is repeated, but 363 mg of p-nitrobenzyl iR, 5R, (R) -oxy-ethyl -1-methyl-230 is used.
35
40
45
50
55
pen-2-em-3-carboxylic acid (prepared as described in Example 5), which gives 110 of this compound.
Nuclear Magnetic Resonance Spectrum (400 MHz,), O, ppm: 1.04 (G, d, J 6.8 G, 1.10 (G, d, J 6.4 Hz); 1.85-2, 0 (1H, m), "2.08 (1.5H, s); 2.09 (1.5 s); 2.2-2.35 (1H, m); 3.2-3.75 ( 611 m); 3.8-3.95 (1H, m); 4.0-4.25 (2N m).
Spectrum UV (H, 0), A nm: 298 (7960).
IR spectrum (KBG), - cm: 3400, 1760, 1675.
Example 7. p-Nitrobenzyl ester 1R, 5R, P (R) -oxyethyl -1til-2-L (3S) -1- (p-nitrobenzyloxy-bonyl) pyrrolidine-3-ilthio carbapene-2-em-3-carboxylic acid.
The process described in Example 1 is repeated, but in this case 1.35 g of p-nitrobenzyl ester lR, 5R, M (R) -oxyethyl -2-ox-carbapenam-3-carboxylic acid and 1.43 g 3 are used ( 5) -mercapto-1- (1t-nitrobenzyloxycarbonyl) -pyrrolidine, which allows to obtain 1.8 g of the indicated compound.
NMR spectrum (CBC1), Y, h on mpn 1.30 (ZN, d, J 6 Hz), 1.38 (ZN, d J 6 Hz) 1.6-2.5 (2H, m), 3 , 1-4,4 (UN, m); 5, 17 (1H, d, J 15 Hz); 5.20 (2H, s); 5.52 (1H, d, 3 15 Hz
0
-oxocarbapenam-3-carboxylic acid and 430 mg of 3 (K) -merk PTO-1- (Mp-nitrobenzyl-hydroxy-parabot ilacetate forces) pyrrolidine, resulting in 430 mg of the title compound.
NMR spectrum (60 MHz, CDC1, 4 CD, CD in an amount sufficient to dissolve this compound), S, ppm: 1.3 (G, d), 1.4 (G, d), 1, 8- 2,4 (ZN, M) i 2,3 (ZN, s); 3.0-4.3 (8H, m); 5.20 (2H, s); 5.35 (2H, AB); 7.5; 8.2 (4H,); 7.7, -. 8.2 (4H, A B).
EXAMPLE 6. LR, 5R, (3R) - -1-Acetimidoylpyrrolidine-3-ylthio-6- - p (K) -oxyethyl -1-methylcarbapen-2-β-em-3-carboxylic acid.
The catalytic hydrogenation process described in Example 2 is repeated, but using 430 mg of 1R, 5R p-nitrobenzyl ester, (K) -oxyethyl -1-methyl-2- (LC) -1-1 (N-p- nitrobenzyloxycarbonyl acetate5
25 imidoyl) pyrrolidin-3-ilthio carba30
five
0
five
0
five
pen-2-em-3-carboxylic acid (prepared as described in Example 5), which affords 110 mg of the title compound.
Nuclear Magnetic Resonance Spectrum (400 MHz,), O, ppm: 1.04 (3N, d, J 6.8 Hz); 1.10 (3N, d, J 6.4 Hz); 1.85-2.05 (1H, m), "2.08 (1.5H, s); 2.09 (1.5H, s); 2.2-2.35 (1H, m); 3.2-3.75 (611, m); 3.8-3.95 (1H, m); 4.0-4.25 (2H, m).
Spectrum UV (H, 0), A nm: 298 (7960).
IR spectrum (KBG), - cm: 3400, 1760, 1675.
Example 7. 1R, 5R, P (R) -oxy-ethyl-1-methyl-2-L (3S) -1- (p-nitrobenzyloxycarbonyl) pyrrolidin-3-ylthio-carbaphen-2-em-p-nitrobenzyl ester 3-carboxylic acid.
The process described in example 1 is repeated, but in this case 1.35 g of p-nitrobenzyl ester of lR, 5R, M (R) -oxy-2-oxo-carbapenam-3-carboxylic acid and 1.43 g 3 ( 5) -mercapto-1- (1t-nitrobenzyloxycarbonyl) -pyrrolidine, which provides 1.8 g of the title compound.
Nuclear Magnetic Resonance Spectrum (CBC1), Y, h on mpn: 1.30 (ZN, d, J 6 Hz), 1.38 (ZN, d, J 6 Hz) 1.6-2.5 (2H, m) , 3.1-4.4 (UN, m); 5, 17 (1H, d, J 15 Hz); 5.20 (2H, s); 5.52 (1H, d, 3 15 Hz),
7.47 (2H, d, J 9 Hz); 7.62 (2H, d, J 9 Hz); 8.20 (4H, d, J 9 Hz).
Spectrum IR - (KBG), ZAOO, 1770, 1705.
Nuclear Magnetic Resonance Spectrum (1) 0), S, parts per million: 1.04 (3N, d, J - 7 Hz); 1.10 (3N, d, Hz); 1.8-2.0 (1H, m); 2.05 (1H,
  ° 2.2-2.4 (1H,
Example lR, 5R, 6Sj-6- l (R) - m); 3.1-4.2 (9H, m). α-oxyethyl -1-methyl-2 (35) pyrrolidine-spectrum IR (KVg),: 3400,
-3-ilthio carbapen-2-em-3-carbonic 1755, 1680, 1635, 1590. acid. UV spectrum (), i m (6)
The catalytic process Q297.2 (8660) is repeated. hydrogenation described in Example 2, but using 0.2 g. lR, 5R, 6SJ p-nitrobenzyl ester Example 10. DR, 5R p-nitrobenzyl ester, (3S, 5S) -5-Kap6a-mo-1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylthio-6-1 (R ) -oxo-1- (p-nitrobenzyl-oxycarbonyl) -pyppo-J5 ethyl -1-methylcarbapen-2-em-3-carbolidin-3-ylthi 6 carbapen-2-em-3-carboxylic acid.
1 g of p-nitrobenzyl ester L1R, 5R, 6SJ-6-LI (R) -oxyethyl 1-1-methyl-2-6-Ij (R) -oxy-ethyl | -1-methyl-2- (3S) new acid (obtained as described in Example 7), which affords 0.25 g of the title compound.
NMR spectrum (), 8, ppm: 1.03 (ZN, d, and 7 Hz), 1.10 (ZN, d, L 6 Hz); 1.7-1.9 (1H, m), 2.2-2.4 (1H, m); 3.0-4.1 (9H, m).
IR spectrum (KBG), - s: 3400, 1760, 1590.
Spectrum UV (), L MQKC, nm (6): 296.8 (8460).
PRI me R 9. lR, 5R, 6Sj-2- (3S) -oxocarbapenam-3-carboxylic acid 20 and 989 mg (25.48) -2-carbamoyl-4-mer-capto-1- (p -nitrobenzyloxycarbonyl) -pyrrolidine is reacted and treated as described in Example 1, resulting in 255 of 385 mg of the indicated compound.
Nuclear Magnetic Resonance Spectrum (CDjCOCi) ,,), S, hours per million: 1.25 (6H, d, J 7 Hz); 2.90 (2H, s); 1.7-4.7 (11H); 5.22 (2H, s);
-1-acetimidoylpyrrolidin-3-ilthioZ-Q 5.30, 5.48 (2H, quartet, 5–14 Hz);
-6-1 (R) -oxyethyl -1-methylcarbapen--2-em-3-carboxylic acid.
7.60, 8.13 (2H, AB quartet, 3,8 Hz); 7.76, 8.20 (2H, AB-quartet, 3 8 Hz).
IR spectrum (KBG), X „atcc 3450, 3350, 1770, 1700.
100 mg of lR, 5R, (R) -OKCH-β-methyl-2- (35) -pyrrolidine-3-yltir} carbapen-2-em-3-carboxylic acid (prepared as described in Example 8) is dissolved in 1.2 mb of phosphate buffer (pH 7.1), the pH of this solution was adjusted to 8.5 by adding 1N. aqueous solution of sodium hydroxide while cooling with ice. To the resulting solution, 200 mg of hydrochloric ethyl imidate is added, and the pH value of Example 10) is exposed to this mixture again adjusted to 8.5 by catalytic hydrogenation, opium
