SU1395142A3 - Method of producing carbapenems - Google Patents

Abstract

The invention relates to a method for producing carbapenems of the formula OHCH2 + .CH. ГУ S-CH2-RI, / where R is a cation 2- (N-methyl-pyridium), or 2- (I, 6-dimethyl pyridinium) "or 4- (1 3-dimethyl pyridinium) attached through a ring carbon atom, or H, H-dimethyl-1,2,3-triazolium, or 2-methyl-1,2,3-thiodiazolium, or the potassium salt of 4-Sh1i-5- (l-carbox-methyl 3-methyl-l, 2,3- triazolyl) or 5- (1,4-dimethyltetrazol); 3- (I 3-dimethylpyridin-4-yl), 3- (1,6-dimethylpyridin-2-yl) -e ta-methyl, 3- (1,6-dimet l-pyridin-2 -yl), (1, 3-dimethylimngazole) |, 3-3- (, 2-dimethylpyrndyl). (1-methypyridyl), Nmethyl-pyridyl), 3- 2- (1,4-dimethylpyridyl J, 3 - 2- (N-methylpyridyl), 3,5- (1,4-dimethyl-1,2,4-triazolyl), 3- (2,4-dimethyl-1,2,4-triazolyl) , 3- (2,4-dimethyl-1,2,4-triazolyl), 2-methyl-1,2,3-thiodiazolyl; 5 - (, 4-dimethyl-1,2,4-triazolyl), 3- (G; 3-dimersh-1-5-tetrazolyl); Rj is H or the methyl group, which is used in medicine. Receipt. The target compounds are derived from the corresponding enol phosphate and compound (HS-CH1. -R,) + (CF, SO,), where R is indicated above, in an aqueous-tetrahydrofuran mixture in the presence of an alkali metal hydroxide or in acetonitrile in the presence of diisopropylethylamine. The process is carried out at (-30) - (+ 5) followed by the removal of the protective group to obtain the target compound, 3 tab.

Description

H3o6peteHHe relates to a new way of obtaining carbapenem antibiotics having a 2-substituent of the formula and

he. .g

sa -...-sNg-to the CIS-O-Hsooo ;.

(.

where R, is a cation of 2- (N-methylpyridinium), or 2- (J, 6-dimethylpyridinium) attached through a ring carbon atom, or A- (I, 3-dimethylpyridinium), or H, H-dimethyl-1,2 , 3-triazolium, or 2-methyl-1,2,3-thiodiazolium, / or potassium salt 4- or 5- (1-carboxymethyl-3-methyl-1,2,3-triazoles or 5- (I, A-dimethyltetrazolium); 3- (I, 3-dimetypyridin-A-yl), 3- (1,6-dimethylpyridin-2-yl) - beta-methyl, 3- (1,6-dimethyl- pyridin-2-yl), (l, 3-dimethylimidazolyl) J (1,2-dimethylpyridyl), (I-methyl pyridyl) 1, 3- U- (1 - methyl pyridyl) 3, 3-2-0, A

dimethylpyridyl), 3-GZ- (1-methylpyridyl) 3, (1-methylpridium) 3, 3- 2- (1,4-dimethylpyridyl) 3, 3- 2- {K-methylpyridyl) , 3, 5 (1,4-dimethyl-1-1,2,4-triazolyl), 3- (2.4 Dimethyl-l, 2,4-triazolyl), 3- (2,4-dimethyl-, 2 , 4-triazolyl), 2-; methyl-1,2,3-thiodiazolyl, 5- (1,4-dimetid-.1, 2, 4-thiazolyl), 3- (1.З-dimethyl - Z-tetrazolyl);

R is a hydrogen or a methyl group. The aim of the invention is PU (an improvement in the method of synthesis of new carbapenems derivatives that exhibit improved pharmacological activity.

. Example. Preparation of (N, K-dimethyl-1,2,3-triazolium) methylthio-6et-1- (n) -oxistil-7-oxo-1-azabicylo 3,2,0 hept-2-en-2-carboxylate .

A, Preparation of isomer A. Methyl trifluoromethanesulfonate (0.58 ml; 5.16 mmol) was added dropwise to an ice-cooled, stirred solution of 4- {methanethioacetate} -1-methyl-1,2,3-triazole (590 mg; 3.52 mmol) in dry methylene chloride (2 ml), under nitrogen.

o

5 0 5

0

j Oh

with

,,

After 0.5 h, Sanya is removed and, via rh, the solvent is removed with an aspirator. The remaining oil is dissolved in several ml of water and the solution is cooled in an ice bath. A cold solution of sodium hydroxide (305 mg; 7.59 mmol) in a few ml of water is then added and the reaction is carried out with stirring for 0.75 hours. The solution is diluted to 25 ml with water and the pH is adjusted to 7.5 with solid. sodium hydrophosphate monohydrate. Then, J4 ml of this solution (about 1.9 mmol of triazolithiol) is added to an ice-cooled, stirred enol phosphate solution (1.0 g; 1.72 mmol) in

10 ml of tetrahydrofuran (THF). The mixture is left to stir for 0.75 hours (during the reaction some amount of crystalline compound precipitates, preferably). The suspension is transferred to an autoclave with the addition of a certain amount of THF (20 ml) and water (20 ml). Diethyl ether (30 ml) and 10% palladium on carbon (1.0 g) are added and the mixture is hydrogenated at a pressure of 2.8 atm for 1 hour. The organic phase is separated and washed with water (ml). The combined aqueous phases are filtered off and the filtrate is concentrated under high vacuum (about 0.5 ml, 1.5 h). After that, the yellow solution is chromatographed (medium-pressure column with reversed phase 35x90 mm, water as eluent) and after lyophilization, 395 mg of carbapenem slightly contaminated with inorganic compounds is obtained. It is purified by HPLC (Waters Micrcbondapack 0-18 column, 10x300 mm repeated administration, water as a solvent) and ZU.Mg (57%) of isomer A is obtained in the form of reddish brown. th powder: H-NMR (B, o): S 1.23 (3N, d, 4 Hz), 3.10 (2H, d, 1-9.1 Hz)., 3.24 (1H, k, 1.7.6.1 Hz), 4.03- 4.71 (UN, m), 8.46 (IH, s); IR (NU-iol): 1760 CM V UV (phosphate buffer, pH 7.4,, 05) 296 (-7500) ..

B. Preparation of isomer B and isomer C. Methyl trifluoromethanesulfate (1.60 ml {14.0 mmol) is added dropwise to an ice-cooled solution of 4- (methanethioacetate) -2-methyl-1,2,3-triazole ( 1.20 g} 7.02 mmol) in dry methylene chloride (6 ml) under a nitrogen atmosphere. Allow to warm to room temperature and mix.

16 hours. Additional methyl fluoromethanesulfonate (ml; 3.56 mmol) is added and, after 3 hours at room temperature, the solvent is removed with an aspirator. The residual oil is triturated with sulfuric ether and the resulting resinous compound is dissolved in water (5 ml). The solution is cooled in an ice bath and a solution of sodium hydroxide 10 (84A mg; 21.1 mmol) in water (5 ml) is added. After stirring for 0.75 hours, this solution was diluted to 60 ml with water and the pH was adjusted to 8 with the addition of solid potassium dihydrogen phosphate. After this, 15 g of this solution (about A, 7 mmol of a mixture of isomeric triazolithiols) are added to an ice-cooled, stirred solution of an enol-v phosphate (2.00 g of 3.45 mmol) in THF 20 (60 ml) . This mixture was allowed to stir in an ice bath for 0.5 h, after which it was transferred to an autoclave containing lOZ-aO suspension.

Note eor 2. 5R, 6SJ-6- () -3- (2-methyl-l, 2,3-thiadiaz-4-yl-metshthio) -7-oxo-azab f3,2,0 hept-2- ene-2-carboxylate

A. Eti lovy ester 1,2,3-thiad-4-carboxylic acid. Solution of ei-N-carboxyhydrazopionic acid ester (31.2 g, 0.1 5 in thionyl chloride (80 ml)) was stirred for 3 hours and heated at 70 ° C for 20 minutes. The thiore was evaporated and the residue was grown in hexane (ml). The red compound is dissolved in dichloro (150 ml) and the solution is washed with a bicarb sodium solution. After drying over sodium, the solution concentrates the crystallization of the compound. Set at 23 ° C for a new period, filter iu, ui, 69 %). The filtrate is concentrated and

Crista time (16.8 g, mp. 8

thirty

35

palladium on carbon (2.00 g) and diethyl on a column of silica gel with the left ether (60 ml). The mixture was hydrogenated (2.8 atm) for 1 hour. The organic phase was separated and washed with water (2 x 10 ml). The combined aqueous phases are filtered off and the filtrate is concentrated under high vacuum (about 0.5 ml, 1.5 h). The remaining solution is then chromatographed (medium-pressure reverse-phase column, mm, water as eluent) (And after lyophilization, 595 mg of a mixture of isomeric carbapenems contaminated with a small amount of inorganic compounds are obtained. It is then separated and purified by HPC. (Column Waters Microbondapack G-18, 10,300 mm, repeated administration, water as eluent) and isomer B is obtained in the order of elution: 153 mg (13%); I-NMR (D, 0) S: 1.23 (3N, d, 1-6.4 Hz), 3.12 (2H, q, 1-1.4, 8.9 Hz), 3.39 (W, q, 1-2.7, 6.0 Hz), 4.07-4.68 (YUN, m), 8.19 (1H, s); F (Nujol); 1755, UV (phosphate buffer, p 7.4, 05), A "aks-. 296 nm (g-6700)

40

by obtaining dichloromethane as a grade, 3.17 g are obtained, m.p. 8 13%; IR (KBg) mo, 720 (ether); H-NMR (CDCl) S: 1.52 triplet, 1 Hz, CH, CHiO), 4 (2H, h, 1 Hz,), 9, s, H thiadiazole).

B. 1,2, W-Thiadiazol-4-yl-meth To a suspension of ethyl ether 1, taadiazol-4-ip-carboxylic acid (18.35 g, 0.116 mol) in diethyl ether (400 ml) in parts Lithium aluminum hydride (2.47 g, 0.065 mol) is added. The reaction mixture was stirred at 7 h and treated with lithium-alumina (2.47 g, 0.065 ml). Stirring is continued for 24 hours, after which water is gradually added (7 ml of 45 15% solution of sodium hydroxide

; (7 ml) and water (21 ml). After staining for 15 min, the ethereal jCTBOp is decanted and resinous precipitates are extracted with diethyl (5100 ml). The ether extracts are dried and the magnesium sulfate is concentrated (5.4 g). The crude solution is purified on a column of silica (120 g, 4X16 cm), the ester is used as an eluent and prepared for 1, (7%) 1,2,3-thiad 4-yl-carboxylic acid ethyl ester and 2.45 (18%) 1,2,3-thiadiazol-4-yl-met IR (film), 3880 s; m (OH)

50

: and isomer C: 284 mg (24Z); n-NMR (DjO) S: 1.23 (3N, d, 4 Hz), 3.15 (2H, q, 1-3.7, 9.0 Hz), 3.37 (IH, q, 1 -2.6, 6.0 Hz), 3.95-4.65 (UN, m),. 8.62 (1H, s); IR (Nujol) J 1750 cm; UV (phosphate buffer, pH 7.4,, 05) dm1 |, p. 298 nm (7600).

Note eor 2. 5R, 6SJ-6- (lR-oxy) -3- (2-methyl-l, 2,3-thiadiazolium-4-yl-metshtio) -7-oxo-azabioiklo f3.2, 0 hept-2-en-2-carboxylate.

A. Eti lovy ester 1,2,3-thiadiazole-4-carboxylic acid. A solution of ei-N-carboxyhydrazonopropionic acid ethyl ester (31.2 g, 0.154 mol) in thionyl chloride (80 ml) was stirred for 3 hours and heated at 70 ° C for 20 minutes. The thionyl chloride is evaporated and the residue is triturated in hexane (ml). The red solid was dissolved in dichloromethane (150 ml) and the solution was washed with saturated aqueous sodium bicarbonate. After drying over sodium sulfate, the solution is concentrated to crystallize the compound. After standing at 23 ° C for a certain period of time, filter (iu, u i, 69%). The filtrate is concentrated and the purity of the crystals from- (16.8 g, mp. 8b,

are put on a silica gel column

0

five

5 are put on a silica gel column.

use0

Using dichloromethane as an enta and get 3.17 g, so pl. , 13%; IR (KBG) mo, 720 (ester); H-NMR (CDCl) S: 1.52 (3N, triplet, 1 Hz, CH, CHiO), 4.57 (2H, c, 1 Hz,), 9.47 (IH, s, H thiadiazole) .

B. 1,2, 3-Thiadiazol-4-yl-methanol. To a suspension of 1,2,3-taadiazol-4-ip-carboxylic acid ethyl ester (18.35 g, 0.116 mol) in diethyl ether (400 ml), lithium aluminum hydride (2.47 g, 0.065 mol). The reaction mixture is stirred at 7 hours and treated with lithium aluminum hydroxide (2.47 g, 0.065 ml). Stirring is continued for 24 hours, after which water (7 ml), 5-15% sodium hydroxide solution are added successively.

; (7 ml) and water (21 ml). After stirring for 15 minutes, the ethereal p-jCTBOp is decanted and the resinous compound is extracted with diethyl ether (5100 ml). The ether extracts are combined, dried over magnesium sulphate and concentrated (5.4 g). The crude compound is purified on a column of silica gel (120 g, 4X16 cm), the ether is used as 1.3 g, (7%) ethyl ester 1,2,3-tiad tagol- 4 -yl-carboxylic acid and 2.45 g (18%) of 1,2,3-thiadiazol-4-yl-metaiol; IR (film) ,, 3880 s; m (OH);

0

five

H-NMR (CpCl,): 2.31 (H; s, OH), 5.22 (2H, s,), 8.5i (1H, s, H thiadiaole).

