Method of producing derivatives of 7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carbolic acid

专利摘要:
Disclosed are novel carbapenem derivatives characterized by a 2-substituent of the formula <IMAGE> in which A represents a C1-C6 straight or branched chain alkylene group; R<5> represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical and <IMAGE> represents a nitrogen-containing aromatic heterocycle attached to the alkylene group A at a ring carbon atom and quaternized by substituent R<5>. Such derivatives are useful as potent antibacterial agents.
公开号:SU1493108A3
申请号:SU833648007
申请日:1983-09-27
公开日:1989-07-07
发明作者:Ун Ким Чунг
申请人:Бристоль-Мейерз Компани (Фирма)；
IPC主号:

专利说明:

H3C-CH (OH) j-C (-HVHCRi-f | -5-A-O g
C (0) -ORi
where R is C; - C4 is an evil; C-C-alkyl, benzyl or alkylcarboxymethyl; R- - H, napa-nitrobenzyl protective group in the presence of counter-ion; A - - (CH) - or - (CHj) -; mono- or disubstituted With, - With 4-alkyl groups
  Nn
- @; 4j; AJ)
V
Nn
H i
41
N and the specified ring is attached to A through carbon rings and contains nitrogen, quaternized R., which have antibacterial activity that can be used by medicine. The goal is to create new tivny (and low-toxic substances of the specified class. Synthesis is carried out by the reaction of the corresponding ketoester (instead of
at
VHCRi-f | -5-AO g
and
soy
at
C (0) -ORi
RIB group f-le (I)
0) diphenylchlorophosphate in the presence of diisopropylamine in an inert organic base, followed by treatment with a derivative
mercaptan formula HS-A - r- N
 see above, in an inert environment
an organic solvent in the presence of diisopropylethylamine and further alkylation of the compound of the formula RJ - X, where X is a halogen or a sulfonate ester group; RI see above. The selection of the target product is carried out in a free form or, if necessary, when R 3 is a napa-nitrobenzyl group, by removing the carboxy protecting group. In another case, it comes from a compound containing
-S-A-Q J groups that alkylate
about s
cl
four
with
SA9
00

sc
combi) 1ennsm f-ly RjX with a similar selection or removal of the carboxy-protecting group. New substances have low toxicity, for example, l-i mg / kg with an active dose of 5 mg / kg
(no sign of toxic guests) in relation to various gram-negative) 1nm and gram-positive bacteria m. 2 sec. f-ly, 8 tab.
The invention relates to the field of production of new carbapenem derivatives, namely, 7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylic acid derivatives of the general formula
OH I
RI
HC S-A-C - R
0
de I hydrogen or C -C alkyl;
WITH
R-C-C-alkyl, benzyl or alkylcarboxymethyl; R is hydrogen or para-nitrobenzyl zaptstsna troupe with
there is also a counterion; A - group (CHj) j ,, where n 1
or 2; one -. mono- or disubstituted
C-C4 alkyl groups:
O-fy
N K
1U-TU: 1
moreover, said ring is attached to A via a carbon atom of the ring and contains a nitrogen atom, which is quaternized by a group R, which has antibacterial activity with respect to various gram-negative and gram-positive bacteria.
The aim of the invention is to develop, on the basis of known methods, a method for the preparation of new compounds possessing valuable pharmacological properties with low toxicity.
Example 1. Preparation of the inner salt of 1-methyl-4- (2-carboxy) -6o (- {t1- (R) -oxyethyl-7-oxo-1-azabi5
0
five
0
five
0
five /

cyclo (3,2,0) hept-2-en-3 -thiomethylI-pyridine hydroxide.
A. A solution of 673 mg (1.86 mmol) of para-nitrobenzyl-6o / - 1- (R) -OKCH3Tmi J- 3,7-dioxo-1-azabicyclo (3.2.0) hept-2-ene -2-carboxylate (compound I) in 10 ml of acetonitrile is cooled in a nitrogen atmosphere. A solution of 245 mg (1.90 mmol) of diisopropylethylamine in 1 ml of acetonitrile is added, and then 510 mg (1.90 mmol) of diphenylchlorophosphate in 1 ml of acetonitrile are added dropwise over 2 minutes. The resulting solution was stirred for 15 minutes to obtain 3- (diphenylphosphoryloxy) -6o (-1- (R) -oxy-ethyl J-7-OKCO-1-azabicyclo (3,2,0) para-nitrobenzyl ester). hept-2-en-2-carboxylic acid. To this solution was added a solution of 245 mg (1.90 mmol) of diisopropylethylamine in 0.5 ml of acetonitrile, and then a solution of 270 mg (2.16 mmol) of 4-mercaptomethylpyridine in 0.5 ml of acetonitrile. The reaction mixture is stirred at 60 minutes and the white precipitate formed is collected by filtration, washed with 5 ml of ice-cold acetonitrile and 660 mg is obtained (yield 76%) P-nitrobenzyl-3- (pyridin-4-yl-methanethio) -6o (-1- (R) -oxyethyl 3-7-oxo-1-azabicyclo (3,2,0) hept-2-en- 2-carboxylate in the form of white crystals, mp, 145 ° C.
Calculated: C 58.01; H 4.56; N 9.23; S 7.04. , N /) S
Found: C 57.74; H 4.56; N 9.58; S 7.21.
To a solution of 660 mg (1.41 mmol) of intermediate 2 in 140 mp of acetone was added 5 ml of methyl iodide. The reagent solution is stirred at 25 ° C for 8 hours. The solvent is introduced under vacuum and a pale yellow solid is obtained, which is triturated with diethyl ether and 779 mg (yield 90%) of p-nitrobenzyl-3- (L-methylpyridin-4J 1D are obtained
Il-metathio) -Hhz (-H1- (K) -oxyethyl 1-7-oxo-1 azabium 1klo (3, 2, 0) hept-2-ene-2-carboxylate as a white amorphous solid, m.p. . (g decomposition).
Calculated: C, 44.39; H 4.22; N 6.82; S 5.20.
C2EH24MeOBZ E20
Found: C, 44.66; H 4.0; N6.84; S 5.64.
B. To a solution of 779 mg (1, 27 mmol) of compound 3 in a mixture of tetrahydrofuran water - diethyl ether (80 ml - 80 ml - 100 mA), 140 mg (1.4 mmol) of potassium bicarbonate and 125 mg (0.7 mmol a) dipotassium phosphate. Then, 700 mg of 10% palladium on carbon was added and the mixture was hydrogenated at 2.8 atm for 45 minutes in a Parr era. The mixture is then filtered and the catalyst is washed with water (2x10 ml). The combined filtrate and washings were extracted with diethyl ether (150 ml), lyophilized, and a brown powder was obtained. This crude compound is purified on a reverse phase column with 30 g of C jBONDAPAK (Water Associates), eluting with water at a pressure of 0.56 atm. Each fraction (20 ml) was analyzed by high pressure liquid chromatography, the UV absorbing fractions of 300 nm were collected, lyophilized, and 135 mg (32% yield) of the title compound 4 was obtained as a slightly yellow solid.
Example 2, Method of obtaining 3- (H-methylpyridin-4-yl-ethanethio) 1- (i) -oxyethyl} -7-oxo-1-azabicyclo- (3,2,0) hept-2-en-2- carboxylate.
A. A suspension of 1.1 g (2.93 mmol) of DI ((K) -oxyethyl 3-4 (3-diazo-Z-P-nitrobenzyloxycarbonyl-2-oxopropyl) azetidin-2-one in 30 ml of dry benzene for The mixture is purged with nitrogen at room temperature for 5 minutes. 25 mg of dimer rhodium acetate is treated with it and the mixture is heated under reflux for 45 minutes. The warm solution is diluted with ethyl acetate (25 ml), the catalyst is removed by filtration, the residue is dried. p-nitro-benzyl-6-1- (R) -oxyethyl J-3,7-dioxo-1-azabicyclo (3,2,0) hept-2-ene-carboxyl silate is obtained. This compound is dissolved in ; ho acetonitrile (20 ml ) and cooled to -10 ° C. To this solution, while flushing with nitrogen, add 417 mg (3.2 mmol) of diisopropylethylamine, and
Q
g p 5 about

0
five
0
08
then 810 mg- (3.0 mmol) diphenyl.:; (p phosphate, and the reaction smelt is stirred at for 20, then the reaction mixture is treated with diisoproglylamine (420 pg, 3.2 mmol) and 2- (4-pyridyl) ethanethiol (560 mg, 4.03 mmol) in 2 ml of acetonitrile. The reaction mixture was stirred at -5 to -10 C for 1 h, then diluted with methylene chloride (100 mg) and thoroughly washed with brine - ( 1: 1), 4% phosphoric acid, 5% sodium bicarbonate, water and brine. The organic phase is dried (over magnesium sulphate), evaporated and a white solid is obtained. This solid is washed with a mixture of diethyl ether - hexane (1: 1), cyuiai over a high vacuum and gives 901 mg (63.9%) of P-nitrobenzyl-3-Iv-methylpyridin-4-yl-ethantio -bcf - (1- (R) -oxyethylJ-7-OXO-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate.
B. Suspension of Carbapenem obtained in Step A (890 mg, 1.85 mmol)
and 7 ml of iodomethane in 200 ml of dry acetone and 12 ml of methylene chloride are stirred at 25 ° C for 24 hours. The reaction mixture forms a clear solution in 18 hours. The solvent is removed under reduced pressure, the residue is washed with diethyl ether and 920 mg (1 , 48 MMOLE} 79.8%) 3- (N-methylpyridin-4-Sh1-ethantio) -6B (- f1- (R) -oxyethyl-3-oxo-1-azabicyclo (3,2,0) - hept -2-o1; -2-carboxylate as a solid foam.
C. Carbapenem from stage B (920 g,
1.47 mmol) is dissolved in 90 ml of tetrahydrofuran, 90 ml of diethyl ether and 90 ml of water and treated with 265 g (1.51 mmol) of dipotassium phosphate, 190 mg (1.9 mmol) of potassium bicarbonate and 800 mg of 10% - Palladium on coal. Hydrogenation is carried out at 3.15 atm for 1 hour. The filtrate is filtered on
. CELITE and washed with diethyl ether (3x25 ml). The aqueous layer was lyophilized to give a brownish compound, which was then chromatographed twice on a reverse phase column with 12 g of C fi / C (jBONDAPAK (Waters
 Associates) using water as eluent, and 55 mg of 3- (N-methylpyridin-4-yl-ethanthio-6c G1 - (R) -oxyethyl 1-7-OXO-1-azabicyclo- (3,2,0 ) hept-2-e-carboxylate
7
Example 3. Preparation of 3- (N-methylpyridin-3-ylmethanto) 1- (R) - hydroxyethyl-7-oxo-1-azabicyclo (3,2,0) - hept-2-ene-2-carboxylate.
A.Para-nitrobenzyl ester of 3- (pyridin-3-yl-methylthio) (K) -oxoxyethyl-7-oxy-1-azabicicyclo (3,2,0) - hept-2-en-2-carboxic acid .
To a cooled (Oh C) solution of 925 mg (2.66 mmol) of p-nitrobenzyl-3,7-dioxo-1- (K) -oxyethyl 3 1-azabicyclo (3,2,0) -heptan-2- carboxylate in
14 ml of acetonitrile was added a solution of 377 mg (2.9 mmol) of diisopropylethylamine in 1 ml of acetonitrile, and then a solution of 786 mg (2.9 mmol) of diphenyl chlorophosphonate in 1 ml of acetonitrile under a nitrogen atmosphere. The resulting solution is stirred at 0 ° C for
15min, and then a solution of 377 mg (2.9 mmol) of 3-mercaptomethylpyridine in 2 ml of acetonitrile is added. The reaction solution was stirred for
90 min at The precipitate is collected by filtration, washed with 20 ml of acetylacetate and 950 mg (60% yield) of the title compound are obtained as white crystals.
Calculated: C 58.01; H N 9.23; S 7.04.
.
Found: C57.19; H 5.19; N 8.76; S 7.08.
B. Preparation of 3- (H-methylpyridin-3-yl-methantio) -6o {-1- (K) -oxyethyl-7-oxo-1-azabicyclico (3.2.2) hept-2-encarboxylate.
To a solution of 730 mg (1.56 mmol) of the obtained compound in 120 ml of acetone was added 5 ml of methyl iodide and the reaction mixture was stirred for 18 hours at room temperature. The precipitate was collected by filtration, washed with acetone (10 ml) and 940 mg (yield 100%) of pyridine-quaternized sodium 3- (H-methylpyridin-3-yl-methantio-6o (-1 - (R) -oxyethyl J-7) were obtained. - oxo-1-azabitsyklo (3,2,0) hept-2-en-2-carboxylate - in the form of a pale yellow powder.
Calculated: C 46.24; H 4.05; 7.03; S 5; 37.
4.65;
N
q, H2, N ,, i,
Found: C 45.82; H4.11; N6.87; S 6,10.
To a solution of 933 mg (1.6 mmol) of the obtained compound in 90 ml of tetrahydrofuran and 90 mp of ether is added
ten
20

