KR830001903B1 - Method for producing peniclanate derivative - Google Patents

Abstract

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Description

Method for producing peniclanate derivative

The present invention relates to a method for preparing the β-lactam compound of the following general formula (1), which is an antibiotic useful for humans and animals.

The present invention also relates to a process for preparing β-lactam compounds, which have not been known so far, comprising pharmaceutically acceptable salts thereof which are non-toxic acids or bases.

According to the present invention there is provided novel compounds useful for the treatment of bacterial infections. The novel compounds are particularly effective against β-lactamase producing bacteria.

In general, the term "lower alkyl" is a C ₁ -C ₆ straight or branched chain alkyl group, aryl is a monocyclic or bicyclic, carbocycle group, and acylamino refers to a group present in the side chains of known penicillins. The asterisk (*) in the side chain and the + mark of the ester (unless R ₃ is not hydrogen) refer mostly to the chiral center which produces the diastromeric form of the compound of general formula (1).

Salts of the compound of the invention are pharmaceutically acceptable salts which are non-toxic acids or bases. (Depends on whether R ₂ is a primary amino group or a carboxy group).

Suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, P-toluene sulfonic acid, methanesulfonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, pamoic acid, and P- (dipropylsulfyl) Benzoic acid (probeneside) and the like. Suitable basic salts include alkali or alkaline earth metal salts such as sodium, potassium, magnesium and calcium salts, as well as salts with ammonia or suitable nontoxic amines, for example triethylamine, hydroxy-lower alkyl amines (e.g. Lower alkylamines such as 2-hydroxyethyl) -amine), bishydroxy-ethyl)-(amine or tris- (2-hydroxyethyl) -amine), and cycloalkylamines (e.g., dicyclohexylamine) Or benzylamines (eg, N, N-dibenzylethyldidiamine or dibenzylamine), but the present invention is not limited thereto. Also salts with acid or base antibiotics are within the scope of the present invention. In some cases, easily soluble salts are suitable for use, while for this purpose only slightly soluble salts may be suitable, for example, for long-term effects. In particular, long-term effects can be obtained using salts with probenesides that block tubule excretion of the β-lactam compound.

In the clinical treatment of bacterial infections, there are several problems with the rapid increase in β-lactamase producing bacteria. This enzyme inactivates penicillin and cephalosporins, and β-lactamase from gram-positive and gram-negative bacteria confers bacterial resistance to β-lactam antibiotics.

Some naturally occurring β-lactamase inhibitors include clavulanic acid and olibanic acid. Recently, many semisynthetic β-lactam compounds such as peniclanic acid 1,1-dioxide, ₆ α-chlorophenicylic acid 1,1-dioxide, clavulanic acid derivatives ₆ β-bromophenicylanic acid, methicillin sulfone , And quinacillin sulfone have been found to have similar biological properties. Except for a few, these compounds show only weak antibacterial activity against gram-positive and gram-negative organic agents but are potent inhibitors of a wide range of β-lactamases. Upon binding of the selected penicillins and cephalosporins, the compounds act adjuvant against many β-lactamase producing bacteria because the compounds protect penicillins and cephalosporins against inactivity.

As noted above, the present invention provides compounds that are potently antibacterial effective, particularly for intestinal use and in vivo. A beneficial effect on β-lactamase producing bacteria is achieved because the compound is contained in one and half of the antibacterial highly effective penicillin and half of the potent β-lactamase inhibitor together in the same molecule. However, two indispensables are needed to exploit the features of the novel compounds. It must be absorbed into the gastrointestinal tract and must be freed and hydrolyzed during or after penicillin and β-lactamase inhibitors. Prepared by carrying out this indispensable condition, the present compounds are thus useful subsidiary agents of penicillin and β-lactamase inhibitors.

Thus, studies in arbitrary humans and animals have shown that new compounds are readily absorbed from the stomach. During or after absorption they liberate the animal mass of the two components in question, namely penicillin and β-lactamase inhibitors, and hydrolyze to simultaneously increase the high blood and tissue concentrations of both components. In this way penicillin is protected from inactivation by β-lactamase.

The effective absorption and in vivo hydrolysis of the compounds of the present invention is achieved by one novel compound, namely 1,1-di-oxophenylananoyloxymethyl-6- (D-α-amino-α-phenylacet-amido) Peniclanate (hereinafter referred to as VD-1827) has been studied and shown in any group of humans who have been orally administered.

For comparison, an equal molar amount of ampicillin preparative, fib ampicillin, and potassium peniclanate 1,1-dioxide were also orally administered to any of the same groups, respectively. The results of the study are summarized in Table 1 and Table 2.

TABLE 1

Ampicillin serum levels and excretion in urine when oral administration of

A. 125 mg fib ampicillin free base in tablet form

B. 170 mgvp-1827 ×) hydrochloride in liquid form (corresponding to 125 mg of fib ampicillin freebase)

×) VD-1827 is 1,1-dioxophenylininoyloxymethyl 6- (D-α-amino-α-phenyl acetamido) peniclanate

+) No sample

TABLE 2

When oral administration of the following drugs to any group of fasting, excretion of urine for 0-6 hours of peniclanic acid 1,1-dioxide

A. 73 mg of potassium penicillate 1,1-dioxide in liquid form

(Equivalent to 63 mg of peniclanic acid 1,1-dioxide)

B. 170 mg of VD-1827 hydrochloride in liquid form (equivalent to 63 mg of peniclanic acid 1,1-dioxide)

It can be seen from Table 1 that oral administration of VD-1827 results in elevated serum levels of ampicillin similar to those obtained after an equimolar dose of fib ampicillin. In addition, it can be seen from Table 1 that the recovery of ampicillin into urine after administration of VD-1827 can be compared with that shown after administration of fib ampicillin.

As indicated in Table 2, only 5.2% of peniclanic acid 1,1-dioxide was excreted in urine after oral administration of the corresponding potassium salt. In comparison, 71% of peniclanic acid 1,1-dioxide becomes urine when an equimolar amount of VD-1827 is administered, which also shows an absorption effect upon oral administration of VD-1827.

Using the compound prepared according to the present invention, the antibacterial range of penicillin itself becomes very wide, so that the strain producing β-lactamase will be able to be treated. As described above, the increased frequency of such β-lactamase producing monarchs is a serious problem in clinical treatment. The present invention is very useful for this purpose. Therapeuticly, the compound has obvious advantages over simply mixing hydrolyzed penicillin and β-lactamase inhibitors or using orally active esters thereof.

For example, many β-lactamase inhibitors, including peniclanic acid 1,1-dioxide, are insufficiently or irregularly absorbed in the gastrointestinal tract (see Table 2). Many penicillins, including ampicillin and carbenicillin, are also incompletely absorbed. In addition, the absorption rates of various penicillin and β-lactamase inhibitors have been varied, and in many cases, both drugs were administered simultaneously. Even if the active ingredient is not present at the same time or in an appropriate ratio.

Esters of some easily hydrolysable penicillin and β-lactamase inhibitors are absorbed better in the gastrointestinal tract than the corresponding free acids. However, hydrolysis of such esters in an organism results in the formation of inert byproducts, and it is not desirable to allow the organism to perform unnecessary metabolism even if these byproducts are relatively nontoxic. Another disadvantage when using a mixture of esters of penicillin and β-lactamase inhibitors that can be easily hydrolyzed is that the ester moiety increases the molecular weight of the compound and consequently the size of the dosage unit. By using the compounds of the present invention, the size of the dosage unit can be significantly reduced.

In addition, the absorption of these esters simultaneously administered the compound to the patient. They usually don't happen at the same time. For example, the pivaloyloxy methyl ester of ampicillin is absorbed very rapidly, while the poorly soluble pivaloyloxy methyl ester of the β-lactamase inhibitor peniclanic acid 1,1-dioxide is absorbed very slowly. All these disadvantages can be eliminated by using the compounds prepared according to the invention.