P. 1,2,3-Tiadeaol-A yl-methanol-methanol-sulfonate. Plant 1,2,3-thiadia-sol-5-yl-methacol (0.75 g, 6.5 mol) in dichloromethane (20 ml) cooled to nitrogen and treated with triethylamine (1.018 ml} 7.3 mmol) and methanesulfonylchloride (0.565 cells; 7.3 mmol). After 15 minutes, ice-cold. The bath was removed and the reaction mixture was stirred for 2 hours. Solution 10

A, 58 (2H, s, CH4), 8.4A (iH, s, H thiadiazole).

Calculated Z: C 34.47; H 3.47; N 16.08; S 36.80

Found Z: C 34.48; H 3.83; N 16.28; S 36.80,

E. 4-Acetylthiomethyl-2-metsh1-1,2, 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 diethyl ether (4 ml) and dichlorome e) Shuyut 1N. 15% solution of hydrochloride (0.4 ml) was added a little acid (2x2 ml) and water, the crystals of the target compounds and tri-dried over a mixture of sulphate and magnesium oxide. . fluoromethyl sulfonate (0.407 ml, and concentrated. The residue is purified by chromatography (silica gel column, 6 mmol) for 5 minutes. The reaction mixture is stirred at 23 ° C in

Lem, 1, cm) using di-Ztilovoy ether as eluent and get 0.90 g (71%) 1,2,3-thiadiazol-4-yl-methanol methanesulfrnata {IR (film) |

20

"Ax.

1350 cm- (SO)

1172 cm (SOj) i H-NMR (CDC1,) S 3.09 (3N, s, CH,), 5.75 (2H, s, CH), 8.72 () H, s, H thiadiazole); UV (chloride (chetylen). (- 1990).

Calculated,%: C 24.78; H 3.11; N 14.42; S 33.02

C ,, S

Found,%: C 24.78; H 3.09; N 14.66; S 31.94

and 0.13 g (19%) of di- (|, 2,3-thiadiaeol-4-yl methyl) ether: IR

25

thirty

(film) 9

.

1272, 1242, 1200,

35

986, 805, 728 H-NMR (CDC1,) S 5.16 (s, 4H, CHj), 8.42 (s, 2H, H thiadiazole) ..

D. 4-Acetylthiomethyl-1,2,3-thiadiazole. To a solution of 1,2, 3-thiadiazol-4-yl-methanesulfonate (0.90 g; 4.6 mmol) in tetrahydrofuran (9 ml) is added an aqueous solution (2 ml) of sodium thiol acetate obtained from: thiol acetic acid (o , 38 ml; 5.3 mmol) and sodium bicarbonate (0.445 g; 5.3 mmol). The resultant mixture was stirred for 1 h and diluted with diethyl ether (75 ml). The organic solution is washed with water (3 ml), dried over magnesium sulphate and concentrated. The crude mixture was purified chromatographically (silica gel column, 1, cm) using 50% diethyl ether and hexane as the solvent and 0.60 g (75%) was obtained; JK (film) MD KS 1675 cm (), H-DMR (CDC1,): 2.37 (3N, s, GHj),

nitrogen atmosphere for 6 hours. The white solid compound, which is a mixture of the two target compounds, is filtered off, washed with distil ether and 1.05 g (90%) of IR (KBg) is obtained. 1675 cm CR) ;. H-NMR (DMCO d-6) S: 2.43 (3N, s, CHjCOS), 3.33 (s, si, per N-3), 4.57 (s, CH, at N-2 4, 66 (2H, s, CHj), 9.55 (H per N-2) thiadiazole), 9.66 (H per N-3 thiadiazyl).

Calculated Z: C 20.27; H 2.38; N 9.45; S 32,46

C, H, N, 0, S, F,. . .

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, diazolium trifluoromethanesulfonate.

A solution of a mixture of 4-acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-1,2,3-thiadnazolium trifluoromethanesulfonate {1.05 g, 3.1 mmol) in 6N. hydrochloric acid (10 ml) is heated under a nitrogen atmosphere for an hour. The solvent is evaporated under reduced pressure to give 0.91 yellow syrup-like compounds. This compound is used in the next step without purification.

G., (1H-hydroxyethyl) -3- (2-methyl-I, 2, 3-thiadiazolium-4-yl-methyl-thio) -7-oxo-1-azabicyclo 1z, 2.0) hept-2- en-2-carboxylate.

Cold () solution of 5R, ra-nitrobenz p-6- (1K-hydroxyethyl) -3- (di-phenylfeufono) -7-oxo-1-azabicyclo 3, 2, o1-hept-2-en-2-carboxylate (1 -7 g

40

55

A, 58 (2H, s, CH4), 8.4A (iH, s, H thiadiazole).

Calculated Z: C 34.47; H 3.47; N 16.08; S 36.80

Found Z: C 34.48; H 3.83; N 16.28; S 36.80,

E. 4-Acetylthiomethyl-2-metsh1-1,2, 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 diethyl ether (4 ml) and dichloromethane (0.4 ml) was added a few crystals of the desired compounds. and trifluoromethyl sulfonate (0.407 ml,

3.6 mmol) for 5 min. The reaction mixture is stirred at 23 ° C.

nitrogen atmosphere for 6 hours. The white solid compound, which is a mixture of the two target compounds, is filtered off, washed with distil ether and 1.05 g (90%) of IR (KBg) is obtained. 1675 cm CR) ;. H-NMR (DMCO d-6) S: 2.43 (3N, s, CHjCOS), 3.33 (s, si, per N-3), 4.57 (s, CH, at N-2), 4.66 (2H, s, CHj), 9.55 (H per N-2) thiadiazoles), 9.66 (H per N-3 thiadiazols).

Calculated Z: C 20.27; H 2.38; N 9.45; S 32,46

C, H, N, 0, S, F,. . .

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, diazolium trifluoromethanesulfonate.

A solution of a mixture of 4-acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-1,2,3-thiadnazolium trifluoromethanesulfone and {1.05 g, 3.1 mmol) in 6N. hydrochloric acid (10 ml) is heated under nitrogen for hours. The solvent is evaporated under reduced pressure to obtain 0.91 g of a yellow syrup-like compound. This compound is used in the next step without purification.

G., (1H-hydroxyethyl) -3- (2-methyl-I, 2, 3-thiadiazolium-4-yl-methyl-thio) -7-oxo-1-azabicyclo 1z, 2.0) hept-2- en-2-carboxylate.

A cold () solution of 5R, ra-nitrobenz p-6- (1K-hydroxyethyl) -3- (diphenylfeoyono) -7-oxo-1-azabicyclo 3, 2, o1-hept-2-en-2-carboxylate ( 1-7 g

2.92 mmol) in tetrahydrofuran (10 ml is treated with a solution of sulfuric mixture A-mercaptomethyl-2-metsh1-1,2,3-thiadiaeolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-1,2,3-triadio-3 lithrifluoromethanesulfonate (0.9 g) in a mixture of phosphate buffer (pH 7.2, 0, 3M, 15 ml) and tetrahydrofuran 5 ml). The reaction mixture was stirred for 1 h and the pH was maintained at 7.2 with 2N. sodium hydroxide solution. Stirring is maintained for an additional hour, then diethyl ether (50 ml) and 10% palladium on carbon (I g) are added. The resulting mixture is hydrogenated at and 3–15 atm for 2 h and filtered through zeolite. The organic phase is separated, diluted with diethyl ether (50 ml) and phosphate buffer (pH 7.2, 0.3 M, 20 ml) and hydrogenated (2 g IOZ-palladium on carbon) for 2 hours at 3, 5 atm. The aqueous phases are combined (from the first and second hydrogenolysis),: washed with diethyl ether and purified by chromatography and Prep Puk 500-C / I8 using water as an eluting solvent and 0.22 g of crude compound is obtained. : It was re-purified by HPLC | using water as eluent, iHTa, and 0.040 g (4%) of the title compound was obtained after lyophilization; IR (KVg) moxa, 3400 (broad peak, OH), 1745 () p-lactam), 1580 (carboxilate) H-NMR (): 1.23 (ZN, d, 1-6.3 Hz, СН , SNON), 3.04. . 3.05, 3.16 (2H, m, H-4), 3.38. (1H. Double doublet,, 8 Hz,, 0 Hz, - H-6), 3.9-4.6 (2H , m, H-5, iCHjCHOft), 4.51, 4.53 (2H, s, ZSNg), 4.61 (s, N®CH,); UV (water). 224 (e-4345). 262 (g "4980), .296 (b: -6885), M 18 (, 18, water) T (, 8 p (measured at a concentration of Yu. M in phosphate buffer pH 7.4 at 36.8 s). ;

PRI me R 3. Kaliev salt of (1-carboxylate methylamine-3-methyl-1,2,3-triazolium) methanethio3-6 «i-fl- (R) -ox-. ethyl 7-oxo-J-azabicylo 3,2, 0 hept-2-ene-2-carboxylic acid .-.

Lithium aluminum hydride (2.83 g, 70.9 mmol

in small portions add a mixed suspension of I-methyl-1,2,3-triazole-4-carboxylic acid (9.00 g, 70.9 mmol) in dry THF (200 ml) in nepig. The mixture was allowed to stir at room temperature for 15. h.

thereafter, about 20 ml of 20% aqueous sodium hydroxide solution are carefully added in 1 ml portions. The resulting granulation slurry is filtered off and the solid residue is washed with additional THF (5x75 ml). The combined THF solutions are dried over magnesium sulfate and the solvent is removed. The resulting yellow oil is purified by chromatography on a 90x35 mm snpicagel column (100 ml portions of hexane, ethyl acetate hexane 1: 1 and 1 mixture; 3 and in conclusion ethestacetate-methanol 9: 1 as eluent). Thus, 4-hydroxyvtil-1-methyl-1,2,3-triazole (3.18 g, 40%) is obtained as a colorless oil: H-NMR (CDCl,): 4.07 (3N, s), 4 , 73 (2H, d), 7.52 (1H, c) j IR (pure) 3320 cm-.

Methanesulfonylchloride (3.82 ml, 49.6 mmol), dropwise m1tribavl in ice-cold, stirred solution of alcohol (5.67 ml | 41.3 mmls) and triztilamine (7.47, ml 53.7 mmol) in methylene chloride ( 20 ml). After 0.5 h, the solvent is removed and the remaining solid is dissolved in acetonitrile (30 ml). Potassium thiol acetate (7.06 g, 62.0 mmol) is added and the suspension is stirred at room temperature for 3 hours. An additional amount of potassium thiol acetate (3.0 g; 26.3 mmol) was added and the suspension was stirred for another 16 hours, then the suspension having a dark color was concentrated and water (10 ml) was added. This mixture was extracted with methylene chloride (5x40 ml). The combined extracts were dried over magnesium sulphate and the solvent was removed. The remaining oil is purified by chromatography on a column of silica gel, mm (hexane is used as eluent, and then hexane – ethyl acetate 1: 1). 4- (methanthyrlace and t) -1-methyl-1, 8-triazole (5.95 g; 84%) are obtained in the form of a pale pink solid compound:% NMR (CDCl,); 2.40 (ZN, singlet), 4.10 (ZN, s), 4.20 (2H, s), 7.53 (1H, s), IR (Nujol): 1675 cm.

. A solution of triazole (1.00 g; 5.85 mmol) and ethyl bromoacetate (1, L8 ml, 13.3 mmol) in dry acetonitrile (10 ml) is heated for 90 hours under nitrogen atmosphere. Ragtailer

Macrfo is removed and triturated with diethyl ether (l ml) and 1-methyl-3- (ethylcarboxymethyl) -A-methanethioacetate-1,2,3-tri-aeolium bromide is obtained in the form of a brownish resinous compound, which is directly used as an epoxy.

fO

15

A cold solution of KOH (0.66 g; 12 mmol) in water (5 ml) was added to an ice-cooled, stirred solution of tri-aeolium bromide in water (20 ml). After 20 minutes, it was diluted to 35 ml and such an amount of solid potassium dihydrogen phosphate was added so that the pH of the solution was 8.0. This solution was then added to a stirred, ice-cooled solution of phenol phosphate in THF (35 ml). After JQ 0.5 h, this mixture was transferred to an autoclave containing diethyl ether (35 nl) and 10% palladium on carbon (1.5 g). Conducts hydrogenation at 2.8 atm.

 for 55 minutes The organic phase from -25 is divided and flushed with water (2 x 5 ml). The combined aqueous phases are filtered off and the mixture is concentrated under high vacuum. The residual compound is chromatographed on a reverse-JQ phase column - (35x120 mm) using water as eluent. Lyophilization of the fractions containing carbapenem gives 1.20 g of a green solid compound. It is chromatographed again using a Waters Prep HPLC (Prep column. PAK-500 / C “9), using 2% acetonitrile in water as eluent. The fractions containing i carbapenem are combined and lyophilized. This compound is again chromatographed on a HPLC (YLGZOO mm column. Waters Microbondapack C-18) using water as a mixture; and, after lyophilization, a pure target compound (190 mg, 17%) is obtained as pale yellow yellow solid compound: H-NMR (S): 1.24 (3N, d, A Hz), 3.07 (2H, d, 1–9 Hz), 3.38 (1H, c, 7, 6 , 0 Hz), 4.02-4.30 (ZN, m), 4.29 (ZN, s), 5.28 (2H, s), 8.52 (1H, s); IR (Nu-Yol): 1750 cm; UV (phosphate buffer, pH 7.4), 296 nm (7520).