IR spectrum (KBG), X „atcc 3450, 3350, 1770, 1700.
Example 11. PR, 5R, - (3S, 55) -5-carbamoylpyrrolidin-3-ylthio | -6-1 (R) -oxy-ethylZ-1-methyl-carbapen-2-em-3-carboxylic acid. . 225 mg of p-nitrobenzyl ester of t, 5K, (35.55) -5-carbamoyl--1- (p-nitrobenzyloxycarbonal) pyrrolidin-3-Ilthio (R) -oxo-ethyl | -1-m tilcarbapen-2-em- 3-carboxylic acid (prepared as described in
adding 1 n. an aqueous solution of sodium hydroxide, the mixture is then stirred for 30 minutes while cooling with ice. The pH of this solution was adjusted to 7 by the addition of dilute hydrochloric acid, after which the mixture was purified by chromatography on a column of Dione HP 20 AG. The fraction, which was eluted with an aqueous solution of acetone with a 3% volume ratio, was lyophilized to yield 102 mg of the title compound.
Nuclear Magnetic Resonance Spectrum (1) 0), S, parts per million: 1.04 (3N, d, J - 7 Hz); 1.10 (3N, d, Hz); 1.8-2.0 (1H, m); 2.05 (1H,
-oxocarbapenam-3-carboxylic acid and 989 mg of (25.48) -2-carbamoyl-4-mercapto-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine are reacted and treated as described in Example 1, as a result of which 385 mg of the title compound are obtained.
Nuclear Magnetic Resonance Spectrum (CDjCOCi) ,,), S, hours per million: 1.25 (6H, d, J 7 Hz); 2.90 (2H, s); 1.7-4.7 (11H); 5.22 (2H, s);
5.30, 5.48 (2H, quartet, 5–14 Hz);
example 10) exposed to catalytic hydrogenation, opi
7.60, 8.13 (2H, AB quartet, 3,8 Hz); 7.76, 8.20 (2H, AB-quartet, 3 8 Hz).
IR spectrum (KBG), X „atcc 3450, 3350, 1770, 1700.
Example 11. PR, 5R, - (3S, 55) -5-carbamoylpyrrolidin-3-ylthio | -6-1 (R) -oxy-ethylZ-1-methyl-carbapen-2-em-3-carboxylic acid. . 225 mg of p-nitrobenzyl ester of t, 5K, (35.55) -5-carbamoyl-1- (p-nitrobenzyloxycarbonal) pyrrolidin-3-ylthio (R) -oxy-ethyl | -1-methyl-carbapapen-2- em-3-carboxylic acid (prepared as described in
0
five
sled in example 2, resulting in 51 mg of the indicated compound.
Nuclear Magnetic Resonance Spectrum (400 MHz, DjO), f, ppm: 1.02 (3N, d, J 7.3 Hz); 1.10 (3N, d, J 6.3 Hz); 1.62 (1H, m); 2.55 (1H, m); 2.85 (1H, q), 3.17-3.25 (2H, m); 3.56-3.64 (1H, m); 3.78 (1H, t, 3 8 Hz), 4.00-4.10 (2H, m).
Spectrum IR (KBG), masses: 3270, 3200, 1750, 1670, 1590.
Example 12. 5R, 6sl-6-l (R) -oxy-ethyl-1-methoxy-2- (3S) -1 p-nitro-6-l-1-methoxy-2- (3S) -1 - (p-nitro6-phenyloxycarboNIL) pyrrolidin-3-yl-carbaphen-2- p-nitrobenzyl ester em-carboxylic acid.
1 g of pK-nitrobenzyl ester of 15K, 6SJ-6- (1 (R) -oxyethyl-1-methoxy-2-ox-socarbapenam-3-carboxylic acid and 820 mg of 3 (5) -mercapto-1- (p-nitroben- Zyloxycarbonyl) pyrrolidine is reacted and then treated as described in Example 1, yielding 392 mg of the title compound.
Nuclear Magnetic Resonance Spectrum (60 MHz, CDC1,), S, ppm: 1.35 (G, d, J 6 Hz); 1.8-2.4 (2H, m); 3, DO, 3.45 (together with each other, each c), 3.2–4.4 (9H, m); 5.18 (2H, s), 5.18 5.46 (21 AB, J 14 Hz) 7.46, 8.13 (4H, and 9 Hz); 7.57, 8.13 (AH, A, J 9 Hz).
Example 13. 5R, (R) - -Oxyethyl J-1-methoxy-2- (35) -pyrrolidin-3-ylthio7 carbapen-2-em-3-carboxylic acid.
150 mg of p-nitrobenzyl ester of 5R, (R) -oxyethylZ-1-methoxy-2 (3S) -1 - (p-nitrobenzeneloxycarbonyl) pyrrolidin-3-ylthio-carbapen-2-em-3-carboxylic acid (prepared as described in Example 12) is subjected to the catalytic hydrogenation described in Example 2, resulting in 13 mg of the title compound.
Nuclear Magnetic Resonance Spectrum (400 MHz,), 8, ppm: 1.04, 1.16 (together, 3N each, d, YY 6.4 Hz); 1.85-1.95 (2H, m); 2.2-2.35 (4H, m); 3.13-3.5 (2H, m) 3.31 (3N, s); 3.8- 3.9 (1H, m); 4.05, 4.07 (each 1H, d, 3 3.4 Hz); 4.08-4.18 (1H, m).
IR spectrum (KBG), ",: 3450, 1765, 1610.
Spectrum UV (NPO), L, M (): 278 (7320).
Example 14. 5R, (K) -oxyethylZ-1-methoxy-2- (35) -1- (H-p-nitrobenzyloxy-carbonyl acetymidolyl) pyrrolidin-3-ylti6 carbapen-2-em p-nitrobenzyl ester 3-carboxylic acid.
270 mg of p-nitrobenzyl ester | 5R, l (R) -oxyethyl -1-methoxy-2-oxocarbapenam-3-carboxylic acid and 292 mg of 3 (S) -MepKanTo-1- (N- -p-nitrobenzyloxycarbonylacetimide- yl) pyrrolidine is reacted and treated as described in Example I, in the course of which 670 mg of the title compound is obtained in crude form.
Nuclear Magnetic Resonance Spectrum (CDCl,), i, ppm: 1.2-1.5 (ЗН, m); 2.36 (3N, s); 2.9- 3.5 (2H, m); 3.0-4.4 (9H, m); 3.47 (ЗН, s); 5.20, 5.46 (2H, AB, Hz); 5.25 (2H, s); 7.4-8.2 (8H, x 2).
0 Example 15. 5R, (3S) -1- Actium Ido shprolidin 3-ylthioJ -2 -2 (I) -oxyethyl - 1-methoxycarbapen-2-em-3 carboxylic acid.
670 mg p-nitrobenzyl ether
5 5R, (K) -oxyethyl -1-methoxy- -2- (3S) -1- (Nn-nitrobenzyloxycarboNYL-acetimidone) pyrrolidin-3-ylthio-carbapen-2-em-3-carboxylic acid (prepared as described in
0 Example 1) is subjected to the catalytic hydrogenation described in Example 2, resulting in 74 mg of the title compound.
NMR spectrum (400 MHz,), S, h
5 per million: 1.13-1.18 (ZN, m), 1.87-2.02 (1H, m), 2.05; 2.07; 2.09; 3.00 (together with ST, separately from); 3.29 3.31 (together with GZ, separately from c); 3, 4–4,15 (ЗН, m).
0 IR spectrum (KBG),): 3330, 1765, 1675, 1590.
UV spectrum (), A, nm (): 202.8 (16800), 296.6 (5490).