It has been found that synergism in vivo between different β-lactamase inhibitors and various penicillins occurs especially when the ratio between the two components is 3: 1-1: 3. Because the various penicillins have slightly different physiological half-life and distributional properties, the ratio of the components of the new compounds in organs and tissues may vary somewhat, but will usually fall within these preferred limits.

The present invention therefore consists of a process for the preparation of the compounds described above. According to one method of the present invention, the compound of formula (5) is provided.

The compound may be hydrocracked or hydrolyzed depending on A and B.

The reaction is carried out at a temperature of 0 ° -30 ° C. with a mixture of a suitable organic solvent (such as ethyl acetate or tetrahydrofuran) and water in a ratio of 3: 1-1: 3, preferably 1: 1. When β is an azido or other group, it can be hydrocracked to change to an amino or carboxyl group (pallaium supported on carbon can be used as a catalyst ao), and when β is hydrolyzable, acids such as hydrochloric acid, It may be catalytically reacted with hydrobromic acid or sulfuric acid or p-toluenesulfonic acid.

Intermediates of general formula (5) can be prepared by reacting the compound of general formula (6).

The reaction is carried out in a suitable solvent such as dimethylformamide, ethyl acetate, dichloromethane, acetone or hexamethylphosphoric acid triamide at a temperature suitable for achieving the desired conversion for a sufficient time, usually 0 ° -60 ° C. .

Another method for preparing an intermediate of formula (5) consists of one step of reacting compound A-M with a compound of formula (7) to provide an intermediate of formula (8).

The reaction is carried out in the same manner as described for the preparation of known compounds of general formula (4) and is usually zero in a suitable solvent such as dimethylformamide, ethyl acetate, dichloromethane, acetone or hexatylphosphoric acid triamide. Occurs at a temperature of -60 ° C.

In the second step, the intermediate of formula (8) is reacted with the penicillin derivative of formula (9) to prepare the intermediate of formula (5).

Food,

(R ₁ , B and M are as described above).

If necessary, X in formula (8) may be substituted with a free group in advance. In another aspect of the material process, a compound of formula (AM) is reacted with a 6-amino penicsilane acid ester of formula (10) or an amino-protecting derivative thereof such as trialkyl silyl derivative to give a compound of formula (11). It consists of steps.

Food,

(R ₃ , A and X are as described above.)

The reaction is carried out at a temperature between 0 ° C.-30 ° C. in a suitable organic solvent, e.g. dimethylmeformamide. Alternatively, intermediates of formula (11) can be prepared by reacting 6-amino peniclanic acid or a salt or amino-protecting derivative thereof with a compound of formula (8). In the second step, a compound of formula (11) or a trialkylsilyl derivative thereof is reacted with a reactive derivative of acid of formula (12).

Reactive derivatives include, for example, acid halides such as acid chlorides or acid bromides, acid anhydrides, and mixed anhydrides with alkyl-carboxylic acids, carboxylic acids, inorganic acids or sulfonic acids, or free acids of general formula (12) with carbodiimide or Group prepared by reacting with N, N'-carbonyl-diimidazole or like compound. The reaction can be carried out at low or slightly elevated temperatures in an organic solvent or in a mixture with water.

Suitable solvents include dichloromethane, chloroform, ethyl acetate, acetone, dimethylyl formamide, dimethylacetamide, ether, dioxane or other inert solvents. Starting materials and intermediates of the general formulas (5), (8) and (11) are novel compounds and are also within the scope of the present invention.

In another embodiment, that is, the compound of formula (1) (R ₂ is a primary amino group) is a salt of an amino penicillin, such as ampicillin or amoxycillin, which is a compound of formula (13), with a compound of formula (8) The reaction may be prepared directly in a one step process.

The reaction is carried out at 0 ° -40 ° C., preferably at room temperature, in a suitable organic solvent such as ethyl acetate, dichloromethane, chloroform, dimethylformamide. Starting materials of the general formulas (6), (7), (9) and (10) are known and can be prepared by methods analogous to the preparation of similar known compounds.

Most of the starting materials of the general formula AM or of the compatible acid are known compounds. The novel compounds are acids and salts corresponding to A with the group of formula (2) wherein R ₅ is some acylamino group. The latter compound is penicillin sulfo which can be prepared by a known method.

The compound of formula (1) may be purified and separated by conventional methods and may be obtained as such or in the form of a salt. In some cases, the compounds may be obtained as known diastereomer mixtures, which may be separated by known methods when necessary, for example by chromatography.

The compounds of the present invention can be used for enteral parenteral or topical administration as used in pharmaceutical compositions useful for the treatment of infectious diseases in human and veterinary cases. Such compositions comprise, as active ingredient, at least one member selected from the group consisting of a compound of formula (1) and salts thereof as described above with a solid or liquid pharmaceutical carrier and / or diluent.

In the compositions described above, the ratio of therapeutically effective material to the carrier substrate can vary from 1% to 95% by weight. The compositions are formulated in the form of various pharmaceutical preparations such as tablets, pills, dragees, suppositories, capsules, sustained release forms, suspensions, and the like, including compounds of the general formula (1) or unsatisfactory salts as described above, including carriers and And / or mixed with a diluent.

Pharmaceutically acceptable non-toxic, organic or inorganic, solid or liquid carriers and / or diluents may be used to prepare compositions containing the compounds of the present invention. Suitable nutrients are all suitable for gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gums, polyalkylene glycols, buffers or other known carriers, adjuvants and / or diluents.

Furthermore, the composition may comprise a therapeutically effective ingredient with the compound of the present invention that can be appropriately administered for the treatment of an infectious disease, such as other antibacterial agents, antitussives, anti-pain medications, probenesidates and the like. Suitable antibacterial agents are those which synergize with the active ingredient of one or water formed by the in vivo hydrolysis of the compounds of the invention.

The compound of formula (1) may be used as such or in the form of a salt. Such compounds are poorly soluble in water, while many salts (such as hydrochloride and sodium salts) are readily soluble in water. As mentioned above, the compounds of the present invention may be formulated in the form of preparations comprising suspensions and non-aqueous ointments. Pharmaceutical formulations for oral treatment may be in the form of suspensions of one of the compounds of the invention, wherein the formulation comprises 10-100 mg per ml of excipient.

By administering the compounds prepared according to the invention in such doses, the desired activity is achieved simultaneously without a secondary effect. In treating humans, the compounds of the present invention are conveniently administered (to adults) in dosage units of compositions containing from 50 to 2500 mg, preferably 100-1000 mg, calculated as compounds of formula (1). A “dose unit” is a single dose that can be administered to a patient, that is, a physically stable substance such as an active substance or composed of a mixture of solid or liquid pharmaceutical diluent, carrier, solvent and / or adjuvant. By unit dose is meant a unit that remains easy to handle and can be easily packaged.

The compound may be administered more than once a day at appropriate intervals in the form of dosage units, but everything depends on the condition of the patient and the prescription made by the physician. Therefore, the daily dose may be 0.25-15 g of the compound of formula (1), or the same amount of salt as described above, which can be conveniently separated into several single doses. In the continuous treatment of a patient suffering from an infectious disease, the tablets or capsules are in the form of suitable pharmaceutical formulations and may be in sustained release as needed.

In veterinary cases, the above-described pharmaceutical compositions can also be preferably used in the form of dosage units containing 50 mg-25 g of the compound of formula (1) or containing a compatible amount of salt. For the treatment of breast diseases, in particular bovine mastitis, antibacterial agents can be administered to the breast in semi-liquid form, such as liquids or ointments, or in the form of granules, together with water insoluble and oil insoluble binders.

The compound of formula (1) is typically administered in an amount of 3-200 mg / kg patient weight / day, with the amount corresponding to an adult patient being 0.25-15 g per day or the same amount of the salt of formula (1) . In the treatment of a patient, the compounds of the present invention can be administered alone or in combination with other therapeutically active compounds, such as probebenesid, that help fight bacterial infections. Such combination therapy may be carried out in preparations containing all or more of the therapeutically active ingredients or in separate preparations, which are administered simultaneously or at appropriate intervals.

