JPH0369352B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a series of antimicrobial agents incorporating a 2-azetidinone (beta-lactam) ring. Chemically, the antimicrobial agent of the present invention is identified as a 6-alpha-1-hydroxyethyl-2-substituted-2-penem-3-carboxylic acid compound. BACKGROUND OF THE INVENTION Although some 2-substituted-2-penem-3-carboxylic acid compounds have been previously published, there is a continuing need for new compounds with suitable antimicrobial therapeutic properties. Problems to be Solved by the Invention The present invention is based on the formula or a pharmaceutically suitable salt thereof when R ₁ is hydrogen, where R is [Formula], A is carbonyl, methylene or thiocarbonyl, and B is alkylene having 2 to 5 carbon atoms; alk
is alkylene having 1 to 6 carbon atoms, R ₁ is hydrogen or a group forming an ester that can be hydrolyzed in vivo, and n is 0 or 1). Means for Solving the Problem What falls within the scope of the present invention is the formula or a pharmaceutically suitable salt thereof when R ₁ is hydrogen, where R and R ₁ are as defined above for a compound of formula. Preferred compounds of the formula or have R ₁ hydrogen, B
is ethylene, A is carbonyl, n is 1, alk is methylene, and especially R is 1,3-dioxacyclopent-4-ylmethyl or 1,3-dioxacyclopent-2-ylmethyl. Also, R ₁ is hydrogen, B is ethylene, A is carbonyl, n is 1, alk is methylene, and especially R is 2
-oxo-1,3-dioxacyclopent-4-
Compounds of the formula or which are ylmethyl are also suitable. Also suitable are compounds of the formula or in which R ₁ is hydrogen, B is propylene, A is methylene, n is 0, and in particular R is 1,3-dioxacyclohex-5-yl. In addition, R ₁ is hydrogen, B is propylene, A is carbonyl, n is 0, and in particular R is 2-oxo-1,
Also suitable are compounds of formula or which is 3-dioxacyclohex-5-yl. Also included in this invention are pharmaceutical compositions comprising a compound of formula or and a pharmaceutically suitable diluent or carrier, and methods of treating bacterial infections in a mammal by administering an antimicrobially effective amount of a compound of formula or . Compounds of formula and are effective as antibacterial agents, and compounds of formula It is a bicyclic skeleton derivative of The backbone of the formula is herein identified by the name "2-penem" and the ring atoms are numbered as shown. The carbon atom attached to the cyclic carbon at the 6th position becomes the 8th position. Also, the abbreviation "PNB" is used herein for the p-nitrobenzyl group. The relationship between the hydrogen on the 5-position carbon of the bridge head and the hydrogen on the 6-position carbon of the compound of formula may be cis or trans. The present invention includes both isomers as well as mixtures thereof. The trans isomer is generally used in pharmaceutical applications, and the cis isomer can readily convert to the trans isomer. Generally, the carbon at position 5 has an absolute stereochemistry designated R using the Prelog-Ingold RS stereochemistry nomenclature and is used in this application. For example, a compound of formula (5R,6S ₎ -6-[(R)-1-hydroxyethyl]-2-( It is named 1,3-dioxacyclohex-5-yl)thio-3-carboxyl-2-penem. As contemplated, various optically active isomers of the new compounds are possible. The present invention includes optically active isomers thereof as well as mixtures thereof. The present invention relates to penems substituted in the 2-position by a group of the general formula P-S-. The present invention includes penems in which the 3-carboxyl group is esterified with a non-toxic ester-forming residue that is hydrolyzed in vivo. These esters rapidly degrade in mammalian blood or tissue to release the corresponding penem-3-carboxylic acid. Typical examples of such ester-forming residues that can be rapidly hydrolyzed include alkanoyloxymethyl having 3 to 8 carbon atoms and 1-(alkanoyloxy) having 4 to 9 carbon atoms.
