NO180489B - Intermediate which is an optionally protected 5R, 6S-6- (1R-hydroxyethyl) -2- (1S-oxo-3R thiolanylthio) -2-penem-3-carboxylic acid derivative - Google Patents

Description

Background for the invention

The present invention relates to intermediates for the production of antibacterial compounds which are diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acids, i.e. 2- (1R-oxo-3S-thiolanylthio)-variant of the formula (II) set forth below; the pharmaceutically acceptable salts and in vivo hydrolyzable esters thereof.

Antibacterial 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acid, which is a diastereomeric mixture of two compounds, has previously been mentioned as a value- fully antibacterial substance, by Hamanaka, US Patent 4,619,924 and European Patent Application 130,025. Although they have been able to be detected analytically, the pure diastereomeric compounds with the given structure have so far not been available. Mention of an improved process for the preparation of the diastereomeric mixture from racemic cis-3-(acetylthio)thiolane-1-oxide, which makes use of mixed diastereomeric intermediates which are otherwise similar to those now used, will be found in a European patent application by Volkmann et al., published 27 May 1987 under No. 223,397.

With respect to the optically active precursors, Brown et al., J. Am. Chem. Soc, vol. 108, pp. 2049-2054 (1986) described the synthesis of (S)-3-hydroxythiolane [mistakenly shown as the (R)-isomer, but in reality with the reverse configuration of the present (R)-3- hydroxythiolane of formula (XI) below] by asymmetric hydroboration of 2,3-dihydrothiophene. Partial Enzymatic Oxidation of Racemic 3-Hydroxythiolane by Jones et al., Can. J. Chem. Vol. 59, pp. 1574-1579 (1981) made it possible to recover 3-hydroxythiolane containing a slight excess of the (R)-isomer. Present optically active precursor (R)-(2-methanesulfonyloxyethyl)oxirane with the formula (XIII) indicated below where R<9> = CH3] and (S)-2-bromo-1,4-di-(methanesulfonyloxy)butane [ with the formula Xa given below, where R<8> = CH3] are known compounds which can both be prepared according to Shibata et al., Heterocycles, vol. 24, pp. 1331-1346 (1986); the former also according to Boger et al., J. Org. Chem., vol. 46, pp. 1208-1210 (1981).

The compounds that can be prepared using the intermediates according to the invention are 5R,6S-6-(1R-hydroxyethyl)-2-(1R-1-oxo-3S-thiolanylthio)-3-carboxylates with the absolute stereochemical formula

where R is hydrogen or pivaloyloxymethyl; and the pharmaceutically acceptable cationic salts thereof when R is hydrogen. The intermediates according to the invention have the absolute stereochemical formula

where R<4> is hydrogen or t-butyldimethylsilyl,- R<5> is hydrogen, -CH2-CX=CH2, or-CH2-0-CO-C(CH3)3 (with the proviso that R<5> is -CH2-CX=CH2 when R<4> is hydrogen); and X is chlorine or a salt thereof when R<5> is hydrogen.

They can be prepared from compounds of the formula

where R<6> is t-butyldimethylsilyl protecting group; R<7> is hydrogen or which in turn can be prepared from compounds with the formula where R<10> is -CH2-CX=CH2 or -CH2-0-CO-C (CH3) 3, X is hydrogen or chlorine, Y is CH3CO, M®, or M® <©>S

and M© is a

alkali metal cation, preferably Na®.

Preparation of the compounds of formula II from the fobin parts of formula IV is the subject of the parent application, patent 173,654.