In the treatment of patients, they are administered in one daily dose or in separate doses, such as twice, three or four times daily. The actual starting materials and intermediates according to the present invention will be described in detail based on the preparation examples.

[Example 1]

6α-bromophenic silane acid 1,1-dioxide

To a stirred solution of potassium permanganate (1.90 g, 12 mmol) in water (35 ml) and acetic acid (1.36 ml, 24 mmol) was added an ice cold solution of potassium 6α-bromophenylsilanate (1.91 g, 6 mmol) in water (25 ml). It was added dropwise at ° -5 ℃. After the addition was complete (about 15 minutes), the mixture was stirred for another 20 minutes at low temperature. The cold bath was removed and solid sodium pyrosulphite (1.52 g, 8 mmol) was added to the mixture to reduce excess oxidant. Precipitated manganese oxide was filtered off and filtrate (about 60 ml) was added solid sodium chloride (20 g) and ethyl acetate (50 ml). The pH of the mixture was adjusted to 1.5 by adding 4N hydrochloric acid with stirring and the organic phase was separated. The aqueous phase was reextracted with ethyl acetate (25 ml) and the combined organic extracts were washed with saturated aqueous sodium chloride, dried and evaporated in vacuo. The amorphous residue thus obtained was crystallized from ether-diisopropyl ether to obtain 6α-bromopheny silanoic acid 1,1-dioxide having a melting point of 124-127 占 폚.

The crystalline potassium salt of the compound was prepared by stirring a solution of 6α-bromophenic silane 1,1-dioxide (0.94 g, 3 mmol) in acetone (12 ml) to 1 M potassium 2-ethylhexahexane in acetone (3.6 ml). It was obtained by addition.

The NMR spectrum of potassium 6α-bromophenicylanate 1,1-dioxide (CD ₃ OD) was δ = 1.48 (s, 3H; 2-CH ₃ ), 1.59 (s, 3H; 2-CH ₃ ), 4.48 ( s, 1H; 3-H), 5.10 (d, J = 2Hz, 1H; 6-H), and 5.35 (d, J = 2Hz, 1H; 5-H) ppm and internal reference to tetramethylsilane Used as material.

[Example 2]

6α-chlorophenicylanic acid 1,1-dioxide

Potassium 6α-bromophenicilanate was prepared using potassium 6α-chlorophenicilanate in the preparation of the preparation of Example 1 to convert 6α-chlorophenicyl 1,1-landeoxide dioxide having a melting point of 134-137 ° C. into diisopropyl ether. Obtained as a crystal.

NMR spectrum (CDCl ₃ ) is δ = 1.50 (s, 3H; 2-CH ₃ ), 1.64 (s, 3H; 2-CH ₃ ), 4.46 (s, 1H; 3-H); Tetramethylsilane was used as an internal reference at 4.70 (d, J = 1.5 Hz, 1H; 6-H) and 5.18 (d, J = 1.5 Hz, 1H; 5-H) ppm.

The crystalline potassium salt of the compound was obtained by adding an equimolar amount of 0.8 M potassium 2-ethylhexanoate in acetone to a stirred solution of 6α-chlorophenicylic acid 1,1-dioxide in acetone.

[Example 3]

Chloromethyl penicilanate 1,1-dioxide

To a solution of peniclanic acid 1,1-dioxide (1.17 g, 5 mmol) in dimethylformamide (7.5 ml) was added triethylamine (0.98 ml, 7 mmol) and chloroiodomethane (2.18 ml, 30 mmol) to prepare the mixture at room temperature. Stir at 4 h.

After dilution with ethyl acetate (30 ml), the mixture was washed with water (3 x 10 ml), then washed with saturated aqueous sodium chloride (5 ml), dried and evaporated in vacuo to crystallize from ether-petroleum ether 94 The desired compound at -96 ° C. was obtained as a yellowish oil.

NMR spectrum (CDCl ₃ ) is δ = 1.47 (s, 3H; 2-CH ₃ ), 1.66 (s, 3H; 2-CH ₃ ), 3.53 (d, J = 3Hz, 2H; 6α-H and 6β-H ), 4.46 (s, 1H; 3-H), 4.68 (t, J = 3 Hz, 1H; 5-H) and 5.85 (ABq, J = 6 Hz, 2H; OCH ₂ Cl) ppm and tetramethylsilane Was used as internal reference.

[Example 4]

1-chloroethylphenicylanate 1,1-dioxide

In addition to using 1-chloro-1-iodoethane instead of chloroiodo methane and increasing the reaction time to 16 hours, crude 1-chloroethyl penicillate 1,1-dioxide was prepared according to the Preparation Example 3 method. Anhydrous column chromatography on ethyl acetate-petroleum ether, 7: 3) afforded as a purified yellow oil.

[Example 5]

Chloromethine 6α-bromophenicylanane 1,1-tdioxide

The chloromethyl 6α-bromophenicylanate 1,1-dioxite was yellowed by the method of Formulation Example 3 using 6α-bromophenicylanic acid 1,1-dioxide instead of peniclanic acid 1,1-dioxide. Obtained as an oil.

NMR spectrum (CDCl ₃ ) is δ = 1.48 (s, 3H; 2-CH ₃ ), 1.64 (s, 3H; 2-CH ₃ ), 4.46 (s, 1H; 3-H); 4.71 (d, J = 1.5 Hz, 1H; 6-H) and 5.17 (d, J = 1.5 Hz, 1H; 5-H) and 5.80 (ABq, J = 6 Hz, 2H; OCH ₂ Cl) ppm And TMS was used as internal reference.

[Example 6]

Chloromethyl 6β-bromophenicylanate

Chloromethyl 6β-bromopheniclanate was obtained as a viscous oil by the method of Formulation Example 3 using potassium 6β-bromopheniclanate in place of peniclanic acid 1.1-dioxide and triethylamine.

[Example 7]

Chloromethyl clavulanate

Chloromethyl clavulanate was obtained by the method of Formulation Example 3 using sodium clavulanate in place of peniclanic acid 1,1-dioxide and triethylamine.

[Example 8]

Chloromethyl penicilanate 1,1-dioxide

Bis-chloromethylsulfate (1.6 g) was added to a suspension of potassium penicillate 1,1-dioxide (1.08 g) in dimethylformamide (12 ml) and the mixture was stirred at room temperature for 45 minutes. After diluting with ethyl acetate (50 ml), the mixture was washed with water, then washed with aqueous sodium bicarbonate, dried and evaporated in vacuo to purify the remaining oil by chromatography on silica gel to obtain the same desired compounds as described in Formulation Example 3. The compound was obtained.

[Example 9]

Chloromethyl 6α-chlorophenicylanate 1,1-dioxide

Chloromethyl 6α-chlorophenicilanate 1,1-dioxide was obtained as a viscous oil by the method of Formulation Example 3 using 6α-chlorophenicsilane 1,1-acid dioxide instead of penicilanic acid 1,1-dioxide.

NMR spectrum (CDCl ₃ ) is δ = 1.48 (s, 3H; 2-CH ₃ ), 1.64 (s, 3H; 2-CH ₃ ), 4.47 (s, 1H; 3-H); 4.68 (d, J = 1.5 Hz, 1H; 6-H) and 5.17 (d, J = 1.5 Hz, 1H; 5-H) and 5.81 (ABq, J = 6 Hz, 2H; OCH ₂ Cl) ppm And TMS was used as internal reference.

[Example 10]

Iodomethyl Penicillate 1,1-Dioxide

To a solution of chloromethyl penicillate 1,1-dioxide (5.6 g, 20 mmol) in acetone (45 ml) was added sodium iodide (9 g) and the mixture was plated at room temperature for 16 hours. Precipitated sodium chloride (1.15 g) was filtered off and the solvent was removed in vacuo and the residue obtained was treated with ethyl acetate-ether (1: 1). Insoluble sodium iodide (6 g) was filtered and the filtrate was evaporated under reduced pressure.