Ethyl, 1-methyl-1-(alkanoyloxy)ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1 having 4 to 7 carbon atoms
-(Alkoxycarbonyloxy)ethyl, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminoethyl having 3 to 9 carbon atoms, 4 to 10 carbon atoms
1-(N-[alkoxycarbonyl]amino)ethyl, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, carboxyalkylcarbonyloxymethyl having 4 to 12 carbon atoms, or 5-methyl-2 -oxo-1,3-dioxolen-4-ylmethyl. To prepare compounds of formula or in which R ₁ is an ester group that is hydrolyzed in vivo, an acid of formula or (where R ₁ is hydrogen) is reacted with a base to form the corresponding anion. Suitable cations include sodium, potassium, calcium, and tetra-
Included are alkylammoniums and their analogs. Yin ions can also be produced by freezing an aqueous solution of or, for example, an aqueous solution of tetrahydrofuran and sodium bicarbonate or tetrabutylammonium hydroxide. The resulting anion of or is reacted with the corresponding chloride or bromide of R ₁ in a reaction-inert solvent such as acetone or dimethylformamide at about 20 to 50°C (25°C is preferred). Compounds of formula can be synthesized according to schemes AC. As shown in Scheme A, compounds of formula
(1981) from the known dibromopenam of the formula. dibromopenam () in a reactive inert solvent medium such as tetrahydrofuran, diethyl ether or toluene (tetrahydrofuran is preferred) at a temperature between about -90 and -40°C (about -78°C is preferred) as well as t-butylmagnesium chloride. An exchange reaction is carried out with Other organometallic reagents can also be used. The resulting reaction mixture is treated with a suitable aldehyde, such as acetyl aldehyde for the 1-hydroxyethyl derivative. Aldehydes are about −80 and −60
The addition is carried out at a temperature between 0.degree. Hydrogenation of the resulting bromohydroxypenam removes the 6-bromo substituent. Suitable hydrogenation catalysts are noble metal catalysts such as palladium.
The reaction is carried out in an aqueous medium such as methanol-water (1:1) or tetrahydrofuran-water (1:1) (methanol-water (1:1) is preferred) from about 1 to 4 atmospheres (4 atmospheres is preferred). At temperatures between approximately 0 and 30°C (approximately
(preferably at 25°C). Formula the alcohol of the resulting formula (wherein each R ₉ is alkyl having 1 to 6 carbon atoms and Q is chloro, bromo or iodo). in a polar non-aqueous solvent such as N,N-dimethylformamide in the presence of an amine proton acceptor such as imidazole at a temperature between about 5 and 40°C (about
(preferably at 25 DEG C.) dimethyl- t -butylchlorosilane forms a trialkylsilyl hydroxyl protecting group as shown in the formula. treatment with mercuric acetate in acetic acid at a temperature of about 90°C yields an olefin. To obtain the desired azetidinone, the olefin is dissolved in a reaction-inert solvent such as dichloromethane.
Ozone treatment at a temperature between about -80 and -40°C (about -78°C is preferred). Treatment of the reaction product with an alkanol such as methanol produces azetidine. As shown in Scheme B, a compound of formula
M ⁺ R ₁₀ -S-C(S)-S ^- (In the formula, R ₁₀ has 1 to 1 carbon atoms
Treatment with the trithiocarbonate salt of alkyl (ethyl is preferred) of 4, where M is sodium or potassium, provides compounds of formula. This conversion is carried out in a reaction-inert organic solvent, water or a mixture thereof (a mixture of water and dichloromethane is preferred) at a temperature in the range of about 0 DEG to 35 DEG C. (about 25 DEG C. is preferred). Condensation of a compound of formula with p -nitrobenzylchlorooxalate in the presence of a tertiary alkylamine in which each alkyl has from 1 to 4 carbon atoms, such as ethyldiisopropylamine, provides a compound of formula XI. This condensation reaction is carried out in a reaction inert solvent (dichloromethane is preferred) at a temperature range of about 5 to 25 °C (about 10
℃ is preferable). The resulting compound of formula
Cyclization using a trialkylphosphine having an alkyl of 1 to 4 carbon atoms, such as triethylphosphine, at 60 DEG C. (preferably 60 DEG C.) provides the penem of formula XII. The thio group of compound
Oxidation with an oxidizing agent such as m-chloroperbenzoic acid at 20 DEG C. (preferably 20 DEG C.) yields the corresponding sulfoxide. The sulfoxide in a polar organic solvent such as ethanol or acetonitrile at approximately -50 to -10°C.
(approximately -35° C. is preferred) using a sodium or potassium salt of the mercaptide which reacts with the sulfoxide to replace the mercaptide of the formula R- ^S- . The starting materials, mercaptans of the formula R-SH or thioacetates of the formula R-S-C(O) _CH3 , are known for a number of useful R's, and those not known can be synthesized by analogous methods known in the art. Ru. Review articles include "The Chemistry of the Thiol Group" in "Preparation of Thiols" by J.L.Wavdell, and "The Chemistry of the Thiol Group" by S.
Edited by Patai, John Wiley & Sons, London,
1974, see Chapter 4. Volante also describes the conversion of alcohols to thiols and thiol esters using triphenylphosphine and dialkyl azodicarboxylates in the presence of an alcohol and a suitable thiol acid.
