JPH0528237B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to antibacterial agents incorporating a 2-azetidinone (beta-lactam) ring. Chemically, the antibacterial agent of the present invention is identified as a 6-α-hydroxyethyl-2-substituted-2-penem-3-carboxylic acid compound. Although certain 2-substituted-2-penem-3-carboxylic acid compounds have been previously disclosed, there remains a need for new compounds with desirable antibacterial therapeutic properties. The present invention is based on the formula [Wherein, R is 2-(methylsulfonyl)ethyl,
(methylsulfonyl)methyl, 3-thietanyl,
1-oxo-3-thietanyl, 1,1-dioxo-3-thietanyl, 2-thiolanyl, 1-oxo-2-thiolanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1-dioxo-3- Thiolanyl, 3-hydroxy-4-thiolanyl, 1-
Oxo-3-hydroxy-thiolanyl, 1,1-
Dioxo-3-hydroxy-4-thiolanyl, 2
-oxo-1,3-dithiolan-4-ylmethyl, 3-thianyl, 1-oxo-3-thianyl,
1,1-dioxo-3-thianyl, 4-thianyl, 1-oxo-4-thianyl or 1,1-dioxo-4-thianyl, and R ₁ is hydrogen or forms an ester that is hydrolyzed in vivo Particularly suitable compounds include R is 1-oxo-3-thiolanyl, 1,1-dioxo-3-thiolanyl,
1-oxo-3-thietanyl, 1-oxo-3-
thianyl, 1,1 dioxa-4-thianyl, 4-
It is thianil. formula Also included within the scope of the present invention are compounds of the formula (as defined above for compounds of R and R ₁ ) or a pharmaceutically acceptable salt thereof. Suitable compounds include those as described as preferred for compounds of formula R. Particularly preferred are those in which R is cis or trans-1
-oxo-3-thiolanyl, 1,1-dioxo-
3-thiolanyl, cis or trans-1-oxo-3-thietanyl, cis or trans-1-oxo-3-thianyl, 1,1-dioxo-4-thianyl, 4-thianyl, or cis or trans-
Includes those of the formula 1-oxo-4-thianyl. a pharmaceutical composition further comprising a compound of formula or and a pharmaceutically acceptable diluent or carrier, and administering an antibacterial effective amount of a compound of formula or Also encompassed by the invention are methods of treating infections. Compounds of formula and are useful as antibacterial agents, and compounds of formula It is a derivative of the bicyclic nucleus of. Throughout this specification,
The nucleus of the formula is called "2-penem",
Ring atoms are numbered as shown. The carbon atom bonded to ring carbon 6 is given the number 8.
Also, throughout this specification, the abbreviation "PNB" is used for the p-nitrobenzyl group. The relationship between the hydrogen of bridgehead atom 5 and the remaining hydrogen of carbon 6 in the compound of formula may be either cis or trans. The present invention includes both these isomers as well as mixtures thereof. The trans isomer is generally useful for pharmaceutical applications, and the cis isomer can be easily converted to the trans isomer. Generally, carbon 5 is used herein
It would have the absolute configuration R according to the Prelog-Ingold R,S-stereochemical designation. That is, for example R ₁
The compound in which is hydrogen and R is 4-thianyl is named (5R,6S)-6-[(R)-1-hydroxyethyl]2-(4-thianyl)thio-3-carboxyl-2-penem. be done. As will be appreciated, various optically active isomers of the novel compounds are possible. The present invention includes such optically active isomers as well as mixtures thereof. The present invention includes penems in which the 3-carboxyl group is esterified with a non-toxic group that is hydrolyzed in vivo. These esters are rapidly degraded in mammalian blood or tissues to form the corresponding penem-3
- liberates carboxylic acid. Representative examples of such readily hydrolyzable ester-forming residues are: C3-C8 alkanoyloxymethyl, C4-9 1-(alkanoyloxy).
Ethyl, 1-methyl-1-(alkanoyloxy)ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-methyl having 4 to 7 carbon atoms
(Alkoxycarbonyloxy)ethyl, carbon number 5
~8 1-methyl-1-(alkoxycarbonyloxy)ethyl, C3-9 N-(alkoxycarbonyl)aminomethyl, C4-10 1-
(N-[alkoxycarbonyl]amino)ethyl,
3-phthalidyl, 4-crotonolactonyl, γ-
butyrolactone-4-yl, carboxyalkylcarbonyloxymethyl having 4 to 12 carbon atoms, or (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl. To produce compounds of formula or in which R ₁ is a group that forms an ester that is hydrolyzed in vivo, an acid of formula or (R ₁ is hydrogen) is reacted with a base to produce the corresponding anion. Particular cations include sodium, potassium, calcium, tetraalkylammonium, and the like. The anion can be prepared by lyophilizing an aqueous solution of or containing, for example, tetrahydrofuran and sodium bicarbonate or tetrabutylammonium hydroxide. or the resulting anion of R ₁
react with the symmetrical chloride or bromide of Compounds of the formula or salts thereof where R ₁ is hydrogen can be synthesized according to Schemes AC. As shown in Scheme A, a compound of formula
Yoshida et al., Chem.Pharm.Bull., 29 , 2899~
2909 (1981) from the known dibromopenem of formula. Dibrompenem (V)
undergoes the exchange reaction with t-butylmagnesium chloride in a reaction-inert solvent such as tetrahydrofuran, diethyl ether or toluene, preferably tetrahydrofuran, at a temperature of about -90 to -40°C, preferably about -76°C. . Other organometallic reagents can also be used. The resulting reaction mixture is treated in situ with a suitable aldehyde, for example acetaldehyde for the 1-hydroxyethyl derivatives. The aldehyde is added at about -80 to 60<0>C in the case of acetaldehyde, preferably about -76<0>C. The resulting bromohydroxypenem V is hydrogenated to remove the 6-bromo substituent. Suitable hydrogenation catalysts are noble metal catalysts such as palladium. This reaction is carried out in a protic solvent such as 1:1 methanol-
It is carried out in water or 1:1 tetrahydrofuran-water, preferably 1:1 methanol, at a pressure of about 1 to 4 atmospheres and a temperature of about 0 to 30°C, preferably 25°C. The resulting alcohol of Eq. It can be protected with a trialkylhalosilane in which R ₉ is in each case alkyl having 1 to 6 carbon atoms and Q is chloro, bromo or iodo. That is, in the presence of an amine proton acceptor in a polar neutral solvent such as N,N-dimethylformamide,
At about 5 DEG to 40 DEG C., preferably about 25 DEG C., dimethyl-t-butylchlorosilane provides the hydroxyl protecting group of the trialkylsilyl as shown in the formula. Treatment with mercuric acetate in acetic acid at a temperature of about 90°C produces olefins. To obtain the desired azetidinone, the olefin is ozonated in a solvent inert to the reaction at a temperature of about -80 DEG to 40 DEG C., preferably -76 DEG C. This reaction product is treated with an alkanol such as methanol to produce azetidine. As shown in Scheme B, a compound of formula
R ₁₀ is alkyl having 1 to ₄ carbon atoms, ^preferably ethyl, and M is sodium or potassium. Obtain the compound. This conversion to is carried out in an organic solvent or in water, preferably in a mixture of water and dichloromethane, at a temperature of about 0 DEG to 35 DEG C., preferably about 25 DEG C. A compound of formula is condensed with nitrobenzyl chlorooxalate in the presence of a tertiary alkylamine in which each alkyl has 1 to 4 carbon atoms, such as ethyl-di-isopropylamine, to give a compound of formula. This condensation reaction is carried out in a reaction-inert solvent, preferably dichloromethane, at a temperature of about 5-25°C, preferably at about 10°C.
It is carried out at a temperature of °C. The resulting compound of formula is cyclized using a trialkyl phosphite in which the alkyl group has 1 to 4 carbon atoms, such as triethyl phosphite, in a reaction-inert solvent such as trichloromethane at about 40 to 80°C, preferably about 60°C. By converting the formula into Panem. The thiol group of the compound is oxidized to the corresponding sulfoxide with an oxidizing agent such as m-chloroperbenzoic acid at a temperature of about -10 to -30°C, preferably -20°C in a reaction-inert solvent such as dichloromethane. . The sulfoxide is then dissolved in a polar organic solvent such as ethanol or acetonitrile at about 35%
At a temperature of ~-50°C, preferably about -35°C,
Substitution with mercaptides of formula R-S is achieved by using sodium or potassium salts that react with sulfoxides. Starting mercaptan of formula R-SH or formula R-S-
The starting thioacetate of C(O)CH ₃ is known for many values of R, and those not known can be prepared by analogous methods known in the art. For a review, see “Preparation of
Thiols” (edited by S. Patai, The Chemistry of the
Thiol Group, John Wiley & Sons,
London, 1974, Chapter 4). Further, for the conversion of alcohols to thiols and thiol esters by using triphenylphosphine and dialkyl azodicarboxylates in the presence of alcohols and appropriate thiol acids:
Volante, Tetrahedron Letters, 22 , 3119~
See 3122 (1981). When the R group contains an S(O)n group and n is 1 or 2, the corresponding sulfide (n is 0) thioacetate R-S-C(O) _CH3 is added in a suitable equimolar amount of m - Can be oxidized with chloroperbenzoic acid to the sulfoxide (n=1) or with m-chloroperbenzoic acid to the sulfone (n=2) without further oxidation of the sulfur of the thioacetate. The sulfoxide may also be oxidized to the sulfone with potassium permanganate at about 20-25°C, preferably about 25°C, in an aqueous solvent, such as aqueous acetone, buffered to a pH of about 7. This method is particularly suitable for R groups containing hydroxyl groups. Furthermore, cyclic sulfones containing double bonds are Prochazka
et al., Collection Czech.Chem.Comm., 31 , 3744
(1966) can be easily isomerized. For compounds of formula, the trialkylsilyl group is preferably removed prior to hydrogenolysis to remove the acid protecting group (PNB) to provide a compound of formula. The trialkylsilyl group can be removed with a tetraalkylammonium fluoride in an ethereal solvent such as tetrahydrofuran at a temperature of about 15-40°C, preferably about 25°C. Conversion of compounds of formula to compounds of formula is accomplished using conventional hydrogenolysis reactions, which are carried out in a manner conventional for this type of conversion. That is, a solution of a compound of the formula is mixed with hydrogen or an inert diluent such as nitrogen or argon in an atmosphere of hydrogen and a catalytic amount of a noble metal hydrogenolysis catalyst, such as palladium-supported calcium carbonate or palladium-supported celite (diatomaceous earth). Stir or shake in the presence of catalyst. Common 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. However, it is common to choose conditions such that the starting materials are soluble. Hydrogenolysis is usually carried out at room temperature and from about 0.5 to about 5 Kg/cm ²
It is carried out at a pressure of The catalyst is normally present in an amount from about 10% by weight based on the starting material to an amount equal to the weight of the starting material, although larger amounts may be used. The reaction usually takes place for about 1 hour and then the compound of formula is recovered by simple filtration and the solvent is then removed under vacuum. When palladium-supported calcium carbonate is used as a catalyst, the product is often separated as the calcium salt, and when palladium-supported celite is used, the product is often separated as the sodium salt. Compounds of formula or can be purified using conventional methods for β-lactam compounds. For example, a compound of formula or can be purified by column chromatography, gel filtration on Sephadex, or recrystallization. An alternative synthesis method is shown in Scheme C. In this case, an azetidine of the formula M ⁺ R, where M is a metal such as sodium or potassium, can be prepared by using the method described above to prepare an azetidine of the formula M + R
-S-C(S)-S''. The resulting trithiocarbonate a is reacted in a neutral solvent such as benzene, toluene or dimethylformamide, preferably benzene, at about 25-110°C.
Treatment with (p-nitrobenzyloxycarbonyl)(dihydroxy)methane, preferably at a temperature range of about 80°C, provides the alcohol of formula. The corresponding chloride is prepared from thionyl chloride in an organic solvent inert to the reaction, such as dichloromethane, in the presence of a sterically hindered amine, such as 2,6-lutidine, which serves as the acid acceptor, at about -10 to 75°C, preferably 0°C. It is produced from alcohol by treatment with By reacting this chloride with a triarylphosphine such as triphenylphosphine in the presence of a tertiary amine such as 2,6-lutidine in a reaction-inert solvent such as tetrahydrofuran at a temperature of about 25°C, a compound of formula obtained,
This is cyclized by refluxing in an aromatic solvent such as toluene to produce the penem of formula. Trithiocarbonate salts of formula M ⁺ R-S-(C=S)-S ^- can be prepared from appropriate mercaptans of formula R-SH or from thioacetates of formula RSC(O) _CH3 with alkali metal alkoxides followed by Produced by treatment with carbon disulfide. If we use the method previously mentioned by Yoshida et al.
The stereochemistry at carbon 6 of penem and the hydroxyethyl group attached to carbon 6 is as shown in the formula. The predominant stereochemistry for the products of ring closure using Schemes B or C is that penem ring position 5 is in the trans and alpha configuration to the hydrogen at carbon 6. This stereochemistry is 5R, 6S; 6-
It can be written as (R)-1-hydroxyethyl. Compounds of formula or are acidic and will form salts with basic agents. Such salts are standard technology,
For example, acidic and basic components, if appropriate aqueous,
It can be prepared by contacting in a non-aqueous or partially aqueous medium. It is then recovered by filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent or, in the case of an aqueous solution, lyophilization. Basic reagents suitably used in the formation of salts belong to both organic and inorganic classes and include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, and alkaline earth metal hydroxides. Includes oxides, carbonates, hydrides and alkoxides. Representative examples of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine;
Secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, N-ethylpiperidine, N
- methylmorpholine and 1,5-diazebicyclo[4.3.0]non-5-ene; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides such as sodium ethoxide and potassium ethoxide ;
Hydrides such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long chain fatty acids such as sodium 2-ethylhexanoate. Preferred salts of compounds of formula or are sodium,
Potassium and calcium salts. Pharmaceutically acceptable salts are those in which the resulting compound of formula or is non-toxic, useful as a therapeutic agent, and provides non-toxic metabolic breakdown products. As mentioned above, compounds of formula or and salts thereof are antibacterial agents. The in vitro activity of a compound of formula or and its salts can be demonstrated by determining its minimum inhibitory concentration (MIC) in mcg/ml against various microorganisms. The method used is
International Collaborative Study on
Antibiotic Sensitivity Testing (Ericcson and
Sherris, Acta. Pathologica et Microbiologia
Scandinar, Supp. 217, Section B: 64-68
(1971)) and uses brain heart infusion (BHI) agar and inoculum propagators. The overnight grown tube is diluted 100 times for use as a standard inoculum (20,000-10,000 cells in 0.002 ml of drug are placed on the agar surface; 20 ml of BHI agar/dish). The initial concentration of the test compound is 200 mcg/ml, which is diluted 2 times. Single colonies were ignored when reading plates after 18 hours at 37°C. The test organism sensitivity (MIC) is the lowest concentration of a compound that can produce complete inhibition of growth as judged by the naked eye.
Compounds of formula or and their pharmaceutically acceptable salts are suitable for controlling bacterial infections in mammals, including humans. They are useful in the control of infections caused by susceptible bacteria, such as susceptible species of Staphylococcus aureus, in human subjects. When a compound of formula or a pharmaceutically acceptable salt thereof is used to treat a bacterial infection in a mammalian subject, it may be administered orally or parenterally, i.e. intramuscularly, subcutaneously, intraperitoneally. It may be administered intravenously or intravenously. The compounds may be administered alone or in accordance with standard pharmaceutical techniques.
It may also be combined with a pharmaceutically acceptable carrier.
The proportion of active ingredient and carrier will, of course, depend on the chemical nature, solubility and stability of the active ingredient and on the intended dosage. However, for pharmaceutical compositions containing the antibacterial agents of the present invention, the ratio of pharmaceutically acceptable carrier to penem compound is typically 1:10.
~4:1. For oral administration, the antibacterial penem compounds of the present invention are used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that can be used are lactose, sodium citrate and phosphoric acid salts. Various disintegrants such as starches and lubricants such as magnesium stearate, sodium lauryl sulfate and talc are also commonly used in tablets. For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. Optionally, certain sweetening and/or flavoring agents can also be added. For parenteral administration, sterile solutions of the active ingredient are commonly prepared and the pH of the solution suitably adjusted and buffered. For intravenous use, the total concentration of solutes is adjusted to render the preparation blood isotonic. As mentioned above, compounds of formula or are useful as antibacterial agents against sensitive organisms in human subjects. Doctors treat human objects,
Ultimately, the appropriate dosage will be determined;
It is believed that this may vary according to the age, weight and response of the individual patient, as well as the type and severity of the patient's infection. Compounds of formula or usually have about 10
It is used orally in dosages ranging from about 200 mg/Kg body weight/day and parenterally in dosages ranging from about 10 to about 400 mg/Kg body weight/day. However, these numbers are merely exemplary, and in some cases it may be necessary to use dosages outside these ranges. The following examples and preparations are presented merely for further illustration. Infrared (IR) spectra are measured as potassium bromide tablets (KBr tablets), Nudiol, or solutions in chloroform (CHCl ₃ ), methylene chloride (CH ₂ Cl ₂ ), or dimethyl sulfoxide (DMSO), and characteristic absorption bands are determined. Micron or wavenumber (cm ^-
Report in ¹ ). Nuclear magnetic resonance (NMR) spectra are shown in deuterium chloroform (CDCl ₃ ), unless otherwise specified.
Measurements were taken at 60 MHz for solutions in heavy water (D ₂ O) or deuterated dimethyl sulfoxide (DMSO-d ₆ ) or mixtures thereof, and peak positions are given in ppm downfield from tetramethylsilane. The following abbreviations are used for this peak shape: s,
Single line; d, double line; t, triplet; q, quartet;
m, multiplet; b, brolo; c, complex. The abbreviations "ss" and "sss" indicate that the particular proton appears as two or three single lines, respectively, due to the presence of diastereomers. Throughout the Examples and Preparations, the abbreviation "PNB" represents p-nitrobenzyl group. Example 1 Sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,1-dioxo-3-thiolanyl)thio-2-penem-3-carboxylate 10% palladium supported Suspension of diatomaceous earth (350 mg) in 75 ml of tetrahydrofuran + 75 ml of distilled water
The pH was adjusted to 8.3 with 0.02M aqueous sodium bicarbonate. Then (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,1-dioxo-3-thiolanyl)thio-2-penem-3-carboxylic acid p-
Nitrobenzyl 350 mg, Tetrahydrofuran 50
ml and a solution in 50 ml of water were added and the resulting mixture was hydrogenated under 55 psi of hydrogen for 75 minutes;
mg was added and the pH of the suspension was adjusted to 7.0 using 0.02M aqueous sodium bicarbonate. This mixture was hydrogenated under 55 psi for 75 minutes, the catalyst was removed, and
The liquid was concentrated under vacuum to remove tetrahydrofuran. The pH of the resulting aqueous solution was adjusted to 7, and the solution was extracted twice with 100 ml each of ethyl acetate. The aqueous solution was then lyophilized to yield 224 mg of the title compound as an amorphous solid (82.5% yield). The infrared spectrum of the title compound as a KBr tablet showed absorptions at 2.92, 5.65 and 6.3 microns. Example 2 The method of Example 1 was followed using the corresponding compound of formula to obtain the corresponding sodium salt of formula.
Table 1 shows the R groups of the formula together with the infrared absorption of the products as KBr tablets unless otherwise stated.