The residue oil was purified by column chromatography on silica gel (ethyl acetate-n-hexane, 4: 6) to give the desired compound as colorless crystals from ether with a melting point of 101-102 ° C.

[Example 11]

6β-aminophenicylanic acid 1,1-dioxide hydrate

A. 6β-benzyloxy carbonylaminophenicylanic acid 1,1-dioxide

A solution of potassium permanganate (38 g) in water (915 ml) at 0 ° C. was added to a stirred solution of 6β-benzyloxycarbonylamino peniclanic acid (63.5 g) and potassium hydrogen carbonate (18.1 g) in water (1125 ml) (about 45 Minutes). During oxidation, the pH of the reaction mixture was maintained at 6.5 by addition of dilute sulfuric acid, the insoluble material was filtered off and the filtrate was extracted with ethyl ether. The aqueous phase obtained was filtered again, ethyl acetate (600 ml) was added and the pH was acidified to 2.5 with stirring. The organic layer was separated and the aqueous phase was extracted with additional ethyl acetate (2 x 300 ml), dried and the combined ethyl acetate extracts were evaporated in vacuo. The residue was recrystallized from ethyl acetate (250 ml) -petroleum ether (500 ml) to give a pure compound having a melting point of 153-154 ° C.

B. 6β-Aminophenicylanic Acid 1,1-Dioxide Hydrate

A filtrate of 6β-benzyloxycarbonylamino peniclanic acid 1,1-dioxide (15.3 g) and potassium hydrogen carbonate (4 g) in water (160 ml) was added with 10% pb / BaSO ₄ (4 h at slightly elevated pressure). 5 g) was hydrogenated. After filtration and extraction with ethyl ether (100 ml), the pH of the ice-cold water solution was adjusted to 2.5. The precipitate thus prepared was washed with water and air dried.

Recrystallization from dimethylformamide-water gave pure monohydrate with melting point 199-200 ° C. (decomposition):

[Example 12]

Chloromethyl 1,1-dioxophenicylanate

Potassium 1,1-dioxophenisilanate (2.7 g, 10 mmol), potassium hydrogen carbonate (6.0 g, 60 mmol) and tetrabutylammonium hydrogensulfate (0.34 g, 1 mmol) in water (10 ml) and dichloromethane (15 ml) To the mixture was added chloromethyl chlorosulfide (1.5 ml). After stirring for 1 hour at 30 ° C., the mixture was filtered, the organic layer was separated and dried (sodium sulfate).

After diluting with propanol-2 (25 ml) the solution was concentrated in vacuo to about 10 ml and left at 5 ° C. for 1 h. Crystals were separated. Washed with cold propanol-2 and dried in vacuo to afford the desired compound as colorless crystals with a melting point of 94-96 ° C.

[Example 13]

1-chloroethyl 1,1-dioxophenicylanate

1-chloro-1-iodoethane in a mixture of potassium 1,1-dioxophenicylanate (40.7 g, 0.15 ml), silver nitrate (25.5 g, 0.15 ml) and silver oxide (7.5 g) in acetonitrile (750 ml) (42 ml) was added. After stirring for 48 hours at room temperature, the silver salt was filtered off and the filtrate was dried in vacuo. The residue was dissolved in ethyl acetate (200 ml), the solution was washed with saturated aqueous sodium chloride, filtered and dried and evaporated in vacuo.

The residue was chromatographed on silica gel (hexane-ethyl acetate, 3: 2) to give the desired compound as a crystalline mixture of two diastereomers with a melting point of 130-132 ° C.

[Example 14]

1-iodomethyl 1,1-dioxophenicylanate

To a solution of 1-chloroethyl 1,1-dioxophenicilanate (30 g, 0.1 mol) in acetone (100 ml) was added sodium iodide (30 g, 0.2 mol) and the mixture was stirred at room temperature for 3 days. Acetone was removed in vacuo with aqueous sodium thiosulfate.

The separated oil was dissolved in ethyl acetate and the solution was washed with water, dried and evaporated in vacuo.

The residue oil was chromatographed on silica gel (hexane-ethyl acetate 3: 1) to determine the amount of 1-iodoethyl and 1-chloroethyl ether of the diastereomer containing 40% of the iodo compound depending on the microanalysis of oxo. A binder compound (melting point 134-136 degreeC) was obtained.

[Example 15]

Chloromethyl 6β-bromophenicylanate

Tetrabutyl ammonium hydrogensulfate (0.10 g, 0.3 mmol) in a stirred solution of potassium 6β-bromophenicilanate (0.96 g, 3 mmol) and potassium bicarbonate (1.80 g, 18 mmol) in water (9 ml) and ethyl acetate (9 ml). ) Was added followed by chloromethylchlorosulfonate (0.45 ml, 45 mmol) and the mixture was stirred at rt for 1.5 h.

The organic phase was separated and the aqueous phase was reextracted with ethyl acetate (9 ml).

The combined organic extracts were washed with water (2 x 5 ml), dried and concentrated to about 5 ml under reduced pressure. The concentrate was subjected to anhydrous column chromatography on silica gel (petroleum ether-ethyl acetate 9: 1) to give pure chloromethyl 6β-bromo peniclanate as an almost colorless oil.

NMR spectra (CDCl ₃ ) show δ = 1.54 (s, 3H; 2-CH ₃ ), 1.70 (s, 3H; 2-CH ₃ ), 4.54 (s, 1H; 3-H), 5.35 and 5.59 (2d, J = 4Hz, 2H; 5-H and 6-H) and 5.77 (ABq, J = 5Hz, 2H; OCH ₂ Cl) ppm and tetramethylsilane was used as internal reference.

[Example 16]

Iodomethyl 6β-bromophenicylanate

To a solution of chloromethyl 6β-bromophenicilanate (0.82 g, 2.5 mmol) in acetone (5 ml) was added solid sodium iodide (0.75 g, 5.0 mmol), the light was blocked and the mixture was stirred at room temperature for 24 hours. . Precipitated sodium chloride was filtered off, washed with acetone (2 x 1 ml), the filtrate was evaporated in vacuo and the remaining oily residue was redissolved in ethyl acetate (20 ml). The resulting solution was washed with water (2 × 10 ml), dried (MgSO ₄ ), concentrated to about 5 ml under reduced pressure, and column chromatography on silica gel using 9: 1 of petroleum ether-ethyl acetate as eluent. The fraction containing the pure scavenging compound, as revealed by thin layer chromatography (TLC), was combined and evaporated in vacuo to give iodomethyl 6β-bromopheniclanate as a slightly yellowish oil.

Spectra are δ = 1.55 (s, 3H; 2-CH ₃ ), 1.69 (s, 3H; 2-CH ₃ ), 4.50 (s, 1H; 3-H), 5.34 and 5.57 (2d, J = 4 Hz, 2H) 5-H and 6-H) and 5.97 (ABq, J = 5 Hz, 2H; OCH ₂ Cl) ppm and tetramethylsilane was used as internal reference.

[Example 17]

Chloromethyl 1,1-dioxo-6β- (2,6-dimetholsibenzamido) penicilanate

Chloromethyl chlorosulfate (1.8 ml, 18 mmol) was added 1,1-dioxo-6β- (2,6-dimethoxybenzamido) peniclanic acid (methicillin sulfone in water (15 ml) and dichloromethane (15 ml) 6.2 g, 15 mmol), a mixture of potassium hydrogen carbonate (8.7 g, 87 mmol) and tetrabutylammonium hydrogensulfate (0.51 g, 1.5 mmol) was added at room temperature for 20 minutes.

After stirring for 15 minutes, the organic phase was separated, dried and evaporated in vacuo to crystallize the remaining oil from 96% ethanol to give colorless crystals having a melting point of 142-143 占 폚 (decomposition).

