KR850001339B1 - Process for preparing penicillanic acid 1,1-dioxide and esters therof - Google Patents

Abstract

Penicillanic acid derivs. of formula (I) and their pharmaceutically permissible salts are prepd. by reacting compds. of formula (II) or their salts with a reactant (selected from alkali metal permanganate, alkaline metal permanganate, or organic peroxycarboxylic acid) to yield compds. of formula (III) or their salts, and then catalytically dehalogenating the prods. in an inert solvent. In the formulas, R1 is H or an ester residue that is easily hydrolyzed in vivo; X and Y are each H, Cl, Br, or I, but if the same they must both be Br. (I) are useful as antibiotics and beta-lactamase inhibitors

Description

Peniclanic acid 1,1-dioxide and its preparation method

The present invention relates to a novel process for preparing peniclanic acid 1,1-dioxide of the general formula (I) or an ester thereof which is easily hydrolyzed in vivo.

In the above formula

R ¹ is hydrogen or an ester-forming moiety that is easy to hydrolyze in vivo.

The present invention also includes novel compounds useful as intermediates in the above methods of preparation. The process for oxidizing 6-halo or 6,6-dihalo derivatives of peniclanic acid or its esters, which are readily hydrolysable in vivo, yields the corresponding 1,1-dioxide, followed by dehalogenation thereof. Consists of steps. Novel compounds useful as intermediates here are the 6-halo and 6,6-dihaloderivities of peniclanic acid 1,1-dioxide and their esters which are easy to hydrolyze in vivo.

Peniclanic acid 1,1-dioxide and its easy hydrolysis in vivo are useful as beta-lactamase inhibitors and beta-lactams when the latter compounds are administered to treat bacterial infections in mammals, especially humans It is useful for increasing the effectiveness of antibiotics. Previously, waste nisilane acid 1,1-dioxide and its hydrolyzable esters in vivo have been debrominated to 6-bromophenisilane acid or its hydrolyzable esters in raw vegetables to penisilane acid or bio It was prepared by producing an ester thereof which is easy to hydrolyze in and oxidized it to produce 1,1-dioxide. Although the process of the present invention is based on 6-halophenylanic acid or its ester which is easily hydrolyzed in vivo and includes a dehalogenation and oxidation step, it is surprising if the oxidation step is performed before the dehalogenation step. It was surprisingly found that the product can be obtained in high yield. The preparation of peniclanic acid 1,1-dioxide and its hydrolyzable esters in vivo is described in detail in Belgian Patent No. 867,859 and Dec. 2,824,535, filed December 6, 1978. have.

6-halophenylanic acid is described in U.S. Patent No. 3,206,469 and cignarella et al in the Journal of Organic Chemistry, 27, 2668 (1962), for the conversion of 6-halopenisilane acid to penicylic acid. Hydrolysis reactions are described in British Patent No. 1,072,108.

6-alpha-chlorophenicylic acid and 6-alpha-bromophenicylic acid are prepared by diazotizing 6-aminophenicylic acid in the presence of hydrochloric acid and hydrobromic acid, respectively. Journal of Organic chemistry, 27, 2668 (1962). 6-alpha-iodophenicylic acid is prepared by diazotizing 6-aminophenicylanic acid in the presence of iodine and then hydrolyzing it (clayton, Journal of the chemical society (c), 2123 (1969)). 6-Beta-chlorophenicylic acid, 6-beta-bromophenic silane acid and 6-iodophenic silane acid are 6-chloro-6-iodophenic silane acid, 6,6-dibromophenic silane acid, and Prepared by reduction of 6,6-diiodophenicsilane acid with tri-n-butyltinhydride. 6-Chloro-6-iodophenicylanic acid is prepared by diazotizing 6-aminophenicylanic acid in the presence of iodine chloride, and 6,6-dibromophenylanic acid is prepared by the method of clayton [Journal of the chemical society (London) (c) 2123 (1969)), and 6,6-diiodo peniclanic acid is prepared by diazotizing 6-aminophenicylanic acid in the presence of iodine.

Harrison et al., In the Journal of the Chemical Society (London), Perkin I1772 (1976), (a) oxidizing 6,6-dibromophenicsilane acid into 3-chloroperbenzoic acid to produce the corresponding alpha. And a method for producing a mixture of beta-sulfoxides: (b) methyl 6,6-dibromophenicylanate is oxidized to 3-chloroperbenzoic acid to methyl 6,6-dibromophenicylanate 1,1 A process for producing the dioxide: (c) oxidizing methyl 6-alpha-chlorophenicilanate with 3-chloroperbenzoic acid to produce the corresponding alpha- and beta-sulfoxide: and (d) methyl 6-bro A method of oxidizing mofenicilanate with 3-chloroperbenzoic acid to produce the corresponding alpha- and beta-sulfoxides is described.

Clayton is described in the Journal of the chemical society (London) (c), 2123, (1969), where (a) 6,6-dibromo- and 6,6-diiodophenicylanic acid is Method of preparation: (b) Method of oxidizing 6,6-dibromophenicsilane acid with sodium periodate to produce a mixture of the corresponding sulfoxides: (c) Methyl 6,6-dibromopheniclanate Hydrolysis to produce 6-alpha-bromophenicylanate: (d) Hydrolysis of 6,6-dibromophenicylanic acid and its methylester to produce peniclanic acid and its methyl ester, respectively And (e) hydrolyzing a mixture of methyl 6,6-diiodophenicylate and methyl 6-alpha-iodophenicylate to produce pure methyl 6-alpha-iodophenicylate. The method is described.

The present invention provides a general formula (III) by contacting a compound of formula (II) or a salt thereof with a base thereof with a reactant selected from the group consisting of alkali metal permanganate, alkaline earth metal permanganate and organoperoxycarboxylic acid. (B) dehalogenating a compound of formula (III) by obtaining a salt with a compound or a base thereof, to prepare a salt with a compound of formula (I) or a pharmaceutically acceptable base thereof to provide.

In the above formula

R ¹ is hydrogen or an ester-forming moiety that is easily hydrolyzed in vivo, and X and Y are each selected from the group consisting of hydrogen, chloro bromo and iodo, provided that when X and Y are the same they are both bromo Should be indicated.

A preferred method of carrying out step (b) comprises the steps of (a) and hydrogen in an inert solvent at a pressure of about 1 to about 100 kg / cm ² , a temperature of about 0 to about 60 ° C. and a pH of about 4 in the presence of a hydrogenolysis catalyst. To contact in the range of about 9. The hydrogenolysis catalyst is generally used in an amount of about 0.01 to about 2.5% by weight, preferably about 0.1 to about 1.0% by weight, based on the general formula (III) compound.

X and Y are preferably bromo, and preferred reactants for carrying out step (a) are potassium permanganate and 3-chloroperbenzoic acid.

It is difficult to obtain a compound of formula (II) wherein both X and Y are chloro. If both X and Y are iodo, step (a) of the inventive process proceeds very slowly.

Also included in the scope of the invention are intermediates of general formula (III), wherein X, Y and R ¹ are as defined above. Preferred intermediates are the general formula (III) compounds in which X and Y are bromo and R ¹ is hydrogen, ie 6,6-dibromophenicsilane 1,1-dioxide.

The invention also relates to a process for the preparation of the compound of general formula (I) and to the various types of intermediates used therein. Throughout this specification, these compounds are named peniclanic acid derivatives and are represented by the following general formula (IV).

In the derivatives of peniclanic acid, the intermittent line showing the attachment of a substituent to the acyclic nucleus means that the substituent is present below the plane of the nucleus. Such substituents are said to have alpha-coordination. In contrast, the linear representation of the substituents for the bicycline nucleus means that the substituents are on the plane of the nucleus. This coordination is called beta-coordination. Therefore, in Formula (II), the coordination of group X is alpha-coordination and the coordination of group Y is beta-coordination.

In the present specification, when R ¹ is an ester-forming residue which is easy to hydrolyze in vivo, it is a group conceptually derived from an alcohol of the general formula R ¹ -OH, and thus COOR ¹ in the compound of general formula (I). The group represents an ester group. In addition, R ¹ has a property that the COOR ¹ group is easily decomposed in vivo to free the free carboxy group COOH. I.e., R ¹ is, R ¹ is in vivo hydrolysis easy ester of the general formula (I) compound to form residues in blood, when administered during tissue it is easily R ¹ is hydrogen Formula (I) compounds of the mammalian A group of forms to be converted. Group R ¹ is well known in the penicillin art. In most cases they enhance the absorption properties of penicillin compounds.

In addition, R ¹ should impart pharmacological tolerance to the compound of formula (I) and be able to liberate pharmaceutically acceptable fragments when degraded in the body. Group R ¹ is known and is easily identified by experts in the penicillin art. [Reference Example: German Patent Application Laid-Open No. 2,517,316] Examples of group R ¹ include 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, and the group of the following general formula. .

(Wherein R ² and R ³ are each selected from the group consisting of hydrogen and alkyl having 1 to 2 carbon atoms, R ⁴ is alkyl having 1 to 5 carbon atoms). However, preferred groups for R ¹ include alkanoyloxymethyl having 3 to 7 carbon atoms, 1- (alkanoyloxy) ethyl having 4 to 8 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl having 5 to 9 carbon atoms, and carbon atoms. 3 to 6 alkoxycarbonyloxymethyl, 4 to 7 1- (alkoxycarbonyloxy) ethyl. 1-methyl-1- (alkoxycarbonyloxy) -ethyl, 3-phthalidyl, 4-crotonolactonyl and gamma-butyrolactone-4-yl having 5 to 8 carbon atoms.

3-phthalidyl, 4-crotonolactonyl and gamma-butyrolactone-4-yl are represented by the following structural formulas (VII), (IX) and (IX). Dashed lines represent two epimers or mixtures thereof.

In step (a) of the process of the present invention, the sulfide group of the compound of formula (II) is oxidized to a sulfone group to produce a compound of formula (III). In this step, any of a variety of known oxidants can be used in the oxidation reaction of sulfide to sulfone. However, particularly convenient reagents are alkali metal permanganates such as sodium permanganate and potassium permanganate, alkaline earth metal permanganates such as calcium permanganate and barium permanganate, organic peroxycarboxylic acids such as peracetic acid and 3-chloroperbenzoic acid.