PRI me R 4. Kaliev salt (1-carboxylate-3-methyl-1,2,3- 55

35

40

45

50

triazolium) -methanito -6 "- 1- (K) -oxy-ethyl acetate and get 1- (

Ztilz-7-oxo-1-azabicyclo 3,2, Oj-heppt-carbxymethyl) -4-oxnmetl-1,2,3-triCis mixture of ztilazidoacetate (30.0 g, 0.23 mol) and propyl acid (14, 3 ml, 0.23 mol) in toluene (75 ml) is peremegaivat at room temperature. The reaction is slightly exothermic, and after 1.5 hours it becomes highly exothermic and requires cooling in an ice bath. After completion of the exothermic stage, the reaction is conducted under reflux for 0.5 h. After cooling in an ice bath, the crystalline compound is collected by filtration and washed with a small amount of toluene. The crude compound thus obtained (33.3 g {72%) consists of one isomer: H-NMR (DMSO-dg) 5: 1.20 (3N, triplet, Hz), 4.15 (2H, k, 1-7 Hz ), 5.42 (2H, s), 8.67 flH, W), presumably 1- (methylcarbox-methmethyl) -1,2,3-triazole-4-carboxylic acid.

A solution of carboxylic acid (5.00 rj 25.1) and triethylamine (3.68 ml / 26.4 mmol) in dry methylene chloride (50 ml) was added to an ice-cooled, stirred solution of ethyl chloroformate (2.52 ml; 26.4 mmol) in dry methylene chloride (50 ml). The red solution was stirred for 0.5 h, after which it was washed with water (10 ml), dried over magnesium sulfate and the solvent was removed. The dry mixed anhydride is dissolved in THF (50 ml) and slowly added to an ice-cooled suspension of sodium borohydride (0.72 g; 18.9 mmol) in THF (50 ml). After stirring for 0.5 hour, add an additional amount sodium borohydride (0.30 g 7.9 mmol) and the reaction was carried out in an ice bath for 1 hour. Water (5 ml) was then added and after 10 minutes a 10% aqueous solution of HCl was added (3 ml) After degassing with stirring, solid potassium carbonate is added (- 2 g). The organic phase is then removed and the remaining white paste is further extracted with T Gf. The combined organic phases are dried over magnesium sulphate and the solvent is removed, purified by chromatography on silica gel, eluted with hexane with ethyl acetate-hexane and concentrated in 2-e-2-carboxylic acid.

azole (2.04 g, 44%) as white

O

five

Q

5 Q

five

five

0

five

0

ethyl acetate and get 1- (

carbsmethyl) -4-oxnmetl-1,2,3-triMixture of ztilazidoacetate (30.0 g-, 0.23 mol) and propylonic acid (14.3 ml, 0.23 mol) in toluene (75 ml) are distilled at room temperature temperature The reaction is slightly exothermic, and after 1.5 hours it becomes highly exothermic and requires cooling in an ice bath. After completion of the exothermic stage, the reaction is conducted under reflux for 0.5 h. After cooling in an ice bath, the crystalline compound is collected by filtration and washed with a small amount of toluene. The crude compound thus obtained (33.3 g {72%) consists of one isomer: H-NMR (DMSO-dg) 5: 1.20 (3N, triplet, Hz), 4.15 (2H, k, 1-7 Hz ), 5.42 (2H, s), 8.67 flH, H), presumably 1- (methylcarboxymethyl) -1,2,3-triazole-4-carboxylic acid.

A solution of carboxylic acid (5.00 rj 25.1) and triethylamine (3.68 ml / 26.4 mmol) in dry methylene chloride (50 ml) was added to an ice-cooled, stirred solution of ethyl chloroformate (2.52 ml; 26.4 mmol) in dry methylene chloride (50 ml). The red solution was stirred for 0.5 h, after which it was washed with water (10 ml), dried over magnesium sulfate and the solvent was removed. The dry mixed anhydride is dissolved in THF (50 ml). And slowly added to an ice-cooled suspension of sodium borohydride (0.72 g; 18.9 mmol) in THF (50 ml). After stirring for 0.5 hour, additional sodium borohydride (0.30 g, 7.9 mmol) was added and the reaction was conducted in an ice bath for 1 hour. Water (5 ml) was then added and after 10 minutes 10% aqueous solution of HC1 (3 ml). After degassing, solid potassium carbonate is added with stirring. (2g). The organic phase is then removed and the remaining white paste is further extracted with THF. The combined organic phases are dried over magnesium sulphate and the solvent is removed. Purification is carried out by chromatography on silica gel, eluted with hexane with a mixture of ethyl acetate - hexane and in conctilcarbsimethyl) -4-oxnmetnl-1,2,3-t.

azole (2.04 g, 44%) as white

crystalline compounds: H-JMF (CDCl,) 5: 1.28 (3N, t, Hz), 4.23 (2H, k, Hz), 4.75 (2H, s) / 4.85 (2H, s), 7, 73 (W, s). five

Diieopropylazodicarboxylate (A, II ml; 20.8 mmol) was added dropwise to an ice-cooled solution of triphenylphosphine (5.47 g; 20.8 mmol) in dry THF (100 ml) under aeo-10 ta atmosphere. After 0.5 h, an ice-cooled solution of alcohol (1.93 g; JO, A mmol) and thiol-acetic acid (1.49 ml; 20.8 mmol) in dry THF (50 ml) in an atmosphere of nitrogen. J5 This mixture is kept for 2 hours in an ice bath and then an additional 12 hours at room temperature, and the solvent is removed. The reaction mixture is chromatographed on silica gel (40 g, eluted in portions of 100 ml of hexane, 5, 10, 15,.,., 50% mixtures of ethyl acetate and hexa). fractions containing thiol acetate are combined and re-chromatographed on silica gel 25 (60 g, eluted in 200 ml portions of hexane, 5, 10, 15, and 20; a mixture of ethyl acetate and hexane and 22.5, 25.27, 5 ,., 35% -Hb X mixtures of ethyl acetate and hexa). In this way, (49Z) .1- (ethylcarboxymethyl) -4-e1 antiol acetate-, 2,3-triazole is obtained as a crystalline solid: H-NMR: 1.28 (3N, t, 1-7 Hz), 2.37 (ZN, s), 3.87 (2H, s), 3.90 (2H, „, 1-7 Hz), 5.12 (2H, s), 7.63 (1H;), IR (Uyol): 1735, 1780 cm, and an additional 1.40 g of compound, loaded with triphenylphosphine oxide,

Methyl trifluoromethanesulfonate (0.51 mp, 4.53 mmol) was added dropwise to an ice-cooled, stirred solution of triazole (1.00 g, 4.12 mmol) in dry methylene chloride (5 ml). After 0.5 h, the bath is removed and after another 0.5 h the solvent is removed under vacuum. A white solid is obtained which is suspended in water (15 ml) and the mixture is stirred while cooling.

45

50

and ice bath. Add solution

KOH (0,69 G-, 12,4 mmol) in water (5 ml); and the reaction is carried out with stirring for 1 hour. The mixture is then diluted to 30 ml with water and solid potassium dihydrogen phosphate is added to adjust the pH to 3.0. A portion of this solution (about 22 ml; 3.0 mmol of thiol carboxylate) is added to an ice-cooled

five

0 5 0 5 o

five

0

five

stirred solution of enol phosphate (1.60 g; 2.76 mmol) in THF (30 ml). After 0.5 h, the reaction is terminated and the THF is removed under high vacuum. The yellow solution is then chromatographed on a reverse phase column (35-120 mm) using water as eluent (ZOO ml), and then in 100 ml portions of 5,10,15, ..., 30g acetonitrile-water mixtures. N1Filation of the appropriate fractions gives the para-nitrobenzyl ester as a yellow solid (930 mg). It is transferred to an autoclave containing diethyl ether (25 ml), THF (25 ml), phosphate buffer (25 ml) obtained by dissolving potassium dihydrophosphate (1.36 rj 0.01 mol) in water (loo ml) and adjusted to pH 7.4 by the addition of a 45% aqueous solution. KOH, and YuL-ny palladium on coal (900 mg). Hydrogenation is carried out at 2.8 atm. Per-hour for 1 hour, after which the organic phase is separated and washed with water (2 x 5 ml).

the aqueous phases are filtered and. concentrate under high vacuum. The remaining solution is chromatographed on a reverse phase column (35x120 mm) using water as eluent. the fractions containing carbapep are combined, lyophilized, and 1.21 g of a pale green solid is obtained. It is synthesized by HPLC (10x300 mm column. Water Microbonda-pack C-18, water as zlüheit) and a pure target product of 480 mg (41H :): H-NMR () is obtained: 1.23 (GD, d, 1 -6.4 Hz), 3.11 (2H, d, I- 9 Hz), 3.37 (1H, k, 1-3.0, 6.1 Hz). 4.02 (7H, m), 5.18 (2H, s), 8.53 (1H s); JUS (Nujol) 1750 UF (phosphate buffer, pH 7.4) I; i1x 205 im: :().

EXAMPLE 5: (l, 4-Dimethyl-1, 2, 4-triazolium) methane hyo C (R), axiyl-7-oxo-1-azabicyclo, 2.03-hept-2-ei 2-carboxylate.

A. 1-Methyl-5-methanethiol acetate-1 2, 4-triazl.

/ Methanesulfonyl chloride (0.46 ml; mmol) is added dropwise to an ice-cooled, stirred solution of 1-methyl-5-oximegyl-1,2,4 triazole (565 mg {5.0 mmol) and tr-ethylamine ( 0.91 ml; 6.5 mmol) IB meth- penpenchloride (5 ml). After 20.min - additional TrintilaMin is added.

(l, 05 ml, 7.5 mmol), then thiol-acetic acid (o, 53 ml, 7.5 mmol) and crush for 45 minutes. The reaction mixture is then diluted with methyl chloride and washed with water. The aqueous phase is extracted with methylene chloride (ml), the combined organic phases are dried over magnesium sulphate and the solvent is removed. Column 10 chromatography on silica gel gives the pure J -methyl-5-meta-thiolac1 at-g, 4-triaole (570 mg) as a yellow oil. In addition, the contaminated fraction (200 mg) is again chromatographed (pre-f5 para-tive TLC, silica gel) and another JOO mg of the pure compound is obtained (total yield 85%): 1 H NMR (CDCl 3): 2.38 (3N, s) , 3.90 (AH, s), 4.25 (AH, s), 7.80 (1H, s). 20

B. 3- 5- (1,4-dimethyl-1,2,4-triazb-li) .- methantio-6e - l- (R) toxenetilJ-7-scso-1-azabncyclo f3,2., 0 { hept-2-en-car boxyl,

Methyl transfluoromethanesulfonate (1.20

10.7 mmol) is added dropwise to an ice-cooled solution of 1-methyl-5-. methanethyl acetate, 2,4-triazole (730 mg) (4.27 mmol) in methylene chloride (7 ml). The reaction mixture is slowly heated to room temperature 30 over a period of

3h, after which it is concentrated. The residual oil is triturated with diethyl ester to obtain crude 1,4-dimethyl-5-methanethiol acetate-1,2,4-triazolium trifluoromethanesulfonate (1.46 g), which is used directly.

Sodium hydroxide solution (512 mg; i

12.8 mmol) in water (5 ml) add AL to an ice-cooled solution of the triazolium salt (1.45 g; 4.35 mmol) and water (5 ml). After 45 minutes the mixture was diluted to 25 ml with water and the pH was adjusted to

7.6 solid potassium dihydrophosphate. The solution is then added to an ice-cooled, stirred solution of enol phosphate (2.00 g} 3.45 mmol) in THF. {25 ml). After 30 minutes, the reaction mixture was transferred to an autoclave containing diztile ether (40 ml) and 10% palladium on carbon (2.0 g). The mixture is hydrogenated at 3.15 atm for 1.25 hours. The reaction mixture is then diluted with diethyl ether (25 ml) and filtered. The organic phase 5 is separated and washed with water (2 h5 ml). The combined 1P 1e aqueous phases are rinsed with diethyl zsfir (325 ml) and concentrated under vacuum. Column chromatography (reverse phase, 45 "| 30 mm, water B as eluent) and subsequent lyophilization of the fractions containing carbapenem give 650 mg of the crude compound. It is again chromatographed and a pure desired product is obtained, 450 mg (39): H-SHR (D, 0). 1.24 (ЗН, d, 1 - 6.4 Hz), 3.19 (2Н, к, 1-2.6, 9.2 Hz), 3.45 (Ш, к, I- -2.8 , 6.0 Hz), 3.91 (ZN, s), 4.06 (ZN, s), 4.08-4.36 (2H, m), 4.54 (2H, d, 1-2, 8 Hz), 8.71 (1H, s), F (well, iol): 1755 UV (phosphate buffer, pH 7.4) -294 nm (g-8202), T ,, (phosphate buffer, pH 7 , 4,, 067, T-37 s) 9.1 h,

PRI me R 6. 1 R, 5R, (l, 3-dimethyl-5-tetJ5azolium) -meI1: thio-6 (1 - hydroxyethyl) -7-oxo-1 -az abicyclo 3,2 hept-2 en-2-carboxylate

A, 5-Carbethoxy-2-methyltetrazol and 5-carbztoxy-1-methyltetrazole,

1a Methylation of diazomethane. A solution of 5-carbztoxitetrazole (9.17 rj 0.064 mmol) in 80 ml of diestil zirfir (using a mixture of ethanol and diztile ether gives the same ratio of isomers) is cooled until a solution of diazomethane (3 g, 0) is added dropwise. , 07 mmol) in dithyl ether (200 ml) for 15 minutes. The light yellow solution was taken up in 30 minutes and the excess diazomethane was destroyed by the addition of acetic acid (1 ml). Evaporation of the solvent and distillation of the residue yields a clear oil; t kip. 95-100 C / 0.5 mmHg, 9.64 g (96), n-NMR is compressed into a mixture of 1-methyl and 2-methyl isomers in a ratio of 6 :: 4. The separation of the two isomers is not achieved by distillation. , no HPLC: IR (film) Sms1x: 1740 (C y complex zfira) -, H-NMR (CDClI): 1.53. (3N, two overlapping triplets, 1-7.0, CHjjCH,), 4.46 and 4.53 (3N, 2S, SI, I-methyl and 2-methyltetrazole, 6: 4 ratio, 2-methyl isomer d, in the lower region is not the main product), 4.5 ppm (2H, two overlapping quartets,),

Ib, 5-Carbtoxy-2-methyltetrazol, a mixture of 5-carbethoxy-2-methyltetrazol and 5-carbztoxy-1-methyltetrazole (o, 252 g, 1.61 mmol, the ratio of isomers 1: 1) in methyl iodide (0.5 ml)

sealed in a glass test tube and heated for 15 hours and for 6 hours. Distillation of the reaction mixture yields the desired compound as a pale yellow oil: 0.139 g (55%), b.p. 95-100 C / / 0.5 mm Hg (air bath temperature); IR (film) „ax 1740 cm (С-О ester), n-NMR (CDCl,) S: 1.46 (ZN, t, T-7.0, CHjCH), 4.53 (ZN, s , CH, -2), 4.5 (2H, q, 1-7.0 CHjCH,).