(C=1, CHCl₃)Recrystallization twice from acetone-water yielded an analytical sample having a melting point of 154-155 ° C. (degradation).

(C = 1, CHCl ₃ )

[Example 18]

Iodomethyl 1,1-dioxo-6β- (2,6-dimethoxybenzamado) penicilanate

Sodium iodide (3 g, 20 mmol) was added to a solution of chloromethyl 1,1-dioxo-6β- (2,6-dimethoxybenzamido) penicilanate (2.31 g, 5 mmol) in acetone (10 ml) The mixture was stirred overnight at room temperature. After addition of water, the desired compound precipitated as crystals was collected by filtration and dried in vacuo.

Melting Point 153-156 ° C (Decomposition)

(C=1, CHCl₃)The product was dissolved in a mixture of acetone and 96% ethanol and acetone was removed in vacuo to determine the desired compound. This process was repeated to raise the melting point to 169-170 ° C. (decomposition).

(C = 1, CHCl ₃ )

[Example 19]

Chloromethyl 1,1-dioxo-6α-chloro peniclanate

(C=0.5, CHCl₃)The desired compound having a melting point of 111-113 ° C. in the method of Formulation Example 15 using potassium 1,1-dioxo-6α-chloro-penicylanate instead of potassium 6β-bromophenicylanate is ether-diisopropyl Obtained as colorless crystals from ether.

(C = 0.5, CHCl ₃ )

[Example 20]

Iodomethyl 1,1-dioxo-6α-chloro penicillate

The desired compound was obtained as a colorless bubble by the method of Formulation Example 16 using chloromethyl 1,1-dioxo-6α-chlorophenicylate in place of chloromethyl 6β-bromophenicylanate.

NMR spectra (CDCl ₃ ) show δ = 1.49 (s, 3H; 2-CH ₃ ), 1.62 (s, 3H; 2-CH ₃ ), 4.41 (s, 1H; 3-H), 4.66 and 5.16 (2d, J = 1.5 Hz, 2H; 5-H and 6-H) and 6.01 (ABq, J = 5 Hz, 2H; OCH ₂ Cl) ppm and tetramethylsilane was used as internal reference.

[Example 21]

Chloromethyl 1,1-dioxo-6α-bromophenicylanate

(C=0.5, CHCl₃)The desired compound having a melting point of 93-93 ° C. was dissolved in ether-diisopropyl by the method of Formulation Example 15 using potassium 1,1-dioxo-6α-bromophenicylanate instead of potassium 6β-bromophenicylanate. Obtained as colorless crystals from ether.

(C = 0.5, CHCl ₃ )

Preparation Example 22

Iodomethyl 1,1-dioxo-6α-bromophenicylanate

Using the chloromethyl 1,1-dioxo-6α-bromo-phenylanate in place of chloromethyl 6β-bromophenicylanate, the desired compound was obtained as a colorless bubble without crystallization by the method of Formulation Example 16.

NMR spectra (CDCl ₃ ) show δ = 1.49 (s, 3H; 2-CH ₃ ), 1.63 (s, 3H; 2-CH ₃ ), 4.41 (s, 1H; 3-H), 4.70 and 5.16 (2d, J = 1.5 Hz, 2H; 5-H and 6-H) and 6.01 (ABq, J = 5 Hz, 2H; OCH ₂ Cl) ppm and tetramethylsilane was used as internal reference.

[Example 23]

Chloromethyl 6β-yodophenicylanate

The desired compound was obtained as a slightly yellowish oil by the method of Formulation Example 15 using potassium 6β-iodophenicilanate instead of potassium 6β-bromophenicilanate.

NMR spectra (CDCl ₃ ) show δ = 1.52 (s, 3H; 2-CH ₃ ), 1.71 (s, 3H; 2-CH ₃ ), 4.55 (s, 1H; 3-H), 5.40 and 5.63 (2d, J = 3.5Hz, 2H; 5-H and 6-H) and 5.78 (ABq, J = 5.5Hz, 2H; OCH ₂ Cl) ppm and tetramethylsilane was used as internal reference.

[Example 24]

Iodomethyl 6β-iodophenicylanate

The desired compound was obtained as a yellowish oil by the method of Formulation Example 16 using chloromethyl 6β-iodophenicylanate instead of chloromethyl 6β-bromophenicylanate.

NMR spectra (CDCl ₃ ) show δ = 1.53 (s, 3H; 2-CH ₃ ), 1.70 (s, 3H; 2-CH ₃ ), 4.53 (s, 1H; 3-H), 5.39 and 5.61 (2d, J = 3.5Hz, 2H; 5-H and 6-H) and 6.00 (ABq, J = 5Hz, 2H; OCH ₂ Cl) ppm and tetramethylsilane was used as internal reference.

[Example 25]

Chloromethyl 6β-chlorophenicylate

The desired compound was obtained as a colorless oil by the method of Formulation Example 15 using potassium 6β-chlorophenicilanate instead of potassium 6β-bromophenicilanate.

NMR spectra (CDCl ₃ ) show δ = 1.53 (s, 3H; 2-CH ₃ ), 1.69 (s, 3H; 2-CH ₃ ), 4.54 (s, 1H; 3-H), 5.24 and 5.62 (2d, J = 4Hz, 2H; 5-H and 6-H) and 5.80 (ABq, J = 5Hz, 2H; OCH ₂ Cl) ppm and tetramethylsilane was used as internal reference.

[Example 26]

Iodomethyl 6β-chlorophenicylanate

The desired compound was obtained as a slightly yellowish oil by the method of Formulation Example 16 using chloromethyl 6β-chlorophenicylate instead of chloromethyl 6β-bromophenicylanate.

NMR spectra (CDCl ₃ ) show δ = 1.52 (s, 3H; 2-CH ₃ ), 1.69 (s, 3H; 2-CH ₃ ), 4.52 (s, 1H; 3-H), 5.22 and 5.58 (2d, J = 4Hz, 2H; 5-H and 6-H) and 5.99 (ABq, J = 5Hz, 2H; OCH ₂ Cl) ppm and tetramethylsilane was used as internal reference.

Preparation Example 27

Chloromethyl 6β-bromophenicylanate

A. Chloromethyl 6,6-dibromophenicylanate

(C=0.5, CHCl₃)Using a potassium 6,6-dibromophenicylateate instead of potassium 6β-bromophenicylanate, the desired compound having a melting point of 105-107 ° C. was recrystallized from ether-diisopropyl ether by the method of Formulation Example 15. Obtained as a slightly yellowish oil.

(C = 0.5, CHCl ₃ )

NMR spectrum (CDCl ₃ ) shows δ = 1.54 (s, 3H; 2-CH ₃ ), 1.66 (s, 3H; 2-CH ₃ ), 4.60 (s, 1H; 3-H), 5.80 (ABq, J = It appeared at 5 Hz, 2H; OCH ₂ Cl) and 5.83 (s, 1H; 5-H) ppm and tetramethylsilane was used as internal reference.

B. Chloromethyl 6β-bromophenicylanate

To a stirred solution of chloromethyl 6,6-dibromo-phenylanate (1.63 g, 4 mmol) in arsenic benzene (40 ml) was added tri-n-butyltin hydride (1.16 g, 4 mmol) under nitrogen atmosphere at 0 ° C. Was added. After stirring for 18 hours at room temperature, the mixture was evaporated in vacuo.

The residue oil was purified by anhydrous column chromatography on silica gel (petroleum ether-ethyl acetate, 85:15) to give pure chloromethyl 6β-bromopheniclanate as a slightly yellowish oil.

The NMR spectrum of the product was the same as that of the compound described in Formulation Example 15.