25
493108
200 mg
eight
Khcoj then
thirty
45
50
55
130 ° C (once again, H 5.44;
H 349 mg of KjHPO in 90 cpn of water, and then 1.0 g of palladium on carbon. The mixture is hydrogenated at 3.15 atm in a Parr shaker for 45 minutes. The mixture is filtered on a layer of CELITE and the catalyst is washed with water (2x10 ml). The combined filtrate and washings are extracted with dimethyl ether (2x100 mp), lyophilized, and a yellow solid is obtained, which is purified on a reverse phase column with 8 g C., Waters Associates and eluted with 5% acetonitrile in water at a pressure of 156 atm. Each fraction of 15 MP is analyzed by high pressure liquid chromatography; fractions absorbing UV at 300 nm are collected, lyophilized, and 230 mg (43% yield) of the title compound are obtained as pale yellow crystals, etc. .
Calculated: C, 51.87; N 7.56.
C ,, H ,,, - H, jO
Found: C 51, 95; H 5.66; N 7.56.
Example 4. Preparation of 3- (N-Methylpyridin-2-yl-methantio) -6 rit- 1 - (R) -oxyethyl J-7-oxo 1-azabiciclo (3.2.0) - hept-2- en-2-carboxylate.
A. Para-nitrobenzyl-3- (pyridin-2-yl-methantio)) - hydroxyethyl J-7-oxo-1-azabiciclo (3,2,0) hept-2-en-2-carboxylate.
To a cooled (0 ° C) solution of 925 mg (2.65 mmol) p-nitrobenzyl-3,7-dioxo-1- (K) -oxyethyl-1-azabitziclo (3, 2.0) heptane-2-carboxylate a solution of 377 mg (2.92 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added to 15 ml of acetonitrile, and then 786 mg (2.90 mmol) of diphenylchloro-phosphate in 1 ml of acetonitrile in a nitrogen atmosphere. The resulting solution was stirred for 15 minutes, a solution of 377 mg (2.92 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added, followed by a solution of 350 mg (3.0 mmol) of 2-mercaptomethylpyridine in 1 ml of acetonitripe. The reaction solution is stirred for 2 hours at -H. The precipitate was collected by filtration, and washed with 20 ml of methyl chloride and yield 650 mg (54% yield) of the title compound as a yellow powder.
Calculated: C 58.01; H 4.65; N 9.23; S 7.04.
35
40
.
Found: C 57.56; H4.92; N8.94; S 7.03,
B. Preparation of 3- (L-methylpyrndin-2-yl-methantio) -6o ((K) oxystil J-7-oxo-1-azabicyclo (3.2.0) hept-2-en-2-carboxylate.
To a solution of 650 mg (1.39 mmol) P-nitrobenzyl-3- (pyridin-3 -yl-methane thio) -6o (-1- (K) -oxyethyl J-7 Oxo-1-azabicyclo (3.2, 0) hept-2-en-2-carboxylate in 100 ml of acetone is added
4 ml methyl iodide. The reaction mixture is stirred for 3 days at room temperature. The precipitate is collected by filtration, washed with acetone (10 ml) and 500 mg (60% yield) of the quaternized pyridine-rhodium salt of 3- (L-methylpyridin-2-yl-methantio) without (-1- (R) -oxyethyl J- 7-oxo-1-azabicyclo (3,2,0) hept-2-en-2-carboxylate - as a pale yellow solid.
Calculated: C 46.24; H 4.05; N 7.03; S 5.37.
. ,,
Found: with 45.62; H4.27; N6,80;
55.30.
To a solution of 1.0 g (1.167 mmol) of the obtained compound in 90 ml of tetrahydrofuran and 90 ml of diethyl ether were added 215 mg (2.15 mmol) of KHCOj and 374 mg (2.1 mmol) of KjHPO B with 90 ml of water, and then 1 g of 10% palladium on the ugda. The mixture was hydrogenated at 3.15 atm on a Parr shaker for 45 minutes. The mixture is filtered through a layer of WASTE and the catalyst is rinsed with water (2x10 ml). The combined filtrate and washings were extracted with diethyl ether (2x200 ml), lyophilized, and a yellow solid was obtained, which was purified on a reverse phase column with 10 g C, by Waters Associates at a pressure of 0.56 atm using as eluent a 5% aqueous solution of acetonitrile in water. Each fraction of 15 ml was analyzed by high pressure liquid chromatography, the fractions having UV absorption at 300 nm were collected, lyophilized, and 390 mg (yield 44%) of the indicated product was obtained. By recrystallization of this compound from a mixture of water - acetone - ethanol, thin needles, T-PL, are obtained. 194-196 4: (with decomposition).
.
o
five
0
five
0
five
0
five
O
five
. Calculated: C, 51.87 and 5.44; N 7.56.
CtsH2gNjO S, .2H
Found: C, 51.37; H 5.69; N7.37.
Example 5. Preparation of 3- (N-methylpyridin-2-yl-ethantio) -6o (- (, 1- (R) - hydroxyethyl J-7-OKCO-1-azabicyclo (3.2.0) - hept-2 en-2-carboxylate.
A.Para-nitrobenzyl-3- (pyridine-2-yl-ethantio) -6o ((K) -oxyethyl J-7-oxo-1-azabicyclo (3,2,0) hept-en-2-carboxylate.
To an oxidized fy solution of 1.78 g (5.0 mmol) of p-nitrobenzyl-6c / - 1- (R) - hydroxyethyl J-3,7-dioxo-1-azabicyclo (3,2,0) hept-2 -en-2-carboxylate in 25 ml of acetonitrile was added 710 mg (5.5 mmol) of diisolpropylethylamine in 1 ml of acetonitrile, and then 1.4 g (5, and mmol) of diphenylchlorophosphate in 1 ml of acetonitrile in a nitrogen atmosphere.
The resulting solution is stirred for 20 minutes at 0 ° C, a solution of 710 mg (5.5 mmol) of diisopropylethylamine in 1 ml of acetonitrile is added, followed by a solution of 850 mg (6.1 mmol) of 2-mercaptoethylpyridine in 2 ml of acetonitrile. The reaction mixture is stirred for 60 minutes at. The precipitate was collected by filtration, washed with methylene chloride (20 ml), and 1.3 g (57%) of the title compound were obtained as a yellow solid.
B. Preparation of 3- (N-methylpyridin-2-yl-ethantio) 1g (K) -oxyethyl-7-o-co-1-a-zabicyclico (3, 2, 0) hept-2-en-2-carboxylate .
To a suspended solution of 800 mg (1.7 mmol) of the obtained compound in 50 ml of acetone was added 5 ml of methyl iodide. The reaction mixture is stirred for 48 hours at room temperature. The precipitate is collected by filtration, followed by acetonitrile (15 ml) and 810 mg (76% yield) of quaternized pyridine iodide salt of 3- (H-metsh1Pyridin-2-yl-ethantio) 1- (R) -oxyethyl J-7-OKCO- 1-aabicyclo- (3,2,0) hept-2-en-2-carboxylate - in the form of a pale yellow powder.
To a solution of 790 mg (1.27 mmol) of the obtained compound in 100 ml of tetrahydrofuran and 100 ml of ether was added 100 MP buffer solution pH 7.0, and then 1.0 g of 10% palladium on carbon. The mixture is hydrogenated at 2.8 atm in a Parr shaker for 40 minutes. The mixture is filtered
n14
CELITE is applied to the bed and the catalyst is bubbled (2x10 ml).
The combined filtrate and washings are extracted with ether (3x100 ml, lyofi.p. — and a yellow powder is obtained which is purified on a column with 30 g of CjgBOiroAPAK (Waters Associates) at a pressure of 0.56 atm, using 10% acetonite solution - Rila in water.
Each fraction of 15 ml was analyzed by high pressure liquid chromatography, the fractions having a UV absorption of 300 by them were collected and liOfilized and 65 mg (15% yield) of the title compound were obtained as a yellow powder.
Example 6. Obtaining 3- (N-. Prop1shpyridin-4-yl-methanethio) -6o (- (K) -oxyethylJ-7-oxo-1-aza6 and cyclo- (3, 2, 0) hept-2-en-2 carboxylate
A. Preparation of p-nitrobenzyl-3- (pyridin-4-yl-methantio) (1- (R) -oK-set1) -7-oxo-1-azabicyclo (3.2.0) - hept-2-ene -2-carboxylate.
A solution of 673 mg (1.86 mmol) of para-nitrobenzyl-BS 1 - (K) -oxyethyl 7-3,7-dioxo-1-azabicyclo (3.2.0) hept-2-E-2-carboxylate in 10 ml acetonitrile is cooled to -10 ° C in a nitrogen atmosphere. A solution of 245 mg (1.90 mmol of diisopropylethylamine in 1 ml of acetonitrile is added, and then a solution of 510 mg (1.90 mmol) of diphenylchlorophosphate in 1 ml of acetonitrile is added dropwise over 2 minutes. The resultant solution is stirred at 15 minutes and para-nitrobenzyl-3- (diphenylphosphoryloxy) 1 - (R) hydroxyethyl} -7-oxo-1-azabicyclo (3,2,0) - hept-2-ene-2-carboxy 1 1 is obtained. To this solution is added 245 mg (1.90 mmol) of diisopropylethylamine in Oj5 ml of acetonitrile, and then a solution of 270 mg (2.16 mmol) A-mercaptomethylpyridine in 0.5 ml of acetonitrile. Referring stirred at for 60 min, the resulting white precipitate was collected by filtration, washed with 5 ml of ice-cold acetonitrile to give 660 mg (yield 76%) of product as white crystals, T.SH1. 145 C.
Calculated: C 58.01; H 4.36; N 9.23; S 7.04.
Found: C 57.74; H 4.56; N9.58; S 7.21.
- d
j
0
;five
ZO 0
five
five
081 2
B. Preparation of the Robenzyl-3- (1-allylpyridin-4-yl-methanthio) -6o / - 1 - (K) -oxyethyl J-7-OKCO-1-azabicyclo (3,2,0) Hept Iodine Salt -2-ene-3-2 carboxylate.
To a solution of 900 mg (2.13 mmol) nitrobenzyl-3- (pyridin-4-yl-mntantio) -6o ((K) -oxyethyl-7-oxo-1-azabicyclo (3,2,0) -hept -2-en-2-carboxylate in 150 ml of acetone was added 2 ml of allyl bromide and 380 mg of sodium iodide. The mixture was stirred for 48 hours at room temperature, the solvent was evaporated under vacuum and a yellow solid was obtained. ml of acetonitrile, filtered, evaporated under vacuum and obtain 1.0 g (yield 87%) of the indicated product as a yellow solid.
Calculated: C 48.16; H 4.21; N 6.74; S 5.15.
Czf Z bOiSib
Found: C 48.55; H 4.46; N 6.69; S 5.15.
C. Preparation of 3- (1-propylpyridin-4-yl-methantio) (1- (R) -oxyethyl-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate,
To a solution of 1.27 g (2, T5 mmol) of the compound of stage B in 100 ml of tetrahydrofuran and 100 ml of ether were added 100 ml of buffer 7, and then 1.0 g of 10% palladium on carbon. The mixture is hydrogenated at 2.8 atm in a Parr apparatus for 40 minutes. The mixture is filtered on a layer of zeolite and the catalyst is rinsed with water (2x10 ml). The combined filtrate and industrial water is extracted with ether (3x100 ml), lyophilized, and a yellow powder is obtained, which is purified on a column of 40 g C, g BONDAPAK (Waters Associates) at 0.56 atm using 10% as eluent acetonitrile solution in water. The 15 ml fraction is analyzed by high pressure liquid chromatography, the fractions with UV absorption at 1300 nm are collected, lyophilized and 48 mg (6% yield) of the title compound are obtained as a yellow powder.
Calculated: C 54.52; H 6.10; N 7.07.
 -
Found; C 54.32; H 6.03; N 6.99.
Example 7. Preparation of 3- (N-methyl-3-metsh1pyridin-2-yl-methantio) (K) -oxyethyl} -7-oxo-1-azabicyclo (3,2,0) hept-2-ene- 2-carboxylate.
A. Preparation of 3-methyl-2-mercaptomethylpyridine.
A solution of 2.45 g (17.0 mmol) of 2-chloro methyl-3-methylpyridine and 1.37 g (18.0 mmol) of thiourea in 60 ml of absolute ethanol is boiled under reflux for 5 hours. By evaporation of ethanol and subsequent addition of ether, 3.08 g (yield 72%) of the isothiourea salt is obtained, which is dissolved in 10 ml of water containing 1.44 g (26 mmol) of sodium hydroxide. The solution is then heated under nitrogen for 5 minutes. The reaction mixture is cooled to 5 ° C, adjusted to pH 6.4 with acetic acid and extracted with ether (4 x 50 ml). The combined ether extracts are washed with 5% aqueous sodium bicarbonate and brine. The magnesium sulfate-dried solvent was scorched and 1.4 g (yield 83%) of 3-methyl-2-mercaptomethyl-pyridine was obtained as a yellow oil, which was used in the next step without further purification.
B. Preparation of p-nitrobenzyl-3- (3-methylpyridin-2-yl-methanethio) -6-6-1- (K) -oxyethyl-7-oxo-1-azabicyclo-3,2,0) hept-2- en-2-kabboksilata.
To a cooled (0 ° C) solution of 1.74 g (5.0 mmol) of p-nitrobenzyl-3,7-dioxo-1- (K) -oxyethyl} -1-azabicyclo (3.2.0) heptane -2-carboxylate in 25 ml of acetonitrile was added 960 mg (5.8 mmol) of diisopropylethylamine in 2 ml of acetonitrile, and then 1.4 g (5.8 mmol) of diphenylchlorophosphate in 2 ml of acetonitrile in a nitrogen atmosphere. The resulting solution is stirred for 20 minutes at 0 ° C, a solution of 760 mg (5.8 mmol) of diisopropylethylamine in 2 ml of acetonitrile is added, followed by a solution of 810 mg of 3-methyl-2-mercaptomethylpyridine in 3 ml of acetonitrile. The reaction mixture is stirred for 2 hours. The precipitate is collected by filtration, washed with acetone.
tonitrile and get 1.36 g (yield 66%) of the specified product as a white solid compound, so pl. 145.
Calculated: C 47.91; H 4.69; N 6.98; S 10.66.
, Ca4H7tNj03S,
Found: .C 47.72; H 4.34; N 6.72; S 11.22.
,
O 5 0 5
0
g 0
0
five
C, Preparation of 3- (X-myst. H-3-methylpyridin-2-yl-methanthis) -by-C1- (K) -oxn-ethyl-7-oxo-1-azabicyc. (3,2 , 0) hept-2-en-2-carboxylate.