[Table] Example 3 (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(cis-1-oxo-4-thianyl)
-thio-3-carboxyl-2-penem palladium-supported celite (10%, 3.00 g),
Pre-hydrogenated in a solution of tetrahydrofuran (130 ml) and water (120 ml) under 60 psi for 10 minutes. The pH was adjusted to 7.5 with 1N hydrochloric acid, then (5R,
6S)-6-[(R)-1-hydroxyethyl]-2-
(cis-1-oxo-4-thianyl)thio-2-
p-nitrobenzyl penem-3-carboxylate 6.20
g (12.4 mmol) and the slurry was hydrogenated for 0.5 h. The PH was adjusted to 7.0 for two additions of catalyst (3.00 g) and the reaction mixture was hydrogenated for 0.75 h. The last of the catalyst was added, the PH was adjusted to 7.3, and the reaction mixture was hydrogenated for 1.5 hours. The reaction mixture was passed through a bed of Celite and washed with additional tetrahydrofuran-water (1:1). The tetrahydrofuran was removed under vacuum. Insoluble matter was separated through Celite, and the pH of the liquid was adjusted to 7.0. The aqueous portion of the solution was washed twice with ethyl acetate, concentrated to remove residual ethyl acetate, cooled in an ice bath, and the pH was adjusted to 2.3 with 6N hydrochloric acid. After 30 minutes, the precipitated solid was collected by filtration. This precipitate was dried under vacuum to constant weight and the title compound 3.64
g (yield 81%), melting point 149-151℃, [α] _D
(DMSO): Obtained as a mustard yellow solid at 153°. The nmr spectrum (250MHz) of a solution of the title compound in deuterated dimethyl sulfoxide showed a peak at the following position (ppm). 1.16 (d, J = 6.2Hz, 3H), 1.95−2.3 (m,
4H), 2.7-3.0 (m, 4H), 3.3-3.4 (m, 1H),
3.79 (dd, J=6.1, 1.4Hz, 1H), 3.98 (m, 1H),
5.20 (bs, 1H) and 5.71 (d, J = 1.4Hz, 1H).
The infrared spectra of the title compound as a KBr tablet are 2950(b), 2923, 1782, 1678, 1508,
1400, 1294, 1216, 1197, 1131, 949 and 935 cm ^-1
showed absorption. The UV spectrum of a solution of the title compound in dimethyl sulfoxide showed the following absorption maxima (extinction coefficients in parentheses): 267 (4840) and 337
(6720) nm. Example 4 (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(cis-1-oxo-4-thianyl)
Sodium thio-2-penem-3-carboxylate The title compound of Example 3 (5.09 g, 14.0 mmol) was suspended in 75 ml of water and cooled in an ice bath. The PH of the reaction mixture was adjusted to 7.00 by the addition of 1,00N aqueous sodium hydroxide (13.0 ml, 93% of theory). The homogeneous solution was lyophilized overnight to yield 5.00 g (93% yield) of the title compound as a dark brown solid. [α] _D (H ₂ O): 111.4°. The nmr spectrum (250MHz) of the title compound in D ₂ O showed a peak at the following position: 1.29
(d, J=6.4Hz, 3H), 2.1−2.4 (m, 4H), 2.8−
3.0 (m, 2H), 3.1-3.25 (m, 2H), 3.42 (m,
1H), 3.91 (dd, J=5.9, 1.0Hz), 1H), 4.24
(qd, J=6.4, 5.9, 1H) and 5.67 (d, J=1.0
Hz, 1H) ppm. The infrared spectra of the title compound as a KBr tablet are 3403, 2964, 2917, 1765,
1589, 1514, 1372, 1290, 1126, 1041, 1012,
It showed absorption at 988 and 936 cm ^-1 . The UV spectrum of an aqueous solution of the title compound showed the following absorption maxima (extinction coefficients in parentheses): 259 (5530) and 322
(7260)nm. Example 5 Calcium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(4-thianyl)-thio-2-penem-3-carboxylate 1:1 tetrahydrofuran-5% in water
Using palladium-supported calcium carbonate as a catalyst and (5R,6S)-6-[hydroxyethyl]-2-
Example 1 by using (4-thianyl)thio-2-penem-3-carboxylic acid as starting material
The title compound was obtained in 100% yield by repeating the hydrogenation procedure. The NMR spectrum (2500MHz) of the title compound as a heavy aqueous solution showed peaks at the following positions: 1,29 (3H, d, J = 6.4Hz), 1.7-1.9 (2H,
m), 2.3-2.5 (2H, m), 2.7-2.8 (4H, m),
3.30 (1H, tt), 3.90 (1H, dd, J=6.0, 1.3Hz),
4.24 (1H, m), and 5.65 (1H, d, J = 1.3Hz)
ppm. The infrared spectrum of the title compound as a KBr tablet showed absorptions at 3409, 1770, 1585 and 1385 cm ^-1 . Example 6 p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,1-dioxo-4-thianyl)thio-2-penem-3-carboxylate By following the method of Example 5 using as starting material, (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,1-dioxo-4-thianyl)thio-2- Calcium penem-3-carboxylate was obtained with a yield of 93%. The NMR spectrum of the product as a heavy aqueous solution showed peaks at the following positions: 1.29 (3H, d), 2.15
−2.4 (2H, m), 2.4−2.65 (2H, m), 3.2−3.45
(4H, m), 3.61 (1H, m), 3.95 (1H, dd), 4.26
(1H, m), and 5.68 (1H, d) ppm. The infrared spectrum of the product as a KBr tablet is
It showed absorption at 3421, 1767, 1588, 1382, 1286 and 1112 cm ^-1 . Similarly, (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(trans-1-oxo-4-thianyl)thio-2-penem-3-carboxylic acid p-
Following the method of Example 5 using nitrobenzyl as a starting material, (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(trans-1-oxo-4-thianyl)thio-2-penem Calcium -3-carboxylate was obtained with a yield of 81%. The infrared spectra of KBr tablets of this product are 1769, 1592, 1511, 1383,
It showed absorption at 1294, 1131 and 1021 cm ^-1 . NMR spectrum of heavy aqueous solution of product (250M
Hz) showed a peak at the following positions: 1.29 (3H,
d, J = 6.3Hz); 1.85-2.1 (2H, m); 2.45-2.65
(2H, m); 2.85-3.0 (2H, m); 3.15-3.4 (2H,
m); 3.63 (1H, m); 3.93 (1H, dd, J=6.1
Hz); 4.26 (1H, qd, J=6.3, 6Hz; and 5.68
(1H, d, J = 1Hz) ppm. Example 7 Sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(cis)-1-oxo-3-thiolanyl)thio-2-penem-3-carboxylate Tetrahydrofuran 100ml and in 25 ml of water (5R,
6S)-6-[(R)-1-hydroxyethyl-2-
[(cis)-1-oxo-3-thiolanyl]thio-
p-nitrobenzyl 2-penem-3-carboxylate
To the 6.0 g solution was added a suspension of 3.0 g of 10% palladium on diatomaceous earth in 100 ml of water, then the pH was adjusted to 7.4 and 25 ml of tetrahydrofuran was added. The resulting mixture was hydrogenated under 60 psi of hydrogen for 10 minutes, an additional 3.0 g of catalyst was added, and the PH of the mixture was adjusted to 7.3 with dilute aqueous sodium bicarbonate solution. The mixture was hydrogenated at 60 psi for 25 minutes, then another 4.0 g of catalyst was added and the PH of the suspension was adjusted to 7.4 with dilute aqueous sodium bicarbonate solution. The mixture was hydrogenated at 60 psi for 45 minutes, then the PH was adjusted to 6.9 with aqueous sodium bicarbonate solution and the catalyst was removed by filtration. The liquid was concentrated in vacuo to remove tetrahydrofuran and the aqueous solution was washed with 200 ml of diethyl ether, 200 ml of ethyl acetate and 200 ml of diethyl ether. The solution was filtered and the pH of the solution was adjusted to 7.2. This solution was lyophilized to give the title product
4.3 g (93% yield) was obtained as an amorphous solid. The NMR spectrum (250MHz) of a heavy aqueous solution of the title compound had a peak at the following position: 1.32
(d, 3H); 2.53 (c, 1H); 2.74-3.12 (c,
3H); 3.26 (c, 1H); 3.83-4.09 (c, 3H); 4.27
(m, 1H); and 5.74 (2d, 1H) ppm. The infrared spectrum of the KBr tablet of the title compound is
It showed absorption at 2.93, 5.66 and 6.3 microns. Example 8 Sodium (5R,6S)-6-[(R)-1-hydroxyethyl-2-[(trans)-1-oxo-3-thiolanyl]thio-2-penem-3-carboxylate (5R, Using p-nitrobenzyl 6S)-6-[(R)-1-hydroxyethyl-2-[(trans)-1-oxo-3-thiolanyl]thio-2-penem-3-carboxylate as a starting material and Example 7
The title compound was obtained in 80% yield. The NMR spectrum (250MHz) of a heavy aqueous solution of the title compound had a peak at the following position: 1.32
(d, 3H); 2.27 (m, 1H); 2.78-3.18 (c,
2H); 3.47 (c, 2H); 3.66 (m, 1H); 3.97 (m,
1H); 4.22-4.43 (c, 2H); and 5.74 (d, 1H)
ppm. The infrared spectrum of the KBr tablet of the title compound is
It showed absorption at 2.92, 5.65 and 6.26 microns. Example 9 (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(2-oxo-1,3-dithiolane-
Sodium 4-ylmethyl)thio-2-penem-3-carboxylate A suspension of 110 mg of 10% palladium-supported celite diatomite catalyst in 10 ml of water was adjusted to pH 7. Then (5R,6S)-6-[(R)-
1-hydroxyethyl]-2-(2-oxo-1,
p-Nitrobenzyl 3-dithiolan-4-ylmethyl)thio-2-penem-3-carboxylate 107mg
and the resulting reaction mixture was heated to room temperature and
Hydrogenated at 50 psi for 1 hour. Two more catalyst additions were made at 1 hour intervals. The catalyst was then separated and the liquid was evaporated to remove tetrahydrofuran. The remaining aqueous solution was washed with ethyl acetate and ethyl ether, then filtered. This liquid was freeze-dried to obtain the title compound (60 mg) as a pale yellow powder. IR (KBr): 1600, 1640, and 1778 cm ^-1 . NMR (D ₂ O; 250MHz): 1.29 (3H, d, J=
6); 3.25-3.63 (2H, m); 3.72-4.12 (2H,
m); 4.24 (1H, m); and 5.66 (1H, S) ppm. (Some peaks were blocked by solvent). Example 10 Diastereolysis of sodium (5R,6S)-6-([(R)-1-hydroxyethyl]-2-(1,1-dioxo-3-thiolanyl)thio-2-penem-3-carboxylate Production and separation of mer (5R, 6S)-6-
[(R)-1-t-butyldimethylsilyloxyethyl]-2-(1,1-dioxo-3-thiolanyl)
p-nitrobenzyl thio-2-penem-3-carboxylate was obtained in a yield of 50.8%. The two diastereomers of the product were separated by column chromatography on silica gel by eluting with 1:1 ethyl acetate/hexanes. The less polar diastereomer is 46.5%
It was obtained in a yield of 160.5-162°C and had a melting point of 160.5-162°C.
The infrared spectrum of this KBr tablet is 5.62,