Example 1

a) Sodium 3S-(thio(thiocarbonyl)thio)thiolane-1R-oxide ( VII Ia, M® = Na®)

In a flame-dried flask, a solution of 1.78 g (10 mmol) of 3S-(acetylthio)thiolane IR-oxide in 6 ml of ethanol under nitrogen was cooled to -5°C. Sodium ethoxide (21% by weight in ethanol, 3.73 mL, 10 mmol) was added and the mixture stirred at

-5°C for 30 min., then cooled to -20°C, whereupon 3.0 ml (50 mmol) carbon disulfide was added and stirring continued for 30 min. To this was added 75 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred for a few minutes, seeded with crystals of the title compound, cooled and kept at 15°C and stirred until crystallization was complete. The mixture was filtered, washed with cold tetrahydrofuran and then with ethyl ether. The resulting crystals were air-dried under nitrogen to give 2.10 g of the title product solvated with 0.5 molar equivalents of tetrahydrofuran. A further 592 mg was recovered by working up the mother liquor; m.p. 120-121°C (decomp.), blackens at 155-156°C; [å]D = -79.52° (c = 0.05, in H 2 O). b) 3S,4S-3-[1R-1-(dimethyl-t-butylsilyloxy)ethyl]-4-[1R-oxo-3S-thiolanylthio(thiocarbonyl)thio]-2-azetidinone (VI, R<7>= H,

R6=Me. tBuSi)

In a flame-dried flask, a solution of 3R,4R-4-acetoxy-3-[IR-(dimethyl-t-butylsilyloxy)ethyl]-2-azetidinone [1.87 g, 6.5 mmol; Leanza et al., Tetrahedron 39, pp. 2505-2513

(1983)] in 20 mL of isopropyl alcohol and CS2 (0.15 mL, 2.5 mmol) combined under nitrogen and cooled to 3°C. The product from step a) (1.36 g, 5 mmol) was added portionwise during which the temperature was kept at 3°C. After 0.5 hours at 3°C, the reaction was stopped with 40 ml of saturated ammonium chloride solution and 50 ml of ethyl acetate was then added to the mixture. The organic layer was separated and the aqueous layer extracted with an additional 2 x 25 mL of ethyl acetate. The combined ethyl acetate layers were washed with 2 x 20 mL H 2 O and 2 x 20 mL 20% CaCl 2 , dried over MgSO 4 , filtered and concentrated in vacuo to give the crude title product, 3.04 g. The latter was dissolved in ca. 2 ml of acetone and isopropyl ether added dropwise until precipitation of solids started, after which the mixture was stirred for 1 hour and then, while stirring, quickly added 120 ml of petroleum ether. The resulting solid was filtered off, air dried, then dried in vacuo and finally chromatographed on silica gel using 19:1 ethyl acetate:methanol as eluent to give 1.35 g (61%) of purified title product. Recrystallization from 4 ml of acetone following the same procedure gave 1.15 g of product; [å]D = +109.36° (c = 0.20, GHCCl 3 ), pnmr (CDCCl 3 ) (delta) (ppm) 300 MHz: 0.05 (s, 3H), 0.86 (s, 9H) , 1.18 (s, 3H), 1.74 (s, 2H), 2.68 (m, 3H), 2.82 (m, 1H), 3.17 (m, 2H), 3.74 ( q, 1H), 4.25 (t, 1H), 4.52 (t, 1H), 5.61 (S, 1H), 6.52 (S, 1H), 7.20 (s, 1H).

c) 3S,4R-N-[(2-chloroallyloxy)oxalyl]-3-[IR-(dimethyl-t-butylsilyloxy)ethyl]-4-[1R-oxo-3S-thiolanylthio(thio-carbonyl)thio]- 2-azetidinone

(VI, R6=Me, tBuSi. R7=C0C00CH, CC1CH.

To a flame-dried, three-necked flask fitted with a dropping funnel and a low-temperature thermometer, under a N 2 atmosphere, was added the product from step b) (878 mg, 2 mmol) and 15 mL of dry methylene chloride (passed through neutral alumina). The reaction mixture was cooled to -50° to -55°C internal temperature and added N,N-diisopropylethylamine (0.45 mL,

2.6 mmol), during which the temperature was kept lower than 50°C. Then 2-chloroallyl oxalofluoride (0.34 mL, 2.6 mmol) was added as quickly as possible, during which the temperature was again kept below 50°C, and the reaction mixture was stirred for another 50 minutes at -50° to -55 °C. The reaction was quenched with 15 ml of H 2 O, after which the mixture was allowed to warm to 0°C and was diluted with 20 ml of fresh CH 2 Cl 2 . The organic layer was separated, washed 1 x 15 ml H 2 O, 1 x 20 ml pH 7 buffer and 1 x 25 ml saturated NaCl, dried over MgSO 4 , filtered and concentrated in

vacuum to give 1.05 g of the title product as a yellow foam, which was used in its entirety directly in the next step.