Example 16. 5R, 6s3-1 p-nitrobenzyl ester fluoro-6- 1 (R) -oxy-ethyl-2- (3S) -1 - (N-p-nitrobenzyl-hydroxycarbonyl-acethymidoyl) pyropolydine-3-ylthio-carbapen-2 -em-3-carboxylic acid, 800 mg of p-ncgrobenzyl ester
Q 5R, 6SJ-1-fluorop-6- 1 (K) -oxyethyl -2- - -oxocarbapenam-3-carboxylic acid I 756 MP 3 (5) -mercapto-1- (H-p-nitrobenzyloxycarbonylacetimndoyl) pyrro - lidina is subjected to interaction and
 treat the crates in the same manner as described in Example 1, resulting in 1.2 g of this dinonea soy.
Nuclear Magnetic Resonance Spectrum (), 8, ppm: 1.1-1.3 (ЗН, t); 2.25 (311, s); 2.0-2.3 (2H, m); 3.0-4.4 (9H, m), 3.15 (2H, s); 5.22, 5.42 (2H, LV, J 15 Hz), 7.3-8.3 (8H, x 2).
Example 17. 5R, (3S) - -1-Acetimidoylpyrrolidin-3-ylthio - -1-fluoro-6-l (R) -oKCH3THJi carbapen-2-em-3-carboxylic acid.
670 mg of p-nitrobenzyl ester 5R, 6S3-1-fluoro-6- 1 (R) -oxyethyl -2- -G (35) -1- (N-p-nitrobenzyloxycarbo5
0
five
Nylacetic imidoyl) pyrroldin-3-ylthio - carbopen-2-em-3-carboxylic acid (prepared as described in Example 16) is subjected to the catalytic hydrogenation described in Example 2, resulting in 16 mg of the title compound.
IR spectrum (KBG), - 3250, 1750, 1680.
Example 18. 1R, 5R, (3S, 5S) -5-Kap6o-moyl-1- (1-p-nitrobenzyloxycarbonyl-apetimidoyl) pyrrolidin-3-ylthio-6- (E) -oxyethyl -1-p-nitrobenzyl ester -methylcarbapen-2- -em-3-carboxylic acid.
264 mg of lR, 5R, 6s3-6-D (R) -oxy-3-D-3-methyl-2-oxocarbapenam-3-carboxylic acid p-nitrobenzyl ester and 311 mg of (2S, 45) -2-carbamoyl 4-mercapto-1- (Mn-nitrobenzyloxycarbonylacetimidoyl) pyrrolidine is treated as described in Example 1, resulting in 839 mg of the title compound in an unspecified form. The crude product is used without purification in example 19.
Example 19. lR, 5R, - (3S, 5S) -1-acetylimido-5-carbamoylpyrrolidin-3-ylthio-6-LI (R) -oK-Siethyl -1-methylcarbapen-2-EM-Car - booms acid.
839 mg of the crude product obtained as described in Example 18 is treated in the same manner as Example 2, to give 67 mg of the title compound.
NMR spectrum (270 MHz,), 8, ppm: - 1.00 (ZN, d, 5 6.0 Hz), 1.09 (ZN, d, L 6.0 Hz); 2.06; 2.17 (together with GZ, separately s), 1.97 - 2.25 (1H, m); 2.58-2.86 (2H, m); 3.06-3.22 (1H, m); 3.24-3.40 (2H, m) 3.77-3.94 (2H, m); 3.94-3.96 (2H, m) IR spectrum (KVg),;, ox. 1755 1690, 1390.
UV spectrum (), max 298.
EXAMPLE 20 p-Nitrobenzyl ester 5R, 6s3-6- 1 (K) -oxyethyl -1, 1- dimethyl-2- (35) -1- (p-nitrobenzyloxycarbonyl) pyrrolidine-3 -ltio carb pen-2-EM-Z-carboxylic acid.
1 g of 5R p-nitrobenzyl ester, (K) -oxyethyl -1,1-dimethyl-2-oxocarbapenam-3-carboxylic acid and 840 pinch (35) -mercapto-1- - (p-nitrobenzyloxycarbonyl) pyrrolidine are reacted and about
five
0
five
This is carried out in the same manner as in Example 1, whereby 390 mg of the title compound are obtained.
Nuclear Magnetic Resonance Spectrum (CDCl1), 5 ppm:
1.08 (ZN, d, J 5 Hz), 1.28 (ZN, s); 1.33 (ZN, d, and 4 Hz), 1.7-2.6 (ZN, m); 3.0-4.5 (8H, m); 5.15 (2H, s); 5.20; 5.40 (2H, AB quartet,), 7.47; 8.12 (2H, AB-quartet, 3 9 Hz); 7.59; 8.12 (2H, AB-quartet, J 9 Hz).
EXAMPLE 21 5R, (R) - -Oxyethyl-1, 1-dimethyl-2- / j (3S) -nnppolidin-3-ylthio-carbapen-2-em-3-carbonic acid .
300 mg of the product obtained as described in Example 20 is treated in the same manner as in Example 2, resulting in 49 mg of the title compound.
Nuclear Magnetic Resonance Spectrum (400 MHz,), 8, h per million: 0.93 (ZN, s); 1.09 (3N, d, J 6.3 Hz); 1.14 (3N, s); 1.82-1.88 (1H, m); 2.03 (1H, s); 2.16-2.26 (1H, m); 3.13 (1H, dd, and 12.7 and
3.9 Hz); 3.19-3.24 (1H, m); 3.27 (1H, dz, and 5.9 and 2.9 Hz); 3.32-3.39 (2H, m); 3.68 (1H, d, J 2.4 Hz); 3.88- 3.95 (1H, m); 4.03-4.09 (1H, m).
IR spectrum (KBG),, 3300, 1765, 1600.
Spectrum UV (), yes, nm (): 279 (5750).
PRI me R 22. 5R, 6sl-2- (3S) - -1-Acetimidoyl pyrrolidine-3-ilthio - -6- (R) -oxyethyl -1, 1-dimethylcarbene-2-em-3- carboxylic acid.
190 mg 5R, (R) -oxyethyl--1,1-DIETHIL-2- (38) -pyrrolidin-3-yl-y-u carbapen-2-em-3-carboxylic acid (prepared as described in Example 21 ) and 560 mg of hydrochloride, ethyl imide, is reacted in the same manner as in Example 9, resulting in 120 mg of the title compound.
Spectrum - NM (90 MHz, D, 0), S, h per mnn: 0.92 (ZN, s); 1.09 (ZN, d, L 6.0 Hz) {1.13 (ZN, s), 2.06 (ZN, s); 1.56-2.58 (2H, m), 3.06-4.25 (8H, m).
IR spectrum (KBG),. : .3350, 3250, 1755, 1670, 1630, 1600.
0
five
0
five
0
UV spectrum (), ox, nm (fj: 280 (5250).
EXAMPLE 23 1R, 5R, 6s | -6- (R) -Oxyethyl -2- (2-labels and methyl-3,4,5,6-tetrahydropyrimidin-5-ylthio) -1-methylcarbapen -2-em-3-carboxylic acid.
A. 1.0 g of lR, 5R, 6Sj-6-1 (K) -oxyethyl -1-methyl-2-OK p-nitrobenzyl ester of m-3-carboxylic acid cocarbapen and 2.0 g of 1.3-bis (p-nitrobenzaminocarboxylamino) -2-mercaptopropan impedes the interaction as follows.
Example 24. p-Nitrobenzyl ester 1K, 5K, 65 -1-methyl-2- (3S) -I- (p-nitrobenelloxycarbonyl) pyrrol din-3-ylthio-6- (K) - (trimethylsilyl oxy) ethyl carbapen -2-EM-3-carboxylic acid.
The procedure of Example 1 is repeated, using p-nctrobeneyl 1R,
as described in example 1, resulting in 10R, (H) - (trimethylsilyloxy) - which gives 1.7 g of p-nitrobenzyl ether 1R, 5R, 6S3 1 methyl-2- fl, 3-bis- (p-nitrobenzyloxycarbo - Nylamino) propan-2-ylthio-6-1 (R) -oK-sistil carbapen-2-em-3-carboxylic acid
Nuclear Magnetic Resonance Spectrum (CDCl1), 5 ppm: 1.3 (6H, d); 2.9-3.8 (7H, m); 5.1 (AH, s); 5.1; 5.4 (2H, AB-quartet,: T 13 Hz); 7.4, 8.1 (4H, 3,9 Hz), 7.5, 8.1 (4H, 3,9 Hz).