It had absorptions at 5.97, 6.56, and 6.74 microns, and its NMR spectrum as a deuterated chloroform solution had peaks at the following positions. 0.03(s,
3H); 0.07 (s, 3H); 0.81 (s, 9H); 1.25 (d,
3H); 2.28 (m, 1H); 2.76 (m, 1H); 3.12 (c,
2H); 3.34 (m, 1H); 3.58 (m, 1H); 3.79 (m,
1H); 3.98 (m, 1H); 4.28 (m, 1H); 5.32 (q,
2H); 5.71 (d, 1H); 7.6 (d, 2H); and 8.21
(d,2H) ppm. The more polar isomer was obtained in 40.3% yield and had a melting point of 181.5-182°C. The infrared spectrum of this KBr tablet had absorptions at 5.62, 5.9, 6, 6, and 6.67 microns, and the NMR spectrum (250MHz) of the deuterated chloroform solution had a peak at the following positions: 0.02 (s, 3H); 0.05
(s, 3H); 0.82 (s, 9H); 1.24 (d, 3H), 2.24
(m, 1H); 2.71 (m, 1H); 3.14 (c, 2H); 3.33
(m, 1H); 3.37 (m, 1H); 3.78 (m, 1H); 3.97
(m, 1H); 4.28 (m, 1H); 5.32 (q, 2H); 5.72
(d, 1H); 7.61 (d, 2H); and 8.21 (d, 2H)
ppm. (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,1-dioxo-3-thiolanyl)thio-2-penem from the less polar diastereomer of the silyl ether -3-carboxylic acid p
-Diastereomer of nitrobenzyl The less polar silyl ether was reacted according to Preparation A to give the corresponding 1-hydroxyethyl compound: mp 172-173°C, yield 80%, this product The infrared spectrum of KBr tablet is 5.63,
It showed absorption at 5.94, 6.6 and 6.68 microns. The NMR spectrum (250MHz) of deuterochloroform/deuterium dimethyl sulfoxide of this product had peaks at the following positions: 1.32 (d, 3H); 2.3 (m,
1H); 2.76 (m, 1H); 3.15 (c, 2H) 3.34 (m,
1H); 3.59 (m, 1H); 3.78 (m, 1H); 4.09 (c,
2H), 5.1 (d, 1H); 5.36 (q, 2H); 5.77 (d,
1H); 7.65 (d, 2H); and 8.22 (d, 2H) ppm. (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,1-dioxo-3-thiolanyl)thio-2-penem from the more polar silyl ether diastereomer -3-carboxylic acid p
-Diastereomer of nitrobenzyl The more polar silyl ether was reacted according to Preparation A to give the corresponding 1-hydroxyethyl compound: mp 175-176°C, yield 76%, product The infrared spectrum of KBr tablet is 2.86,
It showed absorption at 5.6, 5.93, 6.59 and 6.68 microns. Also, the NMR spectrum (250MHz) of deuterium chloroform/deuterium dimethyl sulfoxide of this product
had a peak at the following position: 1.34(d,3H);
2.25 (m, 1H); 2.69 (m, 1H); 3.16 (c, 2H);
3.35 (m, 1H); 3.71 (m, 1H); 3.78 (m, 1H);
4.03 (m, 1H); 4.16 (m, 1H); 4.88 (d, 1H);
5.35 (q, 2H); 5.78 (d, 1H); 7.64 (d, 2H);
and 8.23(d,2H)ppm. Diastereomers of the title compound derived from the less polar silyl ether diastereomer. Diastereomers of p-nitrobenzyl 1-hydroxyethyl derived from the less polar silyl ether diastereomer were prepared in Example 1. diastereomers of the title compound by reacting according to
Obtained with a yield of 96%. The infrared spectrum of KBr tablets of this product showed absorptions at 2.93, 5.65 and 6.29 microns. Also, NMR of a heavy aqueous solution of this product
The spectrum (250MHz) had peaks at the following positions: 1.39 (d, 3H); 2.45 (m, 1H); 2.86 (m,
1H); 3.38 (c, 2H); 3.56 (m, 1H); 3.82 (m,
1H); 4.06 (m, 1H); 4.25 (m, 1H); 4.36 (m,
1H); and 5.82 (d, 1H) ppm. Diastereomer of the title compound derived from the more polar silyl ether diastereomer The diastereomer of p-nitrobenzyl 1-hydroxyethyl obtained from the more polar silyl ether diastereomer was prepared in Example 1. diastereomers of the title compound by reacting according to
Obtained with a yield of 95.5%. The infrared spectrum of KBr tablets of this product showed absorptions at 2.94, 5.66 and 6.27 microns. Also, NMR of a heavy aqueous solution of this product
The spectrum (250MHz) had peaks at the following positions: 1.35 (d, 3H); 2.3 (m, 1H); 2.76 (m,
1H); 3.44 (c, 3H); 3.88 (m, 1H); 3.99 (m,
1H); 4.19 (m, 1H); 4.32 (m, 1H); and 5.76
(d, 1H) ppm. Example 11 (5R,6S)-6-[(R)-1-t-butyldimethylsiloxyethyl]-2-[(cis)-3-hydroxy-4-thiolanyl]thio-2-penem-
Preparation, separation and conversion of diastereomers of p-nitrobenzyl 3-carboxylate Absolute ethanol cooled to -30°C under nitrogen 10
A 1M solution of sodium ethoxide in ethanol (0.002 mol) to a solution of 0.272 g (0.002 mol) of cis-4-hydroxythiolanyl-3-thiol in ml.
2 ml was added. After stirring for 30 minutes at -30°C, the solution was cooled to -60°C and then (5R,6S)-6 in 30 ml of tetrahydrofuran, which had been cooled to -60°C.
-[(R)-1-t-butyldimethylsiloxyethyl]-2-ethylsulfinyl-2-penem-3
- p-nitrobenzyl carboxylate 1.08g (0.002
mol) solution was added. After 15 minutes at −60°C, a solution of 0.5 ml of acetic acid in 3 ml of tetrahydrofuran was added,
The resulting solution was warmed to 25°C and concentrated under vacuum. Dissolve this residue in ethyl acetate (100ml),
The resulting solution was washed with 20 ml of water, 20 ml of saturated aqueous sodium bicarbonate solution, 20 ml of water, 20 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was applied twice to a column of silica gel (250 g and 400 g each).
By eluting with 60:40 hexane-ethyl acetate, 0.4 g of the less polar diastereomer (diastereomer A), 0.56 g of the more polar diastereomer (diastereomer B) and diastereomer Obtained 0.12 g of a mixture of (total yield
90.7%). Diastereomer A IR (KBr tablet): 2.86, 5.64, 6.0, 6.55 and 6.75
micron. NMR ( _CDCl3 , 250MHz): 0.04 (s, 3H); 0.07
(s, 3H); 0.83 (s, 9H); 1.25 (d, 3H); 2.47
(d, 1H); 3.0 (m, 2H); 3.15 (m, 2H); 3.68
(m, 1H); 3.78 (dd, 1H); 4.28 (m, 1H); 4.65
(m, 1H); 5.34 (q, 2H); 5.67 (d, 1H); 7.64
(d, 2H); and 8.22 (d, 2H) ppm. Diastereomer B IR (KBr tablets): 2.86, 5.59, 5.94, 6.59 and 6.68
micron. NMR (CDCl ₃ , 250MHz): 0.04 (s, 3H); 0.07
(s, 3H); 0.83 (s, 9H); 1.25 (d, 3H); 2.35
(d, 1H); 3.02 (m, 2H); 3.2 (m, 2H); 3.67
(m, 1H); 3.75 (dd, 1H); 4.28 (m, 1H); 4.59
(m, 1H); 5.34 (q, 2H); 5.67 (d, 1H); 7.62
(d, 2H); and 8.21 (d, 2H); ppm. (5R,6S)-6 derived from diastereomer A
-[(R)-1-hydroxyethyl]-2-[(cis)
-3-hydroxy-4-thiolanyl]thio-2-
By using P-nitrobenzyl penem-3-carboxylate diastereomer A as a starting material and following the method of Preparation A, melting point 187-189
The title diol compound was obtained in 63.4% yield at °C (decomposition). IR (KBr tablets); 2.83, 2.90, 5.61, 5.96, 6.58 and 6.71 microns. NMR (DMSO-d ₆ , 250MHz): 1.28 (d,
3H); 2.74 (dd, 1H); 2.96 (dd, 1H); 3.13 (m,
2H); 3.63 (m, 1H); 3.89 (dd, 1H); 4.02 (m,
1H); 4.54 (m, 1H); 5.24 (d, 1H); 5.36 (q,
2H); 5.74 (d, 1H); 5.81 (d, 1H); 7.69 (d,
2H); and 8.24 (d, 2H) ppm. (5R,6S)-6 derived from diastereomer B
-[(R)-1-hydroxyethyl]-2-[(cis)
-3-hydroxy-4-thiolanyl]thio-2-
By using p-nitrobenzyl penem-3-carboxylate diastereomer B as a starting material and following the method of Preparation A, melting point 206-207
The title diol compound was obtained in 77.3% yield at °C (decomposition). IR (KBr tablets 2.86, 2.91, 5.63, 5.98, 6.57 and
6.77 microns. NMR (DMSO-d ₆ , 250MHz); 1.17 (d,
3H); 2.73 (dd, 1H); 2.93 (dd, 1H); 3.1 (dd, 1H); 3.29 (m, 1H); 3.64
(m, 1H); 3.86 (dd, 1H); 4.02 (m, 1H); 4.5
(m, 1H); 5.24 (d, 1H); 5.37 (q, 2H); 5.77,
(d, 1H); 5.79 (d, 1H); 7.69 (d, 2H); and
8.24(d,2H)ppm. (5R,6S)-6- derived from diastereomer A
[(R)-1-hydroxyethyl]-2-[(cis)-
Sodium 3-hydroxy-4-thiolanyl]thio-2-penem-3-carboxylate (5R,6S)-6 derived from diastereomer A
-[(R)-1-hydroxyethyl]-2-[(cis)
-3-hydroxy-4-thiolanyl]thio-2-
Following the method of Example 1 using p-nitropenzyl penem-3-carboxylate as a starting material, the sodium salt of the corresponding formula was obtained in 90% yield. IR (KBr tablets): 293, 5.65 and 6.31 microns. NMR (DO, 250MHz): 1.32 (d, 3H); 2.92
(m, 2H); 3.22 (m, 2H); 3.78 (m, 1H); 3.95
(dd, 1H); 4.27 (m, 1H); 4.71 (m, 1H); and
5.7(d,1H)ppm. (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(cis)-3-hydroxy-4-thiolanyl]thio-2-penem-3-carvone derived from diastereomer B (5R,6S)-6 derived from diastereomer B
-[(R)-1-hydroxyethyl]-2-[(cis)
-3-hydroxy-4-thiolanyl]thio-2-
Following the method of Example 1 using p-nitropenzyl penem-3-carboxylate as a starting material, the sodium salt of the corresponding formula was obtained in 87% yield. IR (KBr); 2.93, 5.65, and 6.29 microns. NMR ( _D2O , 250MHz): 1.32 (d, 3H): 2.94
(m, 2H): 3.2 (dd, 1H): 3.34 (dd, 1H): 3.78
(m, 1H): 3.94 (dd, 1H): 4.27 (m, 1H): 4.66
(m, 1H): and 5.71 (d, 1H) ppm. (5R, 6S)
-6-[(R)-1-t-butyldimethylsilyloxymethyl]-2-(1-oxo-3-hydroxy-
Preparation and isolation of p-nitropenzyl 4-thiolanyl)thio-2-penem-3-carboxylate In a solution of 0.46 g (0.77 mol) of diastereomer B in 40 ml of methylene chloride cooled to -25° C. under nitrogen,
m-chloroperbenzoic acid (85%) in 20 ml of methylene chloride
0.142 (0.77 mmol) was added dropwise over 15 minutes. After the addition is complete, store the solution at −25°C.
Stir for 10 minutes, then add 40 ml of methylene chloride and 20 ml of water.
ml was added, any excess peracid was destroyed with sodium bisulfite, and the PH of the mixture was adjusted to 7.5 with saturated aqueous sodium bicarbonate solution. The methylene chloride layer was separated, washed with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel (250 g), 92.5:
7.5 Elute with ethyl acetate-methanol and extract 0.136 g of the less polar sulfoxide (isomer E).
(Yield 28.8%) and 0.210 g (44.5%) of the more polar sulfoxide (isomer F) were obtained. Simultaneously, diastereomer A was oxidized with m-chloroperbenzoic acid to produce 0.112 g (38%) of the less polar sulfoxide (isomer C) and 0.18 g (61.2 g) of the more polar sulfoxide (isomer D). %) was obtained. Infrared spectra for isomers C to F
It was measured as a KBr tablet and the NMR spectrum was measured as a deuterated dimethyl sulfoxide solution at 250MHz. The results are shown in Table 2.