Tetrahedron Letters, 22 , 3119-3122 (1981)
See. In compounds of formula, it is preferred to remove the trialkylsilyl group prior to hydrogenolysis to remove the acid protecting group (PNB). The trialkylsilyl group is dissolved in an ethereal solvent such as tetrahydrofuran at a temperature range of about 15 to 40°C (about 25°C is preferred).
with tetraalkylammonium fluoride. Conversion of compounds of formula to compounds of formula is usually accomplished using hydrogenolysis reactions and is carried out in the usual manner for conversions of this type. That is, a solution of a compound of formula is mixed with hydrogen or an inert diluent such as nitrogen or argon in the presence of a noble metal hydrogenolysis catalyst such as palladium/calcium carbonate or palladium/celite (on diatoms) catalyst. Stir or shake under atmosphere. Convenient solvents for this hydrogenolysis are lower alkanols such as methanol, ethers such as tetrahydrofuran and dioxane, low molecular weight esters such as ethyl acetate and butyl acetate, water and mixtures of these solvents. Usually, however, conditions are chosen such that the starting material is soluble in an aqueous ether such as aqueous tetrahydrofuran at a pH of about 7-8. Hydrogenolysis is usually carried out at room temperature and at a pressure of about 0.5 to 5 kg/cm ² . Catalyst is usually 10% by weight of starting materials
Although equal to equal amounts are used, larger amounts can also be used. The reaction usually takes about 1 hour with the compound of formula conveniently recovered by filtration and the solvent removed under vacuum. When palladium/calcium carbonate is used as a catalyst, the product is isolated as the calcium salt, and when palladium/celite is used, the product is isolated as the sodium salt. Compounds of formula or are purified using conventional methods for beta-lactam compounds. For example, compounds of formula are purified by Sephadex gel filtration or recrystallization. An alternative synthetic procedure is shown in Scheme C. Using the procedure already described in the preparation of azetidine of the formula
M ⁺ R-S-C(S)-S ^- (where M is a metal such as sodium or potassium) is reacted with a trithiocarbonate. The resulting trithiocarbonate A is dissolved in a non-aqueous solvent such as benzene, toluene or dimethylformamide (benzene is preferred) at about 25-110%
Treatment with p -nitrobenzyloxycarbonyl)(dihydroxy)methane in the temperature range of 0.degree. C. (approximately 80.degree. C. is preferred) yields an alcohol of formula. The corresponding chloride is prepared in a reaction-inert organic solvent such as dichloromethane in the presence of a sterically hindered amine acting as an acid acceptor, such as 2,6-lutidine, at temperatures ranging from about -5 to 75°C ( 0℃
(preferably) by treating the alcohol with thionyl chloride. Reaction of the chloride with a triallylphosphine such as triphenylphosphine in a reaction-inert solvent such as tetrahydrofuran in the presence of a tertiary amine such as 2,6-lutidine at a temperature of about 25°C gives the formula A compound is obtained which undergoes cyclization upon refluxing in an aromatic solvent such as toluene to yield a penem of formula. Trithiocarbonate salts of formula M ⁺ R-S-(C=S)-S ^- are prepared from appropriate mercaptans of formula R-SH,
or prepared by treating a thioacetate of formula RS(CO) _CH3 with an alkaline metal alkoxide followed by carbon disulfide. Using the procedure already described by Yoshida et al., the penem 6
The stereochemistry of the hydroxyethyl group attached to the carbon position and the carbon position 6 is as shown in the formula. Mechanism B
The main stereochemistry of the ring-closed product using C or C is that the hydrogen at the 5-position of the penem ring is trans to the hydrogen on the 6-position carbon, which is an alpha configuration. or change the stereochemistry to 5R,6S;6-(R)-1-
Can write hydroxyethyl. Compounds of formula or are acidic and form salts with basic substances. This salt is considered to be within the scope of this invention. These salts are suitable aqueous,
They are prepared by standard procedures such as contacting acidic and basic components in non-aqueous or partially aqueous media, usually in stoichiometric proportions. The salts are then recovered by a suitable method such as precipitation with a non-solvent, filtration, distillation of the solvent, or, in the case of an aqueous solution, freeze-drying. The basic substances conveniently used for salt formation belong to both organic and inorganic types and include ammonia, as well as hydroxides, carbonates, hydrides and alkoxides of alkaline earth metals. Included are organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides. Representative examples of such bases include n -propylamine, n -butylamine,
Primary amines such as aniline, cyclohexylamine, benzylamine and octylamine, secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine, triethylamine, N -ethylpiperidine, N- methylmorpholine and 1,5-diazabicyclo[4 ,3,0]
Tertiary amines such as non-5-ene, hydroxides such as sodium hydroxide, calcium hydroxide, ammonium hydroxide and barium hydroxide, alkoxides such as sodium ethoxide and potassium ethoxide, calcium hydride and Alkali metal hydrides such as sodium hydride, carbonates such as potassium carbonate and sodium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate, and long chain fatty acids such as sodium 2-ethylhexanoate. Salt is an example. Preferred salts of compounds of formula or are the sodium, potassium and calcium salts. Pharmaceutically suitable salts of formula or are those salts that do not cause significant adverse side effects at levels of normal use, and include, for example, the sodium, potassium or calcium salts. The in vivo activity of compounds of the formula or their salts is indicated by measuring the minimum inhibitory concentration ( _MICS ) against various microorganisms (mcg/ml). The next step is the International Collaborative Study on Antibiotic Responsiveness Testing (Acta by Ericcson and Sherris).