To a solution of 680 mg (1.45 mmol) of the compound of stage B in 120 ml of methylene chloride was added 270 mg (2.33 mmol) of methyl fluorosulfonate. The reaction mixture is stirred for 3 hours at room temperature. The precipitate is collected by filtration, npohn.iBaJOT methylene chloride (5 ml) and 840 mg (yield 99%) of quaternized pyridine are obtained in the form of white crystals.
Calculated: D 49.14; H 4.47; N 7.13; S 11, 43.
Cj H NjOgG I
Found: C 49.56; H 4.16; N7.26; S 11.03.
To a solution of 810 mg (1.39 mmol) of the obtained 3- (N-methyl-3-methylpyridin-2-yl-methantio) - (K) -oxyethyl J-7-oxo-1-azabicyclo (3,2,0) hept-2-é-3-carboxylate fluorosulfonate in 100 ml of tetrahydrofuran and 100. ether add a solution of buffer pH 7.0 (100 ml), and then 750 mg of 10% palladium on carbon. The mixture is hydrogenated at 3.15 atm in a Parr apparatus for 60 minutes in a cold room (4-6 C). The mixture is filtered on a layer of celite and the catalyst is rinsed with ether (2x10 ml). The combined filtrate and washing solvent is extracted with ether (2x40 ml) is lyophilized and a yellow solid is obtained which is purified on a column of 20 g C, j VOSHARAK (Waters Associates) at 0.56 atm, eluting with 5% acetonitrile in water. Each fraction of 15 ml was analyzed by high pressure liquid chromatography, the fractions having a UV absorbance of 400 nm were collected, lyophilized, and 14 1 mg (yield 30%) of the indicated product were obtained as a yellow solid.
Calculated: C 57.85; H 5.85; N 7.94.
C., X "Ni04Sv 1/4 HjO
Found: C 58.60; H 5.86; N 7.87.
Example 8. Preparation of 3- (2-methyl-M-metsh1-Thiazol-4-yl-methantio) -bc-f 1 - (R) -oxyethyl J-7-OKCO-1-azabi-cyclo (3,2,0 ) heptane-2-carboxylate.
A. Preparation of p-nitrobenzyl-3- (2-methylthiazol-4-yl-methantio) -6o (- P (R) -oxyethyl-7-OKCO-1-azabicyclo- (3,2,0) hept-2- ene-2-carboxylate
To a cooled () solution of 1.4 g (4.0 mmol) of nitrobenzyl-3,7-dinoxo-1- (K) -oxy-ethyl 3-1-azabicyclo (3,2,0) heptane-2 g intermediate carboxylate in 12 ml of acetonitrile was added 0.83 MP (4.6 mmol) of diisopropylamine, and then 1.16 g (4.3 mmol) of diphenyl chlorophosphate in 2 ml of acetonitrile in a nitrogen atmosphere. The resulting pacfBop is stirred at 30 minutes to obtain para-nitrobenzyl-3- (diphenylphosphoryl-1: i) -6c / - 1- (K) -oxyethyl-7-oxo-1-azabicyclo- (3, 2,0) hept-2-en-2-carboxylate. To this solution was added a solution of 0.83 ml (4.6 mmol) of diisopropylethylamine in 2 ml of acetonitrile, and then a solution of 0.62 g (4.2 mmol) of 2-methyl-4-mercaptomethylthiazole in 3 ml of acetonitrile. 20 The reaction solution is stirred at 40 minutes. The precipitate is collected, washed with 30 ml of ether to obtain 943 mg of the title compound of stage A as a white solid.
B. Preparation of 3- (2-methyl-N-methyl-thiazol-4-yl-methanethio) - (R) -oxyethyl 1-7-oxo-1-azabicyclo (3,2,0) hept-2- en-2-carboxylate .30
To a solution of 525 mg (1.1 mmol) of the compound of stage A in 20 ml of methylene chloride, 0.27 ml (3.3 mmol) of methyl fluorosulfonate was added. The reaction mixture is stirred for 90 min. J at room temperature. The precipitate is collected by filtration, washed with methylene chloride (50 ml) and 650 mg (yield 100%) of quaternized thiazole are obtained, which is used in the next step without further purification.
To a solution of 3- (2-methyl-N-methyl-thiazol-4-yl-methanethio) -1- (R) -oxyethyl J-7-OKCO-1-azabicyclo (3.2.2) heptane- 2-carboxylate in j 100 ml of tetrahydrofuran and 100 ml of zofir added 100 ml of buffer solution pH 7.0, and then 500 mg of 10% palladium on carbon. The mixture is hydrogenated at 2.45 atm in a Parr apparatus for 45 minutes. The mixture is filtered through a pad of celite and the catalyst is washed with water.
P
50
-.
COipNB
- p) - | o ro- 1- to- | 5 ml n-. 20 R aa ia about 25
- cipt- 30
yo-) j th
) - j i- o ri y
50
-.
(2x10 megapixel). The combined filtrate and npoMiifflHLie of water are hydrated with ether (2x100 ml), lyophilized, and a yellow powder is obtained, Koropbrii is purified on a reversed-phase column with 8 g C, gBONDARAC (Waters Associates), eluted with 5% solution of hydrochloric acid in water at 0 g pressure 5b atm. Each fraction of 15 ml is transfected using high pressure liquid chromatography, fractions, bar. UV at / d 300 them, collect, lyophilize and get 145 mg (yield, 48%) of the indicated n heading stage B of the compound in white); o-zhs: light powder.
Calculated: C 46, j; H 3.64: N 7.17; S 16.41.
CyjH, gN ,, O S2-2H, 0
Found: C, 46.50; H 5.26; N 7.13; S 16.20.
Example 9. Preparation of 3- (N, N-dimethyl-p1-dazol-2-yl-methanethio) -6o (-C1 - (R) -oxyethyl J-7-OKCO-1-azabicyclo- (3,2,0) hept-2 -e1: -2-carboxylate.
A. Preparation of 2-g.1ercaptomethyl-methylimidazole.
7.1 g (60 mmol) of N-acetylthiourea are added to a solution of 10.4 g (58 mml) of 2-chloromethyl-N-methylimidazole in 200 ml of acetonitrity and the reaction mixture is refluxed. 90 min. The precipitate is filtered off, washed with acetonitrile (20 ml) and an ichocuring salt is obtained, which is dissolved in 120 ml of ethanol and refluxed for 18 hours under nitrogen. The reaction mixture is cooled to room temperature, concentrated under a volume of approximately 60 ml, and the precipitate is removed by filtration. By evaporation of the filtrate under vacuum, 2-mercaptomethyl-methyl imidazole is obtained as a yellow oil, which is used in the next step without further purification.
B. Preparation of p-nitrobenzyl-3- (N-methylimidazol-2-yl-methantio) -6c ((K) -oxyethyl J-7-oxy-1-azabicyclo- (3,2, O) hept-2-ene -2-carboxylate.
Q ip (o "V
HCt (I)
To a cooled () solution of 7.24 g (20.3 mmol) of the intermediate (I -nitrobenznl-3,7-dioxo-1- (K) -oxyethyl -1-azabicyclo (3,2,0) heptane-2 - carboxylate in 35 ml of acetonitrile was added a solution of 2.8 g (21.3 mmol) of diisopropylethylamine in 2 ml of acetonitrile, and then 5.5 g (20.4 mmol) of diphenyl chlorophosphate in 2 ml of acetonitrile 10 in a nitrogen atmosphere. the solution is stirred for 15 minutes and then a solution of 4.1 g (3.0 mmol) of diisopropylethylamine in 2 ml of acetonitrile is added, after which 15 are added 4.6 g (31.0 mmol) of thiol 32. The reaction mixture is left shuffle s at 60 min. The white precipitate was collected by filtration, promshayut metshgenhloridom (20 mL) and 20, 6.6 g (71% yield) of the title product as a white solid, mp 142 C.
Calculated: C 52.18; H 4.79; N 11.59.
CiiH-j N O S ,.
Found: C, 52.22; H 4.91; N 12.16.
C. Preparation of 3- (N, N-dimethylimide 25
with ether (3x100 ml), lyophilized, and a yellow amorphous powder is obtained, which is purified on a column of 30 g of C HOSPITAL (Waters Associates) at 0.56 atm using a 10% aqueous solution of acetonitrile in water as eluent. Each 20 ml fraction was analyzed by high pressure liquid chromatography, the fractions having UV absorption at 300 nm were collected, lyophilized, and 220 mg (yield 35%) of the title product of stage C was obtained as a yellow powder.
Calculated: C, 51.68; H 5.67; N 12.06; S 9.50.
  Hjo
Found: C 49.93; H 5.94; N 11.46; S 9.03.
Example 10. Preparation of 3- (2,3, 4-trimethylthiazol-5-yl-methantio) -6c / - 1- (K) -oxyethyl J-7-OKCo 1-azabicyclo- (3, 2.0) hept- 2-en-2-carbox lata.
A, Preparation of 2,4-dimethyl-5-mercapto-methyl thiazole.
To a solution of 4.8 g (26.0 mmol) of 5-chloromethyl-2-methylthiazole in 50 ml of absolute ethanol is added
for 18 hours. The precipitate is collected by filtration, washed with ether (20 ml) and an isothiuronic salt is obtained, which is dissolved in 22 ml of 1N. NaOH and heated at 100 ° C for i min in a nitrogen atmosphere. Then the reaction mixture is cooled to room temperature, adjusted to pH 7.0 with 1N "
sol-2-yl-methantio) -6s / - 1 - (K) -oxyethyl J-7-oco-1-azabicyclo (3.2.0) hept-30 2.4 g (30 mmol) thiourea. Reaction of 2-ene-2-carboxylate. The mixture is boiled with a reverse holoC suspended solution of 1, 34 g (3.0 mmol) of the compound obtained in Step B, in 2/0 ml of acetone is added 20 ml of methyl iodide. The reaction mixture is stirred for 4 days at room temperature.
The precipitate is collected by filtration, washed with acetone (20 ml) and 1.70 g (yield 96%) of quaternized 40 are obtained, extracted with ether (3 × 50 ml), imidazole — sodium 3- (S, M-dimethyl).
water, brine, and dried over magnesium sulfate.
By evaporation of the dry solvent d5, 780 mg (49% yield) of thiol are obtained in the form of a colorless oil, which is used in the next stage without further purification.
at. Preparation of p-nitrobenzyl-3- (2,4-dimethylthiazol-5-yl-methanethioX-6o (-1- (K) -oxyethyl-7-oxy-1-azabicyclo- (3.2, 0) hept-2- en-2-carboxylate. To a cooled (0 ° C) solution 1, A g (4.0 mmol) of the intermediate ketone compound (Example 9, step B), 610 mg (4.7 mmol) of diisopropylethylamine were added to 25 ml of acetonitrile at
imidazol-2-yl-methantio) C1 - (R) - oxyethyl J-7-oco-1-azabicyclo (3,2, 0) hept-2-ene-carboxylate - in the form of yellow crystals, so pl. 175-177 C.
Calculated: C, 43.08; H 9.60; N 5.48.
.
Found: C 43.02; H 9.02; N 5.44.
To a solution of 1.30 g (1.86 mmol) of the obtained compound in 120 ml of tetrahydrofuran and 120 mp of ether, 120 ml of buffer pH 7.0 were added, and then 900 mg of 30% palladium on celite. The mixture is hydrogenated at 2.8 atm in a Parr apparatus for 40 minutes. The mixture is filtered on a layer of celite and the catalyst is 50
55
water (2 x 1.5 ml). The combined filtrate and industrial waters are extracted
0 5 0
five
with ether (3x100 ml), lyophilized, and a yellow amorphous powder is obtained, which is purified on a column of 30 g of C HOSPITAL (Waters Associates) at 0.56 atm using a 10% aqueous solution of acetonitrile in water as eluent. Each 20 ml fraction was analyzed by high pressure liquid chromatography, the fractions having UV absorption at 300 nm were collected, lyophilized, and 220 mg (yield 35%) of the title product of stage C was obtained as a yellow powder.
Calculated: C, 51.68; H 5.67; N 12.06; S 9.50.
  Hjo
Found: C 49.93; H 5.94; N 11.46; S 9.03.
Example 10. Preparation of 3- (2,3, 4-trimethylthiazol-5-yl-methantio) -6c / - 1- (K) -oxyethyl J-7-OKCo 1-azabicyclo- (3, 2.0) hept- 2-en-2-carbox lata.
A, Preparation of 2,4-dimethyl-5-mercapto-methyl thiazole.
To a solution of 4.8 g (26.0 mmol) of 5-chloromethyl-2-methylthiazole in 50 ml of absolute ethanol is added
for 18 hours. The precipitate is collected by filtration, washed with ether (20 ml) and an isothiuronic salt is obtained, which is dissolved in 22 ml of 1N. NaOH and heated at 100 ° C for i min in a nitrogen atmosphere. Then the reaction mixture is cooled to room temperature, adjusted to pH 7.0 with 1N "
  extracted with ether (3x50 ml), the combined ether phases are washed
1 ml of acetonitrile, and then 1.15 g (4.3 mmol) of diphenylchlorophosphate in 1 ml
acetonitrile in the nitrogen atmosphere. The resulting solution is stirred for 20 minutes at 0 ° C and a solution of 610 mg (4.7 mmol) of dinzoprogilmethylamine in 1 ml of acetonitrile is added, after which 750 mg (4.7 mmol) of the resulting thiol in 2 ml of acetonitrile is added. The reaction mixture is stirred for 3 hours at. The precipitate was collected by filtration, washed with 20 ml of methylene chloride, and 1.14 g (61% code) of the title compound were obtained as a white solid.
Calculated: C 53.73: H 4.71; N 8.57; S 13.44.
 2
Found: C 53.97; H 4.74; N8.58; S 13,10.
C. Preparation of 3- (2, 3,4-trimethylthiazol-5-yl-methantio) -6c / - C1 (R) -oxy-ethyl jf-7-oxo-1 - azabicyclo (2.2.0) hept- 2-en-2-carboxylate.
To a solution of 1.97 g (4.0 mmol) of the compound of stage B in 180 ml of methylene chloride was added a solution of 0.98 ml (13 mmol) of methyl fluorosulfonate in 2 ml of methylene chloride. The reaction mixture is stirred for 70 minutes at room temperature. The reaction mixture was poured into a solution of ether (400 ml and n-pentane (100 ml). The precipitate was collected by filtration, washed with 20 ml of ether, and 1.6 g (yield 65.5%) fluorosulfonate 3- (2.3.4 ) -trimethyl-thiazole-5-sh: -methanto) -6c (- C1- (K) -oxyethyl} -7-oxo-1-azabicyclo (3,2,0) hept-2-encarboxylate (quaternized - azole) in the form of a white amorphous powder.
Calculated: C 45.09; H 4.44; N 6.86.