When X, Y and R ¹ oxidize a compound of formula (II) as defined above to the corresponding compound of formula (III) using metal permanganate, the reaction is generally a compound of formula (II) Is carried out by treatment with about 0.5 to 10 molar equivalents, preferably about 1 to about 4 molar equivalents of permanganate, in a suitable reaction vulcanized solvent system. Suitable reaction-inert solvent systems are those which do not exhibit adverse effects on any of the starting materials or products, and usually use water. In some cases. Co-solvents, such as tetrahydrofuran, which are miscible with water but do not work with permanganate can be added. The reaction is carried out at a temperature range of about -30 ° C to about 50 ° C, preferably about -10 to about 10 ° C. At about 0 ° C. the reaction is usually complete in a short time, for example in 1 hour. The reaction is neutral. Although it can be carried out under acidic or basic conditions, it is preferred to react at a pH in the range of about 4 to about 9, preferably 6 to 8. However, it is essential to select conditions under which the beta-lactam ring system of the formula (II) or (III) compound is not degraded. Indeed, it is mainly advantageous to buffer the pH of the reaction medium to neutrality. The product is recovered by conventional methods. Excess permanganate is generally decomposed using sodium bisulfite and then recovered by filtration if the product precipitates in solution. The product is extracted with an organic solvent and the organic solvent is evaporated off to separate from manganese dioxide. Alternatively, if the product does not precipitate out of solution after the reaction, it is separated by the usual method of solvent extraction.

When X, Y and R ¹ oxidize the general formula (II) compound as defined above to the corresponding general formula (III) compound using peroxycarboxylic acid, the reaction usually reacts the general formula (II) compound. It is carried out by treating with about 1 to about 6 molar equivalents, preferably about 2.2 water equivalents of oxidizing agent in an inert organic solvent. Representative solvents include chlorinated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is generally carried out at a temperature ranging from about -30 to about 50 ° C, preferably from about 15 to about 30 ° C. At about 25 ° C., the reaction time is usually about 2 to about 16 hours. The product is usually separated by evaporating off the solvent in vacuo. The reaction product can be purified by conventional methods known in the art. Alternatively, the product may be used directly in step (b) without further purification.

Step (b) of the process of the invention is a dehalogenation reaction. One convenient way to carry out this conversion is to stir or shake the solution of the compound of formula III in the presence of a hydrogenolysis catalyst under hydrogen or hydrogen mixed with an inert diluent such as nitrogen or argon. Suitable solvents for this hydrogenolysis reaction are solvents in which the starting compound of the general formula (III) is almost dissolved but is not hydrogenated or hydrolyzed. Examples of such solvents are ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane: low molecular weight esters such as ethyl acetate and butyl acetate: N, N-dimethylformamide, N, N-dimethylacet Tertiary amides such as amide and N-methylpyrrolidone, water and mixtures thereof. In addition, the reaction mixture is usually buffered to react at a pH of about 4 to 9, preferably about 6 to 8. Borate and phosphate buffers are generally used. The introduction of hydrogen gas into the reaction medium is generally accomplished by carrying out the reaction in a closed vessel containing the general formula (III) compound, solvent, catalyst and hydrogen. The reactor internal pressure is about 1 to about 100 kg / cm ² . If the atmosphere in the reactor is nearly pure hydrogen, the preferred pressure range is about 2 to about 5 kg / cm ² . Hydrolysis is generally carried out at a temperature of about 0 ° to about 60 ° C, preferably about 25 ° to about 50 ° C. Under desirable temperature and pressure conditions, hydrogenolysis generally occurs within a few hours, for example within two to twenty hours. Catalysts used in such hydrocracking reactions are catalysts of the type known in the art for this type of conversion reaction, and representative examples are precious metals such as nickel, palladium, platinum, rhodium. The catalyst is usually used in an amount of about 0.01 to about 2.5% by weight, preferably about 0.1 to about 1.0% by weight, based on the compound of general formula (III). Sometimes it is convenient to suspend the catalyst on an unstable support, a particularly convenient catalyst being palladium suspended on an inert support such as carbon.

Other methods may be used for the reductive removal of halogen from the compound of general formula (III), ie step (b). For example, dissolved metal reduction systems such as zinc powder in acetic acid, formic acid or phosphate buffers can be used to remove X and Y according to known methods. Alternatively, in step (b), tinhydrides such as trialkyltin hydrides such as tri-n-butyltin hydride may be used.

The experts known were as R ¹ is hydrogen to in the art the general formula (I), if desired to produce the compound, the steps of the present invention the general formula (Ⅱ) compound, R ¹ is hydrogen the step (a) and (b Please follow the instructions below. That is, the 6-halo or 6,6-dihalo derivatives of peniclanic acid having the free carboxy group at the 3-position are oxidized and then dehalogenated. However, according to a further aspect of the invention a carboxy group of three positions is conventional. It is also possible to block with a penicillin carboxyprotecting group and initiate the reaction of any of steps (a) and (b). The protecting group can be removed during or after performing step (a) or (b) to form the free carboxy group. In this case, any of a variety of protection groups commonly used in the penicillin field can be used to protect the 3-carboxy group. An important condition for protecting groups is that they must be able to attach to certain compounds of formula (II) or (III) under conditions in which the beta-lactam ring system remains intact. It should be able to be removed from. Examples of representative protecting groups for each of steps (a) and (b) include tetrahydropyranyl groups, trialkylsilyl groups, benzyl groups, substituted benzyl groups (eg 4-nitrobenzyl), benzhydryl groups , 2,2,2-tri-chloroethyl group, tert-butyl group and phenacyl group. In all cases, no protection group can be used, but experts in the art can easily select a particular group that can be used in a particular case. (See, eg, US Pat. Nos. 3,632,850 and 3, l97,466; UK Pat. No. 1,041,985; Woodward et al, Journal of the American chemical soci-ety 88, 852 (1966); chauvette, journal of Organic Chemistry, 36 , 1259 (1971); Sheehan et al, Journal of Organic Chemistry, 29, 2006 (1964) and HE Flynn, Academic Press, Inc., 1972 "Cephalosporin and Penicillins, Chemistry and Biology") It removes by a well-known method in consideration of ring system instability.

Formulas (I), (II) and (III), wherein R ¹ is hydrogen, are acidic and form basic compounds and salts. Such salts may be prepared by standard methods of contacting acidic and basic compounds, usually in stoichiometric ratios, in a suitable aqueous, non-aqueous or partially aqueous medium. The resulting salt is then recovered by filtration, precipitation with nonsolvent and then filtration, evaporation of the solvent, or lyophilization if aqueous solution. Suitable basic compounds used for salt formation include both organic and inorganic compounds and include alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides as well as ammonia, organic amines, alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Representative examples of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, diethylamine. Secondary amines such as morpholine, pyrrolidine and piperidine, such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo [4.3.0] non-5-ene Tertiary amines, sodium hydroxide, potassium hydroxide, hydroxides such as ammonium 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, sodium bicarbonate and bicarbonate Alkali metal salts of bicarbonates such as potassium and long chain fatty acids such as sodium 2-ethylhexanoate. Preferred salts of the compound of general formula (I) are sodium, potassium and triethylamine salts.

Formula (I) compounds and salts thereof, wherein R ¹ is hydrogen, exhibit activity as an antimicrobial agent with moderate potency in vitro and in vivo, and R ¹ is an ester-forming residue that can be readily hydrolyzed in vivo The general formula (I) compound exhibits activity as an antibacterial agent having moderate effects in vivo. The minimum inhibitory concentration (MIS'S) of peniclanic acid 1,1-dioxide for several microorganisms is shown in Table 1.

TABLE 1

In Vitro Bacterial Activity of Peniclanic Acid, 1,1-Dioxide

Formula (I) compounds and salts thereof, wherein R ¹ is hydrogen, exhibit antimicrobial activity in vitro, and are useful as industrial antimicrobial agents for water treatment, slime control, paint preservation and wood preservation. useful. When these compounds are used topically, it is convenient to mix the active ingredient with non-toxic carriers such as vegetable oil, mineral oil or emollient cream.

Likewise, the active ingredient may be dissolved or dispersed in a solvent such as a liquid diluent or water, alkanols, glycols or mixtures thereof. In most cases, it is appropriate to use the active ingredient in a concentration of about 0.01 to about 10% by weight based on the total composition.

Formula 1 and its salts, wherein R ¹ is hydrogen or an ester-forming residue that is easily hydrolyzed in vivo, and their salts exhibit in vivo activity to treat bacterial infections in mammals, including humans, by oral and parenteral administration. Suitable for The compounds are used in the treatment of infections caused by susceptible bacteria in humans, for example, by infection with Neisseria gonorrea strains.

When the compound of formula (I) or a salt thereof is used for therapeutic purposes in a mammal, especially a human, the compound may be administered alone or in admixture with a pharmaceutically acceptable carrier or diluent. They can be administered orally or parenterally, ie intramuscularly, subcutaneously or intraperitoneally. The carrier or diluent is selected according to the method of administration. For example, in the case of oral administration, the compound may be used according to pharmaceutical practice in the form of a stagnation, capsule, lozenge, troche, powder, syrup, elixir, aqueous solution and suspension. The ratio of active ingredient to carrier is determined by the chemical nature, solubility and stability of the active ingredient as well as the dosage used. However, pharmaceutical compositions containing an antimicrobial agent of general formula (I) generally contain from about 20% to about 95% of the active ingredient. In the case of tablets for oral administration, carriers commonly used include lactose, sodium citrate and phosphate. Tablets also use disintegrants such as starch, glidants such as magnesium stearate, sodium lauryl sulfate and talc. Lactose and high molecular weight polyethylene glycols are useful as diluents in capsules for oral administration. In the case of oral administration in an aqueous suspension, the active ingredient may be mixed with an emulsifier and a suspending agent.