Pathologica et Microbiologia Scandinav, Supplement No. 217, Division B, 64-68 [1971]), and a brain, heart infusion (BHI) agar medium is used as the inoculation device. Dilute the overnight growth tube 100 times to use as standard inoculum (approximately 20,000 to 10,000 cells in 0.002 ml are placed on the surface of the agar, 20 ml BHI agar/
dish). Twelve 2-fold dilutions of test compound are used with an initial concentration of test drug of 200 mcg/ml. Disregard single colonies when judging the medium after 18 hours at 37°C. The susceptibility (MIC) of a test organism is interpreted as the lowest concentration of a compound that can cause complete inhibition of growth as judged by the naked eye. Compounds of formula or and their pharmaceutically suitable salts are suitable for use in mammals, including humans, of Staphylococcus aureus.
Suitable for controlling bacterial infections such as those caused by infectious strains of P. aureus). The compounds of the invention are administered orally or parenterally, ie, intramuscularly, subcutaneously, intraperitoneally or intravenously, alone or in combination with a pharmaceutically suitable carrier.
The ratio of active ingredient to carrier will depend on the chemical nature, solubility and stability of the active ingredient as well as the intended dosage. The ratio of pharmaceutically suitable carrier to penem compound usually ranges from 1:10 to 4:1. For oral administration, the compounds of the invention may be administered as tablets, capsules, lozenges, troches, powders, syrups,
Used in the form of elixirs, aqueous solutions, suspensions and the like. For tablets, carriers that may be used include lactose, sodium citrate and phosphate. Various dispersing substances such as starch and lubricants such as sodium stearate, sodium lauryl sulfonate and talc are commonly used in tabletting. Useful diluents in capsules are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. For parenteral administration, a sterile solution of the active ingredient is usually prepared and the solution
Adjust the pH appropriately and make a buffer solution. Intravenous use renders the overall concentration of solutes isotonic. The prescribing physician will determine the dosage for the human patient to be administered. This amount is expected to vary according to the age, weight, and response of the individual patient, as well as the nature and severity of the patient's symptoms. Compounds of formula or are usually used orally in doses ranging from about 10 to 200 mg per kilogram of body weight per day. It may be necessary to use dosages beyond these ranges. EXAMPLES The following examples and preparations are provided by way of further illustration. Infrared (IR) spectra are measured as solutions of potassium bromide disks (KBr disks), diolmal or chloroform (CHCl ₃ ), methylene chloride (CH ₂ Cl ₂ ) or dimethyl sulfoxide (DMSO), and are characterized by characteristic absorption bands. is reported in microns or wavenumbers (cm ^-1 ). Nuclear magnetic resonance (NMR) spectra are measured in deuterated chloroform ( _CDCl3 ), deuterated water ( _D2O ) or deuterated dimethyl sulfoxide (DMSO- _d6 ) solutions or mixtures thereof, with peak positions ranging from tetramethylsilane to Expressed in ppm to magnetic field. The following abbreviations are used for peak shapes. s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; b, wide; w, weak; c,
complicated. The abbreviations "ss" and "sss" particularly indicate that the protons occur as two or three singlets, respectively, due to the presence of diastereomers. Throughout the Examples and Preparations, the abbreviation "PNB" stands for p-nitrobenzyl group. Example 1 ( 5R , 6S )-6-[( R )-1-hydroxyethyl]-2-(1,3-dioxacyclohex-5-
) Sodium thio-2-penem-3-carboxylate Distilled water (8 ml) and tetrahydrofuran (8 ml)
The pH of a suspension of 41 mg of palladium/diatomaceous earth in a mixture of was adjusted to approximately 7.5 with 0.02 M aqueous sodium bicarbonate solution. 41 mg of p -nitrobenzyl ( 5R , 6S )-6[(R)-1-hydroxyethyl] in a mixture of tetrahydrofuran (4 ml) and distilled water (4 ml)
A solution of -2-(1,3-dioxacyclohex-5-yl)thio-2-penem-3-carboxylate was added and the resulting mixture was heated to 75 psi with hydrogen at 55 psi.