2. Methylation with dimethyl sulfate, A solution of 5-carbethoxytetrazole (l 42rjt5 0.01 mol) in dry acetone (20 ml) is treated with anhydrous potassium carbonate (1.36 g, 0.01 mol) and dimethyl sulfate (1.26 g; 0 , 01 mole). The mixture was heated under reflux for 20 hours. The carbonate was filtered and the solvent was filtered under reduced pressure. The residue was diluted with dichloromethane (30 ml), washed with saturated bicarbonate, cat- ter (10 ml), brine (10 ml) and dried over anhydrous sodium sulfate. Evaporation of the solvent and distillation under vacuum gives a clear oil: 1.45 g (93%), b.p. 85-110 with / ZO / 0,5 mm Hg. H-NMR shows the presence of two isomers in a ratio of 1: 1.35

B, 5-Oxymethyl-2-methyltetrazol. I. Recovery of a mixture of complex efyry. A mixture of 5-carbethoxy-1-methyltet. of razol and 5-carbztoxy-2gmethyltetra9ol in a ratio of 6: 4 (7.60 g O, 049 mol7 in dry THF (50 ml), 40 is blended to O c and treated with lithium aluminum hydride.1.06 g, 0.049 mmol), which is added in small portions over 15 minutes. The mixture is held for an additional 30 minutes and 45 minutes.

then stirred for 4 hours. The mixture is cooled to 0 s and the excess hydride is carefully destroyed.

adding 6n. HCl (pH = 7 after the end of the distribution of gas). Rast-

The solvent is concentrated under vacuum. 3m and the remaining oil is diluted with dichloromethane (200 ml), washed with brine (10 ml) and dried over sodium sulfate. Concentration of the solvent and distillation of the residue under vacuum 5 gives 1.83 g (33%) of a clear. oils. An n-NMR analysis of this compound shows that the product is represented by

5 0 5 About

five

0 5

.

This is 5-hydroxymethyl-2-methyltetrazole.

2. Reduction of 5-carbethoxy-2-methyltetrazole. To a solution of 5-carbethoxy-2-methyltetrazole (0.139 rj 0.89 mmol {obtained by isomerization of a mixture of esters with methyl iodide) in dry tetrahydrofuran (I ml) at 1 ° C was added solid lithium hydride (0.019 G), 0, 87 mmol). The mixture is slowly heated to room temperature and stirred for 4 hours. Excess borohydride is destroyed by careful addition of 6N. HC1 at (pH 7). The solvent is evaporated, the residue is dissolved in dichloromethane (25 ml) and dried over anhydrous sodium sulfate. By evaporation of the solvent, the desired compound is obtained in the form of a transparent mass: 0.092 g (91%) of bp. 90-120 C / O, 5 mmHg, with decomposition, IR (film) dx: 3350 cm (broad peak, OH), n-NMR: 4.4 (2H, s, CH, -2), 4 , 93 (2H, s, CH, -5).

C.5-Acetylmercaptomethyl-2-methyltetrazol.

To a solution of 5-Oxymethyl-2-methyltwt-razol (g {11.7 mmol) in dry dichloromethane (25 ml) at 0 with added methanesulfonyl chloride (1.47 g of 12.9 mmol), and then with triztils (1.30 g, 12.9 mmol) dropwise over 5 minutes. The mixture is stirred for 1 hour and then treated: with potassium thioacetate (1.60 g, i4, b mmol) in dry N, N-dimethylforde amide (10 ml). The resulting gel was stirred at 0 ° C for 3 hours. The reaction mixture was diluted with dichloromethane (200 ml), jpacTBOpoM salt (20 ml) was passed and dried over anhydrous sodium sulfate. By evaporation of the solvent under vacuum and chromatography of the resultant oil on silica gel (2L5 cm, elution with dichloromethane and dichloromethane - 5% mixture), the desired compound is obtained in the form of a clear oil: 1.31 g (65%)} IR (film) - move with: 1696 cm (thioether), H-NMR (CDCl,): 2.43 (ZN, s, SaC), 4.36 (ZN, s, 2- - CH), 4.38 ppm (2H, s , S-CH,}.

D.5-Mercaptomethyl-1,3-dimethyl-, tetrazolium trifluoromethacrylate.

A solution of 5-acetylmercaptomethyl-2-methyltetrazole (O.AOO g; 2.32 mmol)

in dry dichloromethane (3 yl), treated with methyl triflate (0, / 6g, 4.64 mmol) and peremetla at 22 ° C for 16 h. Red oil is obtained by evaporation of the solvent under - vacuum. This salt is dissolved in cold water (5 ml of which oxygen is removed, and treated with 4 M sodium hydroxide solution (o, 8 ml 1 3.2 mmol). The mixture is stirred at O 0 for 40 minutes, diluted with water ( 7 ml) and the pH is adjusted to 7.8 with a saturated solution of KN, P04. The clear resultant solution is stored in a nitrogen atmosphere and immediately used (5 is used for the next stage.

E. l R, 5R, (l, 3-dimethyl-5-tetrazolium) -methylthioZ-6- (1-oxystil) -. 7-oxo-1-azabicyclo 3,2, OG | hept-2-E-2-carboxylate.20

A solution of enol phosphate (0.915 g; 1, S8 mmol) in THF (8 ml) is cooled with -i to O with and treated dropwise with a plant.

A. Preparation of Enol Phosphate II In an ice-cooled solution of the corresponding 3-keto derivative (3 g, 8.62 mmol) in acetonitrile (30 ml), ethyldiisopropamine (9 mmol, 1.04 eq., 1.57 ml) was added over a period of -2 minutes and 9 mmol, 1.04 Sq., 1.87 ml) for -2 minutes. The reaction mixture is stirred for 45 minutes and TCS analysis (ethyl acetate, silica gel) indicates the disappearance of ketone-1. The solution was diluted with ethyl acetate (60 ml), washed with cold water (2 x 50 ml) and brine, dried over sodium sulfate, concentrated (bath temperature below.

by thief 5-mercaptomethyl-1,3-dimetiptet- 25 20 C) and get a foamy compound.

ethylene fluoromethane sulfonate (2.32 mmol). for 20 minutes, the pH of the reaction mixture is 6.5 during the addition. After another 20 minutes, the pH of the solution was adjusted to 7.0 with a saturated sodium bicarbonate solution. The mixture was transferred to a hydrogenation vessel, diluted with THF (10 ml), for ethyl ether (20 ml) and ice (20 g). Carbapene is hydrogenated over 10% palladium on activated carbon at 3.15 atm and a slight temperature rise to 90 M for 1H. The catalyst is filtered off, washed with cold water (5 ml) and diethyl ether (20 ml). The aqueous phase is washed with ether (20 ml) and held under vacuum for 20 minutes to remove traces of organic solvent. Chromatography on Pse PAC 500-C / I8 using water as an e- ment gives the desired compound as a white powder (after lyophilization); 0.0266 g (49%), (s-1.04, water); UV (water, 294 nm (7500); IR (KVg)

thirty

35

40

45

Max

And - "- 1з

pH 7.4). ..., -, „(C 0 i-lactam), 1600 cm 0 (broad peak, from carboxyl ta); H-NMR () J: 1.24 ($ H, d, 4 Hz, CH, CHON), 3.0-3.3 (2H, m, H-4), 3.42 (JH, double doublet , 1 "5.8,, 9, H6), 4-4.2 (2H, m, H5 and CH, SNON), 55 4.34 and 4.57 (, $ 2, CH, -1 and 3 Tetrazole ), 4.49 and 4.51 (2H, 2s, CHjS). The product has a half time of which is used directly,

B. Preparation of N-methylLyridin-2-Sh1-methanethiol. Through an ice-cooled solution of the thioacetate of the corresponding thiol (3.31 rt 10 mmol) in water, nitrogen is passed through for 5 minutes and a cold solution of sodium hydroxide (1.75 equiv., 17.5%) is added dropwise (approximately within 5 minutes). mmol, 0.7 g) in water (8 ml). The mixture turns yellow. Through

75 minutes under nitrogen atmosphere, the pH is adjusted to 7.4 with a saturated aqueous solution of KHjPO. The reaction mixture was diluted with water (15 ml). This aqueous solution of thiol 4 (50 ml, 0.2 mmol / ml) is used as such.

C. Attachment. In an ice-cooled solution of Compound II (crude, prepared in A, 8.62 mmol) in THF (50 ml), an aqueous solution of thiol prepared in B (5 ml of solution every 5 minutes) is added dropwise. When carrying out the reaction, the pH of the reaction mixture is maintained at about 6.5-7.5 (preferably about 7) by adding a cooled 2n. sodium hydroxide solution. After completion of the reaction, TLC is carried out;

a - silica gel, ethyl acetate; b - reverse phase Analtech RPSF acetonitrol buffer with pH 7 (4: 6).

At the end use 1.15 equiv. thiol (5 ml solution). The reaction is completed after 1 h with a mixture of 10.5 H and (with GO M n (3 × sphate buffer, pH 7.4).

Example. Preparation of 3- (H-Methylpyridin-2-yl-methantio) -6oi- 1- (H) -oxyeth-1 -7-oxo-1-azabicyclo 3, 2.0 hept-2-en-2-carbs; . way in one flask.

A. Preparation of Enol Phosphate II In an ice-cooled solution of the corresponding 3-keto derivative (3 g, 8.62 mmol) in acetonitrile (30 ml), ethyldiisopropamine (9 mmol, 1.04 eq., 1.57 ml) was added over a period of -2 minutes and 9 mmol, 1.04 Sq., 1.87 ml) for -2 minutes. The reaction mixture is stirred for 45 minutes and TCS analysis (ethyl acetate, silica gel) indicates the disappearance of ketone-1. The solution is diluted with ethyl acetate (60 ml), washed with cold water (2 x 50 ml) and brine, dried over sodium sulfate, concentrated (bath temperature below

which is used directly,

B. Preparation of N-methylLyridin-2-Sh1-methanethiol. Through an ice-cooled solution of the thioacetate of the corresponding thiol (3.31 rt 10 mmol) in water, nitrogen is passed through for 5 minutes and a cold solution of sodium hydroxide (1.75 equiv., 17.5%) is added dropwise (approximately within 5 minutes). mmol, 0.7 g) in water (8 ml). The mixture turns yellow. Through

75 minutes under nitrogen atmosphere, the pH is adjusted to 7.4 with a saturated aqueous solution of KHjPO. The reaction mixture was diluted with water (15 ml). This aqueous solution of thiol 4 (50 ml, 0.2 mmol / ml) is used as such.

C. Attachment. In an ice-cooled solution of compound II (crude, prepared in A, 8.62 mmol) in THF (50 ml). an aqueous solution of the thiol obtained in B is added dropwise (5 ml of solution every 5 minutes). When carrying out the reaction, the pH of the reaction mixture is maintained at about 6.5-7.5 (preferably about 7) by adding a cooled 2n. sodium hydroxide solution. After completion of the reaction, TLC is carried out;

a - silica gel, ethyl acetate; b - reverse phase Analtech RPSF acetonitrol buffer with pH 7 (4: 6).

At the end use 1.15 equiv. thiol (5 ml solution). The reaction is completed after 1 h with n the mixture is used on the seOe itself to pad after the pH is adjusted to 7.

D, Hydrogenation. The reaction mixture containing the desired product I, sealed in the carboxyl group by para-nitrobenzene (obtained in sec.) Is transferred to a Parr flask with THF (10 ml), phosphate buffer (pH 7.0, 1 M) (10 ml) with ether 75 ml) and Pd-C YuH-nym (5 g), hydrogenated at 3.15, atm and 3-10 C for 2 h. Then the catalyst is filtered off, rinsed with water (S10 ml) and the pH is adjusted to to 6.2, carefully added a cold 2n. NaOH solution. The ether is added, the aqueous phase is separated and again washed with ether. The aqueous phase is purified from the organic solvent under vacuum and then purified on a Bondapak C-18 column (Jub g, A, 5x13 cm) with cold distilled water. The light yellow fractions containing the product (monitored with UV and those) lyophilized 1.46 g (50%, yield on bicyclic keto-6) as a yellow powder.

EXAMPLE 10 Preparation of 5R, 6S- -3-fC (1 3-dimethylpyridinium-4-yl) me- (R) -oxyethyl-7-oxo-I-azabidiclo 3,2, o1hept-2- en-2-carboxyloxylate (10 A) and 4R, 5R, 6sl-3- (1,3-dimet spiridinium-4-yl) methyl-thioj-6-tI- (R) -oxy-j-4-methyl- 7-oxy-I-ase bicyclo-3,2, o1-hept-2-en-2-carboxylate (10 V) -.