If desired, sweetening and / or flavoring agents may be added. In parenteral administration intramuscularly, intraperitoneally, subcutaneously and intravenously, a sterile solution of the active ingredient is generally prepared to properly adjust and buffer the pH of the solution. Intravenous administration controls the total concentration of solutes and makes them isotonic.

The prescriber determines the appropriate dose of the general formula (I) compound for the patient, which is adjusted according to the age, weight and response of each patient as well as the characteristics and severity of the patient's symptoms. Compounds are used at normal doses of about 10 to about 200 mg / kg body weight, and parenterally at doses of about 10 to about 400 mg / kg body weight. In some cases, doses outside this range may be used.

The compound of formula (I) or a salt thereof, wherein R ¹ is hydrogen or an ester-forming residue that is easily hydrolyzed in vivo, enhances the efficacy of beta-lactam antibiotics in vivo.

They reduce the amount of antibiotics needed to protect mice from lethal inoculation of beta-lactamase producing bacteria. Thus, general formula (I) compounds can be administered together with beta-lactam antibiotics for the treatment of bacterial infections in mammals, especially humans.

In the treatment of bacterial infections, compounds of formula (I) and beta-lactam antibiotics may be mixed and administered simultaneously. Alternatively, the compound of formula (I) may be administered separately during treatment with beta-lactam antibiotics. In some cases, it is advantageous to pre-administer the compound of formula (I) to the patient before starting treatment with the beta-lactam antibiotic.

When peniclanic acid 1,1-dioxide, salts or esters that are readily hydrolyzed in vivo are used to enhance the effects of beta-lactam antibiotics, they are formulated with standard pharmaceutical carriers or diluents and administered. It is preferable.

The formulation of peniclanic acid 1,1-dioxide or its readily hydrolyzed estlet as an antibiotic can also be used in combination with other beta-lactam antibiotics. Pharmaceutical compositions consisting of pharmaceutically acceptable carriers, beta-lactam antibiotics and peniclanic acid 1,1-dioxide or its hydrolysable esters are generally pharmaceutically acceptable carriers, from about 5 to about 80 It contains% by weight.

When using peniclanic acid 1,1-dioxide or its easily hydrolyzed ester in vivo in combination with other betalactam antibiotics, sulfone can be administered orally or parenterally, ie intramuscularly, subcutaneously or intraperitoneally. . The dosage used in patients is determined by the prescribing physician, but the ratio of the daily dose of peniclanic acid 1,1-dioxide or its salt or ester and beta-lactam antibiotics is generally in the range of about 1: 3 to 3: 1. . In addition, when using peniclanic acid 1,1-dioxide or an easily hydrolyzed ester in vivo with other beta-lactam antibiotics, the daily oral dose of the individual components ranges from about 10 to about 200 mg / kg body weight. The daily parenteral dose of the individual components is generally from about 10 to about 400 mg / kg body weight. This figure is only an example, and in some cases capacity outside this range may be required.

Representative beta-lactam antibiotics that can be administered with peniclanic acid 1,1-dioxide and its esters, which are readily hydrolyzed in vivo, include 6- (2-phenylacetamido) phenylanic acid, 6- ( D-2-Amino-2-phenylacetamido) phenylanic acid, 6- (2-carboxy-2-phenylacetamido) -phenylanic acid and 7- (2- [1-tetrazolyl] -acetami Fig.)-3- (2- [5-methyl-1,3,4-thiadiazolyl] thiomethyl) -3-desacetoxymethylcephalosporonic acid.

Representative microorganisms that increase the antimicrobial activity of the beta-lactam antibiotics are Staphylococcus oreus, Haemophilus influenzae. Klebsiella pneumoniae and Bacteroides pragilis.

As is known to those skilled in the art, some beta-lactam compounds are effective for oral or parenteral administration while others are effective only by parenteral administration. When peniclanic acid 1,1, -dioxide, a salt thereof, or an ester thereof easily hydrolyzed in vivo with a beta-lactam antibiotic which is effective only by parenteral administration (mixed), a formulation suitable for parenteral administration is required. need. When penicilanic acid 1,1-dioxide or its esters are used orally or parenterally and simultaneously (mixed) with an effective beta-lactam antibiotic, it may be prepared in a formulation suitable for oral or parenteral administration. It is also possible to orally administer a preparation of peniclanic acid 1,1-dioxide or a salt or ester thereof and at the same time to parenterally administer other beta-lactam substances, and to penisilane acid 1,1-dioxide or a salt or ester thereof. Oral administration can also be given orally with other beta-lactam antibiotics.

A detailed description of the use and synthesis of compounds of general formula (I) is given in JP-A-2,824,535.

The following examples and preparation examples are provided for specific description. Infrared spectrum (IR) was performed by potassium bromide disk (KBr disk) method, and the confirmed absorption band is represented by wave number (cm- ¹ ). Nuclear Magnetic Resonance Spectrum (NMR) was measured at 60 MHz for deuterochloroform (CDCℓ ₃ ) solution, perduteroacetone (CD ₃ COCD ₃ ) solution, perteuterodimethyl sulfoxide (DMSO-d ₆ ) solution or deuterium oxide (D ₂ O). The solution was measured using a solution, and the peak position was expressed in ppm indicating shifting from the tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate toward the hypothalamus. The shape of the peak is explained using the following abbreviations: s singlet; d doublet; t triplet; q quartet; m Multiple lines.

Example 1

6-alpha-bromophenic silane acid 1,1-dioxide

To a stirred mixture of 560 ml of water, 300 ml of dichloromethane and 56.0 g of 6-alpha-bromophenic silane acid is added 4N sodium hydroxide solution until the pH is stable to 7.2. In this case 55 ml of sodium hydroxide is used. The mixture is stirred at pH 7.2 for 10 minutes and then filtered. The layers are separated and the organic phase is removed. The aqueous phase is poured quickly into the oxidized mixture prepared as follows with stirring.

63.2 g of potassium permanganate, 1000 mL of water and 48.0 g of acetic acid are mixed in a 3 L flask. The resulting mixture is stirred at 20 ° C. for 15 minutes and then cooled to 0 ° C.

After adding the 6-alpha-bromophenic acid solution to the oxidation mixture, a cooling bath at -15 ° C is maintained around the reaction mixture. The internal temperature rises to 15 ° C and then drops to 5 ° C over 20 minutes. At this time, 30.0 g of sodium metabisulfite was added over 10 minutes at about 10 ° C with stirring. After an additional 15 minutes, the mixture is filtered and 170 ml of 6N hydrochloric acid is added to lower the pH of the filtrate to 1.2. The aqueous phase is extracted with chloroform and then with ethyl acetate. Both the chloroform extract and ethyl acetate extract were dried using anhydrous magnesium sulfate, and then evaporated in vacuo. 10.0 g (16% yield) of the title compound are obtained from a chloroform solution. 57 g of an oily substance is obtained from an ethyl acetate solution and polished with hexane. A white solid is formed, which is filtered to give 41.5 g (yield 66%) of the title compound having a melting point of 134 DEG C (decomposition).

Elemental Analysis: C ₈ H ₁₀ BrNO ₅ S

Calculated (%): C 30.78; H3.23: Br25.60; N4.49; S10.27

Found (%): C31.05; H3.24; Br25.54; N4.66; S10.21

Example 2

According to the process of Example 1, 6-alpha-chlorophenicylic acid and 6-alpha-iodophenicylanic acid were co-oxidized with potassium permanganate to produce 6-alpha-chlorophenicylic acid 1,1-dioxide and 6-alpha-, respectively. Iodophenicsilane acid 1,1-dioxide is obtained.

Example 3

6-beta-chlorophenicylanic acid 1,1-dioxide

An oxidizing solution is prepared from 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 5 ml of water. The resulting oxidation solution is added dropwise to a solution of 150 mg sodium 6-beta-chlorophenicilanate in 5 ml of water at 0-5 ° C. until the purple of potassium permanganate persists. Approximately half of the oxidizing solution is consumed. At this time, sodium bisulfite is added to decolorize the color of potassium permanganate, and the reaction mixture is filtered. Ethyl acetate is added to the filtrate to adjust the pH to 1.8. The layers are separated and the larvae are further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and evaporated in vacuo to yield 118 mg of the title compound. NMR spectrum (in CD ₃ COCD ₃ ) shows absorption peaks at 5.82 (d, 1H), 5.24 (d, 1H), 4.53 (s, 1H), 1.62 (s, 3H) and 1.50 (s, 3H) ppm .

The product is dissolved in tetrahydrofuran and the same amount of water is added. The pH is adjusted to 6.8 using dilute narcium hydroxide, tetrahydrofuran is evaporated off in vacuo, and the residual aqueous solution is lyophilized. This affords sodium of the title compound.

Example 4

6-beta-bromophenic silane acid 1,1-dioxide

To a solution of 255 mg sodium 6-beta-bromophenicilanate in 5 ml of water, a solution prepared from 140 mg potassium permanganate, 0.11 ml of 85% phosphoric acid and 5 ml of water at 0-5 ° C. is added at 0-5 ° C. During application the pH is maintained between 6.0 and 6.4. The reaction mixture is stirred at pH 6.3 for 15 minutes and the purple solution is then covered with ethyl acetate.

Adjust the pH to 1.7 and add 330 mg of sodium bisulfite. After 5 minutes, the layers are separated and the larvae are further extracted with ethyl acetate. The combined ethyl acetate solutions are washed with brine, dried (MgSO ₄ ) and evaporated in vacuo. This affords 216 mg of the title compound as white crystals.

NMR spectra (in D ₂ O) were 5.78 (d, 1H, J = 4 Hz), 5.25 (d, 1H, J = 4 Hz), 4.20 (s, 1H), 1.65 (s, 3H) and 1.46 (s, 3H). Absorption peak in ppm.

Example 5

6-beta-iodophenicylanic acid 1,1-dioxide

According to the process of Example 4, 6-beta-iodophenicsilane acid was oxidized with potassium permanganate to give 6-beta-iodophenicylanic acid 1,1-dioxide.