Hydrogenation was carried out for a minute, an additional 40 mg of 10% palladium/diatomaceous earth was added to the reaction mixture, and the pH of the suspension was adjusted to about 7.0 with 0.02M sodium bicarbonate. The mixture was hydrogenated with 55 psi of hydrogen for 75 minutes, then the catalyst was removed by filtration and the liquid was concentrated in vacuo to remove the tetrahydrofuran. The pH of the resulting aqueous solution was adjusted to 7.0, and the solution was extracted twice with 20 ml of ethyl acetate. The aqueous layer was then lyophilized to yield 30 mg (96% yield) of the title product as an amorphous solid. The infrared spectrum of the title compound had an absorption at 5.67 microns. Repeating the experimental procedure afforded the title compound in 85% yield. The spectral data are as follows. NMR (heavy water, 250MHz): 1.29 [3H, d, J=
6.5Hz]; 3.57 [1H, m]; 3.90 [2H, m]; 3.92
[1H, dd, J=6.0, 1.4Hz]; 4.24 [1H, qd, J=
6.5, 6.0Hz]; 4.29 [2H, m]; 4.86 and 4.94 [2H, both d, J _AB = 6.5Hz]; and 5.68 [1H, d, J = 1.4
Hz〕ppm. IR (KBr disk): 3040(b), 2966(b), 2846
(W), 1770 (S), 1593, 1378, 1295, 1169,
1136, 1053, 1020 and 924 cm ^-1 . UV (water) (extinction coefficient in parentheses): 254 (4470) and 320 (5240) nanometers. [α] _D (Water): +139.0°. Example 2 The procedure of Example 1 was carried out using a compound of formula to obtain the corresponding compound of formula as the sodium salt. The R and infrared spectral characteristics are shown in Table 1. The means in parentheses are the means. [Table] Production example A P-nitrobenzyl (5 R , 6 S )-6-[( R )
-1-Hydroxyethyl]-2-(1,3-dioxacyclohex-5-yl)thio-2-penem-3-carboxylate 70 mg in anhydrous tetrahydrofuran (4 ml)
(0.12 mmole) of P-nitrobenzyl (5 R , 6
S)-6-[( R )-1-t-butyldimethylsilyloxyethyl]-2-(1,3-dioxacyclohex-5-yl)thio-2-penem-3-carboxylate to a solution 0.07 ml (1.2 mmol) of acetic acid and tetrabutylammonium fluoride
0.36 ml (0.36 mmol) of 1M tetrahydrofuran solution was added. After stirring for 40 hours at room temperature under a stream of nitrogen, ethyl acetate was added and the resulting solution was dissolved in 25 ml of saturated aqueous sodium bicarbonate solution, 25 ml of water and 25 ml of water.
and a saturated aqueous solution of sodium chloride. The ethyl acetate solution was then dried over anhydrous sodium sulfate,
Concentrated under vacuum. The crude product (70 mg) was chromatographed on silica gel (35 g) and eluted with chloroform-ethyl acetate 2:1 to give the title product 42
mg (yield 82%) was obtained. The infrared spectrum of a dichloromethane solution of the title compound had absorptions at 5.58, 5.91 and 6.58 microns. The 250MHz NMR spectrum of the title compound in deuterated dimethyl sulfoxide is 1.17 (d, 3H); 3.54 (m,
1H); 3.76-3.95 (c, 3H); 4.02 (m, 1H); 4.2
(m, 2H); 4.82 (q, 2H); 5.25 (d, 1H); 5.38
Peaks were shown at (q, 2H); 5.78 (d, 1H); 7.7 (d, 2H); and 8.25 (d, 2H) ppm. After repeating the experimental procedure, the title compound was obtained in 94% yield, mp: 214-215°C (recrystallized from tetrahydrofuran). The spectral data are as follows. NMR (DMSO-d ₆ , 250MHz): 1.17 [3H, d,
J=6Hz]; 3.53 [1H, m]; 3.82 [2H, m]; 3.90
[1H, dd, J=6,1Hz]; 4.01 [1H, m]; 4.02
[2H, m]; 4.79 and 4.83 [2H, both d, J _AB = 6
Hz]; 5.26 [1H, d, J=Hz]; 5.31 and 5.45 [2H,
Both d, J _AB = 14Hz]; 5.78 [1H, d, J = 1Hz];
7.69 [2H, d, J=9Hz]; and 8.24 [2H, d,
J=9Hz〕ppm. IR (KBr disk): 3452,
2965, 2851 (W), 1776 (S), 1693 (S), 1609
(W), 1520, 1502, 1376, 1220, 1194, 1176,
1135, 1119, 1047 and 1023 cm ^-1 . Preparation Example B The procedure of Preparation Example A was carried out using a compound of formula to obtain the corresponding compound of formula. R, yield, and spectral characteristics (solvent in parentheses) are shown in Table 2. [Table] Production example CP-nitrobenzyl (5 R ,6 S )-6-[( R )
-1-t-butyldimethylsilyloxyethyl]-2-(1,3-dioxacyclohex-5
-yl) thio-2-penem-3-carboxylate Sodium methoxide (27 mg, 0.5 mmole) was dissolved in 1,3-dioxacyclohex-5-ylthioacetate (81 mg, 0.5 mmole) under a nitrogen stream -35
Added to an anhydrous ethanol solution (5 ml) cooled to °C. After 45 minutes, 300mg (approx. 0.5mmole) at -35℃
Crude P-nitrobenzyl ( 5R , 6S )-6-
[( R )-1-t-butyldimethylsilyloxyethyl]-2-ethylsulfinyl-2-penem-
Added to a solution of 3-carboxylate in tetrahydrofuran (5 ml) cooled to -50°C. The resulting solution was stirred at −35°C for 60 min, then 0.029 ml (0.5
mmole) of acetic acid is added and the solution is concentrated under vacuum. The residue was dissolved in 50 ml of ethyl acetate and the resulting solution was dissolved in 25 ml of saturated aqueous sodium bicarbonate solution, 25 ml of ethyl acetate.