Preparation Example 28

Bromomethyl 1,1-dioxophenicylanate

To a solution of sodium bromide (1.0 g) in N, N-dimethylformamide (10 ml) was added chloromethyl 1,1-dioxo penicillate (0.28 g, 1 mmol) and the mixture was stirred at rt for 20 h. After diluting with ethyl acetate (50 ml), the mixture was washed with water (4 x 10 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give the desired compound as a yellowish oil.

NMR spectrum (CDCl ₃ ) is δ = 1.49 (s, 3H; 2-CH ₃ ), 1.64 (s, 3H; 2-CH ₃ ), 3.52 (m, 2H; 6-H, 4.47 (s, 1H; 3H), 4.75 (m, 1H; 5-H), and 5.58 (ABq, J = 4.5 Hz, 2H; OCH ₂ Br) ppm and TMS was used as internal reference.

The present invention will be described in detail based on the following examples.

Example 1

1,1-dioxophenicylanoyloxymethyl 6- (D-χ-amino-χ-phenylacetamido) peniclanate hydrochloride

1,1-dioxophenylanoyloxymethyl 6- (D-α-azido-α-phenylacetamido) penicilanate

Potassium penicillate 1,1-dioxide (1.63 g) in a solution of chloromethyl 6- (D-α-azido-α-phenylacetamido) penicilanate (2.54 g, 6 mmol) in dimethylformamide (35 ml) , 6 mmol) was added and the mixture was stirred at rt for 20 h. After diluting with ethyl acetate (140 ml), the mixture was washed with water (4 x 35 ml) and then with saturated aqueous sodium chloride (20 ml) to dry the organic phase and evaporated in vacuo. The yellow oily residue thus obtained was purified by anhydrous column chromatography on silica gel (cyclohexane-ethyl acetate 1: 1) to obtain the desired compound as a yellowish oil.

NMR spectrum (CDCl ₃ ) is δ = 1.43 (s, 3H; 2-CH ₃ ), 1.52 (s, 3H; 2-CH ₃ ), 1.59 (s, 3H; 2-CH ₃ ), 1.66 (s, 3H 2-CH ₃ ), 3.48 (d, J = 3 Hz, 2H; 6α-H and 6β-H) 4.44 (s, 1H; 3-H), 4.51 (s, 1H; 3-H), 4.63 (t , J = 3 Hz, 1H; 5-H), 5.13 (s, 1H; CHN ₃ ), 5.65 (m, 2H; 5-H and 6-H), 5.92 (s, 2H; OCH ₂ O), and 7.48 (s, 5H; aram. CH) ppm and tetramethylsilane was used as internal reference.

B. 1,1-dioxophenylanoyloxymethyl6- (D-α-amino-α-phenylacetamido) penicilanate hydrochloride

1,1-dioxophenicsilane oiloxymethyl 6- (D-α-azido-α-phenylacetamido) penicilanate (1.77 g, 2.85 mmol) in ethyl acetate (25 ml) was gas inlet / outlet It was loaded into three necked flasks equipped with glass-sensing coupling electrodes and burettes controlled by an autotitrator. 10% palladium supported on water (20 ml) and carbon catalyst (1.77 g) was added and the system was clarified with nitrogen. The hydrogen stream was then bubbled through the suspension with stirring and 0.5N aqueous hydrochloric acid was added through an autotitrator to maintain a pH value of 2.5 in the aqueous phase.

At the end of the acid consumption the flask was purged with nitrogen and all catalysts were removed until all the hydrogen was removed. The aqueous phase was separated and freeze dried to afford the desired compound as a colorless bubble.

NMR spectrum (CDCl ₃ ) is δ = 1.38 (s, 6H; 2-CH ₃ ), 1.46 (s, 3H; 2-CH ₃ ), 1.58 (s, 3H; 2-CH ₃ ), 3.56 (m, 2H ; 6α-H and 6β-H), 4.60 (s, 1H; 3-H), 4.63 (s, 1H; 3-H), 5.03 (m, 1H; 5-H), 5.27 (s, 1H; CH -NH ₂ ), 5.53 (s, 2H; 5-H and 6-H), 5.97 (bs, 1H; OCH ₂ O) and 7.53 (S, 5H; arom. CH) ppm and tetramethylsilane Used as internal reference.

Example 2

1,1-dioxophenylanoyloxymethyl 6- [D-α-amino-α- (P-hydroxyphenyl) acetamido] pheniclanate, hydrochloride

A. 1,1-dioxophenicylanoyloxymethyl 6- [N- (benzyloxycarbonyl) -D-χ-amino-χ- (P-hydroxyphenyl) acetamido] pheniclanate

To a solution of 1,1-dioxide (1.41 g, 5 mmol) of chloromethylphenicilanate in dimethylformamide (25 ml) was added potassium 6- [N- (benzyloxycarbonyl) -D-α-amino-α- (P- Hydroxyphenyl) -acetamido] penicilanate (2.46 g, 5 mmol) was added and the mixture was stirred at rt for 18 h. After diluting with ethyl acetate (100 ml), the mixture was washed with water (4 x 25 ml), dried and evaporated in vacuo. The residue oil was purified by anhydrous column chromatography on silica gel (ethyl acetate-petroleum ether 8: 2) to obtain the desired compound as a yellowish oil.

*) Or equivalent amounts of the corresponding iodomethyl esters end up in a much shorter reaction time.

B. 1, 1-dioxophenicylanoyloxymethyl 6- [D-α-amino-α- (P-hydroxyphenyl) acetamido] phenylanate hydroclyde

The benzyloxycarbonylprotecting group of the compound prepared in Example 2A was removed by hydrogenation at atmospheric pressure using the method described in Example 1B to afford the desired compound as a colorless amorphous product.

Example 3

A. 1- (1,1-Dioxophenylanioyloxy) ethyl 6- (D-α-amino-α-phenylacetamido) phenylanate hydrochlorite

α-Chloroethyl 6- (D-α-azio-α-phenylacetamido) phenylanate was used in place of the corresponding chloromethyl ester in Example 1A to use 1- (1, 1-dioxopheny Silanoyloxy) ethyl 6- (D-α-azino-α phenylacetamido) penicilanate was obtained.

B. 1- (1, 1-dioxophenysilaneoilyloxy) in place of 1, 1-dioxophenicylanoyl-oxymethyl 6- (D-α-azido-α-phenamimitamido) peniclanate Except using ethyl 6- (D-α-azido-α-phenamimitamido) pheniclanate, the method of Example 1B was followed by 1- (1, 1-dioxophenicylanoyloxy) ethyl 6- (D- [alpha] -Amino- [alpha] -phenamimitamido) pheniclanate, hydrochloride, was obtained as an amorphous product.

Example 4

1, 1-dioxophenicylanoyloxymethyl 6- (D, L-α-carboxy-α-phenyl-acetamido) penicilanate sodium salt

A. 1, 1-dioxophenicylanoyloxymethyl 6- (D, L-α-benzyloxy-carbonyl-α-phenylacetamido) penicilanate

Potassium 6- [N-benzyloxycarbonyl-D-α-amino-α- (P-hydroxyphenyl) acetamido] instead of penicilanate sodium 6- (D, L-α-benzyloxycarbonyl-α The desired compound was obtained according to the method described in Example 2A except for using phenylacetamido) penicilanate.

B. 1, 1-dioxophenicylanoyloxymethyl 6- (D, K-α-carboxy-α-phenylacetamido) penicilanate sodium salt

Carbon in a solution of 1,1-dioxophenicylanoxeoxymethyl 6- (D, L-α-benzyloxycarbonyl-α-phenylacetamido) pheniclanate (1.43 g, 2 mmol) in ethanol (20 ml) 10% palladium supported on the catalyst was added and the mixture was hydrogenated at atmospheric pressure until hydrogen consumption was complete. The catalyst was filtered off, washed with ethanol and the filtrate was evaporated in vacuo. The oily residue thus obtained was dissolved in ethyl acetate (15 ml), water (15 ml) was added, and 0.2N aqueous sodium hydroxide was added with stirring to adjust the pH in the aqueous phase to 7.0. The aqueous phase was separated and freeze dried to afford the desired compound as a yellowish bubble.