A. Preparation of 4-hydroxymethyl-3-methylpyridine The process is carried out according to the Bocke Iheide oxymethylpyridine preparation scheme. To this end, a solution of freshly distilled 3,4-lutidine (4b, 0 0.43 mol) in 120 ml of glacial acetic acid is cooled before and 64 ml of SpI-solution is added dropwise to it. The resulting solution is heated for 3 hours at 75 seconds (oil bath temperature), after which another 20 ml of 30% is added to it and the heating is continued for 18 hours. Then 20 ml of 30% - is again added to the reaction mixture. HjO and keep it for another 3 hours. After that, the solution is evaporated in a vacuum created by a water-jet pump to a volume of about 100 ml, 50 ml of H and O are added to it, and the mixture is evaporated to

half the volume, then cooled

It is added up, alkalinized with cooled 40% NaOH aqueous solution to pH 10 and carried out

o e. five

"

five

0

extraction (5 times) .l. The extract is dried () and concentrated using a rotary evaporator, resulting in a yellow solution. When hexane is added to this solution, a solid precipitates, which is filtered off and dried under vacuum. The result is 48.0 g (83% yield) of 3,4-lutwedin-K-oxide in the form of whitish solid matter.

The resulting Nr-oxide is added in portions to 60 MP of acetic anhydride and the resulting orange solution is heated on a water bath for 1 hour at. The excess acetic anhydride is distilled off under reduced pressure and the resulting product is collected (39.0 g), boiling at 90-120 ° C fO (l Torr). After chromatography of this oily product on silica gel using as a eluent a mixture of ethyl acetate and petroleum ether in a ratio of 2: 3, pure 4-acetoxymethyl-3-methylpyridine (19.0 g; yield 30%) is obtained in the form of an oily liquids, IR: 1745 cm,

The resulting acetate is then dissolved in 100 ml of a 10% aqueous solution of HC1 and the solution is boiled for 1 h with refluxing. The resulting solution is cooled to 0 ° C, alkalinized with a solid and subjected to extraction three times with CHjClj in 100 ml portions. The organic phase is washed with brine, dried () and evaporated, resulting in 11.0 g of an off-white solid with mp. 70-72 ° C. This solid was dissolved with cold Ether to give 9.5 g (yield 67%) of pure 4-hydroxymethyl-3-methylpyridine as a white solid with mp. 77-80 ° C. - H-NQR (CDCl1): 8.27, 7.41 (ABq, Hz, 2H), 8.18 (s, 1H), 5.63 (Br, s, -OH), 4.67 (s, CH-d), 2.20 (s, CH, IR (nu-yol): 3160.

B. Preparation of 4- (acetylthiomethyl) -3-methylpyridine. 12.8 ml (0.065 mol) of diisopropyl-aodicarboxonlate is added dropwise to an ice-cooled, mechanically perekleiguated solution (17.04 g; 0.065 mol) of triphenylphosphine in 250 ml of dry THF and the resulting suspension is stirred at 0 ° C for 1 h. To this mixture is added dropwise a solution of 4.0 g (0.0325 mol) of 4-hydroxymethyl-3-methyl pyridim n 100 ml

dry THF and then 4.6A ml (0.065 mol) of freshly distilled thioacetic acid and stir the mixture for 1 hour at and then for 1 hour at room temperature, resulting in an orange color solution. This solution is concentrated on a rotary evaporator, and The mixture is then diluted with petroleum ether. The mixture is filtered and the filtrate is evaporated to give an oily liquid. After chromatography of the oily liquid on silica gel, using hexane first and then a mixture of 10% ethyl acetate and 50% hexane, 7.0 g of oily liquid is obtained, which is distilled in a spherical expansion tube. B. The result is 6,0 g 20 (100% yield) of pure, 1 oily product in the form of a yellow oily liquid. bale (air bath temperature) 95-100 G (at 0.1 Torr). H-NMR (CDCl 3): 8.40, 7.20 (ABg, Hz, 2H), 8.37 25 (s, 1H), 4.08 (s, CH-t), 2.35 (s, CH,), 2.32 (s., CHj), IR (pure); 1695 cm. C. preparation of 4- trifluorosulfonate (acetyltymethyl) ) -, 3-dimethylpyridinine. To an ice-cooled solution of jO, 2.95 g (0.016 mol) of thioadetate in 10 ml of methylene chloride, 4.60 ml (0.04 mol) of methyl trifluoromethanesulfonate are added dropwise and the mixture is stirred under OC under nitrogen atmosphere during I h. After that, the reaction 35 mixture is evaporated to dryness and the residue is triturated with ether. The resulting solid. the product is filtered off and dried in vacuo to give 4.0 g

ice solution of 1.45 g (0,0025 col) enol phosphate in 20 ml of THF. The mixture is stirred for 1 hour at 0 ° C and transferred to an autoclave, 20 ml of ether, 25 ml of 0.1 M phosphate buffer (pH 7.4) and I, 4 g of 10% saline are added to it. charcoal, and then subjected to hydrogenation for 1 h at a pressure of 45 psi. inch. Then the reaction mixture is filtered through a layer of cellite, which is additionally washed with ether and phosphate buffer with a pH of 7.4. The aqueous phase is separated and the solvent is distilled off in vacuo. The aqueous solution is subjected to reverse phase chromatography (C-18 Bonda Pat). The elution is carried out first with water and then with a 10% aqueous solution of acetonitrile. After lyophilization of the corresponding fractions, 0.9 g of an orange-colored solid product is obtained. This product is subjected to re-chromatography, using water as eluent, and then 2% aqueous acetonitrile solution. After lyophilization, 0.25 g (57% yield) of the pure final product (10 A) is obtained in the form of a yellow solid. H-HMP () 5: 8.55 (s. 1H), 8.53, 7.96 (ABq, 8 Hz, 2H), 4.30-3.99 (m, 2H), 4.27 ( s, 5H), 3.35 (dd, 1.2.8 Hz, 12-6.0 Hz ,, 1HK 3.05 (d, 8 Hz, 2H), 2.50 (s, 3N), 1 , 23 (d, 3 Hz, ZN) {IR (KVg): 1755, 1590, UV (phosphate buffer, pH 7) 295 named after (7180).

E. Preparation of 4R, 5R, (1,3-dimethylpyridine-4-yl) methyl-thioi-6-- - - -. .f. | G1- (K) -oxyethyl-4-methyl-7-oxo-1- (yield 72%) of a white solid. azabicyclo 3,2,0 hept-2-en-2-carboxy-H-NMR (CDCl) S: 8.72 (s, W) 8.58, 7.87 (ABq, Hz, 2H), 4.39 (s, .N-CH3), 4.17 (s, CHi), 2.53 (i, CH,), 2.36 (s, aC), IR (pure): 1700.

D. Preparation of 5R, 6s7-3 - {(1,3-di-45 methylpyridinium-4-yl) methyl 3 -thio 6e (l- (n) -oxoethyl-7-oxo-1-azabicyclo 3,2, o hept-2-en-2-carboxylate.

To an ice-cooled and nitrogen-flushed solution of 0.324 g (0.008 mol) of NaOH in 10 ml of water, 1.40 g (0.004 mol) of thioacetate are added and the mixture is stirred under nitrogen for 1 hour. After this, the pH of the solution is set to 7 , 2-7.3 with a 10% aqueous solution of monosodium potassium phosphate and adding it to the cooled

50

lata

An ice-cooled solution of 0.906 g (o, 0025 mol) in 10 ml of acetonitrile is successively treated with diphenyl chlorophosphate (0.544 ml, 0.00263 mol), 0.457 ml (0.00263 mol) of diisopropyl ethylamine and 0.3 mg of 4-dimethylaminopium readin After 50 minutes, the reaction mixture was diluted with cold ethyl acetate, and then washed with cold water and brine. The organic phase is dried () and evaporated at room temperature, yielding the resulting enol phosphate as an off-white pey. This foam is dissolved in 20 ml of THF, cooled to a nitrogen atmosphere, and treated with an aqueous solution of thiolald to a solution of 1.45 g (0.0025 col) of enol phosphate in 20 ml of THF. The mixture is stirred for 1 hour at 0 ° C and transferred to an autoclave, 20 ml of ether, 25 ml of 0.1 M phosphate buffer (pH 7.4) and I, 4 g of 10% saline are added to it. charcoal, and then subjected to hydrogenation for 1 h at a pressure of 45 psi. inch. Then the reaction mixture is filtered through a layer of cellite, which is additionally washed with ether and phosphate buffer with a pH of 7.4. The aqueous phase is separated and the solvent is distilled off in vacuo. The aqueous solution is subjected to reverse phase chromatography (C-18 Bonda Pat). The elution is carried out first with water and then with a 10% aqueous solution of acetonitrile. After lyophilization of the corresponding fractions, 0.9 g of an orange-colored solid product is obtained. This product is subjected to re-chromatography, using water as eluent, and then 2% aqueous acetonitrile solution. After lyophilization, 0.25 g (57% yield) of the pure final product (10 A) is obtained in the form of a yellow solid. H-HMP () 5: 8.55 (s. 1H), 8.53, 7.96 (ABq, 8 Hz, 2H), 4.30-3.99 (m, 2H), 4.27 ( s, 5H), 3.35 (dd, 1.2.8 Hz, 12-6.0 Hz ,, 1HK 3.05 (d, 8 Hz, 2H), 2.50 (s, 3N), 1 , 23 (d, 3 Hz, ZN) {IR (KVg): 1755, 1590, UV (phosphate buffer, pH 7) 295 named after (7180).

E. Preparation of 4R, 5R, (1,3-dimethylpyridine-4-yl) -methyl-thioi-6 | G1- (k) -oxyethyl-4-methyl-7-oxo-1-azabicyclo 3,2.0 hept -2-ene-2-carboxy-

| G1- (k) -oxyethyl-4-methyl-7-oxo-1-azabicyclo 3,2,0 hept-2-ene-2-carboxy-

lata

An ice-cooled solution of 0.906 g (o, 0025 mol) in 10 ml of acetonitrile is successively treated with diphenyl chlorophosphate (0.544 ml, 0.00263 mol), 0.457 ml (0.00263 mol) of diisopropyl ethylamine and 0.3 mg of 4-dimethylaminopium readin After 50 minutes, the reaction mixture was diluted with cold ethyl acetate, and then washed with cold water and brine. The organic phase is dried () and evaporated at room temperature, yielding the resulting enol phosphate as an off-white pey. This foam is dissolved in 20 ml of THF, cooled to a nitrogen atmosphere and treated with an aqueous solution of thiolate prepared in the same manner from 0.3 g of NaOH (7.5 mol) and 1.3 g (3.76 f mm) of thioacetate in 10 ml water. The reaction mixture is stirred at 30 minutes and then at 75 ° C for 75 minutes, after which it is transferred to an autoclave containing 20 ml of ether, 30 ml of 0.1 M phosphate buffer (pH 7, D) and 1.5 g 10% palladium fo on charcoal. After hydrogenation at a hydrogen pressure of 45 psi. an inch for 1 h the mixture is filtered through celite, the aqueous phase of the department is evaporated in vacuo. The resulting solution was subjected to reverse phase chromatography (c-18 Bonda Pak) using water as eltaent. After lysophilization of the corresponding fractions, 1.2 g of a yellow solid 20 are obtained. This substance is subjected to rechromatography, using water as the aluente first, and then a 4% aqueous solution of acetonitrile. After lyophilization, 25 pure desired product (Yu c) (0.250 g, yield 28%) is obtained in the form of a yellow solid. n-NMR (): 8.53 (s, 1H), 8.49, 7.81 (ABq, 2 Hz, 2H), 4.38-3.98 (m, AH), 4.27 (s , ZN), zo 3.49-3.18 (m, 2H), 2.51 (s, ZN), 1.25. (D, 1-6.7 Hz, ZN), 1.16 (d, , 6 Hz, ЗН); IR (KBr): 1750, 1595 UV (phosphate buffer, pH 7) 292 nm (67930).

Example P. Preparation of 5R, 6s3- 3- (1,6-dimethylpyridinium-2-yl) methylthio-6t- (1H-hydroxyethyl) -4P-methyl-7-oxy-1-azabicyclo 3,2 , ozgept-2-en-carboxylate.

A, Trifluoromethanesulfonate (1,6-di-Q methylpyridinium-2-yl) methylthiol.

Purge with nitrogen a solution of 1.0 g (5.52 mmol) (b-methylpyridin-2-yl) methylthioacetate in dry ether (5 ml) is treated with 0.74 ml (6.5 mmol) me-, tiptrifpate and stirred the mixture at for 4 hours. The ether is separated by decantation, and the white precipitate is washed twice with 2 ml of ether and dissolved in 15 C 6N. solution (90.0 mmol) of hydrochloric acid. The resulting solution is heated for 4 hours at 70 ° C. in the atmosphere of nitrogen and then evaporated under reduced pressure to a syrupy consistency. The resulting syrup has a yellow color. The hydrochloric acid residue 55 is removed by co-distillation of the product with water (2 x 10 ml). Purification of the crude product is carried out by

Reverse1 (Ofaz1 {oh chromatography on a column of 2.2 x 13.0 cm (Rher Pak C-18) using water as eluent. The corresponding phases are collected and lyophilized. As a result, 1, 3 g of white powder product. Output 85,4 % IR (KVg) 0 „a,: 2565 (SH), 1626 (pyridium), 1585 (pyridium) cm-, UV () 278 (7355)

Calculated,%: C 35.64; H 3.99; N.4,62; S 21, 14 C, H ,, NO, S, F,

Found,%: C 35.49; H 4.05; N 4.56; S 20.99.

B. 5K, (1, 6-dimesh1-pyridinium-2-yl) methylthio-6- (lR-oxa-ethyl) -4R-methyl-7-oxy-1-azabicyclo 3, 2.03. hept-2-en-2-carboxylate.