Found: C, 44.50; H4.38; N 6.58.
To a solution of 1.0 g (1.72 mmol) of the obtained compound in 100 ml of tetra-idrofuran and 100 mp of ether were added 100 ml of a buffer solution of pH 7.0, and then 1.0 g of 10% palladium on carbon. The mixture is hydrogenated in a Parr apparatus at a pressure of 2.8 atm for 40 minutes. The mixture is filtered on a layer of celite and the catalyst is washed with water (2 x 10 ml). The combined filtrate and washes were extracted with ether (3x x 100 ml), lyogized, and a yellow powder was obtained, which was purified on a 40 g column of Cj BONDAPAK (Waters Associates) at a pressure of 0.56 atm,
,,
15

-, "
25) 35
5 Yu
45
use as eluent 10% -1% solution of acetoningril in the hearth.
Each 15 ml fraction was analyzed by high pressure liquid chromatography and the fractions having a UV absorbance of 300 were collected, lyophilized, and 31 5 mg (50% yield) of the title compound was obtained as a yellow solid.
Calculated: C 48.25; H 6.09; N 7.79.
C, UN, s043 - 2N20
Found: C, 47.96; H 5.83; N 7.89.
Example 11. Preparation of 3-f2- (N-methylthiazoliummethylthio) ((E) -hydroxyethyl J-7-OKCO-1-azabicyclo (3, 2, 0) hept-2 en-2-carboxylate.
A. Poluchrgie 2-mercaptomethylthiazole.
To the solution: -LnopncToro thionyl 3.81 ml (0.052 mmol) in chloroform (30 ml) was added at room temperature 3.60 g (0.026 mmol) of hydroxymethylthiazol, after which the reaction mixture was heated for 2 hours at 50 ° C. Chloroform was distilled off in a vacuum, resulting in a brown solid that was dissolved in 30 ml of absolute ethanol. Then to the resulting solution was added 2.04 g of thiourea. The reaction mixture is heated at reflux for 18 hours. The precipitate is collected by washing and washed with ethanol and ether to obtain 3.4 g (yield 55%) of the isothiouronium salt. Salt the isothiouronium solution with 30 ml of water and purge with nitrogen the resulting solution for 20 minutes. Then, 1.10 g (0.027 mmol) of sodium hydroxide is added to it and the mixture obtained is heated at 100 ° C for 2 minutes, the pH of the solution cooled to 0 ° C is adjusted to 6.0 with acetic acid, after which extraction with two portions of PO 35 Mil ethyl acetate. The organic layer was dried over magnesium sulphate and dispersed in vacuo to yield 0.75 g (yield 42%) of 2-mercaptomethylthiazole as a yellow oil, which was used without special purification.
at. Preparation of p-nitrobenzyl- 3- (2-thiazolmethylthio) -6о {- C1- (I) -hydroxyethyl J-7-OKCO-1-azabicyclo (3.2, 0) - hept-2-y-2- carboxylate.
To a cool down to 0 ° C solution of 1.4 g (4.0 mmol) of the keto derivative (. Example 9, stage A) in 8 ml of acetoitrile, first 0.79 ml (4.4 Å) of diisopropylethylamine is added, and then 1.17 g (4.4 mmol) of diphenyl chlorophosphate in a nitrogen atmosphere. The solution was stirred at 0 ° C for 30 minutes, resulting in p-nitrobenzyl-3- (diphenylphosphoryl-oxy) -6o (-C1 - (K) -hydroxyethyl) 3-7-oxo-1-azabitzne (3 , 2.0) hept-2-en-2-carboxylate. To this solution is added a solution of 0.79 ml (4.4 mmol) of di-isopropylethylamine in 2 ml of acetonitrile, after which a solution of 0.72 g thiol (prepared according to stage A) in 2 ml of acetonitrile. The reaction mixture was stirred for 6 minutes at which it was then diluted with 50 ml of ethyl acetate and washed with 30 ml of water, 20 ml of a 10% aqueous solution of phosphoric acid and 30 ml of brine After distilling off the solution, dried with magnesium sulfate, a crystallization solid is obtained, which is triturated with ether to obtain 782 mg (yield 42%) of the title product as a white crystalline product, mp 158-160 ° C .
Calculated: from 52.05; H 4.15; N 9.10; S 13.89.
C / goH fgWjO Sj
Found: C, 52.35; H 4.40; N 8.72; S 13.90.
C. Preparation of 3- 2- (L-methylthiazolium) methylthio (-Cl - (R) -hydroxyethyl 7-OXO-1-azabicyclo (3,2,0) hept-2-e-2-carboxylate.
To a solution of 782 ml (1.36 mmol) of compound 6 (stage B) in 55 ml of methylene chloride, 0.5 ml of methyl fluorosulfonate is added and the resulting reaction mixture is stirred for 90 minutes at room temperature. The precipitate is collected by filtration and washed with methylene chloride ( 30 ml) and ether (20 ml), resulting in 630 mg of ZCH2- (L-methylthiazr) -methyl-thioJ-6o / - 1- (R) -oxy-ethyl J-7-OKCO-1-azabicyclo (3.2 , 0) hept-2-en-2-carboxylate fluorosulfonate (crude quaternized thiazole), which is used in the next stage without further purification.
To a solution of this compound in 140 tetrahydrofuran and 120 ml of ether is added 140 ml of pH buffer solution
Q 5 0 p
five
five
0
five
7.0, and then 6jO-c-south-mstch pll; - di on actirophia (1G in r-le. The resulting mixture is hydropersed n; ut hydrogen pressure 30 () u1P- / kp. lyim (2.11 kg / cmM on the Parr apparatus for 35 min. Then the mixture is filtered and washed catalyst in two portions of 10 ml of water. The combined filtrate and industrial water are extracted with two 150 ml portions of ether and lyophilized to obtain a yellow powder. The crude yellow powder is purified on a column filled with 1 ml of 7 g C “BONDAPAK (reverse phase, firm Waters Associates), using 5% solution of acetonitrile in water at a pressure of 8 psi for elution lyuim (0.56 kg / cm). Each of the 15 ml fractions is examined by high-pressure liquid chromatography. The fractions are absorbed, and it is collected in an ultraviolet region at 11 ° -L and lyophilized to obtain 23 mg ( yield 5%) of the title compound as an amorphous solid with a yellow color.
Example 12. Preparation of (RS) -methyl-Mmetippir-Vdin-3-yl-me-. tantio-6o (-C1- (K) -hydroxyethi1-1-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate.
A. Preparation of p-nitrobenzyl-3- 1- (RS) -methylpyridin-3-yl-methantio -6o (- (1- (R) -hydroxyethyl} -7-oxo-1-azabocyclo (3.2, 0) hept-2-en-2-carboxylate.
754 mg (5.8 mmol) of diisopropylethylamine in 1 ml of acetonitrile are added to a solution of 1.85 g (5.3 mmol) of the keto derivative (Example 9, stage A) cooled to 0 C in 1 ml of acetonitrile, then solution 1 is added. , 57 g (5.84 mmol) of diphenyl chlorophosphate in
2ml acetonitrile in the atmosphere aloti. The resulting solution was stirred at 0 ° C for 15 minutes, after which a solution of 754 mg (5.8 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added, and then 814 mg (5.8 mmol) of 4- (1-mercaptoethyl) -pyridine in 2 ml of acetonitrile. The resulting reaction mixture was stirred at 0 ° C for
3 hours, after which the reaction mixture is diluted with 200 MP of ethyl acetate and subsequently washed with 200 ml of ice-cold brine, 200 ml of water,
100 ml of an aqueous solution of bicarbonate.
and 100 ml of brine. After drying over magnesium sulfate and distilling off the solvent, a yellow oil is obtained, icoTopoe is subjected to chromatographic purification by chromatography on a column filled with silica gel, using a mixture of 50% acetone and 50% methylene chloride, to elute, to give 1.65 g of the title product. in the form of a yellow solid.
Calculated: C 58.83; H 4.94; N 8.95; S 6.83.
С2зН, ЗН., 0,, 5,
Found: C 57.15; N 5.04; N 8.26; S 6.78.
B. Preparation of 4- (l-mercaptoethyl) -pyridine.
To a solution of 25 g of 1- (4-pyridyl) ethanol in 100 ml of chloroform is added 50 g of thionyl chloride. The reaction mixture is heated under reflux for 2 hours. After distilling off the solvents in vacuo, 1- (4-pyridyl) -chloroethane is obtained in the form of a semi-liquid mass, which is used in the next stage without further purification. Then a hot solution of 14.4 g of thiourea in 75 ml of ethanol is added to a solution of this compound in 160 ml of ethanol. The reaction mixture is heated under reflux for 18 hours. The ethanol is then distilled off and the resulting residue is dissolved in 100 ml of water, until the pH of the resulting solution is equal to 10 using 2N. sodium hydroxide. The resulting mixture was stirred at room temperature for over 90 minutes, adjusted to 6.0 by adding 6 n. HC1 and extracted with ether (two portions of 200 ml). After drying over magnesium sulphate and distilling off the solvent, a yellow oil is obtained, which is dispersed at a pressure of 5 mm Hg, and a fraction having a boiling point is collected. 60-65 ° C, resulting in 11.0 g (38% yield) of pure thiol — 4- (1-mercapto-ethyl) -pyridine as a colorless oil.
C. Preparation of (K8) -methyl-N-methylpyridin-3-yl-methantio (R hydroxyethyl} -7-oxo-1-azabicyclo (3,2,0) hept-2-en-2-carboxylate.
To a solution of 1.1 g (2.34 mmol) of the compound of stage A in 100 ml of acetone was added 10 ml of methyl iodide. Pe0
five
0
five
0
five
0
five
0
five
in 120 ml of tetra is added
Stir the mixture, stir for 18 hours at room temperature. The precipitate was collected by filtration and washed with 10 ml of x-methylene chloride to obtain 1.4 g (yield 100%) of p-nitrobenzyl-3-1 - (KjS) -ms tyl-M-methylpyridin-3-yl-me tantio J -podid 6cl-C1- (K) -oxy-3TnnJ-7-oKco-1-h on a bicycle (5.2.2) hept-2-en-2-carboxate (kplcrrnizirovannoe production /; ns, pyridine) in the form of a yellow powder.
Calculated: C 47.14; H 4.29; N 6.87; S 5.24.
C24H24 jOiSJ,
Found: C, 47.19; And 4.78; N 6.11; S 5.41.
To a solution of 1.45 g (2.37 mmol) of the obtained hydrofuran compound and 120 ml of 120 MP buffer solution pH 7.0, after which 1.5 g of 10% palladium on activated carbon are introduced. The resulting mixture is hydrogenated at a pressure of 45 psi (3.17 kg / cm2) in a Parr device for 60 minutes. Then the mixture is filtered through a layer of celite and a catalyst is watered with water (two portions of 15 ml each). Combine 1NG 1e filtrate and washings were extracted with two 200 ml portions of ether each and lyophilized to give a yellow solid that was purified on a reverse phase column (C j, Waters Lsshoshiets, 50 g), using 57 for bleaching - A solution of acetonitrile in water at a pressure of 8 psig (0.56 kg / cm).