Example 5

Example 1A except for using sodium clavulanate in place of clavulanoyloxymethyl 6- (D-α-amino-α-phenamimitamido) penicillate hydrochloride potassium penicillate 1, 1-dioxide According to the method described, clavulanoyloxymethyl 6- (D-α-azido-α-phenamimitamido) phenylanate was obtained as a yellowish oil.

The intermediate was contacted hydrogenated according to the method described in Example 1B to afford the desired compound as an amorphous powder.

Example 6

1,1-Dioxo-6α-chlorophenicyanoyloxymethyl 6- (D-α-amino-α-phenylacetamido) phenylanate hydrochloride

Chloromethylphenicylanate 1, chloromethyl 6α-chlorophenicilanate 1, 1-dioxide, potassium 6 [N-benzyloxycarbonyl) -D, α-amido-α- (P-hydro instead of 1-dioxide Triethylammonium 6- [N- (1-N, N-dimethylaminocarbonylpropen 2-yl) -D-α-amino-α-phenylacetamido instead of oxyphenyl) -acetamidophenicilanate ] 1, 1-dioxo-6α-chloro penylanoyloxymethyl 6- [N- (1-N, N-dimethylaminocarbonylpropene-) using penicylanate according to the method described in Example 2A 2-yl) -D-α-amino-α-phenylacetamido] pheniclanate was obtained.

The protecting group in the intermediate was removed by acid-contact hydrolysis (ph-3) in a 1: 1 mixture of ethyl acetate and water, and after separation, the resultant aqueous phase was lyophilized to obtain the desired compound as an amorphous product.

Example 7

6β-Bromophenicylanoyloxymethyl 6- (D-α-amino-α-phenymitamido) phenylanate hydrochloride

Chloromethylphenicylanate 1, Chloromethyl 6β-bromophenicylanate instead of 1-dioxide, potassium 6- [N- (benzyloxycarbonyl) -D-α-amino-α- (P-hydroxyphenyl) Triethylammonium 6- [N- (1-N, N-dimethylaminocarbonylpropen-2-yl) -D, α-amino-α-phenylacetamido] penny instead of acetamido] phenylanate Except for using silanate, according to the method described in Example 2A, 6β-bromophenylanoyloxymethyl 6- [N- (1-N, N-dimethylaminocarbonyl-propen-2-yl) -D, α-amino-α-phenylacetamido] penicilanate was obtained.

The protecting group of the intermediate was removed by acid-contact hydrolysis (ph-3) in a 1: 1 mixture of ethyl acetate and water, and the separated aqueous phase was freeze-dried to obtain the desired compound as an amorphous product.

Example 8

1, 1-dioxophenicylanoyloxymethyl 6- (D-α-amino-α-phenamimitamido) -phenylanate hydrochloride

A. Tetrabutylammonium 6- (D-α-amino-α-phenymidamido) -penicylanate

Stirred 6- (D-α-amino-α-phenamimitamido) phenylanic acid trihydrate (8.08 g) and tetrabutylammoniumhydrogensulfate (6.9 g) in water (20 ml) and dichloromethane (40 ml) To the cooled (5 ° C.) mixture was slowly added 2N aqueous sodium hydroxide (20 ml). The organic layer was separated and the aqueous phase extracted with dichloromethane (20 ml). The combined dichloromethane layer was dried (MgSO ₄ ) and evaporated in vacuo leaving viscous oil. The oil was dissolved in ethyl acetate (100 ml) and the residue dichloromethane was removed at reduced pressure. After leaving overnight at 5 ° C., the precipitated crystals were collected, washed with ethyl acetate and evaporated in vacuo to give a slightly hygroscopic crystal having a melting point of 125-130 ° C. (decomposition) as a colorless compound.

B. 1, 1-dioxophenicylanoyloxymethyl 6- (D-α-amino-α-phenamimitamido) phenylanate hydrochloride

Iodine in ethyl acetate (10 ml) to a stirred suspension of tetrabutylammonium 6- (D-α-amino-α-phenamimidamido) phenislanate (2.95 g) in ethyl acetate (20 ml) and dichloromethane (5 ml) A solution of dimethyl 1, 1-dioxophenicylanate (1.9 g) was added. After a few minutes, an almost clear solution was obtained. Dichloromethane was removed under reduced pressure and the precipitated tetrabutylammonium iodide was filtered off. From the filtrate, the desired compound is transferred to an aqueous phase (25 ml) with 1N aqueous hydrochloric acid (ph 3.0, 5 ° C.) and an organic phase (ethyl acetate, 25 ml) with 0.5 M aqueous sodium hydrogen carbonate (ph 7.0, 5 ° C.) from the aqueous phase. Moved to. The organic layer was washed with water and the desired compound was transferred back to the aqueous phase as described above. N-butanol was added to the aqueous phase, and water was distilled in vacuo to remove by azeotropic distillation to give the desired compound as colorless crystals with a melting point of 175-177 占 폚 (decomposition).

Example 9

1, 1-dioxophenicylanoyloxymethyl 6- (D-α-amino-α-phenymidamido) pheniclanate

To a cold (5 ° C.) solution (631 mg) of the compound prepared in Example 8 in water (10 ml) was added ethyl acetate (10 ml) and 0.5M aqueous sodium hydrogen carbonate was added with stirring to adjust the pH of the mixture to 7.0. The organic layer was separated, washed with water, dried (MgSO ₄ ) and evaporated in vacuo to afford the desired compound as a colorless solid.

The IR spectrum (KBr) showed strong bands at 1780 and 1690 cm ⁻¹ .

Example 10

1,1-Dioxophenylanoyloxymethyl 6- [D-α-amino-α- (P-hydroxy-phenyl) acetamido] phenylanate hydrochloride

A. Tetrabutylammonium 6- [D-α-amino-α- (P-hydroxyphenyl) acetamido] penicylanate

To a stirred, cooled (5 ° C.) solution of tetrabutylammonium hydrogen sulfate (3.57 g, 10.5 mmol) in water (10 ml) was added a mixture of dichloromethane and n-butanol (9: 1, 20 ml), followed by 2N sodium hydroxide. Ph was adjusted to 3. The organic layer was separated and the aqueous phase was extracted twice with 10 ml of dichloromethyl: n-butanol (9: 1). The combined extract was concentrated in vacuo to give a viscous oil. The residue was dissolved in ethyl acetate (50 ml).

Crystallized by scratching and left at 5 ° C. for 2 hours, the crystals were separated by filtration, washed and dried to obtain a desired compound having a melting point of 148-151 ° C. (decomposition).

*) 6- [D-α-amino-α- (P-hydroxyphenyl) acetamido] phenylanic acid

B. 1, 1-dioxophenicylanoyloxymethyl 6- [D-α-amino-α- (P-hydroxyphenyl) acetamido] pheniclanate, hydroxide chloride

A stirred, cooled (5 ° C.) solution of tetrabutyl-ammonium 6- [D-α-amino-α- (P-hydroxyphenyl) acetamido] phenislanate (606 mg, 1 mmol) in acetonitrile (5 ml). To iodomethyl 1,1-dioxophenicylanate (363 mg, 1 mmol) dissolved in acetonitrile (2 ml) was added. After stirring for 10 min at 5 ° C., ethyl acetate (50 ml) was added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20 ml), the crystallized tetrabutylammonium iodide was removed by filtration, water (10 ml) was added to the filtrate, pH was adjusted to 3 with 1 N hydrochloric acid, and the desired compound was colorless powdered. Obtained as.