IR spectrum (KBG), -). 3400, 1770, 1705.
B. 0.8 g of the product obtained
ethyl -1-methyl-2-oxocarbapenam-3-car boxylate and 3 (5) -mercapto-1- (p-nitro-benzyloxycarbonyl) pyrrolidine, to give the title compound.
15 NMR spectrum (CDCl), S, hours per million
0.10 (3N, s); 1.25 (6H, d, 3 6 Hz) 1.7-2.4 (2H, m); 3.1-4.4 (9H, m); 5.11 (1H, d, E 14 Hz); 5.15 (2H, s) 5.24 (1H, d,: i 14 Hz), 7.43
20 (2H, d,: J 9 Hz); 7.57 (2H, d, J 9 Hz), 8.14 (2H, d, 7 9 Hz).
IR spectrum (СНС1,),, 1765, 1700.
PRI mme R 25. p-Nitrobenzyl
as described in paragraph A, L1R, 5R, 6S -1-methyl-2- (3S) -1R is dissolved in 80 ml of tetrahydrofuran, then 80 ml of phosphate buffer solution (pH 6.0) and 0.45 g of platinum oxide on coal. This mixture is stirred for 2.5 hours under a stream of hydrogen. At the end of this period, the catalyst is filtered off and the solvent is distilled off at a temperature below 20 T) under reduced pressure. The residue is extracted twice with ethyl acetate. The aqueous layer is filtered to remove insoluble impurities. The filtrate is cooled with ice and adjusted to a pH of 8.5 by the addition of an aqueous solution of sodium hydroxide.
Then 1.7 g of ethylmethoxyacetimidate hydrochloride is added, the pH value of the mixture is adjusted to 8.5. This mixture is stirred for 20 minutes, after which the pH is adjusted to 7.0 by the addition of dilute hydrochloric acid. The mixture is concentrated by evaporation under reduced pressure and at a temperature below to a volume of about 70 ml. The concentrate is subjected to column chromatography using Dione CHP-20P and eluted with an aqueous solution of acetone with a 10% volume ratio. The eluate was lyophilized to give O, 1 g of the title compound.
thirty
35
40
45
50
55
Spectrum IR (KBG),) „d,, 1755, 1660, 1580.
cm
-
3350,
- (N-p-nitrobenzyloxycarbonylacet-imidoyl) pyrrolidin-3-ylthio (R) - - (trimethylsilyloxy) ethyl | carbapen-2-em-3-carboxylic acid.
The procedure of Example 1 is repeated, but using p-nitrobenzyl iR, 5R, (R) -trimethylsilyloxyethyl1-1-methyl-2-oxocarbapenam-3-car bauxyl and 3 (5) -mercapto-1-L- (p - -Nitrobenzyloxycarbonyl) acetimidosyl pyrrole and on, to obtain the specified compound.
NMR spectrum (CDCl,), h. Ppm: 0.12 (9H, s); 1.26 (6H, d, J 7 Hz) 1.7-2.6 (2H, m); 2.28 (3N, s); 3.0-4.4 (ZN, m), 5.13 (1H, d,: J 14 Hz) 5.15 (2H, s)} 5.27 (1H, l; J 14 Hz), - 7 48 (2H, d, J 9 Hz); 7.58 (2H, d, L 9 Hz), 8.15 (4H, d, Cf 9 Hz).
Example 26. P-Nitrobenzyl ester of lR, 5R, (R) -ooxyethylJ-1- -methyl-2- (3S) -1- (p-nitrobenzyloxycarbonyl) pyrrolidin-3-yl THoJ carbapen-2-em -Z-carboxylic acid.
279 mg of the product obtained as described in Example 24 is dissolved in 3 ml of acetonitrile, then a solution of 65 mg of potassium fluoride in 1 ml of water is added, followed by the addition of 130 µl of acetic acid, after which the whole mixture is stirred at room temperature for 1 h. At the end of this period to the reaction mixture to
Example 24. 1K, 5K, 65 -1-methyl-2- (3S) -I- - (p-nitrobenelloxycarbonyl) pyrrolidin-3-ylthio-6- (K) - (trimethylsilyloxy) p-nitrobenzyl ester ethyl carbapen-2-em-3-carboxylic acid.
The procedure of Example 1 is repeated, but using p-nctrobeneyl 1R,
5R, (H) - (trimethylsilyloxy) -
5R, (H) - (trimethylsilyloxy) -
ethyl -1-methyl-2-oxocarbapenam-3-carboxylate and 3 (5) -mercapto-1- (p-nitrobenzyloxycarbonyl) pyrrolidine to give the title compound.
NMR spectrum (CDCl 3), S, ppm:
0.10 (3N, s); 1.25 (6H, d, 3 6 Hz); 1.7-2.4 (2H, m); 3.1-4.4 (9H, m); 5.11 (1H, d, E 14 Hz); 5.15 (2H, s) 5.24 (1H, d,: i 14 Hz), 7.43
(2H, d,: J 9 Hz); 7.57 (2H, d, J 9 Hz), 8.14 (2H, d, 7 9 Hz).
IR spectrum (СНС1,),, 1765, 1700.
PRI mme R 25. p-Nitrobenzyl
25 ether L1R, 5R, 6S -1-methyl-2- (3S) -1
m
thirty
35
40
45
50
55
,
- (N-p-nitrobenzyloxycarbonylacet-imidoyl) pyrrolidin-3-ylthio (R) - - (trimethylsilyloxy) ethyl | carbapen-2-em-3-carboxylic acid.
The procedure of Example 1 is repeated, but using p-nitrobenzyl iR, 5R, (R) -trimethylsilyloxyethyl1-1-methyl-2-oxocarbapenam-3-carboxylate and 3 (5) -mercapto-1-L- (( p- -nitrobenzyloxycarbonyl) acetimidosine pyrrole and on, to obtain the specified compound.
Nuclear Magnetic Resonance Spectrum (CDCl,), in ppm: 0.12 (9H, s); 1.26 (6H, d, J 7 Hz); 1.7-2.6 (2H, m); 2.28 (3N, s); 3.0-4.4 (3N, m), 5.13 (1H, d,: J 14 Hz); 5.15 (2H, s)} 5.27 (1H, l; J 14 Hz) - 7.48 (2H, d, J 9 Hz); 7.58 (2H, d, L 9 Hz), 8.15 (4H, d, Cf 9 Hz).
Example 26. P-Nitrobenzyl ester of lR, 5R, (R) -ooxyethylJ-1- -methyl-2- (3S) -1- (p-nitrobenzyloxycarbonyl) pyrrolidin-3-yl THoJ carbapen-2-em -Z-carboxylic acid.
279 mg of the product obtained as described in Example 24 is dissolved in 3 ml of acetonitrile, then a solution of 65 mg of potassium fluoride in 1 ml of water is added, followed by the addition of 130 µl of acetic acid, after which the whole mixture is stirred at room temperature for 1 h. At the end of this period, ethyl acetate is added to the reaction mixture and the entire mixture is washed with water. The solvent was removed by evaporation under reduced pressure, and the residue was purified by short column chromatography using silica gel, eluted with a mixture of ethyl acetate and methanol with a 10: 1 volume ratio, resulting in 237 mg of the title compound. Nuclear Magnetic Resonance Spectrum (CDCl1), in ppm: 1.30 (3N, d, 3–6 Hz); 1.38 (3N, d, 3–6 Hz); 1.6-2.5 (2H, m); 3.1-4.4 (UN, m); 5.17 (1I, d,: i 15 Hz) 5.20 (2H, s); 5.52 (1H, d, GT 15 Hz); 7.47 (2H, d, P 9 Hz), 7.62 (2H, d, and 9 Hz); 8.20 (4H, d, 3 9 Hz).