Each 20 ml fraction is examined by high pressure liquid chromatography, the fractions having an absorption in the ultraviolet region of 00 nm are collected and lyophilized to obtain 200 mg (24% yield) of the title product as an amorphous yellow solid.
Calculated: C 54.38; H 5.77; N 7.46.
 1-1.5
Greater: C 54.39; H 5.98; N7.68.
Example 13. Preparation of 3- (N-methyl-N-benzylimidazol-2-yl-methane-THo) -6o / -f 1- (R) -hydroxyethyl J-7-oxo-1-azabicyclo (3.2.0 ) hept-2-en-2-carboxylate.
A. Preparation of H-benzyl-2-mercaptomethyl-imidazole.
Found: C 49.39; H 3.97; N 7.20; S 10.98.
To a solution of 1.10 g (1.88 mmol) of the obtained compound in 80 ml of tetrahydrofuran and 80 ml of ether are added a MP MP buffer solution, pH 7.0, after which 800 mg of IOZ-palladium on activated carbon are introduced. The reaction mixture is hydrogeired at a pressure of 30 psi (2.11 kg / cmO in a Flappa apparatus for 40 minutes. The mixture is filtered through a pad of celite and the catalyst is washed with water (two portions of
10 ml). The combined filtrate and pressure prod uct in the resulting waters are extracted with ether (two 100 ml portions) and lyophilized to obtain a yellow powder, which is purified by chromatography on a column (HP-20), using water and then 5% acetonitrile solution in water. from fractions of 15 ml each, the methods of liquid chromatographic chromatography under high pressure are studied, the fractions having an absorbance of 25 in the ultraviolet of 300 nm are collected and lyophilized, giving 614 mg (yield 42%) of the title product as a slightly yellow powder.
Calculated: C 55.73; H 5.46; N 7.65; S 8.74.
C, 7 2o gO2 -HgO
HafuieHo: C 55.50; H 6.05; N 7.74; S 8.68.
Example 15. Preparation of 3-f4- (Ы, M-dimethyl-1,2,3-triazolyl) methyl thio j-Cif-Cl - (R) -hydroxyethyl J-7-OKCO-1-aza bicyclo (3, 2.0) rept-2-en-2-carboxylate.
A. Preparation of Isomer A.
0.58 ml (5.16 mmol) of methylfluoromethanesulfonate is added dropwise to an ice-cooled solution of 590 mg (3.52 mmol) of 4-methanethiol acetate-1-methyl-1,2,3-triazole in 2 ml dry methylene chloride with stirring under a nitrogen atmosphere. After the reaction has been performed for 0.5 hours, the bath is removed and after 1 hour the solvent is removed by means of an exhaust fan. The remaining oil is dissolved in a few milliliters of water and the resulting solution is cooled in an ice bath. Then a cooled solution of sodium hydroxide (305 mg, 7.59 mmol) in a few milliliters of water is added to it and the reaction mixture is left for 0.73 hours with stirring. The solution is diluted with 25 ml of water.
and brings it to the pI; i (i 7,:} i pg; y; iiiT; Ti dobanlepi Tin- | - ;; uirii M lji oi;, p, gga of the substituted phosph / pm and aptic. Erne s 1D MP of this pacTHO , ia (thu; crsi pp-tvstvuet about 1.9 mmo ;;;; - Tpii-i z.thythio. tl) is administered with nepeN L;: iH; HHH and an alumina solution; 1; OC (;;, that (1.0 g, 1.72 mmol) in 10 m 1 of tetrahydrofuran (THF). The reaction mixture is left to stir for 0.75 h, with a part of the crystal; 1pcss1: their products -: Comrade (obviously);; s during i CaK-tion. Suspension suspension (1 t to the reactor
0 5
0
five
Those are additions of tetrahydro 11ura11 1 (20 MI) and Sodium (20 mt) to it. In the same reactor, 30 ml of ether and 1.0 g of palladium are collected on aKTHiinpoBiiHiioM corner and the hydrogenohydrogenation of the reaction mixture is carried out at a pressure of 40 psig; 1, yu (2.8 kg / cm) per for 1 hour. The organic phase is from; 1slot npciNn iPahiT in two portions of AM1.1 of 5 mp. B1) e ;; i1; the recovered aqueous phase is a filter PPT, and the filtrate is concentrated in vacuo (at about 0.5 mm Hg / t (1.5 h). The same product is obtained and then chromium mapping (medium pressure column with reverse (1st phase, 35x90 cm, eluent - water), received lyophilization with 395 mg clrbapenem, slightly contaminated t and amounts of inorganic impurities. The product was subjected to elution by liquid chromatography under high
0
0
five
pressure (to (.) lonka, zapolne1 on With
those
Microbondapac, Waters, 10x x ZOO mm, repeated administration, eluent - water), resulting in 310 mg (57%) of A isomer as a tan powder.
B. Preparation of isomer B and isomer C.
1.60 ml (14.0 mmol) of methyl trifluoromethanesulfonate is added dropwise to an ice-cooled solution of 1, 20 g (7.02 mmol) of 4-methanethiol acetate-2-methyl-1,2,3-triazole in 6 ml dry methylene chloride under nitrogen. The reaction mixture is allowed to warm to room temperature and left under stirring for 16 hours. An additional amount of methyl trifluoromethanesulfonate (0.40 ml, 3.56 mmol) is added to it and, after keeping the reaction mixture for 3 hours at room temperature, the solvent is removed.
15
20
:) fi) e (60 ml). Reactive 25 2.47 g (0.065) of lithium aluminum 1 1 is hydrolyzed by means of an exhaust fan. The remaining oil is triturated with ether and the resulting resin-like resin is:; This mixture was cooled in an ice bath and a solution of 844 mg (21.1 mmol) in 5 ml of water was added. After heating, for 0.75 hours, dilute the G1H solution from 60 ml of water and adjust the pH to a value of 8 by injecting solid monosubstituted potassium phosphate. Then, 40 ml :: of that solution (which co (exists: approx. 4.7 mmol of a mixture of triazolthiol isomers) is added to an ice-cold solution of enolphosphate (2.00 g, 3.45 mmol) in 60 ml of tetra; 1: uranium with nepremeishpini. The resulting mixture was stirred while cooling in a bath with P1) House for 0.5 h, after which it was transferred to a reactor for polypropylene, containing a suspension of 10% palladium on activated carbon (2.00 g)
The mixture is subjected to hydrogenolysis at 40 psi (2.8} U / CM) 73 for 1 hour. The organic phase is separated and washed with two portions of 10 ml of water. The combined aqueous | Lases are filtered and the filtrate is concentrated under high vacuum (about 0.5 mm Hg) for 1.5. The remaining solution is chromatographed (medium-pressure column with reverse phase, 45x130 mm, water as eluent), to give, after lyophilisation, 595 mg of a mixture of isomeric carbene-penems, which is contaminated by nebrids of inorganic products. The reaction product is separated and purified by liquid chromatography at a high pressure (column filled with C and Microbondapak, Waters, 10x300 mm, repeated administration, water as eluent) to give isomer B, 153 mg (13Z) .
Example 16. (5R, 6S) -6- (lR-hydroxyethyl) -3- (2-methyl-1,2,3-thiadiazolium-4-yl methylthio) -7-oxo-1-aza-bicyclo (3.2, .0) hept-2-en-2-carboxyl-1.
L. Ethyl, 2, 3-thiadiazol-4-yl-carb-oxylate.
A solution of ethyl c-H-carbethoxy hydrazonopropionate (31.2 g, 0.154 mol) in 55 80 ml of thioiyl chloride is stirred
Tbtfi thionyl is distilled off and the residue is triturated with hexane (30 ml portions reibijie). The red solid is dissolved in 150 ml of dichloromethane and the solution is washed with a saturated solution of sodium bicarbonate and water. After drying over magnesium sulphate, the solution is concentrated to the Cplplplfllt compound. After keeping at 23 ° C for a certain period of time to form, the crystals are filtered to obtain 16.8 g of product (yield 69%), mp. 86 ° C. The filtrate is endured and purified by chromatography on a column filled with silica gel, using dichloromethane as the solution of IC and tel, to give 3.17 g (13%) of the product having m.p. 86 ° C.
B. 1, 2, 3-Thiadiazyl-4-yl-methanol.
To a suspension of 18.35 g (0.116 mmol) of ethyl-1,2,3-thiadiazol-4-yl-carboxylate in 400 ml of ether is added in portions
thirty
40
for 3 h at and heating - 70 ° C for 20 min. Chlorispry
the reaction was mixed with P reqeirne for 7 hours, after which 2.47 g (0.065 mol) of hydroaluminic hydride was treated. Stirring is continued for 24 hours, after which the well-grower (7 wi), a 15% aqueous solution of sodium hydroxide (7 mt) and water (21 ml) are added. After stirring for 15 Mim, the ethereal solution is decanted and the gummy extract is extracted with ether (5 times 100 m: :). The ether extracts are combined, dried over magnesium sulfate and concentrated to give 5.4 g of product. The crude product was purified on a column filled with silica gel (120 g, 4x16 cm), using ether to elute to give 1.3 g (7%) ett1-1,2,3-thiadiazole-4-pl-carboxylate and 2.45 g (18%) 1,2,3-tippazol-4-yl-methanol.
C. 1,2,3-Tpadiazol-4-yl-methanol-methanesulfonate.
A solution of 1,2, 3-thiadiazol-4-yl-methanol (0.75 g, 6.5 mmol) in dichloromethane (20 ml) is cooled to 5 ° C under nitrogen atmosphere and treated with triethyl amine (1.018 ml, 7.3 mmol) and methanesulfonyl chloride (0.565 ml, 7.3 mmol). After 15 minutes, the ice bath is removed and the reaction is stirred.
mixture for 2 hours. Washed solution J
vayut 1 n. solution of hydrochloric acid (2 times 2 ml) and water, dried over
Tbtfi thionyl is distilled off and the residue is triturated with hexane (30 ml portions reibijie). The red solid is dissolved in 150 ml of dichloromethane and the solution is washed with a saturated solution of sodium bicarbonate and water. After drying over magnesium sulphate, the solution is concentrated to the Cplplplfllt compound. After keeping at 23 ° C for a certain period of time to form, the crystals are filtered to obtain 16.8 g of product (yield 69%), mp. 86 ° C. The filtrate is endured and purified by chromatography on a column filled with silica gel, using dichloromethane as the solution of IC and tel, to give 3.17 g (13%) of the product having m.p. 86 ° C.
B. 1, 2, 3-Thiadiazyl-4-yl-methanol.
To a suspension of 18.35 g (0.116 mmol) of ethyl-1,2,3-thiadiazol-4-yl-carboxylate in 400 ml of ether is added in portions