【table】

[Table] Corresponding (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-oxo-3-hydroxy-4-thiolanyl)thio-2-penem-3-carboxylic acid p - Isomers C to F of nitropenzyl isomers
Preparation Example A using isomers C to F as starting materials
The corresponding compound of formula XV was obtained according to the method of
As shown in FIG. 3, the infrared spectrum was measured as a KBr tablet, and the NMR spectrum was measured as a deuterated dimethyl sulfoxide solution. Melting points were accompanied by decomposition in all cases.

【table】

[Table] (5R,6S)-6- derived from isomers C to F
[(R)-1-hydroxyethyl]-2-(1-oxo-3-hydroxy-4-thiolanyl]thio-2
Preparation of isomers of sodium -penem-3-carboxylate The sodium salt of the compound of the corresponding formula was obtained according to the method of Example 1 using the compound of XV obtained from the corresponding isomers C to F as starting material. . In Table 4, the infrared spectra are shown as potassium bromide tablets and the NMR spectra (250M
Hz) was determined as a solution in heavy water for product compounds of the formula derived from isomers C to F, respectively.

【table】

[Table] (5R,6S)-6-[(R)-1-t-butyldimethylsilyloxy]-2-(1,1-dioxo-cis-3-hydroxy-4-thiolanyl]thio-2-
Preparation of diastereomers of p-nitropenzyl penem-3-carboxylate 25 ml of acetone, 5 ml of water and PH buffer (K ₂
HPO ₄ /NaOH, 0.05M) 0.12 g of isomer F in 5 ml
(0.195 mmol) of potassium permanganate in 30 ml of water.
Added dropwise over a period of minutes. Starting material was present in the reaction mixture as analyzed by thin layer chromatography. Then, an additional 4 mg of potassium permanganate dissolved in 1 ml of water was added. The acetone was then removed under vacuum and the aqueous layer was dissolved in 50 ml of ethyl acetate.
Extracted three times. The combined ethyl acetate extracts were washed with two 30 ml portions of water and 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate,
Concentrated under vacuum. This residue was dissolved in silica gel (50
0.1 g of the corresponding sulfone (diastereomer H) (yield
81%) was obtained as a light yellow foam. Similarly, 95 mg of isomer D was oxidized with potassium permanganate to give the corresponding sulfone (diastereomer G) 76
mg (78%). Diastereomeric G IR (KBr tablets): 2.88, 5.59, 5.58, 6.57 and 6.75 microns. NMR (CDCl _S 250MHz): 0.04 (s, 3H); 0.07
(s, 3H); 0.83 (s, 9H); 1.26 (d, 3H); 3.22
(b, 1H); 3.44 (c, 4H); 3.84 (dd, 1H); 4.04
(m, 1H); 4.28 (m, 1H); 4.73 (m, 1H); 5.34
(q, 2H); 5.68 (d, 1H); 7.63 (d, 2H); and
8.23 (d, 2H) ppm. Diastereomer H IR (KBr tablets): 2.88, 5.58, 5.91 and 6.58 microns. NMR (CDCl _S , 2.50MHz): 0.04 (s, 3H); 0.07
(s, 3H); 0.83 (s, 9H); 1.26 (d, 3H); 3.08
(b, 1H); 3.46 (c, 4H); 3.79 (dd, 1H); 4.02
(m, 1H) / 4.28 (m, 1H); 4.74 (m, 1H); 5.33
(q, 2H); 5.75 (d, 1H); 7.62 (d, 2H); and
8.22 (d, 2H) ppm. (5R,6S)-6-[(R)-1-hydroxyethyl]
-2-(1,1-dioxo-cis-3-hydroxy-4-thiolanyl)thio-2-(1,1-dioxo-cis-3-hydroxy-4-thiolanyl)
Preparation of diastereomers of p-nitropenzyl thio-2-penem-3-carboxylate Following the method of Preparation A using diastereomers G and H as starting materials, the corresponding compounds of formula XV were prepared at 64.2 and 59.7, respectively. % yield. Compound of formula XV derived from diastereomer G NMR (DMSO- _d6 , 250MHz); 1.18 (d, 3H);
3.34 (m, 2H); 3.52 (m, 2H); 3.94 (dd, 1H);
4.03 (m, 1H); 4.15 (m, 1H); 4.68 (m, 1H);
5.23 (d, 1H); 5.38 (q, 2H); 5.78 (d, 1H);
6.46 (d, 1H); 7.7 (d, 2H); and 8.25 (d, 2H)
ppm. Compound IR of formula XV derived from diastereomer H (KBr tablets); 2.89, 5.62, 6.00, 6.58, and 6.73
micron. NMR (dMSO-d ₆ , 250MHz); 1.18 (d, 3H);
3.31 (m, 2H); 3.52 (dd, 1H), 3.74 (dd, 1H);
3.9 (dd, 1H); 4.03 (m, 1H); 4.14 (m, 1H);
4.66 (m, 1H); 5.24 (d, 1H); 5.39 (q, 2H);
5.82 (d, 1H); 6.44 (d, 1H); 7.72 (d, 2H);
and 8.25(d,2H)ppm. (5R,6S)-6-[(R)-1-hydroxyethyl]
Preparation of diastereomer of sodium -2-(1,1-dioxosis-3-hydroxy-4-thiolanyl)thio-2-penem-3-carboxylate Using a compound of formula XV derived from diastereomers G and H Following the method of Example 1, the sodium salts of the compounds of the corresponding formulas were prepared at 45.6 and 45.6, respectively.
Obtained with a yield of 69.6%. Compound IR (KBr) of formula derived from diastereomer G; 2.92, 5.64, and 6.29 microns. NMR (D ₂ O, 250MHz); 1.33 (d, 3H); 3.5 (c,
3H); 3.78 (dd, 1H); 3.98 (dd, 1H); 4.26 (c,
2H); 4.62 (m, 1H); and 5.73 (d, 1H) ppm. Compound IR (KBr) of formula derived from diastereomer H; 2.94, 5.65, and 6.34 microns. NMR (D ₂ O, 250MHz); 1.32 (d, 3H); 3.54
(c, 3H); 3.88 (dd, 1H); 3.97 (dd, 1H); 4.27
(c, 2H); 4.63 (m, 1H); and 5.73 (d, 1H)
ppm. Production example A (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,1-dioxo-3-thiolanyl)thio-2-penem-3-carboxylic acid p-nitropenzyl tetrahydrofuran (5R, 6S)-6- in 6ml
[(R)-1-t-butyldimethylsilyloxyethyl]-2-(1,1-dioxo-3-thiolanyl)
Acetic acid was added to a solution of 1.85 mg (0.303 mmol) of p-nitropenzyl thio-2-penem-3-carboxylate.
0.175 ml (3.03 mmol) and a 1M tetrahydroxy solution of tetrabutylammonium fluoride
0.909 ml (0.909 mmol) was added. After stirring for 20 hours under a nitrogen atmosphere, 50 ml of ethyl acetate was added and the resulting solution was dissolved in saturated aqueous sodium bicarbonate.
2.5ml, 25ml water and 2.5ml saturated aqueous sodium chloride
Washed with. The ethyl acetate solution was then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product (1.38 mg) was chromatographed on silica gel (50 g) eluting with 60:40 chloroform-ethyl acetate to give 72 mg (47.5% yield) of the title compound as an amorphous solid. The NMR spectrum of the title compound in deuterated chloroform is 1.35 (d, 3H); 1.9-4.4 (c,
10H); 5.3 (q, 2H); 5.7 (d, 1H); 7.5 (d,
2H); and a peak at 8.18 (d, 2H) ppm. In addition, the infrared spectrum of the title compound in dichloromethane showed absorption at 5.56, 5.92, and 6.57 microns. Preparation Example B Using the method of Preparation Example A, the corresponding compound of formula
It was transformed into. For the products, IR absorption spectra were performed in dichloromethane solution or
NMR spectra were measured in deuterated chloroform solutions unless otherwise specified.

【table】

【table】

[Table] Production example C p-nitropenzyl (5R,6S)-6-[(R)-1-t-butyldimethylsilyloxymethyl]-2-methylsulfinylmethylthio-2-penem-3-carboxylate To a solution of 76 mg (0.5 mmol) of methylsulfinylmethylthioacetate in 5 ml of absolute ethanol cooled to −40° C. under a nitrogen atmosphere was added sodium mexide (27 mg, 0.5 mmol). −40
After 90 minutes at °C, (5R,6S)-6-[(R)-1-t in 5 ml of tetrahydrofuran pre-cooled to -50 °C
A solution of 300 mg (0.5 mmol) of p-nitropenzyl-butyldimethylsilyloxy]ethyl-2-ethylsulfinyl-thio-2-penem-3-carboxylate was added. The resulting solution was stirred at −40° C. for 65 minutes, then 0.029 ml (0.5 mmol) of acetic acid was added and the solution was concentrated under vacuum. The residue was dissolved in 5.0 ml of ethyl acetate and the resulting solution was washed with 2.5 ml of saturated aqueous sodium bicarbonate solution, 2.5 ml of water and 2.5 ml of saturated aqueous sodium chloride solution. The ethyl layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude title product (2.90 mg) was eluted with silica gel (85:20 chloroform-ethyl acetate).
Chromatography under g) gave 120 mg (42% yield) of the product as a sticky gum. An infrared spectrum of a dichloromethane solution of the title compound showed absorptions at 5.58, 5.9 and 5.6 microns. NMR of title compound in deuterated chloroform solution
The spectrum showed the following position peak; 0.03(s,
3H); 0.05 (s, 3H); 0.83 (s, 9H); 1.24 (d,
3H); 2.7 (s, 3H); 3.7-4.22 (c, 4H); 5.28
(q, 2H); 5.68 (d, 1H); 7.56 (d, 2H); and
8.18(d,2H)ppm. Preparation Example D Using the method of Preparation C, compounds of formula X were prepared from the corresponding thioacetates with R as shown in Table 6. Infrared spectra of the products of formula X were taken in dichloromethane solution and NMR spectra in deuterated chloroform unless otherwise stated.