ml of water and 25 ml of saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Crude product (360mg)
was chromatographed on silica gel (100 g),
Elution with chloroform gave 70 mg (24% yield) of the title product as a sticky gum. The infrared spectrum of a dichloromethane solution of the title compound had absorptions at 5.59, 5.9 and 6.57 microns. The NMR spectrum of the title compound in deuterated chloroform is 0.03 (s, 3H); 0.06 (s, 3H); 0.8
(s, 9H); 1.25 (d, 3H); 3.4-3.86 (c, 4H);
4.0-4.5 (c, 3H); 4.63 (d, 1H); 4.95 (d,
1H); 5.27 (q, 2H); 5.63 (d, 1H); 7.56 (d,
2H) and 8.18 (d, 2H) ppm. Repeating the experimental procedure gave the title compound in 65% yield, mp: 133-134°C (recrystallized from diethyl ether/petroleum ether). The spectral data are as follows. NMR ( _CDCl3 ,
250MH ₃ ): 0.04 [3H, s]; 0.07 [3H, s]; 0.83
[9H, s]; 1.26 [3H, d, J=6.3Hz]; 3.5 to 3.75
[3H, m]; 3.75 [1H, dd, J=4.0, 1.5Hz]; 4.2
~4.4. [3H, m]; 4.67 and 4.97 [2H, both d, J _AB =
6.2Hz]; 5.21 and 5.42 [2H, d, J = 8.7Hz] and
8.21 [2H, d, J = 8.7Hz] ppm. IR (KBr disk): 2946, 2927, 2850, 1797 (S), 1697 (S),
1610, 1512, 1374, 1345, 1320, 1230, 1189,
1168, 1122, 1064, 1025, 982, 931, 835, 801 and 772 cm ^-1 . Preparation D The procedure of Preparation C was followed using the appropriate thioacetate to give the corresponding compound of formula. R,
The yield and spectral characteristics (solvent in parentheses) are shown in Table 3. [Table] Production example E 3-alpha- t -butyldimethylsilyloxyethyl-4-ethylthio(thiocarbonyl)
4.18 g of thio-2-oxo-acetidine ethanethiol (8.5 ml, 0.115 mole)
(0.104 mole) of sodium hydroxide was added to an aqueous solution (250 ml) cooled to 0-5°C under a nitrogen atmosphere. After 15 minutes, 7.73 ml (0.12 mole) of carbon disulfide was added and the mixture was stirred at 0-5°C for 30 minutes. 15.0g (0.0522mole) of 4-acetoxy-3
-t -butyldimethylsilyloxyethyl-2-
Azetidinone methylene chloride solution (500ml)
was added and the mixture was stirred vigorously at room temperature for 24 hours. The aqueous layer was separated and extracted twice with 150 ml of methylene chloride. The methylene chloride portions were combined, washed twice with 200 ml of water and 200 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under vacuum. Crude title product (18g)
was chromatographed on linker gel (500 g),
Elution with chloroform-ethyl acetate (99:1) yielded the title trithiocarbonate as a yellow foam.
Obtained in an amount of 9.1 g (yield 48%). The infrared spectrum of a dichloromethane solution of the title compound had absorptions at 5.62 and 9.2 microns.