- To purged with nitrogen and cooled to 5 C solution |, 11 g (3.06 mmol, R / S: 86/14) 5R, 6sJ para-nitrobenzyl 3,7-dirkso-b- (1R-hydroxyethyl) -4RS-MeTl " T-. 1-azabicyclo 3,2, renTaH-2-R-Kap6oK-silat and 90 ml of dry acetonitrile were simultaneously added with 0.68 ml (3.3 mmol) of diphenyl chlorophosphate and 0.57 ml (3.3 imol) of diisopropylethyl-amine in for 10 minutes The cold mixture () is stirred for -Ih, cooled before and simultaneously a solution of 1.03 g (3.4 mmol) of trifluoromethanesulfonate (1,6-dimethylpyridinium-2-yl) is added to it for 15 minutes. ) -methylthiol in 2 ml of dry acetonitrile and 0.59 ml (3.4 mmol) of diisopropylethylamine. The resulting mixture is stirred for 30 minutes at, warmed up, stirred at this temperature for 1 hour, and diluted with 35 ml of cold water. The resulting emulsion is poured into the top of the column for reverse phase chromatography (Rher Pak C-18, 2.5 to 18 cm) and zylirovanie a mixture of 25-50% acetonitrile in water. By lyophilization of the corresponding fractions, a sticky solid of yellow color (1.69 g) is obtained, which is dissolved in 40 ml of tetrahydrofuran containing water. To the resulting solution, 70 ml of ether, 50 ml of a 0.2 M buffer solution of mono-substituted potassium phosphate and sodium hydroxide with a pH of 7.0 and 10% palladium on charcoal (1.69 g) are added and the mixture is hydrogenated for 2 h at 23 C and daleNII 42 pounds per square meter. inch, then filtered through a layer of cellite. The phases are separated. The aqueous phase is washed twice with ether, in portions of 20 ml, and evaporated under high vacuum at a temperature below 23 ° C to a volume of 15 ml. The residue is subjected to reverse phase chromatography on a column (Rher Pak C-18). Elution is carried out with 10 A% aqueous acetonitrile solution. After lyophilization of the cooTBeTCTpjno-nijix fractions, 0.23 g of the title compound is obtained in a mixture with K, IP diphenylphosphate (24 mol.%). After repeated reverse phase chromatography on a column (2, cm, Rher Pak Pak C-18) using 400 ml of water and 200 ml of 10% vodka (this mixture is solution A) as eluent. A solution of 1.23 g (6.8 mmol) (6-methyl-pyridin-2-yl) methylthioacetate and 10 ml of dry ester is treated with 0.85 ml (7.5 mmol) of methyl triflate and the mixture is stirred for 1.5 at 23 ° C. The ether is separated by decantation, and the white powder is washed twice with ether, in 10 ml portions, and dissolved in water (20 ml). The resulting aqueous solution is cooled in water (20 m. The resulting solution is cooled to CfC in an oxygen-free atmosphere and treated with 3.4 ml of 4N solution for (3.6 mmol) of hydroxide on ri. The mixture is stirred for 1 hour at, after bringing the pH to 7.6 by adding a monosubstituted solution of acetonitrile and a subsequent potassium phosphate to it (hereinafter

mixture - solution B). The cold (5 C) solution A is treated for 30 minutes with solution B, maintaining the pH of the reaction mixture in the range of 7.25-7.35 by adding 4N to it dropwise. a solution of sodium hydroxide. The mixture is stirred for 30 minutes and poured into a reverse phase chromatography column 11 and dimensions 4,018 cm (Rher Pak C-18). The solution is carried out with a 25-50% aqueous solution of acetonitrile. After lyophilization of the respective fractions, the desired compound is obtained as a yellow powder (2.82 g, 51% (PhO) PO, 49% CF, SO;). Yield 80%. IR (KBr): 3700-3000 (he), 1772 (fb-lactam 1700 (ether), 1625 (pyridium), 1590 (pyridium) cm; H-NMR (DMCO,

This lyophilization of the corresponding fractions gives 0.17 g (15.3% yield) of a yellow powder. IR (KVg) / lax: 1750 (lactam), 1625 (py {idiyny), 1600 25 (carboxylate) cm, H-NMR (D) S: 1.12 (d, 2 Hz, CH in С-4), 1.24 (d, 4 Hz, CH, SNON), 2.80 (s, CH on C-6 pyridine), 4.41 (center of the AB-quartet), CHj, S (7.5-o, 4 H ZOR in pyridine); UV (0.05 M buffer with a pH of 7.0) A "" ,,: 278 (E 11504), 4 (s, 0.2,); D "1 20.8 (determined at 37 ° C in the buffer solution with a pH of 7.4 at a concentration of 10 M). ,,

Pr and M er 12, Preparation of 5R, 6s 3- (1,6-dimesh1-pyridinium-2-yl) -metyl-tio-b- (1 R-rxyethyl) -7-oxo-1-azabicyclo 3,2 , 6 hept-2-en-2-carboxyl 4P

that

2.84 (s, CH Cb pyridinium), 4.16 (s, CH, per N pyridinium), 4.79 (s, SCH ;,),

A. Trifluoromethanesulfonate and diphenyl phosphate 5B, .araitrobenzyl-3- ,. .. . (1,6-dimethylpyridinium-2-yl) methylthioZ- / 6.6-7.5 (PhO) jPO ,, 7.5-8.7. (H on pi-.

6- (1E-hydroxyethyl) -7-oxo-1-azabicycloidinium and H on RCH-ether).

45

3,2, o1hept-2-en-2-carboxylate.

Nitrogen-blown cold (5 C) pdCTBopy 2.14 g (6.14 mmol) 5B, 6S3 1-aryl-benzyl-6- (1B-hydroxyethyl) -3.7-dioxo-1-azabicyclo 3,2.0 heptane-2E- carboxylate in 18 ml of dry acetonitrile, 1.37 ml (6.6 mmol) of diphenyl chlorophosphate, 1.15 ml (6.6 mmol) of diisopropylethylamine are added at such a rate that the temperature of the mixture is

50

B, 5R, 6s -3-t (1,6-Dimethylpyridinium-2-yl) methylthio | -6- (1-hydroxyethyl) -7-oxo-1-azabicyclo 3,2.03 Hept-3-E- 3-carboxylate.

To a solution of 0.87 g (1.27 mmol) of a mixture of trifluoromethanesulfonate and diphenylphosphate 5NubB -paranitrobenzyl-3- (1, b-dimethylpyridinium -yl) -methyl- (1R-hydroxyethyl) -7-oxo-1-azabicyclo 3,2,0 hept-2-en-2-carboxy-equivalent 5 C (7-10 minutes addition time) 5 days in the ratio 49:51 in 50 ml of soy 6 mg (0.05 mmol) 4-dimethylamino-containing small amount water

readin A mixture of peremepshvakug over tetrahydrofuran is added 50 ml

1.5 hours at 5 ° C and used as ta-ether, 40 ml of 0.1 M buffer solution

forging (hereinafter, this mixture is solution A). A solution of 1.23 g (6.8 mmol) (6-methyl-pyridin-2-yl) methyl thioacetate in 10 ml of dry ether is treated with 0.85 ml (7.5 mmol) of methyl triflate and stirred for 1, 5 hours at 23 ° C. The ether was separated by decantation, and the white powder was washed twice with ether, in 10 ml portions, and dissolved in water (20 ml). The resulting aqueous solution is cooled in water (20 ml), the resulting solution is cooled to CfC in an oxygen-free atmosphere, and treated with 3.4 ml of 4N. solution for (3.6 mmol) sodium hydroxide. The mixture was stirred for 1 hour at which point, after which its pH was adjusted to 7.6, by adding to it one-substituted potassium phosphate (hereinafter

mixture - solution B). The cold (5 C) solution A is treated for 30 minutes with solution B, maintaining the pH of the reaction mixture in the range of 7.25-7.35 by adding 4N to it dropwise. sodium hydroxide solution. The mixture is stirred for 30 minutes and poured into a reverse phase chromatography column 11) and 4,018 cm in size (Rher Pak C-18). The solution is carried out with a 25-50% aqueous solution of acetonitrile. After lyophilization of the appropriate fractions, the desired compound is obtained as a yellow powder (2.82 g, 51% (PhO) PO, 49% CF, SO;). Yield 80%. IR (KBr): 3700-3000 (he), 1772 (fb-lactam), 1700 (ether), 1625 (pyridium), 1590 (pyridium) cm; H-NMR (DMCO,

): 1.15 (d, 2 Hz, CH, SNON),

2.84 (s, CH Cb pyridinium), 4.16 (s, CH, per N pyridinium), 4.79 (s, SCH ;,),

, .. . 6, 6-7.5 (PhO) jPO ,, 7.5-8.7. (H on pi-.

Indian and H on RKB-air).

five

0

B, 5R, 6s -3-t (1,6-Dimethylpyridinium-2-yl) methylthio | -6- (1-hydroxyethyl) -7-oxo-1-azabicyclo 3,2.03 Hept-3-E- 3-carboxylate.

To a solution of 0.87 g (1.27 mmol) of a mixture of trifluoromethanesulfonate and diphenylphosphate 5NubB -paranitrobenzyl-3- (1, b-dimethylpyridinium -yl) -methyl- (1R-hydroxyethyl) -7-oxo-1-azabicyclo 3.2.0 hept-2-en-2-carboxy5data in a ratio of 49:51 in 50 ml of co-substituted potassium and sodium hydroxide with a pH of 7.0 and 0.87 g of 10% palladium on charcoal, is subjected to hydrogenation of the mixture in for 2 hours at a hydrogen pressure of 36 psi inch and temperature, then filter it through a layer of cellite. The phases are separated, the aqueous phase is washed with ether, in portions of 15 mp, evaporated in high vacuum to a volume of 30 MP and poured into the upper part of the column for reverse phase chromatography (Rger Pak C-18, 2.2X13 cm). Elution is carried out with water. The appropriate fractions were combined and lyophilized, resulting in 0.179 g (yield 40%) of a yellow powder. IR (KBr) .755 (C 0/3-lactam), 1628 (pyridium), 1590 (C “0 carboxylate) H-NMR (D, 0) J: 1.25 (d, 4 Hz, CH-SNON), 2.82 (s, SH in C-6 pyridini), 3.12 (dd, 1-9.2 Hz, 1-2.9 Hz, H-4), 3.39 (dd, 1-6.0 Hz, 1-2.8 Hz, H-6), 3.7-4.4 (H-5, CH, N pyridini), 4.48 (s,), 7.6-8 , 4 (H pyridinium), UV (H40), Amaks 279 (g 9628) with a shoulder at 296 Lei1 55 ° (s, 0.63,), r ,, 5 h (measured at bu35

40

ferric solution with pH 7.4 for concentration).

PRI me R I3. Obtaining 3- / 2- (1,3-dimethylimidazolium-methanti}} - bob- (1-СН) -ooxyatsh1 | -4-methyl-7-ox-with-1-azabicyclo, 2.6 hept-2-eH- 2- carboxylate.

3- f2- (1,3-Dimetipimidazolium-t-TaHTHo) -6ei- (1- (B) -oxyethyl} -4 | 5-methyl-7-oxo-1-azabicyclo 3,2,0 gep - 2-en-2-cara boxylate is obtained as a yellow powder with a yield of 32% from compound II in the same manner as described in example 27. IR (KBG): 3400J 1758 and 1600, cm; UV; (% 0 )) - Gshaks - 294 them (7194); NMR (J) 0} S; 1.10 (ZN, d, 3 Hz, 1.25 (ZN, d, 1-6.3 Hz), 3.30 (Sh. M), 3.42 (H, 1-6.0 Hz and 2.2 Hz), 3.85 (6H, s), 4.2–4.6 (4H, m) and 7.40 (2H, s).

PRI me R 14. Obtaining 3- (2,4-dimethyl-1,2,4-triazolium) -metane- (B) hydroxyethyl) -4-metip-7-oxo-1-az abicyclo 3,2 , 0 hept-2-e -2 carboxylate.

z- | 2.4-Dimethyl-, 2,4-triazolium T 5 methanteo} -6e4-KE) -oxyethyl | -4-methy-TYL-7-OXO-1-azabicyclo 3,2.0 hept-2-en-2 carboxylate is obtained as

20 . : 25 30

45

50

a yellow powder with a puff of 9% from compounds II in the same way as described in Example 27. IR (KBr) for: 3420, 1756 and 1605 cm; UV (H, jO) n ,: 291 nm (7850); NMR (): 1.15 (ZN, d, 1-6.3 Hz), 1.22 (ZN, d, I-, 3 Hz), 3.35 (IH, m); 3.48 (1H, q, 0 and 1.8 Hz), 3.90 (5H, s), 4.05 (ZN, s), 4.2-4.4: (4H, m) and 8 , 80

(W, s).

 Example 15. Preparation of 3-f3- (1,2-dimethylpyridtio) (B) oxyethyl-methyl-7-oxo-1-az abicyclo 3, 2.0 hept-2-ene.

(1, 2-Dimethylpyridinium) methanethyl-6 "{g l- (R) -oxy-ethyl-4-methyl-7-oxy-1-azabicyclo 3,2,0 rgept-2-etf-2-carboxylate.

- The indicated compound is obtained in the form of a yellow powder with a yield of 14% from compound II in the same manner as described in Example 27. IR (YVg)) G g 3410, 1750 and 1600 UV (Hj: 0) (max 296 nm (e 8500); NMR (): 1.25 (3N, d, 5 Hz), 1.30 (3N, d, 5 Hz), 2.95 (3N, s), 3.40 (1H, m), 3.50 (IH, d, 2 and 1.8 Hz), 4.2-4.4 (4H, m), 4.35 (3N, s), 7.82 (1H, t, , 5 and 6.3 Hz), 8.40 (W, d, I-. -8.5 Hz), 8.72 (1H, d, 1-6.3 Hz).