【table】

【table】

【table】

[Table] Production example E (5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-(1-oxo-3
-thiolanyl)thio-2-penem-3-carboxylic acid p-nitrobenzyl -oxo-3-(methylcarbonylthio) in 5 ml of absolute ethanol cooled to -30°C under nitrogen atmosphere
- To a solution of 100 mg (0.552 mmol) of thiolane was added sodium methoxide (30 mg, 0.552 mmol). After 75 minutes at -30°C, (5R, 6S) in 5 ml of tetrahydrofuran pre-cooled to -50°C.
p-nitrobenzyl 6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-ethylsulfinyl-2-penem-3-carboxylate 330 mg
(0.552 mmol) was added. The resulting solution was stirred at -35 to -30 °C for 0 min, then acetic acid
0.032 ml (0.552 mmol) was added and the solution was concentrated under vacuum. This residue was dissolved in 50 ml of ethyl acetate and the solution was subsequently washed successively with 25 ml of saturated aqueous sodium bicarbonate solution, 25 ml of water and saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under vacuum. Chromatography of this crude product (315 mg) on silica gel (100 g) eluting with 925:7.5 ethyl acetate-methanol revealed 53 mg (16%) of the less polar isomer of the title compound and the more polar isomer. 65 mg of the sulfoxide isomer of the title compound (20
%) was obtained. The more polar isomer of the title compound exhibits an infrared spectrum absorbing at 5.56, 5.92 and 6.58 microns for dichloromethane solution and 0.03 (3H) and 10.08 (3H) for deuterium chloroform solution;
0.82 (s, 9H); 1.24 (d, 3H); 1.9-4.4 (c,
9H); 5.28 (q, 2H); 5.68 (d, 1H); 7.6 (d,
2H); and has a peak at 8.2 (d, 2H) ppm
The NMR spectrum is shown. For the less polar isomer of the title compound, the infrared spectrum is
It has absorption at 5.57, 5.92 and 6.57 microns, and
NMR spectrum is for deuterochloroform solution
0.04 (s, 3H); 0.08 (s, 3H); 0.8 (s, 9H);
1.23 (d, 3H); 1.8−4.56 (c, 9H); 5.26 (q,
2H); 5.66 (d, 1H); 7.6 (d, 2H); and 8.2 (d,
2H) It had a peak at ppm. Production example F (5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-(1,1-dioxo-3-thiolanyl)thio-2-penem-3-
p-Nitrobenzyl carboxylate Ethanol cooled to -35°C under nitrogen atmosphere 5
27 mg of sodium methoxide to a solution of 3-sulfolathiol [1,1-dioxo-3-thiolanyl mercaptan) (76 mg, 0.5 mmol) in ml
(0.5 mmol) was added. After 45 minutes at -35°C, anhydrous tetrahydrofuran 5 pre-cooled to -50°C
300 mg (0.5 mmol) of p-nitrobenzyl (5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-ethylsulfinyl-2-penem-3-carboxylate in ml A solution of was added.
The resulting solution was stirred at −35° C. for 60 minutes, then 0.029 ml (0.5 mmol) of acetic acid was added. The solution was concentrated under vacuum and the residue was dissolved in 50 ml of ethyl acetate. The ethyl acetate solution was washed successively with 25 ml of saturated aqueous sodium bicarbonate solution, 25 ml of water and 25 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
The crude product (285 mg) was purified by chromatography on silica gel (100 g) and eluting with 95:5 chloroform-ethyl acetate.
185 mg (60% yield) of the title compound was obtained as a gum. A dichloromethane solution of the title compound is 5.57,
It showed an infrared spectrum with absorption at 5.88 and 6.58 microns. In addition, the NMR spectrum of the title compound in deuterated chloroform solution showed peaks at the following positions: 0.06 (s, 3H); 0.1 (s, 3H); 0.85
(s, 9H); 1.26 (d, 3H); 2.0−4.4 (c, 9H);
532 (q, 2H); 5.72 (d, 1H); 7.6 (d, 2H); and 8.2 (d, 2H) ppm. Production example G (5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-ethylsulfinyl-2-pinem-3-carboxylic acid p-nitrobenzyl under nitrogen atmosphere Methylene chloride cooled to -20℃
(5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-ethylthio- in 125 ml
p-Nitropenzyl 3-penem-3-carboxylate
methylene chloride to a solution of 2.5 g (4.78 mmol)
A solution of 970 mg (4.78 mmol, 85% purity) of m-chloroperbenzoic acid in 2.5 ml was added. The mixture was stirred at -20 DEG C. for 3 hours and then washed twice with 70 ml portions of saturated aqueous sodium bicarbonate solution and successively with 70 ml and 70 ml saturated aqueous sodium chloride solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under vacuum to yield the title compound (2.2 g,
A yellow foam was obtained (yield: 86%). The infrared spectrum of the title compound as a methylene chloride solution had absorptions at 5.54, 5.86 and 6.53 microns. The NMR spectrum of the title compound also had peaks at the following positions as a deuterated chloroform solution: 0.06, 0.08, 0.1 and 0.12 (4s, total
6H); 0.8 (c, 9H); 1.12-1.58 (m, 6H); 3.1
(m, 2H); 3.86 (m, 1H), 4.3 (m, 1H); 5.3
(m, 2H); 5.67 and 5.78 (2d, 1H in total); 7.54
(d, 2H); and 8.18 (d, 2H) ppm. Production example E (5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-ethylthio-2
p-Nitropenzyl -penem-3-carboxylate Methylene chloride 70 cooled to 10°C under nitrogen atmosphere
3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-ethylthio(thiocarbonyl) in ml
Thio-2-oxo-azetidine 7.3g (0.02mol)
and 4.8 g (0.048 mol) of calcium carbonate was added p-nitrobenzyloxalyl chloride (5.85 g, 0.024 mol). methylene chloride
Diisopropylethylamine 4.17ml in 20ml
(0.024 mol) was added dropwise at such a rate as to keep the temperature below 12°C. The mixture was stirred at 10° C. for 60 minutes, then washed with two 50 ml portions of ice-cold water, dried over anhydrous sodium sulfate, and concentrated under vacuum to a viscous oil. The resulting crude p-nitrobenzyl (3-α-t-butyldimethylsilyloxyethyl-2-oxo-acetidinyl)oxoacetate was dissolved in 300 ml of ethanol-free chloroform and then dissolved in triethyl in 50 ml of ethanol-free chloroform. The resulting solution was brought to reflux while a solution of 6.85 ml (0.04 mol) of phosphite was added dropwise over a period of 2 hours. The resulting solution was refluxed for 16 hours, then concentrated under vacuum. This residue was chromatographed on silica gel (800 g), 95:
Elution with 5 toluene-ethyl acetate gave 5.5 g (5.3% yield) of the title compound as a yellow foam. The infrared spectrum of the title compound as a solution in dichloromethane had absorptions at 5.56, 5.89 and 6.54 microns. The NMR spectrum of a solution of the title compound in deuterated chloroform showed peaks at the following positions. 0.07 (s, 3H); 0.1 (s, 3H); 0.85 (s,
9H); 1.12-1.53 (m, 6H); 2.97 (q, 2H); 3.7
(m, 1H); 4.25 (m, 1H); 5.3 (q, 2H); 5.63
(d, 1H); 7.38 (d, 2H); and 8.18 (d, 2H)
ppm. Intermediate 4-ethylthio(thiocarbonyl)thioazetidine as a solution in deuterated chloroform
The NMR spectrum showed peaks at the following positions:
0.06 (s, 6H); 0.8 (s, 9H); 1.14−1.62 (m,
6H); 3.14-3.63 (m, 3H); 4.33 (m, 1H); 5.16
(s, 2H); 6.7 (d, 1H); 7.5 (d, 2H); and
8.17 (d, 2H) ppm. Production Example I 3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-ethylthio(thiocarbonyl)
Thio-2-oxo-azetidine Ethanethiol (8.5 ml, 0.115 mol) was added to a solution of 4.18 g (0.104 mol) of sodium hydroxide in 250 ml of water cooled to 0-5°C under nitrogen. 15
After 7.73 ml (0.12 mol) of carbon disulfide was added.
The mixture was stirred for 35 minutes at 0-5°C. 4-acetoxy-3-[(R)-1-t- in 500 ml of methylene chloride
A solution of 1.50 g (0.0522 mol) of butyldimethylsilyloxyethyl]-2-azetidinone was added and the mixture was stirred vigorously for 24 hours at room temperature. The aqueous layer was separated and extracted with two 150 ml portions of methylene chloride.
The combined methylene chloride portions were washed twice with 200 ml each of water and with 200 ml of saturated aqueous sodium chloride solution,
Dry over anhydrous sodium sulfate and concentrate under vacuum. The crude title product (18 g) was dissolved in silica gel (500
g) and eluting with 99:1 chloroform-ethyl acetate.
9.1 g of the title trithiocarbonate (yield 48%)
was obtained as a yellow foam. The infrared spectrum of the title compound in dichloromethane had absorptions at 5.62 and 9.2 microns.
Also, NMR of a deuterated chloroform solution of the title compound
The spectrum showed absorption at the following position: 0.08(s,
6H); 0.8 (s, 9H); 1.02-1.5 (m, 6H); 3.0-
3.48 (m, 3H); 4.126 (m, 1H); 5.54 (d, 1H);
and 6.57 (b, 1H) ppm. Preparation Example J 3-Methylcarbonylthio-thiolane 1.04 g of tetrahydrothiophene-3-ol in 40 ml of methylene chloride cooled to 0°C under nitrogen
(0.01 mol) and 4-dimethylaminopyridine
Methanesulfonyl chloride (0.8ml, 0.01mol) was added to a solution of 2.44g (0.02mol). 0℃
After stirring for 1.5 hours at room temperature and 2 hours at room temperature, the solution was
Washed with 30 ml of IN aqueous hydrochloric acid solution, 30 ml of water and 30 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under vacuum to an oil of 3-methylsulfonyloxy-thiolane (1.6 g, yield 8.8%). I got it. Crude 3-methylsulfonyloxy in 30 ml of acetone
A mixture of 1.6 g (8.8 mmol) of thiolane and 1.5 g (8.8 mmol) of potassium thioacetate was refluxed under nitrogen for 20 hours. The mixture was then concentrated under vacuum and the residue was partitioned between 40ml ethyl acetate and 40ml water. The ethyl acetate layer was separated, washed with 30 ml of water and 30 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was chromatographed on silica gel, eluting with methylene chloride, yielding 740 mg of the title compound.
(52%). The NMR spectrum of the title compound in deuterated chloroform is 2.35 (s, 3H); 1.6-3.4 (c, 6H);
A peak was observed at 4.1 (m, 1H) ppm. Preparation Example K The same method used in Preparation J in reacting 3-methylsulfonyloxythiolane with potassium thioacetate was applied to 3-chlorothiane and 2
-Methylthioethyl chloride and potassium thioacetate to give the corresponding methylcarbonylthio derivatives in 33 and 100%, respectively. The NMR spectrum of 3-methylcarbonylthio-thiane in deuterated chloroform had peaks at 2.36 (s, 3H); and 1.4-3.86 (c, 9H) ppm. Production example L (methylcarbonylthio) (methylsulfonyl)