Spectrum IR (KBG), “d, cm: 3400 1770, 1705.
Example 27. lR, 5R, 6S -1-Methyl-2- (2S, 4 S) -1-acetylimidoyl-2-methylcarbamoylpyrrolidin-4-ylthio-6- - C (1K) -oxyethyl 1-2- carbapenem-3 carboxylic acid.
p-Nitrobeneyl 1 R, 5R, 65 -1-methyl- -6- (1R) hydroxyethyl -2-oxocarbapenam-3-carbox 1 -shat and 2S, (L-p-nitrobenzyloxycarbonylacetimidoyl) -4--mercapto-2- methylcarbamoylpyrrolidine is reacted and treated as described in Examples 10 and 11 to obtain the indicated compound.
Nuclear Magnetic Resonance Spectrum (), S, ppm: 1.04 (3N, d, P 7 Hz); 1.10 (ZI, d, and 7 Hz); 2.0 and 2.2 (together H, each means c); 2.0-2.2 (1H, m); 2.53 and 2.60. (Together ZN, s); 2.6-2.8 (1H, m), 3.2-3.3 (2H, m), 3.3-3.65 (1H, m); 3.8-4.0 (2H, m); 4.0-4.15 (2H, m); 4.4-4.6 (1H, m).
EXAMPLE 28 lR, 5R, 6S -1-Methyl-2-. (25.45) -1-acetimidoyl-2-dimethylcarbamoyl pyrrolidin-4-ylthio-6- (Sh) hydroxyethyl -2-Carbacem-3-Carboxylic acid.
p-Nitrobenzyl 1R, 5R, 6SJ-1-MeTim-6-L 1K) -oxyethyl. } -2-oxocarbapenam-β-3-carboxylate and (2S, 4S) -1- (N-p-nitrobenyloxycarbonylacetimidoyl) -4-β-mercapto-2-dimethylcarbamoylpyrrolidine are reacted and treated as originally done in examples 1 and 11, to give said compound.
Spectrum (1) 0), S, parts per million: 1.02 (3N, d, –I 7 Hz); 1.08 (3N, d. Hz); 1.93 and 2.18 (together ZN.
each means c); 1.7-2.1 (1H, m), 2.77 and 2.79 (together with MN); 2.89 and 2.93 (together with ST); 2.7-3.1 (1H, m), 3.2-3.3 (2H, m); 3.3-3.6 (1H, m); 3.7-4.2 (4H, m) j 4.7-5.1 (1H, m).
PRI m p 29. lR, 5R, 6sl-2- (3S, 58) -5-carbamoyl-1-formimidoshirolidin-3-ylthio-b-L (Sh) -oxyethyl -1-methylcarbapen-2 em-3-carboxylic acid
The catalytic hydrogenation process described in Example 2 is repeated, but using 297 mg
5 C-nitrobenzyl-2- (35,55) -5-carbamoyl-1- (H-p-nitrobenzyloxycarbonyl-formimidoyl) pyrrolidin-3-ylthio-6- - (1R) -oxie-1-methylcarbapen- 2- - e-3-carboxylate and 597 mg of 10%
Q palladium on carbon, resulting in 36 mg of the final compound.
Nuclear Magnetic Resonance Spectrum (270 MG2, DjO): 1.00 (3N, d, J = 6.9 Hz); 1.09 (3N, d, a 6.2, Hz); 2.02-2.16 (1H, m); 2.655 2.80 (1H, m); 3.07-3.12 (1H, m) j 3.27 (1H, dd, 3 2.5 Hz, 5.5 Hz); 3.34-3.64 (1H, m); 3.68-3.93 (2H, m); 4.00-4.12 (2H, m); 4.49-4.66 (1H, m); 4.49-4.66 (1H, m); 7.81- and 7.91 (1H,
0 each c).
Spectrum IR (KVg), - 5 "d | c, cm: 3360, 1749, 1703, 1588.
EXAMPLE 30 lR, 5R, 6Sj-2- (3S, 55) -5-carbamoyl-1-propioimidoylpyrrolidin-3-yl thio-6- (1R) -ok diethyl -1 - -methylcarbapen -2-em-3-carboxylic acid.
The process of catalytic hydrogenation is repeated, as described in Example 2, but using 227 mg of p-nitrobenzyl-2- (35.55) -5- -carbamoyl-1- (L-p-nitrobenzyloxycarbonyl-propioimidoyl) -pyrrolidine -3-yl- (III) -oxyethyl -1-methylcarbapen-2-em-3-carboxylate and 454 mg of 10% palladium on charcoal, resulting in 45 mg of the compound. Nuclear Magnetic Resonance Spectrum (270 MHz,): 0.99-1.1 (9H, m); 2.09-2.22 (1H, m); 2.32; 2.43 and 2.45 (2H, each quartet, L 7.3 Hz); 2.62-2.84 (1H, m) 3.16- 3.19 (1H, m); 3.28 (1H, dd, L 2.5 Hz, 5.8 Hz); 3.34-3.62 (1H, m); 3.80-4.10 (4H, m); 4.47-4.70 (111, m). P1K-spectrum (KRr) ,,: 3360, 1754, 1687, 1595.
PRI me R 31. lR, 5R, - 1 (35,55) -5-Carbamoyl-1-methoxyacet-imidoylpyrrolidin-3-ilthio G (IR) 5
0
five
0
five
17
α-oxyethyl -1-methylcarbapen-2-em-3-carboxylic acid.
The process of catalytic hydrogenation is repeated, as described in Example 2, but using 240 mg of p-nitrobeneyl-2- (35.55) -5- -carbamoyl-1- (N-p-nitrobenzyloxycarbonylmethoxyacetimidoyl) pyrrolidine -3-ylthio-b- (1K) -oxyethyl-7-1-methyl-carbapen-2-em-3-carboxylate and 480 mg of 10% palladium on carbon, resulting in a yield of 60 ng of compound.
Nuclear Magnetic Resonance Spectrum (270 MHz,): 1.00
(ZN,
5 7.3 Hz); 1.09 (ЗН, д.
3 6.6 Hz); 2.13-2.24 (1H, m); 2.68- 2.83 (1H, M) J 3.06-3.20 (1H, m) {3.26-3.29 (1H, m); 3.27-3.29 (1H, m); 3.27 and 3.33 (3N, each c) j 3.82-4.36 (6H, m); 4.54 (1H, m).
IR spectrum (KBG), 380 1754, 1686, 1594.
Some of the compounds of the general formula (I) themselves have remarkable antibacterial activity, while others, although they exhibit some iti bacterial activity, are of great importance as intermediates for the production of other compounds having good antibacterial activity. The compounds possess antibacterial activity show it against a wide range of pathogenic microorganisms, including gram-positive bacteria (such as Staphylococcus aureus and Bacillus subtilis) and gram-negative bacteria (such as Escherichia coli, Shigella flexneri, Kleb siella pneumoniae, Proteus vulgaris, Serratia spp. for example, Serratia marcescens, Enterobacter spp. for example, Enterobacter cloacae, Salmonella enteritidis and Pseudomonas aeroginosa) and are thus useful in the treatment of diseases caused by such microorganisms.
Certain proposed compounds are tested for their activity against various microorganisms:
A: 1K, 5K, (K) -oxyethyl7 -1 -1-methyl-2- (355-pyrrolidin-3-ylthio-carbapen-2-em-3-carboxylic acid,
B: 1R, 5S, (ZR) -1-acetyl-idoylpyrrolidin-3-ylthio-6-1 (K) -oxy-ethyl -1-methylcarbapen-2-em-3-carboxylic acid.
1922
18