five
0
0
the reaction was mixed with P reqeirne for 7 hours, after which 2.47 g (0.065 mol) of hydroaluminic hydride was treated. Stirring is continued for 24 hours, after which the well-grower (7 wi), a 15% aqueous solution of sodium hydroxide (7 mt) and water (21 ml) are added. After stirring for 15 Mim, the ethereal solution is decanted and the gummy extract is extracted with ether (5 times 100 m: :). The ether extracts are combined, dried over magnesium sulfate and concentrated to give 5.4 g of product. The crude product was purified on a column filled with silica gel (120 g, 4x16 cm), using ether to elute to give 1.3 g (7%) ett1-1,2,3-thiadiazole-4-pl-carboxylate and 2.45 g (18%) 1,2,3-tippazol-4-yl-methanol.
C. 1,2,3-Tpadiazol-4-yl-methanol-methanesulfonate.
A solution of 1,2, 3-thiadiazol-4-yl-methanol (0.75 g, 6.5 mmol) in dichloromethane (20 ml) is cooled to 5 ° C under nitrogen atmosphere and treated with triethyl amine (1.018 ml, 7.3 mmol) and methanesulfonyl chloride (0.565 ml, 7.3 mmol). After 15 minutes, the ice bath is removed and the reaction is stirred.
mixture for 2 hours. Washed solution J
vayut 1 n. solution of hydrochloric acid (2 times 2 ml) and water, dried over
To a solution of 3.23 g (13.0 mmol) of chlorohydrate of 4-benyl-2-chloromethylnmidazole in 80 ml of acetonitrile was added 1.72 g (14.5 mmo.ch) of N-acetylthiourea. The reaction mixture is heated under reflux for 3 hours. The precipitate was collected by filtration and washed with acetonitrile (10 ml) to obtain the isothiouroni salt, which was then dissolved in 80 ml of absolute ethanol and heated for 18 hours at refluxing under nitrogen. The reaction mixture is cooled to room temperature, evaporated in vacuo to a volume of about 30 ml, and the formed precipitate is removed by filtration. After distillation of the filtrate in vacuo, 3.5 g (yield 97%) of the thiol indicated in the title are obtained in the form of a thick yellow syrup,
B, Preparation of P-nitrobenzyl-3- (Pbenzylimidazol-2-yl-methantio) -6c / -G1 (R) -hydroxyethyl J-7-OKCO-1-azabicyclo (3,2,0) hept-2- en-2-carboxylate; To a solution cooled to a solution of 3.03 g (8.5 mmol) of the keto derivative (Example 9, step A) in 70 ml of acetonitrile was added 1.17 g (9.0 mmol) of diisopropylethylamine in 2 ml acetonitrile, and then 2.4 g (9.0 mmol) of diphenyl chlorophosphate in 2 mp of acetonite are introduced under nitrogen atmosphere. The resulting solution was stirred for 20 .i. min at, after which to it a) T solution of 1.17 g (9.0 mmol) of diisopropylethylamine in 2 ml of acetonitrile and 4.8 g (15 mmol) of thiol (product of step A), add another 1 to the reaction mixture. , 93 g (15 mmol) of diisopropylethylamine and allowed to stir for another 2 hours at. The precipitate is collected by filtration and washed with 20 mp of cooled methylene chloride, giving 2.5 g (yield 55%) of the title product as white solid matter.
C. Preparation of 3- (N-methyl-M-benzyl
and razol-2-yl-methano) -6of-C1 (R) hydroxyethyl} -7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate.
To a solution of 1.76 g (3.3 mmol) of the compound obtained in step B in 1.1 l of methylene chloride was added 1.15 ml (13.4 mmol) of methyl fluorosulfonate. The reaction mixture is intermixed.
Q 5 20 5 d 50
55
35
45
for 2 h at room temperature, after which it is finished and vacuum to a volume of about 15 ml. The precipitate is collected by filtration and washed with methylene chloride (10 mp), resulting in 1.58 g (yield 74%) of l-nitro-5-benzyl-3- (H-Me-TiuT-N-benzylimidylzol-2-yl-methantio) -fluorosulfonate- bo - 1- (K) -oxyethyl 7-7-oxo-1-azabicyclo (3,2,0) hept-2-en-2-carboxylate (quaternized imidazole) as a white solid,
Calculated: C, 51.48; H 4.47; N 8.67; S 10.20,
С 2 g Н g О 4 S 2 F
Found: C, 51.84; H 4.52; N 8.65; S 9.87,
To a solution of 1.11 g- (1.71 mmol) of the obtained compound in 100 ml of tetrahydrofuran and 100 ml of ether are added 120 ml of a buffer solution of pH 7.0 after which 1.0 g of 10% palladium on activated coal The resulting mixture is hydrogenated at a pressure of 45 psi, inch (3, I 7 kg / cm) in a Parr apparatus for 45 minutes. The reaction is filtered through a pad of celite and the catalyst is washed with water (2 portions of 10 ml), the combined filtrate and washings are extracted with 2 portions of ether in 70 ml each and lyophilized to obtain a yellow powder that is purified on a column (C jjBONDAPAK, Waters Associates , 40 g), using for elution a 10% solution of acetonitrile in water at a pressure of 8 psi (0.56 kg / cmM,
Each and fractions with a volume of 15 ml is subjected to a high-pressure liquid chromatography method, fractions having absorption in the ultraviolet c. 300 nm, collected and lyophilized, received 305 mg (43%) of the title product D as a slightly yellow amorphous solid.
Calculated: C 57.25; H 5.94; N 9.54; S 7.28.
C HjjNjO S, 1.5
Found: C, 56.66; H 5.70; N 9.49; S 8.30.
Example 14. Preparation of 3- (2-methyl-L-methylpyridin-3-yl-methantio) -6of-O (R) -hydroxyethyl J-7-OKCO-1 - azabicyclo (3.2.0) hept-2- en-2-carboxylate.
A. Preparation of 2-methyl-3-mercaptomethyl pyridine.
6.23 g (0.038 mol) of 2-methyl-3-ethylpyridinecarboxylate ester in 15 ml of tetrahydrofuran is added dropwise to a suspension of 2.86 g of lithium-calcined hydride in 50 ml of succinic tetrahydrofuran added dropwise to 15 ml of tetrahydrofuran over 15 minutes. The resulting mixture is stirred for 60 minutes at which time 50 ml of ethyl acetate are added. The precipitate is filtered off and washed with a valuable aqueous ammonium chloride solution. The organic layer is dried over magnesium sulfate, filtered and the solvent is distilled off in vacuo, resulting in 3.2 g (yield 70%) of 2-methyl-3-hydroxymethylpyridine as a yellow oil.
A solution of 3.2 g (0.026 mol) of the obtained alcohol in 10 ml of methylene chloride is added dropwise to a solution of 4 ml of thionyl chloride in 10 ksh of methylene chloride cooled to 0 ° C in 15 minutes under a nitrogen atmosphere. The cooled bath is removed and the reaction mixture is stirred for 3 hours at room temperature. All solvents were distilled off in vacuo to give 2-methyl-3-chloromethylpyridine as a residue as a brown solid, which was used in the next step without purification. The brown crude product is dissolved in 30 ml of absolute ethanol, 2.5 g (0.032 mmol) of thiourea are added and the reaction mixture is heated at 65-7b C for 18 hours, after which the mixture is cooled to room temperature. The precipitate was collected by filtration and washed successively with ethanol (20 ml) and ether (50 ml) to obtain 30 g of isothioronium salt. This salt is dissolved in 10 ml of water and a solution of 640 mg (0.016 mol) of sodium hydroxide in 10 ml of water under a nitrogen atmosphere is added to the resulting solution. The reaction mixture is heated to 2 minutes, then cooled to OC, the mixture is adjusted to a pH of 6.0 with acetic acid and extracted with two 35 ml portions of chloroform. After drying over magnesium sulphate and distilling off the solvent (chloroform), 941 mg (yield 46%) of the thiol indicated in the title as a yellow oil are obtained.
B. Preparation of p-nitrobenzyl-3- (2-methyl pyridin-3-yl-me tanthio) -6 with | ((K) -hydroxistil-7-oxo-1-azabicyclo (3,2,0) hept- 2-en-2-carboxylate. To a cooled to 0 ° C solution of 1.52 g (4.37 mmol) of keto derivative (Example 9, step A), 0.86 ml (4.80 mmol) is added to 3 ml of acetonitrile.
diisopropylethylamine, after which a solution of 1.17 g (4.37 mmol) of diphenyl chlorophosphate in 3 ml of acetonitrile in a nitrogen atmosphere is introduced. The solution thus obtained is stirred for 30 minutes at 0 ° C to obtain P-nitrobenzyl-3-diphenylphosphoryloxy-6o-C1 (R) -hydroxy-il-7-oxo-1-azabicyclo (3.2.0) hept -2-ene-2 carboxylate. To this solution, a solution of 0.86 ml (4.80) of diisopropylethylamine and 2 ml of acetonitrile is added, followed by a solution of 940 mg (6.76 mmol) of thiol (product of stage A) in 2 ml of acetonitrile. Received
the reaction mixture is stirred for 60 minutes at. The precipitate was collected by filtration and washed with ether (30 ml), resulting in 1.12 g (yield 55%) of the title product as a light yellow solid, mp. 186-188 ° С (with decomposition).
Calculated: C 58.83; H 4.94; N 8.94; S 6.83.
CjjHj jO S Found: C 58.63; H 4.99; N 9.06;
S 6.58.
C. Preparation of 3- (2-methyl-N-methyl-pyridin-3-yl-metathio) -bd-C1 - (R) -ndroxyethyl-7-oxy-1-azabicyclo- (3, 2, 0) hept- 2-en-2-carboxylate.
To a solution of 697 mg (1.19 mmol) of the product of stage B in 100 MP of methylene chloride is added dropwise, under UC, 0.5 ml (6.18 mmol) of methyl fluorosulfonate over 10 minutes. The mixture is stirred for 2.5 hours at room temperature, the precipitate is collected by filtration and washed with 30 ml of methylene chloride to obtain 777 mg (90%) p-n 11Trobenzyl-3- (2-methylpyridin-3-yl-methantio) fluorosulfonate-6 - 1- (K) - hydroxyethyl 1-7-oxo-1-azabicyclo (3,2,0) - hept-2-en-2-carboxylate (quaternized pyridine derivative) as a yellow solid.
Calculated: C 48.91; H 4.55; N 7.23; S 11.04.
 3 eez
with a mixture of sulphate and magnesium oxide and endE1Triut. The residue is purified by chromatography (silica gel column 1.5x21 cm) using ether as an eluting solvent, resulting in 0.90 g (71%) of 1,2,3-thiazolol-4 -yl-methanol-methanesulfonate.
Calculated: C, 24.73; H 3.11; N 14.42; S 33.02.
C IbNjOjS
Found: C 24.78; H 3.09; - N 14.66; S 31.94.
In addition, 0.13 g (19%) of di- (1,2, 3-thiadiazol-4-yl-methyl) ester was found.
D. 4-Lethylthiomethyl-1,2,3-thiadiazole.
To a solution of 1, 2, 3-thiadiazol-4-yl-methaiol methanesulfopate (0.90 g, 4.6 mmol) in tetrahydrofuran (9 ml) is added an aqueous solution (2 ml) of sodium thiol derived from thiol-yKcycHofi acid (0.38 ml, 5.3 mmol and sodium bicarbonate (0.445 g, 5.3 mmls). The resulting reaction mixture was stirred at 23 ° C for 1 h and diluted with 75 ml of ether. The solution was washed with water (3 3 ml each time), dried over magnesium sulphate and concentrated. The crude mixture is purified by chromatography (1.4x19 cm column C.sup.Cl.), using an eluting solvent
a mixture of 50% ether and hexane, getting
as a result, 0.60 g (75%) of the product.
Calculated: C 34.47; H 3.47; N 16.08; S 36.80.
C ,, H, N, OS,
Found: C 34.48; H 3.83; N 16.28; S 36.80.
E. 4-Acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate.
To a solution of 4-acetylthiomethyl-1,2,3-thiadiazole (0.60 g, 3.44 mmol) in a mixture of ether (4 ml) and dichloromethane (0.4 ml) was added a few crystals of the title compound, as well as 0.407 mg (3.6 mmol) of trifluoromethanesulfonate for 5 minutes. The reaction mixture was stirred at 23 ° C. under nitrogen for 6 hours. The white solid, which is a mixture of the two compounds listed in the title, filtered by
five
0 5 Q
five
five
0
five
wave and washed with ether, ppucha
1.05 g of product (90%).,
Calculated: C, 20.27; H 2.38; N 9.45; S 32,46
S7PDY20 5, Gz
Found: C 24.61; H 2.57; N 8.47; S 28.21.
F.4-Mercaptomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and | 4-mercaptomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate.
A solution of a mixture of 4-atstiltilometi.t1-2- metsht-1,2,3-thiadiazolium trifluorometh N sulfonate and 4-acetyl.pyhymethyl-3-methyl-1,2,3-thialiazolium trifluoromethyl sulfonate (1.05 g, 3, 1 mmol) in 6N hydrochloric acid (10 mp) is heated at 1.75 h under nitrogen atmosphere. The solvent is distilled off under reduced pressure, giving a residue of 0.91 g of yellow syrup. This compound is used in the following stage without purification.
G. (5R, 6S) -6- (1K-hydroxyethyl) -3- (2-methyl-1,2, 3-thiadiazolium-4-yl-methylthio) -7-oxo-1-azabicyclo (3, 2.0) - hept-2-ene2-carboxylate.
Chilled to 5 ° С (5R, 6S) solution - para-nitrobenzyl-6- (1R-hydroxyethyl) -3-diphenylphosphone-7-oxo-1-azabicyclo- (3,2,0) hept-2-en-2 -carboxypate (1.7 g, 2.92 mmol) in tetrahydrofuran (10 ml) is treated with a solution of a crude mixture of 4-mercaptomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethane-sulfonate and 4-mercaptometr-3-methyl-1, 2,3-Thiadiazolium trifluoromethanesulfonate (0.9 g) mixed with phosphate buffer (pH 7.2, 0.3 m, 15 ml) and tetrahydrofuran (5 ml). The reaction mixture is stirred for 1 hour, maintaining the pH value by 7.2 by