Example 6

Pivaloyloxymethyl 6-alpha-bromophenicylanate 1,1-dioxide

400 mg of 3-chloroperbenzoic acid was added to a solution of 394 mg of pivaloyloxymethyl 6-alpha-bromophenicilanate in 10 ml of dichloromethane at 0? 5 占 폚. The reaction mixture is stirred at 0 ° to 5 ° C. for 1 hour and then at 25 ° C. for 24 hours. The filtered reaction mixture is evaporated to dryness in vacuo to afford the title compound.

Example 7

Repeat the process of Example 6 using the following compound instead of pivaloyloxymethyl 6-beta-bromophenicylanic acid 3-phthalidyl 6-alpha-chlorophenicilanate, 4-crotonolactonyl 6-beta-chlorophenicylanate, gamma-butyrolactone-4-yl 6-alpha-bromophenicylanate, acetoxymethyl 6-beta-bromophenicylanate, fibaroyloxymethyl 6-beta- Bromophenicylanate, hexanoyloxymethyl 6-alpha-iodophenicylanate, 1- (acetoxy) ethyl 6-beta-iodophenicylanate, 1- (isobutyryloxy) ethyl 6-alpha- Chlorophenicylanate, 1-methyl-1- (acetoxy) ethyl 6-beta-chlorophenicylanate, 1-methyl-1- (hexanoyloxy) ethyl 6-alpha-bromophenicylanate, methoxycarbo Nyloxymethyl 6-alpha-bromophenicylanate, propoxycarbonyloxymethyl 6-beta-bromophenicylanate. 1- (ethoxycarbonyloxy) ethyl 6-alpha-bromophenicylanate, 1- (butoxycarbonyloxy) ethyl 6-alpha-iodophenicylanate, 1-methyl-1- (methoxy Carbonyloxy) ethyl 6-beta-iodophenicylanate and 1-methyl-1- (isopropoxycarbonyloxy) ethyl 6-alpha-chlorophenicylanate.

Thus, each of the following compounds is obtained.

3-phthalidyl 6-alpha-chlorophenicilanate 1,1-dioxide, 4-crotonolactonyl 6-beta-chlorophenicilanate 1,1-dioxide, gamma-butyrolactone-4-yl 6- Alpha-bromophenicylanate 1,1-dioxide, acetoxymethyl 6-beta-bromophenicylanate 1,1-dioxide, pivaloyloxymethyl 6-beta-bromophenicylanate 1,1-dioxide , Hexanoyloxymethyl 6-alpha-iodophenicilanate 1,1-dioxide, 1- (acetoxy) ethyl 6-beta-iodophenicilanate 1,1-dioxide, 1- (isobutyryloxy) Ethyl 6-alpha-fluorophenicylanate 1,1-dioxide, 1-methyl-1- (acetoxy) ethyl 6-beta-chlorophenicilanate 1,1-dioxide, 1-methyl-1- (hexanoyl Oxy) ethyl 6-alpha-bromophenicylanate 1,1-dioxide, methoxycarbonyloxymethyl 6-alpha-bromophenicylanate 1,1-dioxide, propoxycarbonyloxymethyl 6-Beta-bromophenicylanate 1,1-dioxaad, 1- (ethoxycarbonyloxy) ethyl 6-alpha-bromophenicylanate 1,1-dioxide, 1- (butoxycarbonyloxy Ethyl 6-alpha-iodophenicylanate 1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl 6-beta-iodophenicylanate 1,1-dioxide and 1-methyl- 1- (isopropoxycarbonyloxy) ethyl 6-alpha-chlorophenicilanate 1,1-dioxide.

Example 8

Peniclanic Acid 1,1-Dioxide

To 100 ml of water, 9,4 g of 6-alpha-bromophenic silane acid 1,1-dioxide is added at 22 ° C, and then a sufficient amount of 4N sodium hydroxide solution is added to stabilize the pH to 7.3. 2.25 g of 5% palladium on carbon is added to the resulting solution, followed by 6.9 g of dipotassium potassium phosphate trihydrate. The mixture is then shaken under a hydrogen atmosphere at a pressure of 3.5 to 1.8 kg / cm ² . When absorption of hydrogen ceases, the solid is filtered off and the aqueous solution is covered with 100 ml of ethyl acetate. Add 6N hydrochloric acid and slowly lower the pH from 5.0 to 1.5. The layers are separated and the aqueous phase is further extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo.

The residue is triturated with ether and the solid is collected by filtration. This gives 4.5 g (65% yield) of the title compound.

Elemental Analysis: C ₈ H ₁₁ NO ₅ S

Calculated (%): Cl4.20; H4.75; N6.00; S13.75

Found (%): Cl4.16; H4.81; N6.11; S13.51

Example 9

Peniclanic Acid 1,1-Dioxide

The following compounds were each hydrolyzed according to the process of Example 8 to obtain peniclanic acid 1,1-dioxide. 6-alpha-chlorophenicylic acid 1,1-dioxide, 6-alpha-iodophenicylanic acid 1,1-dioxide, 6-beta-chlorophenicylanic acid 1,1-dioxide, 6-beta-bromopheny Silane acid 1,1-dioxide and 6-beta-iodophenicylic acid 1,1-dioxide.

Example 10

Pivaloyloxymethylphenicylanate 1,1-dioxide

To 1.0 g solution of pivaloyloxymethyl 6-alpha-bromophenicilanate in 10 ml of methanol, 3 ml of 1M sodium bicarbonate and 200 mg of 10% carbonaceous palladium are added. The reaction mixture is vigorously shaken under hydrogen atmosphere at a pressure of about 5 kg / cm ² until the uptake of hydrogen is stopped. The mixture is then filtered and most of the methanol is evaporated off in vacuo. Water and ethyl acetate are added to the residue, and the pH is adjusted to 8.5. The layers are separated and the organic layer is washed with water, dried (Na ₂ SO ₄ ) and evaporated in vacuo. This affords the title compound.

Example 11

The appropriate 6-halofenisilane ester 1,1-dioxide in Example 7 was hydrolyzed according to the process of Example 10 to yield the following compounds, respectively.

3-phthalidyl penicilanate 1,1-dioxide: 4-crotonacolatyl penicilanate 1,1-dioxide: gamma-butyrolactone-4-yl penicilanate 1,1-dioxide: acetoxymethyl Penicilanate 1,1-dioxide: pivaloyloxymethyl penicillate 1,1-dioxide: hexanoyloxymethyl penicilanate 1,1-dioxide: 1- (acetoxy) ethyl penicillate 1,1- Dioxide: 1- (isobutyryloxy) ethyl penicillate 1,1-dioxide: 1-methyl-1- (acetoxy) ethylphenicilanate 1,1-dioxide: 1-methyl-1- (hexanoyloxy Ethylphenicylanate 1,1-dioxide: methoxycarbonyloxymethyl penicillate 1,1-dioxide: propoxycarbonyloxymethyl penicilanate 1,1-dioxide: 1- (ethoxycarbonyloxy) Ethylphenicylanate 1,1-dioxide: 1- (butoxycarbonyl) ethylphenicylanate 1,1-dioxide : 1-methyl-1- (methoxycarbonyloxy) ethylphenicylanate 1,1-dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethylphenicylanate 1,1-dioxide.

Example 12

Pivaloyloxymethyl 6-alpha-bromophenicylanate 1,1-dioxide

An oxidation solution is prepared from 4,26 g of potassium permanganate, 2.65 g of 85% phosphoric acid and 40 ml of water. The mixture is stirred for 1 hour and then slowly added to a solution of 5.32 g of pivaloyloxymethyl 6-alpha-bromophenicylanate in 70 ml of acetone and 10 ml of water over 20 minutes at 5-10 ° C. The mixture is stirred at 5 ° C. for 30 minutes and 100 ml of ethyl acetate are added. After 30 minutes, a solution of 3.12 g of sodium bisulfite in 30 ml of water is added at about 10 ° C. over 15 minutes. After stirring for 30 minutes at 5 ° C., the mixture is filtered. The organic phase is separated and washed with saturated sodium chloride solution. Evaporation of the dried organic layer affords 5.4 g of the title compound as an oil which slowly crystallizes. NMR spectra (in CDl 3) are 5.80 (q, 2H), 5.15 (d, 1H), 4.75 (d, 1H), 4.50 (s, 1H), 1.60 (s, 3H), 1.40 (s, 3H) and 1.20 Absorption peak is shown at (s, 9H) ppm.

Example 13

Pivaloyloxymethyl peniclanate 1,1-dioxide

A solution of 4.4 g of pivaloyloxymethyl 6-alpha-bromophenicylanate in 60 ml of tetrahydrofuran is added to 0.84 g of sodium bicarbonate in 12 ml of water. The solution is shaken under 47-51 psig hydrogen atmosphere in the presence of 2.0 g 5% palladium on carbon. The reaction mixture is then filtered and the residue is washed with 100 ml of ethyl acetate and 25 ml of water. Combine the filtrate and wash to separate the layers. The organic layer is washed with saturated sodium chloride, dried (MgSO ₄ ) and evaporated to afford the title compound as an oil. The resulting oily substance is dissolved in ethyl acetate (20 ml). Hexane (100 ml) was slowly added to the solution, and the precipitate was filtered (amount: 2.4 g).

NMR spectra (of DMSO-d ₆ ) are 5.75 (q, 2H), 5.05 (m, 1H), 4.40 (s, 1H), 3.95 to 2.95 (m, 2H), 1.40 (s, 3H), 1.25 (s , 3H) and 1,10 (s, 9H) ppm.

Example 14

2,2,2-trichloroethyl 6-alpha-bromophenicylanate 1,1, -dioxide

2,2,2-trichloroethyl 6-alpha-bromophenicylanate was oxidized to potassium permanganate according to the process of Example 12 to give the title compound in 79% yield. The NMR spectra of the product (in CDl ₃ ) show absorption peaks at 5.30 to 4.70 (m, 4H), 4.60 (s, 1H), 1,70 (s, 3H) and 1.50 (s, 3H) ppm.