P m and me 16, Obtaining 3-GZ- (1-methylpyridinium) methantio-6Y-1-H) - hydroxyethyl-4b-methyl-7-oxo-1-azabitsyklo 3,2,0 -hept -2-carboxylate.

. 3-f3-51-Methyl-pyridic) methantio - 6et- 1- (H) -oxyethyl-4D-methyl-7-oxo-1-azabicyclo 3,2.0 hept-2-ene-2-carboxylate.

The compound was obtained as a yellow powder with a yield of 27% from compound 11 in the same manner as described in Example 27.IR (KBr) jf: 3420, 1750 and 1610 ctT i yit () L-max: 295 nm (68750) ; NMR () 5: 1.10 (3N, d, 9 Hz), 1.25 (3N, d, 1-6.9 Hz), 1.27 (1H, m), 7.43 (IH, q ,, 2 and 1.8 Hz), 4, L4.35 (4H, m), 4.39 (3N, s), 8.0 (W, t, 1-8.5 and 6.2 Hz), 8.45 (1H, d, 5 Hz). 8.70 (1H, d, 2 Hz) and 8.82 (1H, s). Calculated,%: C, 51.90; H 6.36; I am 7.12

C:, 7H2oNj04St2, Found,%: C 51.92; H 5.71; And 6.88.

Example 17. Obtaining (-methylpyridinium methanethio) -6ti-I- (R) hydroxyethyl-4p-methyl-7-oxo-1-azabicyc, 2.0 hept - 2-ene-2-carboxylate,

3- A- (1-Methylpyridinium methanethio) 3-- 6-et-1 (R) -oxyethyl-4p-methyl-7-o-cano-1-azabicyclo 3,2.0 hept-2-en-2-carboxylate C14 ).

The indicated compound is obtained in the form of a yellow powder with the yield of I5Z from compound II as described in Example 27. IR (KBr) Y: 3410, 1750 and 1650 UV (H oNmax - 293 nm (€ 7295); NMR (): 1 , 15 (ZN, d, 1-6.5 Hz), 1.20 (ZN, d, - L10

600 mg of 10% palladium on charcoal is added to the solution and subjected to hydrogenation at a pressure of 35 psi. inch on a shaking unit for 45 min. The mixture is filtered through a layer of acetate and the catalyst is washed with water (twice, in 10 ml portions). The combined filters and washes were extracted with ether (twice, in 100 ml portions). After lyophilization, a yellow powder is obtained, which is purified on a column (C-18 Bond Pak)

6.5 Hz), 3.20 (1H, m), 3.45 (1H, q, 15 MDL chromatography., 0 and 2.0 Hz), 4, P (W, q, 1-8.0 and 2.0 Hz), 4.20 (W, m) and 4.35 (AH, s), 7.95 (2H, d, 2 Hz) and 8.72 (2H, d, 1-5.2 Hz) ..

Ms-p 18. Preparation of (1,4-dimethylpyridinium) methanthioZ-6o6- {| - (H) -oxyethyl-4 methydh-7-oxo-1 - azabicyclo 3, o, hept-2-ene -2-carboxylate.

(1,4-Dimethylpyridine) methane- 25 I) of the title compound as a paleo-6B6-.1- (H) -oxyethylP-4-methyl-7-but-yellow powder. IR (KBr) y: 3400, oxo-1-azabicyclo 3,2,0 -hept-2-en-2- .- "" .r-i. „/ ,. rt

carboxylate} 13).

The indicated compound is obtained as a yellow powder with a yield of I7% from compound II in the same manner as described in Example 27. ICf: 3400, 1755 and 1600, UV (H40) m

Induction is carried out with a 5X aqueous solution of CH | CN at a pressure of 8 pounds per square meter. jcuoAM, 15 ml from each fraction is subjected to high-performance 20 liquid chromatography. Fractions with an absorption maximum in the ultraviolet region at 300 nm are taken out and lyophilized, resulting in 58 mg (yield

thirty

300 nm (e 7600); NMR (DjiO): 1.20 (ZN, d, 1-6.7 Hz), 1.28 (ZN, d, I1750 and 1590 UV (H.40) moms: 292 named after (е7081); NMR (): 1.13 (3N, d, 1-6.5 Hz),, 23 (.1H, d, I- -6.5 Hz), 3.18 (1H, m), 3.45 (1H, q, , 0 and 2.1 Hz), 4.0-4.4 (4H, m), 4.65 (3N, s), 7.79 (2H, m), 8.30 (IH, m), 8 , 60 (1H, m).

G. p-Nitrobenzyl-3-pyridin-2-yl-methanthisG-6bL-l - (H) -oxyethyl -4 / 3-me6, 7-Hz), 2.60 SZN. c), 3.4-3.5 (2H, thyl-7-oxo-1-azabicyclo 3,2, o Еept-2m), 4.2-4.4 (4H, m), 4.52 (3N , c), 7.82 (W, t, 1-6.5 and 4.2 Hz), 8.32 (W, d, 5 Hz) and 8.60 (W, d, I-4, 2 Hz).

I. 3- 2- (N-Methylpyridinium) methane- THo-6ot- {1- (K) -oxyetsh {1-4p-methyl-7-oxo-1-azabicyclo 3,2,0 hept-2-e 2- carboxylate protected by carboxyl group.

To a solution of 1.0 g (2 mmol) of compound I in 10 ml is added 450 mg (3.3 mmol) of methyl trifluoromethanesulfonate and the mixture is stirred at 23 ° C for 90 minutes. After distillation

40

4S

50

en-2-carboxylate.

To cooled to solution

(G, 2 g; 2 mmol) of phosphonate-0 in 10 ml of CHjGN are added, under a nitrogen atmosphere, 390 mg (3 mmol) of diisopropylethylamine and then 370 mg (3 mmol) of 2-mercaptomethylpyridine. The mixture was stirred for 60 minutes at 15 ° C. and then for another 60 minutes at (after which it was diluted with EtOAc, washed with ice water, brine, and dried (MgSO4). After distilling off the solvent in vacuo, a yellow oily liquid was obtained, which was purified by chromatography on a column, filled

600 mg of 10% palladium on charcoal is added to the solution and subjected to hydrogenation at a pressure of 35 psi. inch on a shaking unit for 45 min. The mixture is filtered through a layer of acetate and the catalyst is washed with water (twice, in 10 ml portions). The combined filters and washes were extracted with ether (twice, in 100 ml portions). After lyophilization, a yellow powder is obtained, which is purified on a column (C-18 Bond Pak)

MILK chromatography.

Induction is carried out with a 5X aqueous solution of CH | CN at a pressure of 8 pounds per square meter. jcuoAM, 15 ml from each fraction is subjected to high-performance liquid chromatography. Fractions with an absorption maximum in the ultraviolet region at 300 nm are taken out and lyophilized, resulting in 58 mg (yield

And) the title compound as a pale yellow powder. IR (KBr) y: 3400, .- “«. R-i. „/ ,. rt

1750 and 1590 UF (H.40) moms: 292 named (e7081); NMR (): 1.13 (3N, d, 1-6.5 Hz),, 23 (.1H, d, I- -6.5 Hz), 3.18 (1H, m), 3.45 ( 1H, q, 0 and 2.1 Hz), 4.0-4.4 (4H, m), 4.65 (3N, s), 7.79 (2H, m), 8.30 (IH, m), 8.60 (1H, m).

G. p-Nitrobenzyl-3-pyridin-2-yl-methanthisG-6bL-l - (H) -oxyethyl -4 / 3-methyl-7-oxo-1-azabicyclo 3, 2, o Eept-2-ethyl-7- oxo-1-azabicyclo 3, 2, o Ept-2

en-2-carboxylate.

To cooled to solution

(G, 2 g; 2 mmol) of phosphonate-0 in 10 ml of CHjGN are added, under a nitrogen atmosphere, 390 mg (3 mmol) of diisopropylethylamine and then 370 mg (3 mmol) of 2-mercaptomethylpyridine. The mixture was stirred for 60 minutes at 15 ° C. and then for another 60 minutes at (after which it was diluted with EtOAc, washed with ice water, brine, and dried (MgSO4). After distilling off the solvent in vacuo, a yellow oily liquid was obtained, which was purified by chromatography on a column, filled

 in vacuo, quaternary SiO is obtained. The elution is carried out with pyridine base in the form of a foam, which is directly, without additional purification, subjected to hydrogenation. Crude pyridine cojTfy is dissolved in a mixture of THF, ether, and a buffer solution with a pH of 7 in a 1: 1: 1 ratio (100 ml each of the components).

55

one

20% EtOAc solution. in CHjClj., the result is 375 mg (yield 4 compounds as white amorphous ne. IR (KBr): 3400, 1775 and 1710 cm NMR: (IH, q, T-6,2 and 2.0 Hz) , 3.40 (H, m), 4.0 (1H, d, 1 "7.7 nl), 4, (1H, d, 6 Hz), 4.18 (1H, q, SiO. Elution was carried out are

five

one

20% EtOAc solution. in CHjClj., the result is 375 mg (yield 40X) of the compound as white amorphous ne-j. IR (KBG) for: 3400, 1775 and 1710 cm; NMR: (IH, q, T-6.2 and 2.0 Hz), 3.40 (H, m), 4.0 (1H, d, 1 "7.7 nl), 4.12 (1H, d, 6 Hz), 4.18 (1H, q, I-6, 7 and 2.0 Hz), 4.25 (1H, m), 5.25 (1H, d, 3 Hz), 7 , 15-8,2 (4H, m).

F. p-Nitrobenzyl-3-diphenoxyphosphine nyl-bcC- | - (k) -oxyethyl-4) -methyl-7-oxo-1-aabicyclo 3,2, .0 hept-2-en-2-carboxylate.

To the solution (20.0 g; 55.2 mmol) of the 3-keto compound in 150 ml of CHjCN, 7.18 g (55 mmol) of diisopropylethylamine is added to the solution, and then 14.85 g (55 mmol) of diphenyl chlorophosphonate in 20.mp. within 5 min. The resulting solution was stirred for 60 minutes at then diluted with 600 ml of Etc Ac, washed with ice-cooled 10% solution and brine. After drying (MgSO4) and distilling off the solvent, a crude oily liquid is obtained, which is purified on a column to a solid. M.p. 54-55 C, IR (KBG): 2080 and 1695.

Example 19. Preparation of (N-methylpyridinium) methantio-6B & - 1- (n) -oxyethyl 1-4B-methyl-7-ox i-azabicyclo 3,2, .01 hept-2-en-2-carboxyl ata ,

A solution of 512 mg (12.8 mmol) of sodium hydroxide in 5 ml of water is added to an ice-cooled solution of 1.45 g (4.35 mmol) of the triazole salt in 5 mp of water. After 45 minutes, it. Is diluted with water to 25 ml and using mono-substituted potassium phosphate, its pH is set to 7.6. The solution thus obtained is added to an ice-cooled, stirred solution of 2.00 g (3.45 mmol) of enol phosphate in 25 ml of THF. After 30 minutes, the reaction mixture was transferred to an autoclave containing 40 ml of zfir and 2.0 g of G0% palladium on charcoal, and the mixture was subjected to hydrogenation for 1.25 hours at a pressure of 45 psig. inch. Thereafter, the reaction mixture is diluted with 25 mp ether and filtered. The organic phase is separated and the diloids are washed with water in 25 ml portions. The combined aqueous phases are drunk three times with ether, in 25 ml portions, and evaporated in vacuo. After column reverse phase chromatography (45x130 mm column) using water as eluent and subsequent lyophilization of the carbapenem-containing fractions, 650 mg of the crude product is obtained, which is subjected to repeated chromatography. The result is 450 mg (yield 39%) of pure

target product. H-NMR (): 1.24 (3N, d, 4 r: i), 3.19 (2H, q, 6 and 9.2 Hz), 3.45 (1H, q, 8 and 6 , 0 Пд), 3.91 (ЗН, с), 4.06 (ЗН, с), 4.08-4.36 (2Н, m), 4.54 (2Н, д, 8 Hz), 8 , 71 (1H, s), IR (Nujol): 1755, UV (phosphate buffer solution with pH 7.4): 294 them. (b 8,202); T ,, l h (phosphate buffer solution with pH 7.4,, 067, “37 С); 3.1 (2H, d, Hz), 3.37 (1H, q, 1 Hz), 4.02 (7H m), 5.18 (2H, s), 8.53 (1H, s), IR (Nujol): 1750, UV (phosphate buffer solution with pH 7.4) Ld: 205 it ().

Example 20. (1,4-Dketyl 1,2,4-triazrly) methanethiol | 6et-l- (R) - oxystil-7-oxo-1-azabicyclo 3,2,0 hept-2-en-2-carboxylate.

A.1-Methyl-5-methanethiol acetate-1,2, 4-triazole.

 ml (6.0 mmol) of methanesulfonyl chloride is added dropwise to an ice-cooled, stirred solution of 565 mg (5.0 mmol) of f-methyl-5-hydroxymethyl-1,2,4-triazop and 0.91 mp ( 6.5 mmol) of triethylamine in 5 ml of methylene chloride. After 20 minutes, another 1.05 ml (7.5 mmol) of triztilamine was added and then 0.53 mgg, -. (7.5 mmol) of acetic acid and the mixture is stirred for 45 minutes. Thereafter, the reaction mixture is diluted with methylene chloride and washed with water. The aqueous phase is subjected to extraction with methylene chloride (three times, 5 ml portions). The combined organic layers were dried (MgSO4) and the solvent was distilled off. After column chromatography on a gel gel, neat 1-methyl-5-methanethiol acetate-1,2,4-triazole (570 mp) is obtained as a yellow oily liquid. The impurity-containing fraction (200 mg) is subjected to rechromatography (preparative thin layer chromatography on silica gel), as a result of which an additional 100 mg of pure desired product is obtained. Total yield 85%. H-NMR (CDC1,) S: 2.38 (3N, s), 3.90 (3N, s), 4.25 (3N, s), 7.80 (1H, s).