20
25


C: lR, 5R, (3S) - (5) -S-Kap-bamoylpyrrolidin-3-ilthio-6-1 (R) -oK-seat1 -1 -1 metstcarbapen-2-em-3-carboxylic acid,
D: thienamycin.
The activities of the tested compounds, marked with letters assigned to them by Bbmie, in relation to different personal bacteria are shown in the table in units of minimum inhibitory concentrations (µg / ml).
As can be seen from the data presented in the table, the activities of the proposed compounds detected during the test carried out under laboratory conditions are comparable or better than those of the known compound thienamycin.
However, the proposed compounds are characterized by a much greater stability in the patient’s body compared to thienamycin, thus, the proposed compounds show much better activity,
than thienamycin when tested in vivo.
0
five
0
five
0
It is known that compounds characterized by a low minimum inhibitory concentration, and which, as should be expected, should possess valuable properties in chemotherapy, sometimes do not show a good antibacterial effect when administered to humans or animals. This may be due to various causes, such as chemical or physiological instability of the compounds, poor distribution of the compounds in the body, or binding of the blood compounds to the short. However, the compounds of the general formula I (as evidenced by the higher release rates in the leg) do not cause such problems, and therefore they exhibit high activity in the living body.
Compounds of general formula I can be administered either orally or. parenterally in the treatment of diseases in humans and animals caused by pathogenic microorganisms. These compounds may be given any known administration forms. For example, for oral administration, suitable formulations include tablets, granules, capsules, powders, and syrups, while compositions for parenteral administration include solutions for intravenous
intramuscular injection, or more preferably for intravenous injection.
The compounds are preferably administered parenterally, in particular as an intravenous injection.
The dose of the compound varies depending on the age, body weight and condition of the patient, as well as the form and number of times of administration. However, as a rule, the daily dose for an adult is 200-3000 mg of a compound that can be administered in a single dose or in divided doses.
Thus, the proposed method allows to obtain new carbapeneme derivatives of general formula I or their 4-nitrobenzyl esters, which have improved properties in comparison with the known compounds.

权利要求:
Claims (1)
[1]
Invention Formula
one . Method for preparing carbapenem derivatives of general formula 1
KI.
R,., SR5
where R, is hydrogen, fluorine, methyl or methoxy, R, 2. hydrogen or methyl, wherein R and RJ are not hydrogen at the same time,
RJ is a heterosclic radical of the general formula
N.,
Y
X is hydrogen or -CONH group; Y is hydrogen, 4-nitrobenzyloxycarbonyl group —CCR) NR,
Staphylococcus aureus 209P 0.01 0.01 0.01 0.01
Staphylococcus aureus 56
Escherichia coLi
Escherichia coli 609
Shigella flexneri 2a
Pseudomonas aeruginosa
Klebsiella nneumoniae 806 0.01 0.01 0.01 0.1
1922
20
R. R where R is hydrogen, C —C-alkyl or
C, -C-alkoxy-C, -C-alkyl, hydrogen or D-nitrobenzyl-oxycarbonyl,
1-hydroxyethyl, which can be protected by trimethylsilyl,
or their 4-nitrobenzyl esters, in that the compound of the general formula II
o coocH CeHitW where R, Rg and R4 have the indicated meanings, are reacted with diphenyldiphosphoryl chloride and the resulting compound of general formula III
Ri RZ t-rOrORe
Q K-kcoocH CeH i o
where the values of R, R and R are as defined above,
Rg is diphenylphosphoryl, is reacted with a compound of general formula IV
Rjsh
where Rj has the indicated meanings, provided that the amino group of the radical Rj can be protected by 4-nitrobenzyloxycarbonyl, followed by removing the protective groups if necessary and isolating the target product in free form or as 4-nitrobenzyl ether, or, if necessary, when a hydrogen radical, a compound of general formula I is reacted with an imidoester of formula V
C2H..OC (NH) CH3
with the selection of the target product in the form of an acid or 4-nitrsbenzyl ether.
0.01 0.02 0.01 iO, 01
: 60.01 60.01 0.02: 0.01 6.2 0.8
Microorganism
,, 01 YO, 01 0.1
0.40.2 0.05 3.1
G0.02 "0.01 0.01 0.2
0.020.02 "0.01
0.20.2 0.1
Compound
..L.