d) 2-chloroallyl-5R,6S-6-[1R-(dimethyl-6-butylsilyloxy)ethyl]-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate

(IV. R4=Me„ tBuSi. RS=CH, CC1CH;

To a flame-dried, three-necked flask fitted with a condenser and an equalizing dropping funnel, under a N 2 atmosphere, was added the product from step c) (1.05 g, 2 mmol) and 80 mL of ethanol-free chloroform. The reaction mixture was heated to gentle reflux and triethyl phosphite (0.74 mL, 48 mmol) in 10 mL of ethanol-free chloroform was added dropwise over the course of hours. The mixture was kept under gentle reflux for another 10 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in 5 ml of ethyl acetate. Isopropyl ether (40 ml) was added dropwise with stirring from the start of crystallization. Finally, 40 ml of petroleum ether was added dropwise, the mixture filtered and the solid dried to give 0.47 g (44%) of product; m.p. 140-141°C; [o]D = +36.78° (c = 0.5, CHCl 3 ).

e) 2-chloroallyl-5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2-penem-3-carboxylate

(IV. R<4>=H. R5=CH, CC1CH.,

To a flame-dried, three-necked flask fitted with a thermometer and two dropping funnels, under a N 2 atmosphere, was added the product according to the invention from step d) (0.25 g, 0.46 mmol) and 0.5 ml of dry tetrahydrofuran. To the stirred reaction mixture was added glacial acetic acid (0.26 mL, 4.6 mmol), followed by tetrabutylammonium fluoride in tetrahydrofuran (1 M, 1.38 mL). The resulting solution was stirred for 16 hours at room temperature, diluted with 15 ml of ethyl acetate and 4 ml of water, pH adjusted to 6.4 with potassium acetate, the layers separated and the organic layer washed 3 x 3 ml of water. The latter were combined and extracted 3 x 3 mL CH 2 Cl 2 . The combined organic layers

(ethyl acetate and CH 2 Cl 2 ) was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give a crude product, 0.46 g. The crude product was taken up in 25 mL ethyl acetate and washed 3 x 6 mL H 2 O. The organic layer was dried over Na 2 SO 4 , filtered and evaporated to give purified title product, 88 mg; m.p. 177-178°C; [α]D = +45.28° (c = 0.25 in dimethylsulfoxide).

Conversion of a compound according to the invention

Sodium 5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-2- penem- 3-carboxylate ( II, R=Na)

To a flame-dried flask wrapped in aluminum foil, under N2 was added the product from example le) (3.60 g, 8.5 mmol) in 115 ml of degassed CH2Cl2, after which triphenylphosphine (0.72 g, 2.75 mmol), sodium-2- ethyl hexanoate (6.72 mL of 1.39M in ethyl acetate, 9.34 mmol) and tetrakis(triphenylphosphine)palladium (0.72 g, 0.62 mmol) were added. The reaction mixture was stirred at room temperature for 50 minutes, after which 72 mg each of triphenylphosphine and tetrakis(triphenylphosphine)palladium were added and the reaction mixture stirred at room temperature for another 20 minutes. HPLC grade ethyl acetate (150 mL) was added to the reaction mixture over 15 minutes. The reaction mixture was filtered and the solid air dried to give the crude product, 4.97 g. The latter was slurried with 45 ml of ethyl acetate for 45 minutes, filtered and dried to give 3.96 g of the still crude product. The latter was taken up in 70 ml of water, treated with activated charcoal, filtered and the filtrate freeze-dried to give the title product, 2.63 g.

Claims (1)

intermediate product, characterized in that the absolute stereochemical formula where R<4> is hydrogen or dimethyl-t-butylsilyl group; R<5> is hydrogen, and X is chlorine; with the proviso that R s is -CH 2 -CX=CH 2 when R<4> is hydrogen; or a salt thereof when R<5> is hydrogen.