Example 14A

Peniclanic Acid 1,1-Dioxide

In a stirred slurry of 6.5 g of zinc powder in 100 ml of a 70:30 glacial acetic acid-tetrahydrofuran mixture, 4.0 g of 2,2,2-trichloroethyl 6-alpha-bromophenicylanate 1,1-dioxide was mixed over 5 minutes. Little by little The mixture is stirred at ambient temperature for 3 hours and then filtered. The filtrate is concentrated to a 10 mL solution and the resulting tan solution is mixed with 50 mL of water and 100 mL of ethyl acetate. Adjust pH to 1.3 and separate layers. The organic phase is washed with saturated sodium chloride solution, dried using magnesium sulfate and concentrated to dryness in vacuo. The residue is triturated with ether for 20 minutes. This gives 553 mg of the solid title compound. NMR spectra (from CDl ₃ / DMSO-d ₆ ) were 11.2 (broad s, 1H), 4.65 (m, 1H), 4.30 (s, 1H), 3.40 (m, 2H), 1.65 (s, 3H) and 1.50 Absorption peak is shown in (s, 3H) ppm.

Example 15

Benzyl 6-alpha-bromophenicylanate 1,1-dioxide

Benzyl 6-alpha-bromophenicylanate was oxidized to potassium permanganate following the procedure of Example 12 to afford the title compound in 94% yield. NMR spectra (in CDl ₃ ) are 7.35 (s, 5H), 5.10 (m, 3H), 4.85 (m, 1H), 4.40 (s, 1H), 1.50 (s, 3H) and 1.25 (s, 3H) ppm Absorption peak at.

Example 16

Peniclanic Acid 1,1-Dioxide

A 4.0 g solution of benzyl 6-alpha-bromophenicylanate 1,1-dioxide in 50 ml of tetrahydrofuran is mixed with a solution of 1.06 g of sodium bicarbonate in 50 ml of water. To the mixture is added 2.0 g of a 50% suspension of 5% palladium on carbon in water, followed by shaking for 20 minutes under hydrogen atmosphere at a pressure of 46.5 to 50 psig. After the catalyst is filtered off, 30 ml of tetrahydrofuran and 3.0 g of a 50% suspension of palladium on 5% carbon are added. The resulting mixture is shaken for 65 minutes under a hydrogen atmosphere of pressure 42-45 psi. The reaction mixture is filtered and tetrahydrofuran is evaporated off. Ethyl acetate is added to the aqueous residue and the pH is adjusted to 7.1. The ethyl acetate layer is separated and fresh ethyl acetate is added to the residual aqueous phase. The pH is lowered to 1.5 and the layers are separated. The aqueous phase is further extracted with ethyl acetate, the combined ethyl acetate solutions are washed with saturated sodium chloride solution and dried (MgSO 4).

Evaporation in vacuo affords a rubbery material which is ground with ether. This gives 31 mg of peniclanic acid 1,1-dioxide as a yellow solid. NMR spectra (of CDL ₂ / DMSO-d ₆ ) were 9.45 (broads, 1H), 4.60 (±, 1H) 4,25 (s, 1H), 3.40 (d, 2H), 1.65 (s, 3H) and Absorption peak is shown at 1,30 (s, 3H) ppm.

Example 17

6,6-dibromophenic silane acid 1,1-dioxide

To a dichloromethane solution of 6.6-dibromophenisilane acid obtained from Preparation Example K was added 300 ml of water, followed by dropwise addition of 105 ml of 3N sodium hydroxide over 30 minutes. The pH is stabilized to 7.0. The aqueous layer is separated and the organic layer is extracted with water (2 x 100 ml). Combine the aqueous solution and add a mixed solution prepared from 59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml of water until the pink color of permanganic acid persists at -5 ° C. The addition takes 50 minutes and requires 550 ml of oxidant. At this time, 500 ml of ethyl acetate was added, and 105 ml of 6N hydrochloric acid was added to lower the pH to 1.23. Then 250 ml of 1M sodium bisulfite is added at about 10 ° C. over 10 to 15 minutes. During the addition of the sodium bisulfite solution, the pH is maintained at 1.25 to 1.35 using 6N hydrochloric acid. The aqueous phase is saturated with sodium chloride and the two layers are separated. The aqueous solution is extracted with an additional amount of ethyl acetate (2 x 150 mL), the combined ethyl acetate solutions are washed with brine and dried (MgSO ₄ ). This yields an ethyl acetate solution of 6,6-dibromophenic silane 1,1-dioxide.

The solvent is removed in vacuo to separate 6,6-dibromophenicylanic acid 1,1-dioxide. Melting | fusing point of the isolate | separated sample is 261 degreeC (decomposition). NMR spectra (CDCℓ ₃ / DMSO-d ₆ ) are 9.35 (s, 1H), 5.30 (s, 1H), 5.30 (s, 1H), 4.42 (s, 1H), 1.63 (s, 3H) and 1.50 (s , 3H) absorption peak in ppm. In the IR spectrum (KBr discs) absorption appears at 3846-2500,1818,1754,1342 and 1250-1110 cm- ³ .

Example 18

6-chloro-6-iodophenicylanic acid 1,1-dioxide

50 ml of water was added to a solution of 4.9 g of 6-chloro-6-iodophenicsilane acid in 50 ml of dichloromethane, and the pH was raised to 7.2 using 3N sodium hydroxide. The layers are separated and the aqueous layer is cooled to 5 ° C. Then, a mixed solution prepared from 2.61 g of potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water was added dropwise to the solution over 20 minutes. During the addition, the pH is kept at 6 and the temperature is kept below 10 ° C. Then 100 ml of ethyl acetate is added and the pH is adjusted to 1.5. Maintain the temperature below 10 ° C, add 50N of 10% sodium bisulfite to the mixture while adding 6N hydrochloric acid to maintain the pH at about 1.5. Lower the pH to 1.25 and separate the layers. The aqueous layer is saturated with sodium chloride and extracted with ethyl acetate. The combined organic solutions are washed with brine, dried (MgSo ₄ ) and evaporated in vacuo to yield 4.2 g of the title compound at a melting point of 143 to 145 ° C. NMR spectrum (CDCl ₃ ) shows absorption at 4.86 (s, 1H), 4.38 (s, 1H), 4.38 (s, 1H), 1.60 (s, 3H) and 1.43 (s, 3H) ppm. IR spectra (KBr discs) exhibit absorption at 1800,1740 and 1250-1110 cm ⁻¹ .

Example 19

6-bromo-6-iodophenicylanic acid 1,1-dioxide

50 ml of water is added to a solution of 6.0 g of 6-bromo-6, -iodophenicylic acid in 50 ml of dichloromethane. Using 3N sodium hydroxide raise the pH to 7.3 and isolate the larvae. The organic layer is extracted with 10 ml of water. The aqueous phases are combined and cooled to 5 ° C. and a previously prepared mixed solution of 2 ml of concentrated phosphoric acid and 284 g of potassium permanganate in 50 ml of water is added dropwise at 5-10 ° C. It takes 20 minutes to add. At this time, 50 ml of ethyl acetate was added and 6N hydrochloric acid was added to lower the pH of the mixture to 1.5. 6 N hydrochloric acid is added to the resulting ideal system, and 50 ml of sodium sulfite in 10% is added dropwise while maintaining the pH at about 1.5 degrees. Further 50 ml of ethyl acetate was added and the pH was lowered to 1.23. The layers are separated and the aqueous layer is saturated with sodium chloride. The saturated solution was extracted with ethyl acetate (3 × 50 mL), the ethyl acetate layers were combined, washed with brine, dried (MgSO ₄ ) and evaporated in vacuo. The residue was dried and dried under high vacuum to obtain 4.2 g of the title compound at a melting point of 145 to 147 캜. NMR spectrum (CDCl ₃ ) shows absorption at 4.90 (s, 1H), 4.30 (s, 1H), and 1.60 (s, 3H) ppm. IR spectra (KBr dask) exhibit absorption at 1800, 1740, 1330 and 1250 to 1110 cm ⁻¹ .

Example 20

6-chloro-6-bromophenic silane acid 1,1-dioxide

6-Chloro-6-bromophenic silane acid was oxidized with potassium permanganate according to the process of Example 19 to obtain 6-chloro-6-bromophenic silane acid 1,1-dioxide.

Example 21

Peniclanic Acid 1, 1-Dioxide

The ethyl acetate solution of 6,6-dibromo-phenylanic acid 1,1-dioxide obtained in Example 17 was mixed with 705 ml of saturated sodium bicarbonate solution and 8.88 g of 5% palladium on carbon catalyst. The mixture is shaken under hydrogen atmosphere at pressure of about 5 kg / cm < 2 > for about 1 hour. The catalyst is removed by filtration and the pH of the aqueous phase in the filtrate is adjusted to 1.2 using 6N hydrochloric acid. The aqueous phase is saturated with sodium chloride. The layers are separated and the aqueous phase is further extracted with ethyl acetate (3 x 200 mL). The combined ethyl acetate solutions were dried (MgSO ₄ ) and evaporated in vacuo to yield 33.5 g of peniclanic acid 1,1-dioxide (58% yield from 6-aminophenicylanic acid). The product is dissolved in 600 ml of ethyl acetate and the solution is decolorized using activated charcoal and the solvent is removed by evaporation in vacuo. The product is washed with hexane. 31.0 g of pure product is obtained.

Example 22

6-chloro-6-iodophenicylanic acid 1,1-dioxide.

6-Bromo-6-iodophenicylanic acid and 6-chloro-6-bromophenicylanic acid were respectively hydrolyzed according to the process of Example 21 to obtain in each case phenylanic acid 1,1-dioxide. do.

Example 23

Peniclanic Acid 1,1-Dioxide

To a stirring suspension of 786 mg of 6-chloro-6-iodophenicsilane acid 1,1-dioxide in 10 ml of benzene was added 0.3 ml of triethylamine at about 0 ° C. followed by 0.25 ml of trimethylsilyl chloride. Stirring is continued for 5 minutes at about 0 ° C. and 30 minutes at reflux temperature of the solvent. The reaction mixture is cooled to 25 ° C. and the precipitated material is filtered off. The filtrate is cooled to about 0 ° C. and 1.16 g of tri-n-butyltin hydride and mg of azobisisobutynitrile water are added. The reaction mixture is stirred and irradiated with ultraviolet light for about 1 hour at about 0 ° C. and 3.5 hours at reflux of the solvent. An additional amount of tri-n-butyltin hydride (1.1 ml) and a catalytic amount of azobisisobutyronitrile was added and stirring and irradiation were continued for an additional hour at reflux temperature. The reaction mixture is then poured into 50 ml of cold 5% sodium carbonate bicarbonate and the ideal system is stirred for 30 minutes. Ethine acetate (50 ml) was added. Adjust the pH to 1.5 with 6N hydrochloric acid. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO 4) and evaporated in vacuo. The residue is triturated with hexane and then recovered by filtration. This affords 0.075 mg of the title compound.