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1501922A3|1989-08-15|Method of producing carbapenem derivatives or their 4-nitrobenzyl esters

---

DK169820B1|1995-03-06|Analogous Process for the Preparation of Carbapenem Derivatives

---

FI95470B|1995-10-31|The process is prepared from a 1-methylcarbapenem derivative of formula |

---

EP0591808A1|1994-04-13|Quinolonecarboxylic acids

---

AU669948B2|1996-06-27|Bicyclic amine derivatives

---

FI81576C|1990-11-12|FOERFARANDE FOER FRAMSTAELLNING AV DERIVAT AV 6- | -2- | -2-CARBAPENEM-3-CARBOXYL SYRA, VILKA AER ANVAENDBARA SOM LAEKEMEDEL.

---

KR880001069B1|1988-06-20|Carbapenem antibiotics and process fpr preparation thereof

---

EP0449191B1|1996-07-03|2-|carbapenem derivatives

---

JPH05255250A|1993-10-05|New quaternary aminethiol compound

---

FI81577C|1990-11-12|Process for the preparation of 2- | -6- | -1-carbapen-2-em-3-carboxylic acids useful as a drug

---

EP0238285A2|1987-09-23|2-Heterocyclylthio penems

---

US5360798A|1994-11-01|Aminooxypyrrolidinylthiocarbapenem compounds

---

KR880001055B1|1988-06-18|Carbapenem amitbiotics and process for preparation thereof

---

FI83323C|1991-06-25|FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT AKTIVA KARBAPENEMDERIVAT SOM SUBSTITUERATS I 2-STAELLNINGEN MED EN HETEROTIOALKYLTIOGRUPP.

---

IE920727A1|1992-09-09|Heterocyclic compounds

---

CA2033390A1|1991-06-30|2-| carbapenem derivatives

---

AU651505B2|1994-07-21|Aminoalkylpyrrolidinylthiocarbapenem derivatives

---

EA000878B1|2000-06-26|Cycloalkylaminomethylpyrrolidine derivatives

---

AT387223B|1988-12-27|Process for the preparation of novel carbapenem derivatives

---

KR0167718B1|1999-01-15|Ñô-methylcarbepenem derivative and process for the preparation thereof

---

KR100246950B1|2000-05-01|Novel carbapenem compounds and the process for the preparation thereof

---

WO1994005667A1|1994-03-17|Carbapenem derivatives and processes for preparing the same

同族专利:

---

公开号 | 公开日

---

FI83419B|1991-03-28|

---

DK138885D0|1985-03-27|

---

AU4043185A|1985-10-03|

---

NO851227L|1985-09-30|

---

JPS60202886A|1985-10-14|

---

DK169476B1|1994-11-07|

---

FI83419C|1991-07-10|

---

KR850006418A|1985-10-05|

---

DE3587126D1|1993-04-08|

---

IE850776L|1985-09-27|

---

NO164980C|1990-12-05|

---

FI851240A0|1985-03-27|

---

ZA852251B|1985-12-24|

---

HUT38351A|1986-05-28|

---

IE59708B1|1994-03-23|

---

SU1591810A3|1990-09-07|

---

DE3587126T2|1993-10-07|

---

ES541638A0|1987-01-16|

---

ES8702912A1|1987-01-16|

---

ES550907A0|1987-02-16|

---

JPH0367068B2|1991-10-21|

---

AT86255T|1993-03-15|

---

DK138885A|1985-09-28|

---

EP0160391A1|1985-11-06|

---

NO164980B|1990-08-27|

---

AU582148B2|1989-03-16|

---

KR910010049B1|1991-12-12|

---

EP0160391B1|1993-03-03|

---

HU196800B|1989-01-30|

---

PH25057A|1991-01-28|

---

FI851240L|1985-09-28|

---

ES8703473A1|1987-02-16|

---

NZ211604A|1989-01-06|

---

US5102997A|1992-04-07|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

EP0010317B1|1978-10-24|1983-12-21|Merck & Co. Inc.|6-, 1- and 2-substituted-1-carbapen-2-em-3-carboxylic acids, processes for the preparation of such compounds and pharmaceutical composition comprising such compounds|

---

US4260627A|1978-10-24|1981-04-07|Merck & Co., Inc.|1-, 6- And 2-substituted-1-carba-2-penem-3-carboxylic acids|

---

US4206219A|1978-10-24|1980-06-03|Merck & Co., Inc.|6- and 1-Substituted-1-carbadethiapen-2-em-3-carboxylic acid|

---

US4208422A|1978-10-24|1980-06-17|Merck & Co., Inc.|1-Substituted-pen-2-em-3-carboxylic acids|

---

US4312871A|1979-12-03|1982-01-26|Merck & Co., Inc.|6-, 1- And 2-substituted-1-carbadethiapen-2-em-3-carboxylic acids|

---

EP0060077A1|1981-03-04|1982-09-15|Beecham Group Plc|Beta-lactam antibiotics, their preparation and use|

---

ES8404184A1|1981-08-03|1984-04-16|Merck & Co Inc|1-, and 1,1-disubstituted-6-substituted-2-carbamimidoyl-1-carbadethiapen-2-em-3-carboxylic acids, a process for preparing and an antibiotic composition containing the same.|

---

US4552873A|1981-08-19|1985-11-12|Sankyo Company Limited|Carbapenem compounds, and compositions containing them|

---

EP0089139A2|1982-03-16|1983-09-21|Beecham Group Plc|Antibiotics, their preparation and use|

---

US4650794A|1982-04-29|1987-03-17|Merck & Co., Inc.|6--2-carbamimidoyl-pen-2-em-3-carboxylic acids|

---

JPS5916892A|1982-07-19|1984-01-28|Sankyo Co Ltd|Carbapenem-3-carboxylic acid derivative and its preparation|

---

JPS6254427B2|1982-09-10|1987-11-14|Sankyo Kk|

---

EP0113101A1|1982-12-30|1984-07-11|Merck & Co. Inc.|6--2-SR8-1-methyl-1-carbadethiapen-2-em-3-carboxylic acid esters|

---

CA1283906C|1983-05-09|1991-05-07|Makoto Sunagawa|.beta.-LACTAM COMPOUNDS AND PRODUCTION THEREOF|

---

CH660736A5|1983-10-03|1987-06-15|Sanraku Inc|CARBAPEN DERIVATIVES.|

---

JPS6355514B2|1983-11-11|1988-11-02|Sumitomo Pharma|

---

JPS60178888A|1984-02-22|1985-09-12|Sankyo Co Ltd|Penem or carbapenem derivative or preparation thereof|