Methane 1.0 g (methylcarbonylthio)(methylthio)methane (7.34
To a solution of m-chloroperbenzoic acid (3.0 g, 14.7 mmol, 85% purity) was added.
After stirring at room temperature for 20 hours, the solution was washed twice with 30 ml portions of saturated aqueous sodium bicarbonate solution and with 30 ml of saturated aqueous sodium bicarbonate solution, dried (anhydrous sodium sulfate) and concentrated under vacuum. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate to give 740 mg (60% yield) of the title compound.
was obtained as a thick gum. The NMR spectra of a deuterated chloroform solution of the title compound are 2.5 (s, 3H); 2.94 (s, 3H) and
It had a peak at 4.4 (s, 2H) ppm. Production Example M Using the method of Production Example L, 3-methylcarbonylthio-1,1-dioxo-thiane was produced in a yield of 32.5%.
and 2-(methylcarbonylthio)-1-methylsulfonyl)ethane was obtained in a yield of 5.5%. The NMR spectra of the 1,1-dioxo-thiane product in deuterochloroform are 2.36 (s, 3H) and 1.7
It had a peak at ~3.37 (c, 9H) ppm. Production example N 2-(methylcarbonylthio)-1-(methylsulfonyl)ethane 2-(methylcarbonylthio)-1-(methylthio)ethane in 40 ml of methylene chloride cooled to -10°C
To a solution of 1.5 g (0.01 mol) was added m-chloroperbenzoic acid (2.03 g, 0.01 mol, 85% purity). After stirring for 2 hours at −10° C., the solution was washed twice with 30 ml portions of saturated aqueous sodium bicarbonate solution, 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under vacuum. Column chromatography of the crude product on silica gel, eluting with 10:1 ethyl acetate-methanol, gave 680 mg (38% yield) of the title compound as an amorphous solid. The NMR spectrum of the title compound in deuterated chloroform is 2.4 (s, 3H); 2.68 (s, 3H); and
It had a peak at 2.76-3.46 (c, 4H) ppm. Preparation Example O Using the method of Preparation N, 3-methylcarbonylthio-1-oxo-thiolane was prepared in a yield of 42%.
3-Methylcarbonylthio-1-oxo-thiane and (methylcarbonylthio)- in 91% yield.
(Methylsulfinyl)methane was produced with a yield of 32%. The NMR spectrum of the 1-oxo-thiolane product in deuterated chloroform is 2.36 (s, 3H); and
It had a peak at 1.77-4.75 (c, 7H) ppm. The NMR spectrum of the 1-oxo-thiane product in deuterated chloroform is 2.36 (s, 3H); and
It had a peak at 1.6-3.4 (c, 9H) ppm. (methylcarbonylthio) (methylsulfinyl)
The NMR spectra of methane in deuterated chloroform are 2.5 (s, 3H); 2.94 (s, 3H); and 4.4 (s, 3H);
2H) It had a peak at ppm. According to the method of Production Example N, 1,1-dioxo-4-methylcarbonylthiothiane was obtained in a yield of 4.3% from 4-methylcarbonylthiothiane and 2 equivalents of m-chloroperbenzoic acid. Purification 1:1
Column chromatography was performed, eluting with ethyl acetate:hexane. Elemental _analysis : Calculated values _{for C7H17O3S} : C, 40.37; H, 5.81; Experimental values:
C, 40.62, H, 5.58. The NMR spectrum of a solution of this product in deuterated chloroform had peaks at the following positions. :2.15−25 (4H, m); 2.36 (3H, s);
3.02−3.2 (4H, m); and 3.74 (1H, tt, J=8,
4Hz) ppm. In addition, the infrared spectrum of the product KBr tablet is
It had absorptions at 1687, 1291 and 1116 cm ^-1 . Further, according to the method of Production Example N, 1-oxo-4
-p-Methylphenylsulfonyloxythiane was produced. The obtained cis and trans isomers were divided into 3
Separated by column chromatography on silica gel, eluting with % methanol/ethyl acetate. The cis-1-oxo-4-p-methylsulfonyloxythiane isomer was the more polar one.
The NMR spectrum (250MHz) of a solution of the cis isomer in deuterated chloroform had peaks at the following positions. :
2.0 (2H, m); 2.48 (2H, m); 2.50 (3H, s);
2.75 (2H, dddd); 3.07 (2H, dddd); 4.67 (1H,
tt, J = 3.3, 3.4Hz); 7.41 (2H, d, J = 8Hz);
and 7.85 (2H, d, J = 8Hz) ppm. Preparation Example P 3-chlorothiane 530 mg (4.5 mmol) of tetrahydrothiopyran-3-ol and 1.1 g of 4-dimethylaminopyridine in 30 ml of methylene chloride cooled to 0° C. under nitrogen.
(9 mmol) was added p-toluenesulfonyl chloride (8.57 mg, 4.5 mmol).
The solution was stirred at room temperature for 20 hours, then washed twice with 30 ml each of 1N aqueous hydrochloric acid solution, 30 ml of water and 30 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound. 400
mg (yield 33%). Production example Q (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[2-oxo-1,3-diothyrane-
p-Nitrobenzyl 4-ylmethyl]thio-2-penem-3-carboxylate (5R,6S)-6- in 20 ml of tetrahydrofuran
[(R)-1-t-butyldimethylsilyloxyethyl]-2-(2-oxa-1,3-diothyrane-4
-ylmethyl)thio-2-penem-3-carboxylic acid p-nitrobenzyl 410ml solution was added with 0.383ml of glacial acetic acid.
ml and 20 ml of 1M tetrabutylammonium fluoride solution. This solution was stirred at room temperature for about 24 hours. The solvent was then removed under vacuum and the residue was dissolved in ethyl acetate. The solution was washed with dilute aqueous sodium bicarbonate, water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated. Further product was generated by column chromatography on silica gel using 1:1 hexane/ethyl acetate and pure ethyl acetate as eluents. NMR (CDCl ₃ /DMSO−d ₆ : 1.23 (3H, d, J=
6); 2.92-3.25 (2H, m); 3.42-3.67- (4H,
m); 5.2 (2H, s); 5.30 (1H, d, J=2; and
7.83 (4H, d of d) ppm. IR _{( CH2Cl2} ): 1.792cm ^-1 . Production example R (5R,5S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-(2-oxo-
1,3-diothyran-4-ylmethyl)thio-
p-Nitropenzyl 2-penem-3-carboxylate 4-mercaptomethyl- in 50 ml of dichloromethane
A solution of 0.500 g of 1,3-diothyran-2-one was cooled to 0 DEG C. and then treated with 0.640 ml of diisopropylethylamine. After 1 hour at 0-5℃,
This solution was dissolved in 20 ml of dichloromethane (5R, 6S)-6
-[(R)-1-t-butyldimethylsilyloxyethyl]-(2-ethylsulfinyl-2-penem-
A solution of 0.307 g of p-nitrobenzyl 3-carboxylate was added at 0-5°C. This reaction mixture is
Stirred at 5° C. for 1 hour, then washed successively with water and brine, then dried over anhydrous sodium sulfate. After filtration, the solution was evaporated to give a gum, which was triturated with 1:1 hexane/ethyl acetate to give the product as a pale yellow amorphous solid. NMR (CDCl ₃ ; 60MHz); 0.05 (3H, s); 0.08
(3H, s), 0.83 (9H, s), 1.23 (3H, d, J=
6: 3.28-3.52 (2H, m); 3.67-3.92 (2H, m);
4.02−4.67 (2H, m); 5.30 (2H, d, J=4);
5.68 (1H, s); and 7.8 (4H, d of d) ppm. IR (CH ₂ Cl ₂ ; 1792 cm ^-1 . Production example S (5R, 6S)-6-[(R)-1-hydroxyethyl]-2-[(cis)-1-oxo-3-thiolanyl]thio- p-Nitropenzyl 2-penem-3-carboxylate Anhydrous tetrahydrofuran 50ml Thiolanil (5R,
6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-[(cis)-1-oxo-3-
To a solution of 20.1 g (0.0337 mol) of p-nitrobenzyl]thio-2-penem-3-carboxylate were added 19.9 ml of acetic acid and 118.8 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After stirring overnight at room temperature under nitrogen, the solution was concentrated under vacuum. The residue was dissolved in 500 ml of ethyl acetate, and the resulting solution was washed three times with 200 ml of water each. The product started to crystallize from the aqueous extract and ethyl acetate layer, thus completing the crystallization (30
minutes). The crystalline material was filtered, washed with water and ethyl acetate, then slurried in 200 ml of ethyl acetate and filtered to give 12.03 g (74% yield) of crystalline product. The ethyl acetate and aqueous extracts were combined, the ethyl acetate layer was washed with 300 ml of saturated aqueous sodium bicarbonate solution, 200 ml of water and 200 ml of brine;
Dry over anhydrous sodium sulfate and concentrate under vacuum to obtain 4.6 g of impure product. This material was recrystallized from ethyl acetate to yield an additional 3.0 g of product.
Overall yield 92.2%, melting point 122-125°C. The NMR spectrum (250MHz) of a deuterated chloroform solution of this compound had peaks at the following positions: 1.37 (d, 3H); 2.57-2.95 (c, 4H); 3.15
(c, 1H); 3.62-3.97 (c, 3H); 4.26 (m,
1H); 5.34 (q, 2H); 5.72 and 5.74 (2d, 1H);
7.63 (d, 2H); and 8.23 (d, 2H) ppm. The infrared spectrum of a dichloromethane solution of the title compound had absorptions at 5.56 and 5.86 microns. The method for the cis isomer was modified to (5R,6S)-6-
Applies to p-nitropenzyl [(R)-1-t-butyldimethylsilyloxyethyl-2-[(trans)-1-oxo-3-thiolanyl]thio-2-penem-3-carboxylate starting material The corresponding trans isomer of the title compound is determined by 75
% yield. Melting point 178.5-180℃. of this trans isomer in deuterated chloroform.
The NMR spectrum had peaks at the following positions:
1.4 (d, 3H): 2.22 (c, 1H): 2.62 (c, 1H):
2.8 (m, 1H): 3.04 (c, 2H): 3.18 (c, 1H):
3.52 (m, 1H): 3.83 (m, 1H): 4.27 (c, 1H):
4.43 (c, 1H): 5.36 (q, 2H): 5.76 (d, 1H):
7.64 (d, 2H): and 8.24 (d, 2H) ppm. The IR spectrum of a dichloromethane solution of the trans isomer had absorptions at 5.56, 5.88, and 6.58 microns. Production example T (5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-[(cis)-1-oxo-3-thiolanyl]thio-2-penem-3
- p-Nitropenzyl carboxylate Chia absolute ethanol 110 cooled to -30°C under nitrogen
In a mixture of 10.68 g (0.06 mol) of cis-3-methylcarbonylthio-1-oxo-thiolane in ml,
A solution of sodium ethoxide in ethanol (1M
57.5 ml of solution, 0.0575 mol) was added. The resulting solution was stirred at -30°C for 2 hours and then cooled to -60°C. This cooled solution was added to 200 ml of tetrahydrofuran (5R,
6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-ethylsulfinyl-2-
p-nitrobenzyl penem-3-carboxylate 32.4
g (0.06 mol) of solution was added. The resulting solution was stirred at −60° C. for 1 hour, then a solution of 10 ml of acetic acid in 20 ml of tetrahydrofuran was added, the resulting solution was collected to room temperature and concentrated under vacuum. Dissolve the residue in 500 ml of ethyl acetate and dilute the solution with 300 ml portions of water.
times in 250 ml of saturated aqueous sodium bicarbonate solution.