2i. sodium hydroxide solution. Stirring is continued for another 1 h, after which 50 ml of ether and 1 g of 10% palladium on activated carbon are added. The resulting reaction mixture is hydrogenated at and at a pressure of 45 psi.
(3.17 kg / cm) for 2 hours, then filtered through a layer of celite. The organic phase is separated, diluted with ether (50 mp) and phosphate buffer (pH 7.2, 0, 3M, 20 mp) and hydrogenated (using 2 g of 10% palladium on activated carbon) for 2 hours at 50 psi (3.5 kg / cm). The aqueous phase obtained 10
15
The first and second hydrogenations are combined, washed with ether and purified by chromatography on Prep-Pak 500-C / 18, using water as solvent for the elution, resulting in 0.22 g of the crude product. It is subjected to repeated purification by high pressure liquid chromatography, using water for elution. The resulting 0, g (A%) of the title compound after freeze-drying it.
Example 17. (5R, B5) - p-nitrobenzyl-6- (1K-hydroxyethyl-4E-methyl-3-f (1,2, 3-tpadiazol-4-yl) -; methylthio-7-OKCO-1 -azabicyclo (3,2,0) - hept-2-en-2-carboxylate.
Cold (5 ° С) solution (5R, 6S) - para-nitrobenzyl-6- (1R-hydroxyethyl) -3- (diphele1 phosphono) -4K-methyl-7-oxo-1-azabicyclo (3,2, 0) hept -2-en-2-carboxylate (3.0 mmol) in (12 br) is treated with 4-mercaptomethyl-1, 2, 3-thiadiazole (528 mg, 4 mmol) and diisopropylethylamine (426 mg, 3.3 mmol, 0.58 ml). After stirring for 1 hour, the solution was diluted with EtOAc (35 Nm), washed twice with cold water. The organic solution, dried g of MgSO- is evaporated and the crude product is passed through a high purity SiO layer (40 g). Spray is carried out (10 x 20 ml) and
thirty
16 ml), hydrogenated for 75 min in the presence of Pd / C (1.0 I) at a pressure of 45 psi. Then, the reaction mixture is cooled on ice, filtered, and the filtrate is j-fold and extracold with EtjO. The aqueous phase is chromatographed on reverse phase SiO,) lire and then 5% in water. The described hydrogenation is repeated in the same setting under the same load. Both portions are added and the product is subjected to rechromatography on reverse phase SiO2) eluted with water (175 ml) and 5% CH. B, the corresponding fractions are combined and lyophilized, obtaining carbenem in 164 mg yield (14.8%).
Example 18. (1,3-Dimethylimidazolium-4-yl) methanethiol trifluoromethanesulfonate.
To a solution of (1-methylimidazol-5-yl) methylthiothioacetate (20.43 g, 0.12 mmol) in a mixture of aceto} and tris-ether (1: 2, 180 ml) is added dropwise (0.5 h) methyl trifdate (15 , 84 mg, 0.14 mol). The mixture is stirred under nitrogen for 1 hour and then diluted with ether (500 ml). The liquid was decanted, leaving a red syrup, which was washed twice with ether (100 ml) before adding 1 m of hydrochloric acid (200 ml, 6N). The resulting aqueous solution is heated at 65 ° C in air for 4 hours and evaporated. Traces of hydrochloric acid are removed by distillation.
40
then EtOAc (10x20 mt), corresponding to water, leaving the yellow fractions evaporated to obtain 1.18 g (82.5%) of a pale yellow foam.
(5R, 6S) -6- (1R-hydroxyethyl) -4R-methyl-3-SZ-methyl-1, 2, 3-thiadiazolium-4-yl) methylthio J-7-oxo-1-azabicyclo- (3, 2.0) hept-2-en-2-carboxylate (VMU-26659).
To a solution of (5R, B5) -para-nitrobenzyl-6- (1R-hydroxyethyl) -4R-methyl-3- (1,2, 3-thiadiazol-4-yl) methylthio-7-oxo-1- azabicyclo (3.2.0) hept-2-en-2-carboxylate (2.25 g, 4.72 mmol) in CnjCl2 (14 ml) and EtjO (9.5 g-sh) methyl trifluoromethanesulfonate (775 g , 4.72 mmol) at room temperature 5. The solution becomes cloudy and the oil drops out. V After stirring for 2 hours, the supernatant, decanter sweat, and the oil is triturated to obtain a yellow poro
syrup (32,4
92l) A portion of the syro.cha is purified on a column with the reverse of the ji j phase with water and a stripping solvent, IR (undiluted).
(5R, 6S) -3-C (1, 3-dimethylimidazolium-yl) -methylthioJ-6- (IR-hydroxyethyl) -4R-methyl-7-oxo-1-azabicyclo- (3,2, 0) hept-2-one-2-carboxylate (VMU-27463).
To the cold (-20 ° C) solution (5R, b3) -para-nitrobenzyl-3,7-dioxo-6- (1R-hydroxyethyl) -4R-methyl-1-azabicyclo (3.2,2) heptane -2K-carboxylate (34.78 g, 0.096 mol) in dry acetonitrile (150 ml), in a nitrogen atmosphere, was added diphenyl chlorophosphate (20.73 ml, 0.10 mmol), diiso propylethylamine (17, 42 ml, 0.10 mol) for 5 min and 4-dimethylaminopyri
shock (2.08 g, 68.8%). 55 dyn (0.040 g) are quaternized. The cooling bath with a carbapenem (1.0 g, 1.56 mmol) is dissolved in THF (25 ml), Et20 (25 ml) and phosphate buffer (0.2 mol, pH 7,
change to an ice water bath. The mixture is stirred at 1 h, cooled to -20 ° C and successively
0
five
0
16 ml), hydrogenated for 75 min in the presence of Pd / C (1.0 I) at a pressure of 45 psi. Then the reaction mixture is cooled on ice, filtered, and the filtrate is j-extracted twice with EtjO. The aqueous phase is chromatographed on reverse phase SiO,) lire and then 5% in water. The described hydrogenation is repeated in the same unit under the same charge. Both portions are combined and the product is subjected to rechromatography on reverse phase SiO2) is eluted with water (175 ml) and 5% CH.CN B, the corresponding fractions are combined and lyophilized, to obtain a carbopenem with the release of 164 mg (14.8%).
Example 18. (1,3-Dimethylimidazolium-4-yl) methanethiol trifluoromethanesulfonate.
To a solution of (1-methylimidazol-5-yl) methyl thioacetate (20.43 g, 0.12 mmol) in a mixture of aceto} and triethyl ether (1: 2, 180 ml) is added dropwise (0.5 h) methyl trifdate ( 15.84 mg, 0.14 mol). The mixture is stirred under a nitrogen atmosphere for 1 hour and then diluted with ether (500 ml). The liquid is decanted, leaving a red syrup, which is washed twice with ether (SOO ml) before adding 1 m hydrochloric acid (200 ml, 6N). The resulting aqueous solution is heated at 65 ° C in air for 4 hours and evaporated. Traces of hydrochloric acid are removed by distillation.
with water left yellow
syrup (32.4 g
92l) A portion of the syro.cha is purified on a column with the reverse of the Hoi j phase with water and a zerous solvent, IR (undiluted).
(5R, 6S) -3-C (1, 3-dimethylimidazolium-yl) -methylthioJ-6- (IR-hydroxyethyl) -4R-methyl-7-oxo-1-azabicyclo- (3,2, 0) hept-2-one-2-carboxylate (VMU-27463).
To the cold (-20 ° C) solution (5R, b3) -para-nitrobenzyl-3,7-dioxo-6- (1R-hydroxyethyl) -4R-methyl-1-azabicyclo (3.2,2) heptane -2K-carboxylate (34.78 g, 0.096 mol) in dry acetonitrile (150 ml), under nitrogen atmosphere, added diphenyl chlorophosphate (20.73 ml, 0.10 mmol), diisopropylethylamine ( 17.42 ml, 0.10 mol) for 5 minutes and 4-dimethylaminopyridine (0.040 g). Cooling bath
change to an ice water bath. The mixture is stirred at 1 h, cooled to -20 ° C and successively
treated with a solution (1, 3-dimeth n-dazolium-4-tsl) -methanthsp (32.4 g, 0.11 nol) in acetonitrile (130 ml) and diisopropylethylamine (19.16 ml, 0.11 mol) with such speed so that the temperature is maintained from -15 to -20 C (10 min). The cooling bath is replaced with an ice water bath. The mixture is stirred at 1.5 hours, then diluted with water (840 ml. The resulting mixture is treated with Dowex 1x8 50 SG (200 kp) and drank on a layer with reversed phase (14x14 cm). A mixture (25-35%) is used as eluting solvent acetonitrile and node. Fractions containing pure car 3apenem are passed through a column with Dowex 1x8 50 C1 (4x5 sk) at a rate of 3 ml / min. Lyophilization of an aqueous solution gives a yellow dry residue of 27.6. (55%), which is dissolved in buffer (-NaOH, 0.3, and., 615 ml, pH 7.0). After adding 10% palladium on carbon (20 g), tetragon idrofuran (400 ml) and ether (600: -s) the mixture is hydrogenated at 23 ° C and 45 psi for 2 hours and the corm of the celite layer is filtered (Sepite). The EnglishJ phase is separated and extracted with water (2x50 NLT). ml), pumped out under high vacuum in order to remove traces of organic solvents, and pour out a reversed phase layer (14x13 cm). The elution is carried out with a mixture (0–4%) of acetonitrile in water, after Both fractions give a yellow powder (14.6 g, 78.8%).
Example 19. (5R, 6S) 3- (3,4-dimethylthiazolium-5-yl) methylthio-6- (1 K-hydroxyethyl) -4Ph.-meth1-7-oxo-1-azabicyclo- (3,2, 0) hept-2-en-2-carboxylate (VMU-27061).
A solution of (5R, 63) -allyl-6- (1 RCh.-hydroxyethyl) -4K-methyl-3- (4-methylthiazol-5-yl) methylthio-7-oxo-1-azabicyclo ( 3,2,0) hept-2-en-2-carboxylate (1.15 g, 3.34 mmol) B dry dichloromethane (25 ml) is cooled to 0 C and treated by dropwise addition (2 min) with methyl trifluoromethanesulfonate ( 0.53 g, 3.24 mmol). After keeping the AO at 0 ° C, triphenylphosphine (0.080 g) and tetrakis (triphenylphosphine) palladium (0.080 g) are added, then a 0.5m solution of potassium 2-ethylhexanate (6.7 ml, 3.33 mmol) in ethyl acetate is added .
After being kept for 30 Ntiin at 0 ° C, the reaction mixture was allowed to warm to 22 ° C and at 30-minute intervals another 3 times palladium and triphenylphosphine was added (ka; each 0.080 g). After 3 hours at 22 ° C, the languid reaction mixture was evaporated under reduced pressure and the residue was partitioned between water (15 ml) and ether (15 m, l). The organic phase is extracted again with water (5 ml) and the combined aqueous phases are purified on a reverse phase silica gel column (2.5x12 cm) using water and then aceto1P1trile (9: 1) as eluent. After repeated chromatography, the main product in white nida is obtained.
0 powder after lyophilization (0.248 g, 21%).
Example 20. (5R, 65) - 1ara-nitrobenzyl-6- (1K-hydroxyethyl) -4K-methyl) -3-C (1-methyl-1,2, 3-triazol-4-yl) 5 methylthioJ-7-ocean-1-azabicyclo (3,2,0) - hept-2-en-2-carboxylate.
Cold (5 ° С) solution (5R, 6S) - para-nitrobenzyl-6- (1Я-gyroxyethyl) -3- (diphenylphosphono) -4K-methyl-7-oxo-1-azabicyclo (3,2,0) hept -2-en-2-carboxylate (4.0 mmol) in CHjCN (20 ml) is treated with 4-mercaptometry-1-methyl-1, 2,3-triazole (735 ml, 5.7 you-yul) and diisopropylether1 1 (646 mg, 5 mmol, 0.87 ml). After stirring at 5 ° C for 15 minutes and room temperature for 1 hour, the reaction mixture was diluted with EtOAc (75 ml), washed with cold water, dried with MgSO4 and evaporated. The remaining foam is chromatographed on high-purity SiO (50 g), eluting with cold EtOAc (200 ml) and then CHjCN (200). The corresponding 1e fractions are combined and evaporated to leave a solid foam. Yield 1.1 g (58.1%).
(5R, 6S) -6- (1R-hydroxyethyl) -4R-methyl-3- (1, 3-dimethyl-1,2,3-triazolium-4-yl) methylthio-7-oxo-1- azabicyclo (3,2,0) hept-2 ene-2-carboxylate
0 (VMU-26873).
To a solution of (5R, 6S) -papa-nitrobenzyl-6- (1R-hydroxyethyl) -4R-methyl) -3- f (1-ethyl-1,2,3-triazol-4-yl) methylthio } -7-oxo-1-azabicyclo (3,2,0) hept 5 2-en-2-carboxylate (1.1 g, 2.32 mmol) in (6 ml) and (5 ml) is served at room temperature temperature trifluoromethanesulfonate (419 mg, 2, 55 mmol,
0
five
0
five
0.29 Mji). Immediately drops oil. After stirring for 1 h, the supernatant liquid is decanted and the oil is triturated in Et20, a pale yellow powder is formed. The yield of 1.31 g (88.6%). The quaternized compound (1.02 g, .1.6 mmol) dissolved in THF (25 ml), (25 ml) and phosphate buffer (1.2 M, pH 7.0, 16 ml) was hydrogenated for 60 min in the presence of 10% Pd / C (1.0 g) at a pressure of 40 psi Then the reaction mixture is cooled on ice, filtered and the filtrate is extracted (2x20 ml). The aqueous solution is chromatographed for phase-shift SiOj (20 g), eluted with cold () water (200 mp) and 57 ° per (100 mp). The appropriate fractions are combined and lyophilized. Yield 320 mg (56.9%).
S. pneumonia
S. pyogenes
S. aureus
S. aureus + 50
serum
S. aureus
(Pen-res.)
S. aureus
(Meth-res.)
S. faecalis
E. coli
(
E. coli
(10-3)
E. coli.
(10-o
E. coli
(ten-)
E. coli
Lo-)
 E. coli
(10-2)
)
K. K.
p. p.
p.
pneumonia
pneumonia
mirabilis
vulgaris
morganii