---

US4696923A|1984-04-23|1987-09-29|Merck & Co., Inc.|6-[1-hydroxyethyl]-2-SR8 -1-methyl-1-carbadethiapen-2-em-3-carboxylic acids|

---

DE3579888D1|1984-11-08|1990-10-31|Sumitomo Pharma|CARBAPENE COMPOUNDS AND THEIR PRODUCTION.|

---

FI81576C|1984-12-25|1990-11-12|Sankyo Co|FOERFARANDE FOER FRAMSTAELLNING AV DERIVAT AV 6- -2- -2-CARBAPENEM-3-CARBOXYL SYRA, VILKA AER ANVAENDBARA SOM LAEKEMEDEL.|CA1283906C|1983-05-09|1991-05-07|Makoto Sunagawa|.beta.-LACTAM COMPOUNDS AND PRODUCTION THEREOF|

---

US4696923A|1984-04-23|1987-09-29|Merck & Co., Inc.|6-[1-hydroxyethyl]-2-SR8 -1-methyl-1-carbadethiapen-2-em-3-carboxylic acids|

---

US4665169A|1985-09-11|1987-05-12|Bristol-Myers Company|Carbapenem antibiotics|

---

JPS6363680A|1986-09-05|1988-03-22|Nippon Redarii Kk|-1-methylcarbapenem-3-carboxylic acid derivative|

---

ES2053508T3|1986-11-24|1994-08-01|Fujisawa Pharmaceutical Co|COMPOUNDS OF 3-PIRROLIDINYL-THIO-1-AZABICICLOHEPT-2-ENO-2-CARBOXILICOS.|

---

KR880006244A|1986-11-24|1988-07-22|후지사와 도모 기찌 로|3-Pyrrolidinylthio-1-azabibischloro [3.2.0] hapt2-ene-2-carboxylic acid compound and preparation method thereof|

---

JPS63255280A|1987-04-11|1988-10-21|Nippon Redarii Kk|-2-substituted-6--1-hydroxyethyl)-1-methyl-carb apenem-3-carboxylic acid derivative|

---

US4925838A|1988-03-18|1990-05-15|Fujisawa Pharmaceutical Company, Ltd.|3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds|

---

US5242914A|1988-04-01|1993-09-07|Sankyo Company, Limited|2- carbapenem derivatives, their preparation and their use as antibiotics|

---

NO168304C|1988-04-01|1992-02-05|Sankyo Co|ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-CARBAPENE SUBSTANCES|

---

GB8811237D0|1988-05-12|1988-06-15|Fujisawa Pharmaceutical Co|3-pyrrolidinylthio-1-azabicyclohept-2-ene-2-carboxylic acid derivatives|

---

US4963544A|1988-05-23|1990-10-16|Fujisawa Pharmaceutical Company, Ltd.|3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds|

---

CA2022382A1|1989-08-02|1991-02-03|Susumu Nakagawa|Piperidylthiocarbapenem derivatives|

---

GB8923844D0|1989-10-23|1989-12-13|Fujisawa Pharmaceutical Co|Carbapenem compounds|

---

FI96311C|1989-12-04|1996-06-10|Squibb Bristol Myers Co|Process for the preparation of pharmaceutically useful 6--3--7-oxo-1-azabicyclo / 3.2.0 / hept-2-en-2-carboxylic acid derivatives|

---

WO1991009860A1|1989-12-28|1991-07-11|Banyu Pharmaceutical Co., Ltd.|New carbapenem derivative|

---

US5672701A|1990-01-16|1997-09-30|Bristol-Myers Squibb Company|4-substituted alkyl carbapenem antibiotics|

---

US5554606A|1990-03-12|1996-09-10|Zeneca Limited|Antibiotic compounds|

---

CA2050255C|1990-09-07|1997-02-04|Tameo Iwasaki|1-methylcarbapenem derivatives and process for preparation thereof|

---

US5208348A|1990-09-07|1993-05-04|Tanabe Seiyaku Co., Ltd.|Mercaptan compound|

---

GB9107341D0|1991-04-08|1991-05-22|Ici Plc|Antibiotic compounds|

---

GB9202298D0|1992-02-04|1992-03-18|Ici Plc|Antibiotic compounds|

---

CA2091309A1|1992-03-26|1993-09-27|Frederic H. Jung|Antibiotic compounds|

---

GB9304156D0|1992-03-26|1993-04-21|Zeneca Ltd|Antibiotic compounds|

---

EP0937725A3|1992-04-28|2004-12-01|Tanabe Seiyaku Co., Ltd.|Method for removing the protecting group for hydroxy group|

---

US5587474A|1992-06-18|1996-12-24|Tanabe Seiyaku Co., Ltd.|Method for removing the protecting group for carboxyl group|

---

CA2099818A1|1992-07-21|1994-01-22|Frederic H. Jung|Antibiotic compounds|

---

CA2099811A1|1992-07-21|1994-01-22|Frederic H. Jung|Antibiotic compounds|

---

CA2099817A1|1992-07-21|1994-01-22|Frederic H. Jung|Antibiotic compounds|

---

JP2696807B2|1992-08-06|1998-01-14|田辺製薬株式会社|Preparation of carbapenem derivatives|

---

KR940007029A|1992-09-02|1994-04-26|손정삼|New carbapenem derivatives and preparation method thereof|

---

CA2106141A1|1992-09-28|1994-03-29|Michael J. Betts|Antibiotic compounds|

---

US5442055A|1992-11-13|1995-08-15|Tanabe Seiyaku Co., Ltd.|Azetidinone compound and process for preparation thereof|

---

US6011150A|1992-11-13|2000-01-04|Tanabe Seiyaku Co., Ltd.|Azetidinone compound and process for preparation thereof|

---

US5631363A|1992-11-13|1997-05-20|Tanabe Seiyaku Co., Ltd.|Azetidinone compound and process for preparation thereof|

---

US5602118A|1993-03-16|1997-02-11|American Cyanamid Company|2-thiosubstituted carbapenems|

---

US5550229A|1993-06-23|1996-08-27|Tanabe Seiyaku Co., Ltd.|Alkylation process for preparing azetidinone compound and starting compound therefor|

---

US5783703A|1993-07-01|1998-07-21|Lederle , Ltd.|Sulfur-containing compounds method for their use and prodction|

---

AU682510B2|1993-07-01|1997-10-09|Pfizer Japan Inc.|2-azetidin-3-yl)thio-carbapenem derivatives|

---

WO1996038450A1|1995-05-31|1996-12-05|Microcide Pharmaceuticals, Inc.|Cephalosporin antibiotics|

---

US5688786A|1994-04-01|1997-11-18|Microcide Pharmaceuticals, Inc.|β-lactam antibiotics|

---

WO1996026939A1|1995-03-02|1996-09-06|Takeda Chemical Industries, Ltd.|Carbapenem compounds, their production and use|

---

TW420681B|1995-12-08|2001-02-01|Lederle Japan Ltd|Carbapenem-3-carboxylic acid ester derivatives|

---

US8729260B2|2010-05-19|2014-05-20|Savior Lifetec Corporation|Process for the preparation of carbapenem using cabapenem intermediates and recovery of cabapenem|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

JP59059279A|JPH0367068B2|1984-03-27|1984-03-27|

---