Washed with three 300 ml portions of water and 200 ml of brine, dried over anhydrous sodium sulfate and concentrated under vacuum.
The crude product was dissolved in ethyl acetate/methanol (95:5).
Chromatography was performed on silica gel (1.5 Kg), which was eluted at The resulting pure product was soothed with diethyl ether (150ml) overnight to yield 14.25g of crystalline product. A further 5.0 g of the impure product obtained from the chromatography is dissolved in 5 ml of methylene chloride and the solution is dissolved in diethyl ether.
Diluted with 150ml. After stirring overnight, 3.42 g of crystalline product was obtained (overall yield 51.5%), melting point 137-138
℃. The NMR spectrum (250MHz) of a solution of the title compound in deuterochloroform had peaks at the following positions: 0.04 (s, 3H); 0.07 (s, 3H); 0.82 (s,
9H); 1.25 (d, 3H); 2.45-2.9 (c, 4H); 3.14
(c, 1H); 3.55-4.0 (c, 3H); 4.27 (m, 1H);
5.32 (q, 2H); 5.67 and 5.7 (2d, 1H); 7.62 (d,
2H); and 8.2 (d, 2H) ppm. Also, the infrared spectrum of a methylene chloride solution of the title compound is 5.56,
It had absorptions at 5.92 and 6.58 microns. According to this method, trans-3-methylcarbonylthio-1-oxothiolane is used as the starting material (5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-[(trans )-1-
Oxo-3-thiolanyl]thio-2-penem-3
The corresponding trans isomer was prepared in 2.5% yield by obtaining p-nitropenzyl -carboxylate. The trans isomer was less polar than the cis isomer. NMR spectrum of the corresponding trans isomer of the title compound in deuterated chloroform (250MHz)
showed a peak at the following position: 0.06 (s, 3H);
0.1 (s, 3H); 0.86 (s, 9H); 1.3 (d, 3H);
2.25 (m, 1H); 2.82 (m, 1H); 2.94-3.33 (c,
3H); 3.55 (m, 1H); 3.82 (d, 1H); 4.33 (c,
1H); 4.45 (c, 1H); 5.36 (q, 2H); 5.76 (d,
1H); 7.66 (d, 2H); and 8.22 (d, 2H) ppm. The infrared spectrum of a methylene chloride solution of the trans isomer had absorptions at 5.57, 5.92, and 6.57 microns. Production example U cis-3-methylcarbonylthio-1-oxo-thiane trans-1-oxo-3-p- in 20 ml of acetone
Methyl-phenylsulfonyloxythiane 300mg
(1.04 mmol) and 3.96 mg (1.25 mmol) of tetrabutylammonium thioacetate was refluxed overnight under nitrogen atmosphere. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel (80g). 50 mg (25 mg) of the title compound by eluting with acetone/hexane
%) was obtained. The NMR spectrum of a deuterated chloroform solution of the title compound is 1.2-3.1 (c) and 2.28 (s) (total
10H); and 3.34 (c, 2H) ppm. Similarly, trans-3-methylcarbonylthio-1-oxo-thiane was obtained in 50% yield by using cis-1-oxo-3-p-methylphenylsulfonyl-oxythiane as the starting material. The NMR spectra of this trans isomer in deuterated chloroform are 1.42-3.24(c) and 2.22
(s) (11H in total) and 4.06 (c, 1H) ppm. Preparation Example V 1-oxo-3-p-methylphenylsulfonyloxythiane 1 in 80 ml of methylene chloride cooled to 0°C under nitrogen
-oxo-3-thianol (2.14g, 0.016mol)
and 4-dimethylaminopyridine (3.9g, 0.032
To a solution of p-toluenesulfonyl chloride (3.65 g, 0.019 mole) was added. This solution was then washed with 50 ml of 1N aqueous hydrochloric acid solution, 50 ml of water and 50 ml of saline, dried over anhydrous sodium sulfate,
Concentrated under vacuum. Silica gel (1Kg) was drained with acetone/hexane (4:1).
300 mg of the title trans compound, a mixture of cis and trans compounds.
1.4 g and 1.5 g of cis compound were obtained (total yield 70%). The NMR spectrum of the cis isomer of the title compound in deuterated chloroform had peaks at the following positions: 1.4-2.92 (c) and 2.46 (s) (9H in total);
3.4 (c, 2H); 4.54 (c, 1H); 7.36 (d, 2H); and 7.8 (d, 2H) ppm. The NMR spectrum of the trans isomer of the title compound in deuterated chloroform had peaks at the following positions: 1.4−3.3(c) and 2.44(s) (in total
11H): 5.1 (c, 1H): 7.32 (d, 2H): and 7.77
(d,2H) ppm. Preparation Example W 3-Hydroxy-1-oxothiane In a solution of 2.0 g (0.017 mol) of thian-3-ol in 60 ml of methylene chloride cooled to 0° C. under nitrogen,
m-Chlorperbenzoic acid (3.44 g, 0.017 mol, 8.5% purity) was added in portions. The reaction mixture was stirred at 0° C. for 35 minutes and then at room temperature for 2 hours.
This was concentrated under vacuum and the residue was washed with silica gel (200
g) was subjected to chromatography. Elution with ethyl acetate/methanol (9:1) gave 2.14 g (94% yield) of a mixture of cis and trans 3-hydroxy-1-oxo-thiane. Production Example X 4-Methylcarbonylthiothiane 4-(p-
-methylphenylsulfonyloxy)thiane and
4-Methylcarbonylthiothiane was prepared by reacting 1.5 equivalents of potassium thioacetate in dimethyl formaldehyde at 80°C.
Obtained in 69% yield after chromatography on silica gel eluting with % ethyl acetate/hexane.
The NMR spectrum of a solution of 4-methylcarbonylthiothiane in deuterochloroform had peaks at the following positions: 1.62-2.2 (4H, m); 2.32 (3H, s); 2.5
−2.8 (4H, m); and 3.52 (1H, tt, J=9,3
Hz) ppm. Production Example Y Using the same method as Production Example X, trans-4-
cis-1-oxo-4- by starting with p-methylphenylsulfonyloxythiane
(Methylcarbonylthio)-thiane was obtained. The NMR spectrum (250MHz) of a solution of this product in deuterated chloroform had peaks at the following positions. :1.97
(2H, m); 2.33 (3H, s); 2.42 (2H, dddd);
2.66 (2H, ddd); 3.02 (2H, m); and 3.56 (1H,
tt, J = 11.13.6Hz) ppm. Similarly, trans-1-oxo-4-(methylcarbonylthio)thiane was obtained by using the method of Production Example Ta. The deuterochloroform NMR spectrum of this product had a peak at: 1.83 (2H,
m); 2.33 (3H, s); 2.65 (2H, m); 2.87 (4H,
m); and 3.80 (1H, m) ppm. Preparation Z Following the method of Preparation V, trans-1-oxo-4-hydroxyatine (see Klain et al.
Tetrahedron, 30 , 2541 (1974)) trans.
1-Oxo-4-p-methylphenylsulfonyloxythiane is prepared and the desired compound has a melting point of 99 to
Obtained as a white solid at 102°C in 83% yield. NMR spectrum of deuterated chloroform solution (250MHz)
had a peak at the following position: 1.94 (2H, m);
2.5 (3H, s); 2.6 (2H, m); 2.84 (4H, m);
4.80 (1H, m); 7.41 (2H, d, J=8Hz); and
7.85 (2H, d, J = 8Hz) ppm. According to Preparation Example V, using 1.2 equivalents of p-toluenesulfonyl chloride, 0.1 equivalents of 46 dimethylaminopyridine and 1.2 equivalents of triethylamine,
It was then subjected to column chromatography on silica gel using 1:1 ethyl acetate/hexanes.
-Preparation of 4-p-methylphenylsulfonyloxythiane from hydroxythiane (prepared from 4-oxo-thiane by reduction with di-isobutylaluminum hydride) to obtain the desired product in 95% yield. . A solution of this product in deuterated chloroform
The NMR spectrum had peaks at the following positions:
1.8-2.2 (4H, m); Production example AA cis-1-oxo-3-methylcarbonylthiothilane trans-1-oxo-3- in 180 ml of acetone
p-Toluenesulfonyloxythiolane (25.5g,
A solution of 0.093 mol) and tetra-n-butylammonium thioacetate (59 g, 0.186 mol) was reduced under nitrogen for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed on silica gel. By eluting with ethyl acetate, 13.4 g (8.1% yield) of cis-1-oxo-3-methylcarbonylthiothiolane was obtained with a melting point of 52.5
Obtained as a solid at ~54°C. The NMR spectrum of a solution of the title compound in deuterochloroform had a peak at the following position: 2.06−
3.26(c) and 2.34(s) (8H in total); and 3.26−
4.21 (c, 2H) ppm. Similarly, trans-1-oxo-3-methylcarbonylthiolane was obtained from cis-1-oxo-3-p-toluenesulfonyloxythiolane in a yield of 47%. The NMR spectrum (250 MHz) of a solution of this trans isomer product in deuterochloroform had peaks at the following positions: 2.1 (c, 1H): 2.36 (s,
3H): 2.9 (c, 3H): 3.17 (m, 1H): 3.36 (m,
1H): and 4.48 (m, 1H) ppm. Preparation Example BB 1-oxo-3-p-methylphenylsulfonyloxythiane 3-p-toluenesulfonyloxythiolane (1.29
m-chloroperbenzoic acid (85% purity, 1.19 g, 0.005 mol) was added in portions over 5 minutes. After 30 minutes at 0°C, the reaction mixture was diluted with 12.5 ml of methylene chloride and treated with 20 ml of dilute aqueous sodium bisulfite solution to destroy excess peracid. Adjust the pH of the mixture with sodium bicarbonate
7.5, wash the methylene chloride layer with 20 ml of water and 20 ml of brine, dry with anhydrous sodium sulfate,
Concentrated under vacuum. Elute this residue with 95:5 ethyl acetate/methanol on silica gel (200 g)
chromatography to give 0.175 g of the more polar cis isomer and 0.92 g of the less polar trans isomer as a solidifying oil (80% yield). The melting point of the trans isomer was 85-87°C, and the cis isomer was a waxy solid with a low melting point. The NMR spectrum of the trans isomer of the title compound in deuterated chloroform had peaks at the following positions: 2.2−3.63 (c) and 2.5 (s) (in total
9H); 5.42 (m, 1H); 7.34 (d, 2H); and 7.78
(d,2H) ppm. The NMR spectrum of the cis isomer of the title compound in deuterated chloroform had peaks at the following positions: 1.95-3.23 (c) and 2.46 (s) (9H in total):
5.2 (c, 1H); 7.3 (d, 2H); and 7.76 (d, 2H)
ppm. Preparation Example CC 3-p-Methylphenylsulfonyloxythiolane Thiolan-3-ol (0.52 g, 0.005 mol) and 4-dimethylaminopyridine (1.22 g, 0.01 mol) in 20 ml of methylene chloride cooled to 0° C. under nitrogen. To a solution of p-toluenesulfonyl chloride (0.95 g, 0.005 mole) was added. 1.5 at 0℃
After stirring for an hour, the reaction was allowed to warm to room temperature. The reaction was complete after 4 hours at room temperature. The reaction mixture was diluted with 80 ml of methylene chloride, 20 ml of dilute aqueous hydrochloric acid solution, 20 ml of water
ml and 20 ml of saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to an oil. This solidified upon standing (1.3 g, yield 100
%), melting point 56.5-58℃. The NMR spectrum of a solution of the title compound in deuterochloroform had peaks at the following positions: 1.5~
2.52(c) and 2.44(s) (5H in total); 2.56−3.02
(c, 4H); 5.13 (m, 1H); 7.28 (d, 2H); and
7.72 (d, 2H) ppm.