The NMR spectrum of the title compound in deuterated chloroform is 0.08 (s, 6H); 0.8 (s, 9H), 1.02-1.5
(m, 6H); 3.0-3.48 (m, 3H); 4.12 (m, 1H);
Peaks were shown at 5.54 (d, 1H); and 6.57 (b, 1H) ppm. Production example F 1,3-dioxacyclohex-5-yl p-
Toluenesulfonate p -toluenesulfonyl chloride (3.81g,
20.8 g (0.2 mole) of glycerol formal (1,3-dioxan-5-ol, 67
% and (1,3-dioxolan-4-yl)methanol, 33%) was added to a pyridine solution (200 ml) cooled to 0°C under a nitrogen stream, and the reaction mixture was stirred at 0°C for 30 minutes. Then at 25℃ for 20
Stir for hours. The mixture was added to 500ml of 6N hydrochloric acid and the resulting mixture was extracted four times with 200ml of ethyl acetate. 200ml of the combined ethyl acetate extracts
twice with 1N hydrochloric acid, twice with 200 ml of water, and 200 ml of water.
ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give an oil. The crude product was dissolved in 500 ml of diisopropyl ether to crystallize the desired 1,3-dioxacyclohex-5-yl tosylate. The tosylate was obtained as 17.4 g of white crystals by filtration, mp 91-92°C. 4.3g more than mother liquor
of crystalline tosylate was obtained (42% overall yield).
The NMR spectrum of the title compound in deuterated chloroform is 2.45 (s, 3H); 3.54-4.13 (c, 4H); 4.26
~4.6 (m, 1H); 4.75 (s, 2H); 7.3 (d, 2H);
A peak was observed at 7.8 (d, 2H) ppm. Production example G 1,3-dioxacyclopent-4-ylmethyl p -toluenesulfonate p -toluenesulfonyl chloride (76.2g,
0.4 mole) to 104.1 g (1 mole) of glycerol fosmal (1,3-dioxacyclohexa-5-
(mixture consisting of 67% alcohol and 33% (1,3-dioxacyclopent-4-yl)methanol)
A pyridine solution (1000
ml). After standing for 20 hours at 0° C., the reaction mixture is warmed to room temperature and added to 1500 ml of 6N hydrochloric acid.
The resulting mixture was extracted four times with 500 ml of ethyl acetate,
twice with 500 ml of 6N hydrochloric acid, twice with 500 ml of water and
Washed with 500 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The oily product (78.4 g) consisted of an approximately 2:1 mixture of 1,3-dioxacyclopent-4-ylmethyl tosylate and 1,3-dioxacyclohehex-5-yl tosylate and was not purified. was used in the next step (Production Example I). Preparation Example H 1,3-Dioxacyclohex-5-ylthioacetate 280 g (0.108 mole) of 1,3-dioxacyclohex-5-yl p -tracito and 24.6 g
(0.216 mole) of potassium thioacetate in dimethylformamide (500 ml) under a nitrogen atmosphere.
℃ for 20 hours. The reaction mixture was then cooled to room temperature and diluted with 1000 ml of water. the resulting mixture
Extracted 6 times with 300 ml of ethyl acetate. The combined ethyl acetate extracts were diluted with 500 ml of water four times and 500 ml of water was added.
was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to give an oil. Distillation of the product yields 6.25 g (yield 36
%) title thioacetate was obtained, bp70
°C (0.4mm). The NMR spectrum of a deuterated chloroform solution of the title compound showed peaks at 2.34 (s, 3H); 3.4-4.36 (c, 5H); and 4.8 (q, 2H) ppm. After repeating the experimental procedure, the title compound was obtained in 49% yield, bp 85-89°C (0.7 mm). NMR
( _CDCl3 , 250MHz): 2.34 (3H, s); 3.7-3.85
(3H, m); 4.05~4.2 (2H, m); 4.79 (1H, d,
J _gen =6.2Hz); and 4.89 (1H, d, J _gen =6.2Hz)
ppm. Production example I (1,3-dioxacyclopent-4-yl)
Methylthioacetate An acetone solution (1500 ml) of a mixture of 78 g (0.3 mole) of 1,3-dioxacyclopent-4-yl tosylate (from Preparation G) and 27.4 g (0.24 mole) of potassium thioacetate was added under a nitrogen stream. The mixture was refluxed overnight. The reaction mixture was then concentrated under vacuum and the residue was dissolved in a mixture of 500ml ethyl acetate and 500ml water. The aqueous layer was extracted with 500 ml of ethyl acetate and the combined ethyl acetate extracts were washed twice with 500 ml of water and 500 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue of solid suspended in oil was filtered and the liquid was distilled under reduced pressure to yield 20.8g (54%) of 1,
3-Dioxacyclopent-4-ylmethyltosylate was obtained, bp 65-70°C (0.2 mm). Washing the solid product with ether gave 18.4 g of 1,3-dioxacyclohex-5-yl tosylate. The NMR spectrum of the title compound in deuterated chloroform is 2.37 (s, 3H); 3.1 (d, 2H); 3.4-4.4