Example 24

Peniclanic Acid 1,1-Dioxide

To a stirred suspension of 0.874 g of 6-bromo-6-iodophenicsilane acid 1,1-dioxide in 10 ml of benzene was added 0.3 ml of triethylamine at about 5 ° C. followed by 0.25 ml of trimethylsilyl chloride. Stirring is continued for about 5 minutes at about 5 ° C. and 30 minutes at reflux temperature of the solvent. The reaction mixture is cooled to room temperature and the solid is filtered off. The filtrate is cooled to about 5 ° C. and 1.05 ml of tri-n-butyltin hydride and azobisisobutyronitrile in catalytic amounts are added. The mixture is irradiated with ultraviolet light at about 5 ° C. for 1 hour and then poured into 30 ml of cold 5% sodium bicarbonate. The mixture was stirred for 30 minutes and then 50 ml of ethyl acetate was added. The mixture is acidified to pH 1.5 and the layers are separated. The aqueous layer is extracted with ethyl acetate (2 × 25 mL), the combined ethyl acetate layers are washed with brine, dried (MgSO ₄ ) and evaporated in vacuo. The residue is dried under high vacuum and 30 ml of hexane is added. The inert material was recovered by filtration to give the title compound.

Example 25

Pivaloyloxymethyl 6,6-dibromophenicylanate 1,1-dioxide

3.80 g of 3-chloroperbenzoic acid are added to a solution of 4.73 g of pivaloyloxymethyl 6,6-dibromophenicylanate in 15 ml of dichloromethane at 0? 5 占 폚. The reaction mixture is stirred at 0-5 ° C. for 1 hour and at 25 ° C. for 24 hours. The filtered reaction mixture is evaporated to dryness in vacuo and the residue is partitioned between ethyl acetate and water. The pH of the aqueous phase is adjusted to 7.5 and the layers are separated. The ethyl acetate phase is dried (Na ₂ SO ₄ ) and evaporated in vacuo to afford the title compound.

Example 26

The 6,6-dihalophenicylic acid esters of Preparation Example P were each oxidized to 3-chloroperbenzoic acid according to the process of Example 25 to obtain the following compounds.

3-phthalidyl 6,6-dibromophenicylanate 1,1-dioxide, 4-crotonolactonyl 6-chloro-6-iodophenicylanate 1,1-dioxide, gamma-butyrolactonyl 6-Bromo-6-iodinephenylanate 1,1-dioxide, acetoxymethyl 6-chloro-6-bromophenicylanate 1,1-dioxide: pivaloyloxymethyl 6-chloro-6-iodo Penicilanate 1,1-dioxide: hexanoyloxymethyl 6,6-dibromophenicylanate 1,1-dioxide 1- (acetoxy) ethyl 6,6-dibromophenicylanate 1,1-dioxide : 1- (isobutyryloxy) ethyl 6-bromo-6-iodophenicylanate 1,1-dioxide: 1-methyl-1- (acetoxy) ethyl 6,6-dibromophenicylanate 1 , 1-dioxide: 1-methyl-1- (hexanoyloxy) ethyl 6-chloro-6-bromophenicylanate methoxycarbonyloxy methyl 6,6-dibromophenicylanate 1,1-dioxide: Propoxycarbonyloxymethyl 6-chloro-6-iodophenicylanate 1,1-dioxide: 1- (ethoxycarbonyloxy) ethyl 6,6-dibromophenicylanate 1,1-dioxide: 1- (butoxycarbonyl Oxy) ethyl 6-bromo-6-iodophenicilanate 1,1-dioxide: 1-methyl-1- (methoxycarbonyloxy) ethyl 6,6-diboromo-penicilanate 1,1- Dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethyl 6,6-dibromo-penicilanate 1, 1-dioxide.

Example 27

Pivaloyloxymethylphenicylanate 1,1-dioxide

To a solution of 1.0 g of pivaloyloxymethyl 6,6-dibromophenicylanate 1,1-dioxide in 10 ml of methanol, 3 ml of 1M sodium bicarbonate and 200 mg of 10% palladium on carbon were added. The reaction mixture is vigorously shaken under hydrogen atmosphere at a pressure of about 5 kg / cm ² until the absorption of hydrogen is stopped. The mixture is filtered and most of the methanol is removed by evaporation in vacuo. Water and ethyl acetate are added to the residue, and the pH is adjusted to 8.5. The layers are separated and the organic layer is washed with water, dried (Na ₂ SO ₄ ) and evaporated in vacuo. This gives pivaloyloxymethyl penicillate 1,1-dioxide.

Example 28

The 6,6-dihalo-phenicylic acid ester 1,1-dioxide obtained from Example 26 was hydrolyzed according to the process of Example 27 to obtain the following compounds. 3-phthalyridylphenylanate 1,1-dioxide 4-crotononolactonyl penicilanate 1,1-dioxide: gamma-butyrolactone-4-yl penicilanate 1,1-dioxide: acetoxymethyl penny Silaneate 1,1-dioxide: pivaloyloxymethyl penicillate 1,1-dioxide: hexanoyloxymethyl penicillate 1,1-dioxide 1- (acetoxy) ethyl peniclanate 1,1-dioxide: 1- (isobutyryloxy) ethyl penicillate 1,1-dioxide: 1-methyl- (acetoxy) ethyl penicillate 1, 1-dioxide: 1-methyl-1- (hexanoyloxy) ethyl penicila Nate 1,1-dioxide: methoxycarbonyloxymethyl penicillate 1,1-dioxide: propoxycarbonyloxymethyl penicilanate 1,1-dioxide: 1- (ethoxycarbonyloxy) ethyl penicula Nate 1,1-dioxide: 1- (subspecific carbonyl) ethyl penicillate 1,1-dioxide : 1-methyl-1- (lypoxycarbonyloxy) ethyl penicillate 1,1-dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethyl penicillate 1,1-dioxide.

Example 29

Pivaloyloxymethyl 6,6-dibromophenicylanate 1,1-dioxide

A stirring solution of 3.92 g of 6,6-dibromophenic silane acid 1,1-dioxide in 20 ml of N, N-dimethylformamide was cooled to 0 ° C and 1.29 g of diisopropylethylamine were added. Then 1.51 g of chloromethylpivalate is added. The reaction mixture is stirred at 0 ° C. for 3 hours and then at room temperature for 16 hours. The reaction mixture is then diluted with 25 mL of ethyl acetate and 25 mL of water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The ethyl acetate layers were combined and washed with cold 5% sodium bicarbonate solution, water and brine. The ethyl acetate solution is then treated with Darco (activated carbon), dried (MgSO ₄ ) and evaporated in vacuo to give 2.1 g of a brown oily substance. The resulting oil is chromatographed on 200 g of silica gel using chloromethane as eluent. Do it. Fractions containing the desired product are combined and rechromatography on silica gel to afford 0.025 g of the title compound. NMR spectra show absorption at 6.10 (q, 2H), 5.00 (s, 1), 4.55 (s, 1H), 1.60 (s, 3H), 1.50 (s, 3H) and 1.15 (s, 9H) ppm.

Example 30

Pivaloyloxymethyl peniclanate 1,1-dioxide

55 µl of tri-n-butyltin hydride is added to a stirred solution of 60 mg of pivaloyloxymethyl penicillate 1,1-dioxide in 5 ml of benzene, followed by addition of azobisisobutyronitrile in a catalytic amount. After cooling the reaction mixture to about 5 ℃ irradiated with ultraviolet light for 1 hour. The reaction mixture is poured into 20 ml of cold 5% sodium bicarbonate and stirred for 30 minutes.

Ethyl acetate is added and the pH of the aqueous phase is adjusted to 7.0. The layers are separated and the aqueous phase is further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO ₄ ) and evaporated in vacuo. The residue is dried under high vacuum for 30 minutes. This affords 70 mg of a chromatic oily substance, which can be seen by NMR spectroscopy to contain some impurities containing n-butyl groups with the title compound.

Example 31

6,6-dibromophenic silane acid 1,1-dioxide

380 mg of 3-chloroperbenzoic acid is added to a solution of 359 mg of 6,6-dibromophenicsilane acid in 30 ml of dichloromethane at 0? 5 占 폚. The reaction mixture is stirred at 0-5 ° C. for 30 minutes and then at 25 ° C. for 24 hours. The filtered reaction mixture is evaporated in vacuo to afford the title compound.

Example 32

Benzyl 6,6-dibromophenicylanate 1,1-dioxide

A mixture of 10.0 g of 6,6-dibromophenic silane 1,1-dioxide, 2.15 g of sodium bicarbonate, 3.06 ml of benzylbromide and 100 ml of N, N-dimethylformamide is stirred overnight at ambient temperature. Most of the solvent is evaporated off in vacuo and the residue is partitioned between ethyl acetate and water. The organic layer was separated, washed with 1N hydrochloric acid and saturated sodium chloride, and dried (Na ₂ SO ₄ ). Evaporation in vacuo afforded 11.55 g of the title compound. NMR spectra (CDCℓ ₃ ) were found at 7.40 (s, 5H), 5.30 (m, 2H), 4.95 (s, 1H), 4.55 (s, 1H), 1.50 (s, 3H) and 1.20 (s, 3H) ppm Absorption.