Claims (1)

[Claims] 1 formula [Wherein, R is 2-(methylsulfonyl)ethyl,
(methylsulfonyl)methyl, 3-thietanyl,
1-oxo-3-thietanyl, 1,1-dioxo-3-thietanyl, 2-thiolanyl, 1-oxo-2-thiolanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1-dioxo-3- Thiolanyl, 3-hydroxy-4-thiolanyl, 1-
Oxo-3-hydroxy-thiolanyl, 1,1-
Dioxo-3-hydroxy-4-thiolanyl, 2
-oxo-1,3-diolain-4-ylmethyl, 3-thianyl, 1-oxo-3-thianyl,
1,1-dioxo-3-thianyl, 4-thianyl, 1-oxo-4-thianyl or 1,1-dioxo-4-thianyl, and R ₁ is hydrogen or forms an ester that is hydrolyzed in vivo or a pharmaceutically acceptable salt thereof. 2 R ₁ is hydrogen, and R is 2-(methylsulfonyl)ethyl, (methylsulfonyl)methyl,
3-thietanyl, 1-oxo-3-thietanyl,
1,1-dioxo-3-thietanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1-dioxo-3-thiolanyl, 3-hydroxy-4-
Thiolanyl, 1-oxo-3-hydroxy-thiolanyl, 1,1-dioxo-3-hydroxy-4
-thiolanyl, 3-thianyl, 1-oxo-3-
thianyl, 1,1-dioxo-3-thianyl, 4
-thianyl, 1-oxo-4-thianyl, 1,1
-dioxo-4-thianyl, or 2-oxo-
The compound according to claim 1, which is 1,3-dithiolan-4-ylmethyl. 3 formulas [Wherein, R is 2-(methylsulfonyl)ethyl,
(methylsulfonyl)methyl, 3-thietanyl,
1-oxo-3-thietanyl, 1,1-dioxo-3-thietanyl, 2-thiolanyl, 1-oxo-2-thiolanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1-dioxo-3- Thiolanyl, 2-oxo-1,3-dithiolane-4-
ylmethyl, 3-thianyl, 1-oxo-3-thianyl, 1,1-dioxo-3-thianyl, 3-
Hydroxy-4-thiolanyl, 1-oxo-3-
Hydroxy-thiolanyl, 1,1-dioxo-3
-hydroxy-4-thiolanyl, 4-thianyl,
1-oxo-4-thianyl or 1,1-dioxo-4-thianyl, and R ₁ is hydrogen or a group that forms an ester that is hydrolyzed in vivo. or a pharmaceutically acceptable salt thereof. 4 R ₁ is hydrogen, and R is 2-(methylsulfonyl)ethyl, (methylsulfonyl)methyl,
3-thietanyl, 1-oxo-3-thietanyl,
1,1-dioxo-3-thietanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1-dioxo-3-thiolanyl, 3-hydroxy-4-
Thiolanyl, 1-oxo-3-hydroxy-thiolanyl, 1,1-dioxo-3-hydroxy-4
-thiolanyl, 3-thianyl, 1-oxo-3-
thianyl, 1,1-dioxo-3-thianyl, 4
-thianyl, 1-oxo-4-thianyl, 1,1
-dioxo-4-thianyl or 2-oxo-1,
4. The compound according to claim 3, which is 3-dithiolan-4-ylmethyl. 5. The compound according to claim 4, wherein 5R is trans-1-oxo-3-thiolanyl. 5. The compound according to claim 4, wherein 6R is cis-1-oxo-3-thiolanyl. 7 R is 1,1-dioxo-3-thiolanyl, trans-1-oxo-3-thianyl, cis-1-
Oxo-3-thianyl, trans-1-oxo-
3-thietanyl, 1,1-dioxo-4-thianyl, 4-thianyl, trans-1-oxo-4-
5. The compound according to claim 4, which is thianyl, cis-1-oxo-4-thianyl, or cis-1-oxo-3-thietanyl.