(c, 3H); 4.86 (s, 1H); and 5.02 (s, 1H)
It showed a peak at ppm. Production example J (1,3-dioxacyclopent-2-yl)
Methylthioacetate 5.0g (0.03mole) of 2-bromomethyl-1,
3-dioxacyclopentane and 5.13g
An acetone solution (60 ml) of a mixture of potassium thioacetate (0.045 mole) was refluxed overnight under a nitrogen atmosphere. The mixture was filtered and the liquid was concentrated under vacuum. The residue was partitioned between 100 ml of ethyl acetate and 60 ml of water, the aqueous layer was extracted with 50 ml of ethyl acetate and the combined ethyl acetate portions were washed with 50 ml of water and 50 ml of saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel eluting with methylene chloride to give 4.0 g of the desired thioacetate as an oil. The NMR spectrum of the title compound in deuterated chloroform is 2.36 (s, 3H); 3.16 (d, 2H); 3.94
(c, 4H); and peaks at 5.0 (t, 1H) ppm. Production example K 2-oxo-1,3-dioxacyclopent-
4-ylmethylthioacetate diisopropylazodicarboxylate (3.9
ml, 0.02 mole) was added to anhydrous tetrahydrofuran (50 ml) cooled to 0°C under a nitrogen stream. Precipitation occurred while the solution was stirred at 0° C. for 30 minutes. A solution of 1.18 g (0.01 mole) glycerin carbonate and 1.04 ml (0.02 mole) thioacetic acid in anhydrous tetrahydrofuran (20 ml) was added dropwise to this mixture at 0°C. The mixture was heated at 0°C for 1 hour, then at room temperature.
Stirred for 2.5 hours, concentrated under vacuum and the residue was partitioned between 70ml ethyl acetate and 70ml water. The ethyl acetate layer was diluted twice with 50 ml of saturated aqueous sodium bicarbonate solution.
Washed with 50 ml of water and 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel eluting with methylene chloride to give 600 mg of impure material. The impure product was further purified by chromatography on silica gel, eluting with hexane/ethyl acetate (3:1) to yield 220 mg (13% yield) of the desired thioacetate as an oil. The NMR spectrum of a deuterated chloroform solution of the title compound is 2.4 (s, 3H); 3.25 (d, 2H); and
A peak was shown at 3.94 to 5.07 (c, 3H) ppm.

Claims (1)

[Claims] 1 formula (In the formula, R is [Formula], A is carbonyl, thiocarbonyl or methylene, B is alkylene having 2 to 5 carbon atoms, alk
is alkylene having 1 to 6 carbon atoms, R ₁ is hydrogen or a group that forms an ester that can be hydrolyzed in vivo, and n is 0 or 1) or R ₁
When is hydrogen, its salt suitable as a medicine. 2 R ₁ is hydrogen, B is ethylene, A is methylene,
2. The compound according to claim 1, wherein n is 1 and alk is methylene. 3 R is 1,3-dioxacyclopent-4-ylmethyl or 1,3-dioxacyclopent-
The compound according to claim 2, which is 2-ylmethyl. 4. The compound according to claim 1, wherein R ₁ is hydrogen, A is carbonyl, n is 1, and alk is methylene. Claim 4 in which 5 R is 2-oxo-1,3-dioxacyclopent-4-ylmethyl
Compounds described in Section. 6. The compound according to claim 1, wherein R ₁ is hydrogen, B is propylene, A is methylene or carbonyl, and n is 0. 7. The compound according to claim 6, wherein R is 1,3-dioxacyclohex-5-yl or 2-oxo-1,3-dioxacyclohex-5-yl. 8 formula or a pharmaceutically suitable salt thereof when R ₁ is hydrogen (wherein R is [formula], A is carbonyl, thiocarbonyl or methylene, B is alkylene having 2 to 5 carbon atoms, alk is carbon number 2. The compound according to claim ₁ , wherein R1 is hydrogen or a group forming an ester that can be hydrolyzed in vivo, and n is 0 or 1. 9 R ₁ is hydrogen, R is 1,3-dioxacyclopent-4-ylmethyl, 1,3-dioxacyclopent-2-ylmethyl, 2-oxo-1,3-
Dioxacyclopent-4-ylmethyl, 1,3
-dioxacyclohex-5-yl or 2-oxo-1,3-dioxacyclohex-5-yl. 10. An antibacterial composition comprising a compound of the following formula or a pharmaceutically suitable salt thereof when R ₁ is hydrogen and a pharmaceutically suitable diluent or carrier. (In the formula, R is [Formula], A is carbonyl, thiocarbonyl or methylene, B is alkylene having 2 to 5 carbon atoms, alk
is alkylene having 1 to 6 carbon atoms, R ₁ is hydrogen or a group that forms an ester that can be hydrolyzed in vivo, and n is 0 or 1)