The resulting compounds (1) are strong antibiotics, are active against various Gram-negative and Gram-positive bacteria.
In vitro activity. It was established that the samples of carbapenemic compounds of examples 1 and 2, after dissolving in water and diluting with nutrient broth, showed minimal inhibitory concentrations (MIC), expressed in µg / ml, relative to the indicated microorganisms, as determined by incubation at 37 ° C for overnight with dilution in vitro.
I .....
In tab. 1 is given antibacterial
in vitro activity of the carbapenem derivatives of examples 1 and 2. (N-formimidolylthienamycin is included as a reference compound). Table 1
Example 1

0.004 0.001 0.004 0.016

0,008
0.5 0.5
0.016
0.03
0.06
0.03
0.03
0.13 0.13 0.06 0.06 0.03 0.13
41
In tab. 2 given the minimum inhibitory concentrations of predpamine and
1D9310842
Continued table.
known compounds.
§8Я88
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51493108
Therapeutic efficacy in mami is presented in TaOl. 3, where the vivo of the compound of Example 1 and N-is indicated by HPS (dose expressed in α-formimidolylthienamycin after intramg / kg, requiring 50% of myopic administration to protect mice experimentally infected with different mice to protect).
Note. With the exception of E. coli A15119 and K. pneumoniae A9964, the drug was administered intramuscularly to mice after 0 and 2 hours after infection. In the case of E. coli and K. pneumoniae, treatment is carried out 1 and 3.5 hours after infection. In each trial, at each dose, 5 min each are used. Toxicity. A current has been determined
the severity of the compound of Example 1 after intracranial administration to the mucous. The results are presented in table. four.
Table 4
For example, 1 14
Brem polurazlo marry.
The area under the curve of blood concentration versus time.
Mami is represented by the indicated ZDD (dose mg / kg, requiring
infected with smaller).
15119 Nutrition. coli, 5 hours Oz and Continuation of table 4 v y ---- N-formimidolylthienamycin
32
The average value of 25 mice.
Blood content and time of decomposition of the compound of Example 1 after intramuscular administration. 20 mg / kg mice are shown in Table. 5, (the compounds are dissolved in 0.1 M phosphate buffer at pH 7; data from one test: 4 mice per compound).
Table 5
 7U93108
The urinary excretion of the compound of Example 1 after intramuscular administration of 20 mg / kg to the mice is presented in Table. 6 (compounds are dissolved in
In example 1
N-formimidolylthienamycin
In tab. Table 7 shows the 3D action with intramuscular injection. Table. 8 given blood levels and half-life, suggest compounds after intramuscular administration of 20 mg / kg (compounds dissolved in O, 1 M phosphate buffer pH 7; values based on one test: 4 mice per compound).
Table 8
 Time of semi-decomposition. The area under the curve of blood concentration versus time. AL N-Fortmidolylthienamic.
48
0.1 M phosphate buffer pH 7; data from one test: 4 mice per connection).
26.1 0.5 12.1 0.1
0.1 26.7 + 6.7 0.1 12.2 + 3.6
Denia infected} 1st mice proposed and known compounds.
Tvblnts 7

权利要求:
Claims (2)
[1]
1. A method of producing 7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylic acid derivatives of the general formula
H
H3C-HC.S-A-OJ-R2
where R, is hydrogen or C -C-alkyl;
R.- - C, -C-alkyl, benzyl or alkylcarboxymethyl; R J is hydrogen or a para-nitrobenzyl protecting group if there is also a counterion; A is a group (CH), where n 1 4- or 2;
N mono or dismixed C-alkyl groups
:
H -N s.
xGH / G4-1 IN-1 z-,
- -9-
N
N
t,
t5
N N (
moreover, said ring is attached to A through the carbon atom of the ring and contains a nitrogen atom that is quaternized with the group R2,
different in that
ketoester general formula
OH „RI
I n I
ABOUT
where R. and R have the indicated meanings, are reacted with diphenyl chlorophosphate in the presence of diisopropylethylamine in an inert organic base medium, to the compound obtained by the general formula
° n, nzs-saDCh
Q - COOR;
where R and RJ have the indicated meanings; L - diphenoxyphosphinyloxy,
act on a mercaptan derivative of general formula 20
HS-A-GN
where A and- ;; have the following meanings, in an environment of inert organic diluent-35 believer in the presence of diisopropyl-ethylamine, followed by alkylation of the resulting compound of the general formula
 R,. ° H3C-HC ..
0 СООКз
where R, R, Au have specified
meanings
alkylating with an agent of general formula
Rj - X
where R has the indicated meanings;
X is a halogen or a sulfonate ester group,
and isolating the desired product or, if necessary, when the Rj is a para-nitrobenzyl group, removing the carboxy-protecting group.
[2]
2. A method for producing prodipod 7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylic acid of the general formula
OH jjRi
HC-pfV QJ-N, -h
COORj
where R (is hydrogen or C -C-alkyl; R-- Cf, C.-alkyl, benzyl or
alkylcarboxymethyl; R is hydrogen or para-nitrobenta
Protective group
if there is also a counterion;
group (CH), where n - 1
or 2,
mono- or disubstituted
C, - Cd-alkshyum group
N-. NN NN & 4) 4J 1,4 1iJlА -CN-О
N
N
N
t
.-y-n. y-N N1 lx J-x N 3 N IJ
moreover, said ring is attached to A via a carbon atom of the ring and contains a nitrogen atom that is quaternized with R,
characterized in that
compound of general formula
9 B NS
R
S-A-Ol UNS
where R, Rj, Au have specified
meanings
treated with an alkylating agent
general formula
 X
where R has the indicated meanings; I X is a halogen or sulfonate ester group, followed by isolation of the desired product, or, if necessary, when the R j is a para-nitrobenzyl group, by removing the carboxy-protecting group.
Priority featured:
09/28/82 when R is hydrogen.
09.09.83pri With, -C-alkyl.

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同族专利:

---

公开号 | 公开日

---

IE55947B1|1991-02-27|

---

IE832266L|1984-03-28|

---

IT8323022D0|1983-09-27|

---

DD212255A5|1984-08-08|

---

OA07548A|1985-03-31|

---

AT382621B|1987-03-25|

---

PT77404A|1983-10-01|

---

FR2533568A1|1984-03-30|

---

SE8305217L|1984-03-29|

---

NO163284B|1990-01-22|

---

NZ205626A|1986-12-05|

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SE8305217D0|1983-09-27|

---

GB2128187A|1984-04-26|

---

IL69824D0|1983-12-30|

---

FR2533568B1|1990-01-26|

---

SE461734B|1990-03-19|

---

AR241785A1|1992-12-30|

---

ZW20783A1|1984-11-28|

---

CH656130A5|1986-06-13|

---

FI78094C|1989-06-12|

---

FI78094B|1989-02-28|

---

IT1163944B|1987-04-08|

---

PT77404B|1986-06-26|

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KR890002228B1|1989-06-24|

---

LU85021A1|1984-04-24|

---

DE3334937A1|1984-04-05|

---

FI833417A0|1983-09-23|

---

GR78696B|1984-09-27|

---

HU191066B|1987-01-28|

---

ATA344983A|1986-08-15|

---

YU43196B|1989-04-30|

---

CS247168B2|1986-12-18|

---

ES525983A0|1985-02-16|

---

ES8503354A1|1985-02-16|

---

DK442383D0|1983-09-27|

---

CA1269978A|1990-06-05|

---

DE3334937C2|1991-05-02|

---

GB2128187B|1986-06-18|

---

DK442383A|1984-03-29|

---

AU1934283A|1984-04-05|

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KR840006249A|1984-11-22|

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NL8303310A|1984-04-16|

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NO163284C|1990-05-02|

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GB8325744D0|1983-10-26|

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FI833417A|1984-03-29|

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IL69824A|1991-04-15|

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YU190683A|1985-10-31|

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NO833479L|1984-03-29|

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AU575541B2|1988-08-04|

引用文献:

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EP0017992A1|1979-04-19|1980-10-29|Merck & Co. Inc.|2-Substituted-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids, processes for preparing them, antibiotic pharmaceutical compositions containing same and process for preparing intermediates|

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IE52147B1|1980-03-27|1987-07-08|Merck & Co Inc|4--azetidin-2-ones and process for their preparation|

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EP0038869A1|1980-04-30|1981-11-04|Merck & Co. Inc.|Process for the preparation of 1-carbapenems, and intermediates for their preparation|

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DE3169567D1|1980-10-25|1985-05-02|Beecham Group Plc|The preparation of beta-lactam antibiotics|

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EP0074599A1|1981-09-09|1983-03-23|Takeda Chemical Industries, Ltd.|5,6-cis-Carbapenem derivatives, their production and use|US4683296A|1983-03-07|1987-07-28|Bristol-Myers Company|Carbapenem intermediates|

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CA1273011A|1984-07-02|1990-08-21|Susan M. Schmitt|Carbapenems having an externally alkylated mono- orbicyclic 2-quaternary heteroarylalkylthio substituent|

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CA1273012A|1984-07-02|1990-08-21|Burton G. Christensen|1-methylcarbapenems having an externally alkylatedmono- of bicyclic 2-quarternary heteroarylalkylthiosubstituent|

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US4729993A|1984-12-13|1988-03-08|Merck & Co., Inc.|Carbapenems and 1-methylcarbapenems having an externally alkylated mono- or bicyclic 2-quaternary heteroarylalkyl substituent|

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

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US4880922A|1985-11-22|1989-11-14|Bristol-Myers Company|Carbapenems with quaternized heterothioalkylthio substitution at position 2|

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NZ219892A|1986-04-15|1991-02-26|Merck & Co Inc|N-amino quaternised heteroarylium carbapenem derivatives and pharmaceutical compositions thereof|

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DK168047B1|1987-12-07|1994-01-24|Lederle Japan Ltd| -2-SUBSTITUTED THIO-6-OE-1-HYDROXYETHYLAA-1-METHYL-CARBAPENEM-3-CARBOXYLIC ACID DERIVATIVES, PROCEDURES FOR PREPARING THEREOF, MIXTURES AND PREPARATION|

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EP0876370A1|1996-01-12|1998-11-11|Takeda Chemical Industries, Ltd.|Carbapenem compounds, their production and use|

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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US42575582A| true| 1982-09-28|1982-09-28|

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US53001183A| true| 1983-09-09|1983-09-09|

---