B. (I, 4-Limethyl-I, 2,4-tri-azolium) methane-6th; - 1- (k) -oxyethyl 7-oxo-1-azabicyclo-f3,2, Ojhept-2-en- 2- carboxylate.

1.20 ml (10.7 mmol) of trifluoromethanesulphate is added dropwise to an ice-cooled solution of 730 mg (A, 27 mmol) of 1-methyl-5-methanethiol acetate-1.2 2 triazole in 7 m of methylene chloride. The reaction mixture is heated (to 3 hours) to room temperature. the residue is then concentrated in the form of an oily liquid and triturated with ether, resulting in a yield of 1.4 grams of crude 1,4-dimethyl-5-methanethiol etatat-1, 2, 4-tria olium trifluoromethanesulfonate, which is used without additional cleaning,

P.P. and Mer. 21, Preparation of (N-mylpyridinium) OZ-6b6-tl- (R) -hydroxyethyl-4 (1 metsh-7-oxo-1-az-az abicyc 5,2,0j) hept 2-e-2-carboxylate,

A. p-Nitrobenzyl-3-diphenoxyphosphinyl-beS-p- (R) -oxyethyl-4y-methyl-7-oxo-1-azabicyclo 3,2, oj hept-2-ene-2-carboxylate (II) .

7.18 g (55 mol) of di - nsopropylethylamine, then 14.85 g (55 mmol) are added to the cooled () solution of 20.0 g- (55.2 iiol) of a 3-keto intermediate in 150 ml of acetonitrile. diisopropylethylamine, then 14.85 g (55 mmol) of diphenylchlorophosphonate in 20 ml of acetoiitrile for 5 minutes. The resulting solution was stirred for 60 minutes at, then diluted with 600 ml of ethyl acetate, washed with ice-cold 10% phosphoric acid solution and brine. Evaporation of the dried (magnesium sulfate) solvent gives an oil, which is purified on a column of silica gel}) and from the adsorbent in an lOZ column in methylenchloride gives 3.7 g (lt, 5Z) of phosphonate-10 in white form substances. IR (СНС1,) Ir: 3400, 1790 and 1720 cm-.

NMR (deuterated chloroform) (Y: 1.20 (ZN, doublet, Na), 1.3V (ZN, - doublet, 3 Hz), 3.35 (1H, 1,, 7, 0 Hz), 3, 50 (IH, multi- plet), 4.2-4.25 (2H, ltiplel), 5.20 (IH, doublet, J-10.5 Hz), 5.37 (IH, dugshet, J-10 , 5 Hz), 7.1–7.4. (LOH, 1multiplet), 7.56 (IH, doublet, J “9.0 Hz) and 8.10 (IH, doublet, J 9.0 Hz). -

The nuclear effects of the Overhauser are used to determine the 4-methyl configuration of compound 10. In the case of irradiation of I, no increase in signal is observed for 4-methyl, which indicates a trans-dependence of H and 4-methyl.

B. p-Nitrobeneyl-3 pyridin-2-yl-methanethio-p-p (n) -oxyethyl-4 methyl-7-oxo-1-azabicyclo 3,2,0 hept-2-en-2-carboxylate . .

To a cooled (-15 ° C solution of 1.2 g (2 mmol) of phosphonate-10 in 10 ml of acetonitrile, 390 mg (3 mmol) of diisopropylethylamine are added, then 370 mg (3 mmol) of 2-mercaptomethylpyridine under nitrogen. The reaction mixture is stirred for 60 minutes at -15 ° C, then for an additional 60 minutes at about 0 ° C. The reaction mixture is diluted with ethyl acetate, washed with ice water, brine, and dried (magnesium sulfate). Evaporation of the solvent under vacuum gives a yellow oil, which is purified on a column of silica gel; washing from the adsorbent a column of 20% ethyl acetate in methylene chloride gives 375 mg (40% output for) Compound II as a white amorphous spongy mass. IR (KBr) 5: 3400, 1775 and 1710 NMR (leuterated chloroform) 5: 2.14 (3N, doublet, 7 Hz), 2.19 (3N, doublet ,, 7 Hz), 3.14 (IH,. Quartet, J, 2 and 2.0 Hz), 3.40 (IH, multiplet), 4.0 (IH, doublet, J "7.6 Hz), 4.12 ClH, doublet, 6 Hz 4.18 (IH, quartet, 7 and 2.0 Hz), 4.25 (IH, multiplet), 5.25 (IH, doublet, 3 Hz), 5 , 40 (W, doublet, J n n, 3 Hz), 7.15-8.2 (4H, multi-, plet). .

C, (N-methylpyridinium) methanethys -6ot-1- (R) -oxyethyl-4-methyl-7-oxo-1-azabicyclo 3,2,0 -2-en-2-carboxylate.

450 ml (3.5 mmol) of methyl trifluoromethanesulfonate are added to a solution of 1.0 g (2 mmol) of the compound prepared in B in 10 ml of methylene chloride and stirred at 23 seconds. Evaporation of methylene chloride in vacuum gives fourfold pyridine in the form of a sponge, which is exactly hydrogenated without pre-treatment. The crude pyridinium salt is dissolved in a mixture of THF - simple zfir - buffer solution with a pH of 7 in the ratio of 1: 1: 1 (100 ml each), then 600 mg of 10% palladium on activated carbon are added. The mixture is hydrogenated at 2.46 kg / cm.

(35 psi) in a shaker by shaking for 45 minutes. The mixture is filtered through a pad of celite and the catalyst is washed with water (2x10). The combined filtrate and washings are extracted with ether (ml) and lyophilized to give a yellow powder, which is purified on a Bond Pak C-18 reverse phase column (10 g) and recovered from the adsorbent with 5% acetonitrile in water under a pressure of 0.56 kg / cm (8 psi). Each fraction (15 mp) is evaluated for purity by liquid chromatography using high pressure, the fraction having ultraviolet absorption at

 maize 300 nm, collected and liofilizi20

25

This gives 58 mg (HRP) of the title compound as a light yellow powder. IR (KBG) D: ZAOO, 1750 and 1590 cm ,, (s (H, 0) 92 vm (s "7081); NMR (deuterium oxide) S: 1.13 (3N, doublet, 5 Hz) ,. 1.23 (ZN, doublet, 1-6.5 Hz), 3.18 (H, multiplet), 3.45 (1H, Quartet, 0 and 2, Hz), 4.0-4, A (4H, multiplet), 4.65 (ZN, singlet), 7.79 (2H, multiplet), 8.30 (1H, multiplet) and 8.60 3i, (IH, multiplet).

Data on biological activity are given in table. 1-3 ..

In tab. I shows in vitro activity, carbapenem samples (indicated by the number of the corresponding example) after dissolving in water and diluting with nutrient broth (incubation was carried out at 37 ° C overnight at dilution in a test tube; for 0 comparison, N-formamidoylthienamycin - MK.0787 was used ).

In tab. Figure 2 presents data on the in vivo therapeutic activity of some proposed compounds d and R-formamidoyl-thienamycin (MK.0787), injected intramuscularly into mice, artificially) infected with various microorganisms.

35

In tab. 2, for each compound, a dose (PDjo, µg / kg) is indicated, protecting 50% of the infected mice.

Example 5

8. aureus E. coli K. pneumoniae R. mirabilie R. aeruginosa A9843 1.6

Concentration of test compounds in the blood of mice after intramuscular administration.

In tab. Table 3 shows the concentrations of some proposed compounds in the blood of mice and the period of their pool decomposition after intramuscular administration in the amount of 20 mg / kg (combined {1 was dissolved in 0.1 M phosphate buffer solution with pH 7, each of which was tested for 4 mice) ..

Claims (1)

Invention Formula The method of obtaining carbapene emov General formula 20 3i where n is a cation 2- (N-methylpyrindinium), iri- (I, 6-dimers-pyridinium), or 4- (I, 3-dimethylpyridinium), or N, N-dimethyl-1,2 , 3-triazolium, or 2-methyl-1,2,3-thiodiaeolium, or potassium salt 4- or 5- (1-carboxymethyl-3-methyl-1, 2, 3-triazol) or 5- (I, 4-dimeshteterazoLIA); 3- (1,3-dimethylpyri-DIN-4-IL), 3- (I, 6-dimethyl-pyridin-2-yl) -beta-methyl, 3 (I, 6-dimethyl-shhridin-2-yl), ( 1,3-dimethylimidazolyl I; 3-Cz- (1,2-dimethylpyridyl), 3-GZ- (1-netilgyridyl), 3- C4- (1-methylpyridyl)}, (1,4-dimethylpyridyl), 3- C2 (N-methylpyridyl), 3,5- (1,4-dimethyl-1,2,4-triazolyl}, 3- (2,4-dimethyl-1,2,4-trilzolyl), 3- ( 2,4-dimethyl-1,2,4-triazolcp), 2-methyl-1,2,3-thiodiazolyl; 5- (1,4-dimethyl-l, 2,4-triazolyl), 3- (1 , 3-dimethyl-5-tetrazolyl; R is hydrogen or a methyl group; different dinene general formula 2 the fact that soy "--r-rV ° - -i °. where Rj is indicated above, pilethylamine with HS-CH-B compound, interact in water-CCF, SO ,, where R, as defined above, tetrahydrofuran drift in the presence of a temperature of from -30 to 5 C with pegvin alkali metal hydroxide or the next removal of the protective group for in acetonntrile in the presence of diisopropane preparation of the target compound. t o l and n I nineteen Mikrvorp em H "Inny.1M1" Kontsegntr ny IngiSirop KP HIC, NG / N11, by example and 114 G microns 1 If 17 pcs. T 18 T | 9 Tgo Tmk. .LJiiiLJ .... i -... L ... i ..... .S.pncuffloniat Z.ruozsp S.r cc “ll S.iurtui ".Urcui) OZ crum S.iureu (Pn-r ««) S.aurcui. (etti. -rci) E.Coii e.CoK K.pneuooni K.poetinoni B.clocca B.etoacM P. "lr" b lli P. "ul |" r (" N. "South (PN P.r "tt | cri S.B. raiun T, "" nitino " P.. "" En | ino (" N BtinfluttiM B.influ "ni" "S.fratUii B." | iUi A-958JO.OOOS0,000} 0, O020, O020,016 O.OOII A-96O d, OOOS0,000 $ 0,0020,0020,016 0,001. 2 A206b8I.IJ0.130.25I4 0.25 "3 A-95J70.00 eO.OOIA0.0020.0080.25 0, A-953T0,0160.03. 0,0080,03I 0, 0,0020,060,001 0.020.13- 0.002 0.5160.25 0.00 "0.50.002 0,008г0,004 A-9606 0.008 0.0160.008 0.016 0.5 0.002 I25 0.016 2J O .OO A15097 At5U9 A2034I-I A-9664 A2046v A-9659 A-9656 A-9900 A2I559 AI3I53 A22424 A200t9 A-9v43A A2I2I3 A2l5tB A22B62 A2Z969 0.0040.00e O, 0080,000 0.030.03 0,00,03 0,0) 6 0,016 0,03 0,06 0.03, 0.030.06 0,0160,0160,016 0,0080,0160,016 0,0160,030,06 0,230,06OJ3 0,0160,0160.03 328I r0,50,13 0,016 0,016 0,06 0,06 0,06 0,0 "0,06 0,03 0,13 0,25 0,06 0,25 0,13 0,60,008 0,60,008 0,130,03 0.50.06 20.06 20.06 0.130.016 0.130.008 0.50.06. 30.06 0.130, 630.5 160.13 sixteen sixteen 32 63 63 125 32 32 32 32; 32 63 63 O, OCM I 0,0082 0.034 . 0.064 0.03e 0.0316 0.034 0,0164 0.06, e 0, t38 0.034 0.53J 0.06Г6 0.01 0.016 0, OJ 0.06 0.06 0.06 0.016 0.016 0.0 0.13 0.03 0, J 0.13 Mafoorg "m .r: i L9606 0.07 0.1. FDff, msg / kg, for the connection example 7 TNK.0787Tb T 9 J 12 Tit T, 15A T 15 8, “urcUtА9606 0.070,1.0,20,07 E.eoliAI5II9 I0,40,23. K. potoMmiMA9664 W .3IЗ R, “{в00 гИ А9900. 242 "49 P, eerueinoeaA9v43A 0,50,20,20,5 R. "eruelnoMA2408I 0,90,20,10,4 0.21 0.86 1.8 I; A 0.89 1.2 - 1.8 - L 0, 07 0, 4 0.19 0.19 1.8 0.33 0, t9 - - 0.45 0.39 J, 89 I395u2 40 Continuation of table 1 0,0020,060,001 0.020.13- 0.002 0.5160.25 0.00 "0.50.002 0,008г0,004 , 016, 016, 06, 06 0.06 0.0 ", 06, 03, 13, 25, 06, 25, 13 0,60,008 0,60,008 0,130,03 0.50.06 20.06 20.06 0.130.016 0.130.008 0.50.06. 30.06 0.130, 630.5 160.13 sixteen sixteen 32 63 63 125 32 32 32 32; 32 63 63 O, OCM I 0,0082 0.034 . 0.064 0.03e 0.0316 0.034 0,0164 0.06, e 0, t38 0.034 0.53J 0.06Г6 0.01 0.016 0, OJ 0.06 0.06 0.06 0.016 0.016 0.0 0.13 0.03 0, J 0.13 t f c "2 MK.0787 0.21 0.86 1.8 I; A 0.89 1.2 - 1.8 - L 0.07, 4 0.19 0.19 1.8 0.33 0, t9 - 0.07 3 3 - t 0.45 0.39 J, 89 I 0.4 4t g Table 3 iZ