Example 33

Peniclanic Acid 1,1-Dioxide

To a solution of 2.0 g of benzyl-6,6-dibromophenicylanate 1,1-dioxide in 50 ml of tetrahydrofuran, a solution of 0.99 g of sodium bicarbonate in 50 ml of water is added followed by 2.0 g of palladium on 2.0 g carbon. The mixture is shaken for 70 minutes under about 50 psig of hydrogen atmosphere. Tetrahydrofuran is evaporated off and the residue is partitioned between ethyl acetate and water at pH7.37, the aqueous layer is removed and fresh ethyl acetate is added. The pH is lowered to 1.17, the ethyl acetate is removed, and then washed with saturated sodium chloride solution. Evaporation in vacuo afforded 423 mg of the title product.

Example 34

2,2,2-trichloroethyl 6,6-dibromophenicylanate 1,1-dioxide

The title compound is prepared according to the procedure of J in the preparation from 6,6-dibromophenicsilane acid 1,1-dioxide and 2,2,2-trichloroethylchloroformate. The product is purified by chromatography on silica gel. NMR spectrum (CDCℓ ₃ ) of the product is 4.85 (m, 2H). Absorption is shown at 1.65 (s, 3H) and 1.45 (s, 3H) ppm.

Example 35

Peniclanic Acid 1,1-Dioxide

2,2,2-t is reduced using zinc powder according to Example 14A in a mixture of chloroethyl 6,6-dibromophenicylanate 1,1-dioxide in glacial acetic acid and tetrahydrofuran. Yield 27%.

Example 36

1- (ethoxycarbonyloxy) ethyl 6,6-dibromophenicylanate 1,1-dioxide

2.26 g of 6,6-dibromophenisilane acid 1,1-dioxide, 1.02 ml of 1- (ethoxycarbonyloxy) -ethylchloride, 1.32 ml of diisopropylethylamine and 10 ml of N, N-dimethylformamide The mixture is stirred at rt for 28 h.

The reaction mixture is diluted with 100 ml of ethyl acetate and washed successively with water, diluted hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. Anhydrous ethyl acetate solution was evaporated in vacuo to yield 1.50 g of an oily material which was chromatographed on silica gel. This affords 353 mg of the title compound contaminated with a small amount of 1- (ethoxycarbonyloxy) ethyl 6-bromophenicylanate.

Example 37

1- (ethoxycarbonyloxy) ethyl penicillate 1,1-dioxide

A portion (230 mg) of the product of Example 36 was dissolved in 10 mL of toluene. 0.4 ml of tri-n-butyltin hydride was added thereto, followed by 0.164 g of azobis isobutyronitrile, and the mixture was heated to 70 to 80 ° C. for 3.5 hours. The solvent is removed by evaporation in vacuo and the residue is dissolved in 25 ml of acetonitrile. The acetonitrile solution is washed several times with hexane and evaporated in vacuo. The residue is dissolved in ether and the ether solution is washed with 5% potassium fluoride followed by saturated sodium chloride. The dried (NaSO ₄ ) ether solution is evaporated in vacuo and the residue is chromatographed on silica gel to give 0.049 g of the title product. NMR spectra (CDCl ₃ ) exhibit absorption at 6.75 (m), 4.60 (m), 4.30 (m), 4.15 (s), 4.00 (s), 3.30 (d) and 1.75 to 1.00 (m) ppm.

Production Example A

6-chloro-6-iodophenicsilane acid

To 1.38 g of 2.5 N sulfuric acid is added to 3.38 g of iodine monochloride in 30 ml of dichloromethane at 0-5 ° C., followed by 1.92 g of sodium nitrite. At this time, 3.00 g of 6-aminophenic silane acid was added all at once, and stirring was continued at 0 to 5 ° C for 30 minutes. Thereafter, 22.8 ml of 1 M sodium arsenite solution was added to the reaction mixture several times, and the layers were separated. The aqueous layer is further washed with dichloromethane and all organic phases are washed with saturated sodium silver. The dichloromethane solution is dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 3.48 g of the title compound.

The above product was dissolved in 30 mL of tetrahydrofuran and 30 mL of water was added thereto. Dilute sodium hydroxide is added to adjust the pH to 6.8 and the tetrahydrofuran is removed in vacuo. The residue aqueous phase is lyophilized and the residue is washed with diethyl ether. This affords 3.67 sodium salt of the title compound.

Preparation Example B

6-beta-chlorophenic silane acid

2.95 g of a sodium 6-chlor-6-iodophenicylanic acid sample are converted to free acid, which is dissolved in 125 ml of benzene under nitrogen. To the resulting solution is added 1.08 mL of triethylamine, and the mixture is cooled to 0-5 ° C. 0.977 mL of trimethylsilyl chloride is added to the cooled mixture, and the reaction mixture is stirred for 5 minutes at 0 to 5 ° C, 60 minutes at 25 ° C, and 30 minutes at 50 ° C. The reaction mixture is cooled to 25 ° C. and triethylamine hydrochloride is removed by filtration. 15 mg of azobisisobutyronitrile is added to the filtrate, followed by 2.02 ml of tri-n-butyltin hydride. The mixture is irradiated with ultraviolet light for 15 minutes while cooling to maintain the temperature at about 20 ° C. The solvent is removed by evaporation in vacuo and the residue is dissolved in a 1: 1 mixture of tetrahydrofuran-water. The pH is adjusted to 7.0 and tetrahydrofuran is evaporated off in vacuo. After washing the aqueous phase with ether, an equal volume of ethyl acetate is added. The pH is adjusted to 1.8 and the ethyl acetate layer is separated. The aqueous phase is further extracted with ethyl acetate, the combined ethyl acetate solutions are dried and evaporated in vacuo. This affords 980 mg of 6-beta-chlorophenicylanic acid.

The product is dissolved in tetrahydrofuran and equal volume of water is added. The pH is adjusted to 6.8 and tetrahydrofuran is removed by evaporation in vacuo. The residue aqueous phase is lyophilized to yield 850 mg of sodium 6-beta-fluorophenicylanate. NMR spectra (D ₂ O) are 5.70 (d, 1H, J = 4 Hz), 5.50 (d, 1H, J = 4 Hz), 4.36 (s, 1H), 1.60 (s, 3H) and 1.53 (s, 3H) Absorption is shown at ppm.

Preparation Example C

6-beta-bromophenic silane acid

A mixture of 5.0 g of 6,6-dibromophenisilane acid, 1.54 ml of triethylamine and 100 ml of benzene is stirred under nitrogen until a solution is produced. The solution is cooled to 0-5 [deg.] C. and 1.78 mL of trimethylsilyl chloride is added. The reaction mixture is stirred at 0-5 ° C. for 2-3 minutes and at 50 ° C. for 35 minutes. The cooled reaction mixture is filtered and the filtrate is cooled to 0-5 ° C. A small amount of azobisisobutyronitrile is added followed by 3.65 ml of pre-n-butyltin hydride. After irradiating the reaction flask with 15 parts of ultraviolet rays, the reaction solution was stirred at about 25 ° C. for 1.75 hours.

The reaction mixture was re-examined for 15 minutes and then stirred for 2.5 hours. At this time, a small amount of bisisobutyronitrile was further added, followed by addition of 0.6 ml of tri-n-butyltin hydride, followed by 20 minutes of mixture. Reexamine while The solvent is evaporated off in vacuo and 5% sodium bicarbonate solution and diethyl ether are added to the residue. The formed ideal system was vigorously shaken for 10 minutes and the pH was adjusted to 2.0. The ether layer is separated, dried and evaporated in vacuo to yield 2.35 g of oily material. Water containing sodium bicarbonate equivalents is added to the oily substance, and then the resulting solvent is lyophilized to switch to sodium salt. This affords sodium 6-beta-bromophenicilanate contaminated with a small amount of alpha isomer.

Sodium salt is purified by chromatography on Sephadex LH-20 and rechromatography combined with the same amount of material. NMR spectrum (D ₂ O) shows absorption at 5.56 (s, 2H), 4.25 (s, 1H), 1.60 (s, 3H) and 1.50 (s, 3H) ppm.

Preparation Example D

6-beta-iodophenicylanic acid

The title compound is prepared by reducing 6,6-diiodophenicylanic acid with tri-n-butyltinhydride following the procedure of Preparation Example B.

Production Example E

Pivaloyloxymethyl 6-alpha-bromophenicylanate

To a solution of 280 mg of 6-alpha-bromophenicsilane acid in 2 ml of N, N-dimethylformamide, 260 mg of dipropylpropylamine was added followed by 155 mg of chloromethyl pivalate and 15 mg of sodium iodide. The reaction mixture is stirred at room temperature for 24 hours and then diluted with ethyl acetate and water. The pH is adjusted to 7.5, the ethyl acetate layer is separated and washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution is then dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title compound.

Production Example F

Suitable 6-halofenisilane acid is prepared according to the process of Preparation Example E, 3-phthalidyl chloride, 4-crotonolactonylchloride, gamma-butyrolactone-4-yl chloride or alkanoyloxy chloride, 1- (Alkanoyloxy) -ethylchloride, 1-methyl-1- (alkanoyloxy) ethyl chloride, alkoxycarbonyloxymethyl chloride, 1- (alkoxycarbonyloxy) -ethylchloride or 1-methyl-1- (alkoxy Carbonyloxy) -ethyl chloride to give the following compounds, respectively:

3-phthalidyl 6-alpha-chlorophenicylanate 4-crotonolactonyl 6-beta-chlorophenicilanate: gamma-butyrolactone-4-yl 6-alpha-bromophenicylanate: acetoxymethyl 6-Beta-bromophenicylanate: pivaloyloxymethyl 6-beta-bromophenicylanate: hexanoyloxymethyl 6-alpha-iodinephenylanate 1- (acetoxy) ethyl 6-beta-iodopheny Silaneate: 1- (isobutyryloxy) ethyl 6-alpha-chlorophenicilanate: 1-methyl-1- (acetoxy) ethyl 6-beta-chlorophenicilanate: 1-methyl-1- (hexanoyl Oxy) ethyl 6-alpha-bromophenicylanate: methoxycarbonyloxymethyl 6-alpha-bromophenicylanate: propoxycarbonyloxymethyl 6-beta-bromophenicylanate: 1- (ethoxy Carbonyloxy) ethyl 6-alpha-bromophenicylanate 1- (butoxycarbonyloxy) ethyl 6-alpha-iodophenicylanate: 1-methyl-1- (methoxy Carbonyloxy) ethyl 6-beta-iodophenicylate and B-methyl-1- (isopropoxycarbonaloxy) ethyl 6-alpha-chloro-penicylanate.

Production Example G

15.23 g 6,6-Diiodophenicylanate Iodine A mixture of 10 ml of 205N sulfuric acid, 2.76 g of sodium nitrite and 75 ml of dichloromethane is stirred at 5 ° C. and 4.32 g of 6-amibenbenylsilic acid is added over 15 minutes. After the addition is complete, stirring is continued for 45 min at 5-10 ° C. 45 and 100 ml of 10% sodium bisulfite are added directly. The layers are separated and the aqueous layer is further extracted with dichloromethyl. The combined dichloromethyl layers are washed with brine, dried (MgSO ₄ ) and evaporated in vacuo. This affords 1.4 g of the title compound contaminated with a small amount of 6-iodinephenic acid. The melting point of this product is 58 to 64 ° C. NMR spectrum (CDCl 3) shows absorption at 5.77 (s, 1H), 4.60 (s, 1H), 1.71 (s, 3H) and 1.54 (s, 3H) ppm.

Production Example H

Pivaloyloxymethyl 6-alpha-bromophenicylanate

To the stirred mixture of 11.2 g of 6-alpha-bromophenisilane acid, 3.7 g of sodium bicarbonate and 44 ml of N, N-dimethylformamide was added dropwise 6.16 g of chloromethylpivalate over 5 minutes at ambient temperature. After continuing stirring for 66 hours, the reaction mixture is diluted with 100 ml of ethyl acetate and 100 ml of water. The layers are separated and the ethyl acetate layer is washed successively with water, saturated sodium chloride, sodium bicarbonate, water and saturated sodium chloride. The decolorized ethyl acetate solution is dried (MgSO ₄ ) and evaporated to dryness in vacuo. This affords 12.8 g (yield 80%) of the title compound.

Preparation Example I

Benzyl 6-alpha-bromophenicylanate

The title compound was prepared by esterifying 6-alpha-bromophenic silane acid with benzyl bromide following the procedure of Preparation Example H (yield 83%). NMR spectra (CDCℓ ₃ ) are 7.35 (s, 5H), 5.35 (m, 1H), 5.15 (s, 2H), 4.70 (m, 1H), 4.60 (s, 1H), 1.55 (s, 3H) and 1.35 Absorption is shown at (s, 3H) ppm.

Production Example J

2,2,2-trichloroethyl penicillate

To a stirring solution of 11.2 g of 6-alpha-bromophenisilane acid in 50 ml of tetrahydrofuran, 3.48 g of pyridine was added at 0 ° C. over 1 minute. To the resulting cloudy solution is added 8.47 g of 2,2,2-trichloroethyl chloroformate over 10 minutes while maintaining the temperature between 0 and 2 ° C. Stirring is continued for 30 minutes and the cooling bath is removed. Continue stirring overnight at ambient temperature. The reaction mixture is then warmed to 35 ° C. for 5 minutes and filtered. The filtrate is evaporated and the residue is dissolved in lO00 l of ethyl acetate. The ethyl acetate solution is washed successively with saturated sodium bicarbonate, water and saturated sodium chloride. The ethyl acetate solution is then decolorized, dried and concentrated in small portions. 100 mL of hexane was added to the resulting mixture, and the solid was filtered to obtain 10.5 g of the title compound having a melting point of 105 to 110 ° C. NMR spectrum (CDCℓ ₃ ) is 5.50 (d, 1H), 4.95 (d, 1H), 4,90 (s, 2H), 4.65 (s, 1H), 1.70 (s, 3H) and 1.55 (s, 3H) Absorption is shown at ppm.

Production Example K

6,6-dibromophenic silane acid

To 500 ml of dichloromethane cooled to 5 ° C., 119.9 g of bromine, 200 ml of 2.5N sulfuric acid and 34.5 g of sodium nitrite are added. 54.0 g of 6-aminophenicylanic acid is added little by little over 50 minutes, maintaining the temperature at 4-10 degreeC to the stirring mixture. Stirring was continued for 30 minutes at 5 ° C, and 410 ml of 1.0M sodium bisulfite solution was added dropwise over 20 minutes at 5-10 ° C. Separate the layers. The aqueous layer is extracted twice with 150 ml of dichloromethane. The original dichloromethane layer is combined with the two extracts to give a 6,6-dibromophenic silane acid solution. This solution is used directly in Example 17.

Preparation Example L

6-chloro-6-iodophenicsilane acid

To 100 ml of dichloromethane cooled to 5 ° C., 4.87 g of iodine chloride, 10 ml of 2.5N sulfuric acid and 2.76 g of sodium nitrite are added. To the stirred mixture is added 4.32 g of 6-aminophenic silane acid in small portions over 15 minutes. Stirring is continued for 20 minutes at 0-5 ° C., then 100 ml of a 10% sodium sulfite solution is added dropwise at about 4 ° C. After stirring for 5 minutes, the layers are separated. The aqueous layer was extracted with dichloromethane (2-50 ml), the dichloromethane solution was combined and washed with brine. After drying (MgSO ₄ ), evaporation in vacuo affords the title compound as a tan solid having a melting point of 148 to 152 ° C. The NMR spectrum (CDCl ₃ ) of the product shows absorption peaks at 5.40 (s, 1H), 4.56 (s, 1H), 1.67 (s, 3H) and 1.50 (s, 3H) ppm. IR spectrum (KBr Disco) shows absorption at 1780 and 1715 cm ⁻¹ .

Production Example M

6-bromo-6-iodophenicylanic acid

To 100 ml of dichloromethane cooled to 5 ° C., 10 ml of 2.5N sulfuric acid, 6.21 g of iodine bromide and 2.76 g of sodium nitrite are added. To the mixture is added 4.32 g of 6-aminophenicsilane acid over 15 minutes with vigorous stirring at 0-5 ° C. After an additional 20 minutes of stirring at 0-5 ° C., 100 ml of 10% sodium bisulfite are added dropwise at 0-10 ° C. The layers are then separated and the aqueous layer is extracted with dichloromethane (3 x 50 ml). The combined dichloromethane layers are washed with brine, dried (MgSO ₄ ) and evaporated in vacuo. The residue was dried under high vacuum for 30 minutes to give 6.0 g (72% yield) of the title compound at a melting point of 144 to 147 ° C. NMR spectrum (CDCl ₃ ) shows absorption at 5.50 (s, 1H), 4.53 (s, 1H), 1.70 (s, 3H) and 1.53 (s, 3H) ppm. IR spectrum (KBr disc) shows absorption peaks at 1755 and 1710 cm ⁻¹ . The mass spectrum represents the main ion at m / e = 406.

Production Example N

6-chloro-6-bromophenic silane acid

6-Aminophenicylanic acid is diazotized according to the process of Preparation Example M and then reacted with bromine chloride to produce 6-chloro-6-bromophenic silane acid.

Production Example O

Pivaloyloxymethyl 0,6-dibromophenicylanate

To a stirred solution of 3.59 g of 6,6-dibromophenic carboxylic acid in 20 ml of N, N-dimethylformamide was added 1.30 g of diisopropylethylamine at about 0 ° C., followed by 1.50 g of chloromethyl pivalate. The reaction mixture is stirred at about 0 ° C. for 30 minutes and at room temperature for 24 hours. The reaction mixture is then diluted with ethyl acetate and water and the pH of the aqueous phase is adjusted to 7.5. The ethyl acetate layer was separated and washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution is then dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title compound.

Production Example P

A suitable 6.6-dihalofenisilane acid can be prepared according to the procedure of Example 0, 3-phthalidyl chloride, 4-crotonolactonyl chloride, gamma-butyrolactone-4-yl chloride or alkanoyloxymethyl chloride, 1 -(Alkanoyloxy) -ethylchloride, 1-methyl-1- (alkanoyloxy) ethylchloride, alkoxycarbonyloxymethyl chloride, 1- (alkoxycarbonyloxy) ethylchloride or 1-methyl-1- (alkoxy Reaction with carbonyloxy) ethyl chloride affords the following compounds, respectively.

3-phthalidyl 0,6-dibromophenicylanate: 4-crotonolactonyl 6-chloro-6-iodophenite: gamma-butyrolactyl 6-bromo-6-iodopenicila Nate: acetoxymethyl 6-chloro-6-bromophenicylanate pivaloyloxymethyl 6-chloro-6-iodophenicylanate: hexanoyloxymethyl 6,6-dibromophenicylanate: 1- (Acetoxy) ethyl 6,6-dibromophenicylanate 1- (isobutyryloxy) ethyl 6-bromo-6-iodophenicylanate 1-methyl-1- (acetoxy) ethyl 6,6 -Dibromophenicylanate: 1-methyl-1- (hexanoyloxy) ethyl 6-chloro-6-bromophenicylanate methoxycarbonyloxymethyl 6,6-dibromophenicylanate: propoxy Carbonyloxymethyl 6-chloro-6-iodophenicylanate 1- (ethoxycarbonyloxy) ethyl 6,6-dibromophenicylanate: 1- (butoxycarbonyloxy) ethyl 6-bromo -6-iodophenicylanate: 1-methyl-1- ( Methoxycarbonyloxy) ethyl 6,6-dibromophenicylanate and 1-methyl-1- (isopropoxycarbonyloxy) ethyl 6,6-dibromo-penicylanate.

Claims (1)

A compound of formula (III) by contacting a compound of formula (II) or a salt with a base thereof with a reactant selected from the group consisting of alkali metal permanganate, alkaline earth metal permanganate and organic peroxycarboxylic acid A process for preparing a salt of the compound of formula (I) or a pharmaceutically acceptable base thereof, characterized by obtaining a salt thereof and dehalogenating the resulting compound by catalytic hydrogenolysis in an inert solvent.

In the above formula R ₁ represents hydrogen or an ester-forming residue which is easy to hydrolyze in vivo, and X and Y are each selected from the group consisting of hydrogen, chloro, bromo and iodo, provided that both X and Y are the same bromine Should be indicated.