NMR spectrum [(CD ₃ ) ₂ SO] is δ = 1.37 (s, 6H; 2-CH ₃ ), 1.50 (s, 6H; 2-CH ₃ ), 3.46 (m, 2H, 6α-H and 6β-H ), 4.46 (s, 1H; 3-H), 4.57 (s, 1H; 3-H), 5.04 (bs, 1H; CHNH ₂ ), 5.27 (m, 1H; 5-H), 5.58 (m, 2 -H; 5-H and 6-H), 5.96 (bs, 2H, OCH ₂ O), 6.87 and 7.37 (2d, J = 8.5 Hz, 4H; arom. CH) ppm, TMS internally referenced Used as material.

Example 11

1- (1,1-Dioxophenylanoyloxy) ethyl 6- (D-α-amino-α-phenymidamido) peniclanate hardchloride

To a solution of tetrabutylammonium 6- (D-α-amino-α-phenamimidamido) phenylanate (5.9 g, 10 mmol) in dichloromethane (10 ml) and ethyl acetate (40 ml), to ethyl acetate (30 ml) Dissolved 1-iodoethyl 1, 1-dioxophenicylanate (4.22 g) corresponding to 40% purity of 1.55 g, 10.9 mmol) was added. After correcting the solution immediately with tetrabutylammonium iodide, dichloromethane was removed in vacuo and the separated tetrabutylammonium iodide was filtered off. From the margin the desired compound was transferred to an aqueous phase (50 ml) with 1N hydrochloric acid (pH 3.0, 5 ° C.) and from an organic phase to an organic phase (ethyl acetate, 50 ml) with sodium hydrogen carbonate (pH 7.0, 5 ° C.). The organic phase was washed with water and the desired compound was relocated to the aqueous phase as described above. The aqueous phase was lyophilized to give the desired compound as a color powder.

NMR spectrum (D ₂ O) is δ = 1.38 (s, 6H; 2-CH ₃ ), 1.43 (s, 3H; 2-CH ₃ ), 1.55 (s, 3H; 2-CH ₃ ), 1.56 (d, 3H; CHCH ₃ ), 3.50 (m, 2H; 6α-H and 6β-H), 4.53 (s, 1H; 3-H), 4.55 and 4.59 (2s, 1H; 3-H), 4.96 (m, 1H 5-H), 5.26 (s, 1H, CHNH ₂ ), 5.51 (s, 2H 5-H and 6-H), 6.95 (m, 1H; CHCH ₃ ), and 7.51 (s, 5H; arom, CH ) ppm.

Example 12

6β-Bromophenicylanoyloxymethyl 6- (D-α-amino-α-phenymitamido) phenylanate hydrochloride

Stirred Application of Tetrabutylammonium 6- (D-α-amino-α-phenylacetamido) phenylanate (0.82 g, 1.4 mmol) in a mixture of ethyl acetate (2.8 ml) and dichloromethane (1.4 ml) To the solution was added a solution of iodomethyl 6β-bromophenicylanate (0.60 g, 1.4 mmol) in ethyl acetate (5.6 ml). After stirring for several minutes at room temperature crystalline tetrabutylammonium iodide began to precipitate.

Dichloromethane was removed from the reaction mixture under reduced pressure, and the crystals were filtered off and washed with ethyl acetate (2 x 2.5 ml). The filtrate was washed with water (5ml), fresh water (loml) was added to the organic phase, and the pH of the aqueous phase was adjusted by adding 1N hydrochloric acid with stirring to control No. 3.1. The aqueous phase was separated and freeze dried to afford the desired product as a colorless bubble.

NMR spectrum (D ₂ O) is δ = 1.34 (s, 3H; 2-CH ₃ ), 1.36 (s, 3H; 2-CH ₃ ), 1.43 (s, 3H; 2-CH ₃ ), 1.58 (s, 3H; 2-CH ₃ ), 4.54 (s, 1H; 3-H), 4.75 (s, 1H; 3-H), 5.24 (s, 1H; CHNH ₂ ), 5.46-5.62 (m, 4H; 5- H and 6-H), 5.88 (bs, 2H; OCH ₂ O), and 7.47 (s, 5H; arom. CH) ppm.

Example 13

1,1-Dioxo-6α-dichlorophenicylanoyloxymethyl 6- (D-α-amino-α-phenymidamido) peniclanate hydrochloride

Example 12 In the method, iodomethyl 6β-bromophenicylanate was substituted with iodomethyl 1, 1-dioxo-6α-chlorophenicilanate to obtain the desired compound as a colorless bubble.

NMR spectrum (D ₂ O) is δ = 1.35 (s, 6H, 2-CH ₃ ), 1.41 (s, 3H; 2; CH ₃ ), 1.53 (s, 3H; 2-CH ₃ ), 4.57 (s, 1H; 3-H), 4.57 (s, 1H; 3-H), 5.08 (s, 1H; 5-H or 6-H), 5.26 (s, 1H; CHNH ₂ ), 5.34 (s, 1H; 5 -H or 6-H), 5.49 (s, 2H; 5-H and 6-H), 5.94 (b, 2H; OC ₂ O), and 7.41 (s, 5H; arom. CH) ppm.

Example 14

1, 1-dioxophenicylanoyloxymethyl 6- (D-α-amino-α-phenamimitamido) -phenylanate hydrochloride

A. 1, 1-dioxo-6α-bromophenicylanoyloxyketyl 6- (D-α-amino-α-phenylacetamido) phenylanate hydrochloride

In the method of Example 12, iodomethyl 6β-bromopheniclanate was replaced with iodomethyl 1,1-dioxo-6α-bromophenicylanate to obtain the desired compound as a colorless bubble.

6-H), 5.27(s, 1H; CHNH₂), 5.35(s, 1H; 5-H 또는 6-H), 5.50(s, 2H ; 5-H 및 6-H), 5.95(b, 2H; OC₂O), 및 7.50(s, 5H; arom. CH) ppm에서 나타났다.NMR spectrum (D ₂ O) is δ = 1.36 (s, 6H, 2-CH ₃ ), 1.41 (s, 3H; 3-CH ₃ ), 1.54 (s, 3H; 2-CH ₃ ), 4.57 (s, 1H; 3-H), 4.71 (s, 1H; 3-H), 5.09 (s, 1H; 5-H

6-H), 5.27 (s, 1H; CHNH ₂ ), 5.35 (s, 1H; 5-H or 6-H), 5.50 (s, 2H; 5-H and 6-H), 5.95 (b, 2H OC ₂ O), and 7.50 (s, 5H; arom. CH) ppm.

B. 1, 1-dioxophenicylanoyloxymethyl 6- (D-α-amino-α-phenyl-mistamamido) phenylanate hydrochloride

1, 1-dioxo-6α-bromophenylanoyloxy-methyl 6- (D-α-amino-α-phenylacetamido) phenylanate (1.36 g of the corresponding hydrochloride in ethyl acetate (50 ml) To 10% palladium supported on water (25 ml) and carbon catalyst (0.7 g) and the mixture was shaken in hydrogen atmosphere for 40 minutes. After removing the catalyst by filtration, the pH of the aqueous phase was adjusted to 2.5 with 1N hydrochloric acid. From the separated aqueous phase the desired compound was transferred to an organic phase (ethylacetate, 25 ml) with aqueous potassium bicarbonate (pH 7.0, 5 ° C.) and returned to fresh aqueous phase as IN hydrochloric acid (pH 2.7). The aqueous phase was lyophilized to give the desired compound as a colorless powder.

The NMR spectrum of the product was the same as that of the compound described in Example 1.

Example 15

β-iodophenicylanoyloxymethyl 6- (D-α-amino-α-phenylacetamido) -phenylanate hydrochloride

The desired compound was obtained as a colorless foam according to the method described in Example 12 except for replacing iodomethyl 6β-iodophenicylate in place of iodomethyl 6β-bromophenicylanate.

NMR spectrum (D ₂ O) is δ = 1.33 (s, 3H, 2-CH ₃ ), 1.38 (s, 3H; 2-CH ₃ ), 1.45 (s, 3H; 2-CH ₃ ), 1.60 (s, 3H; 2-CH ₃ ), 4.56 (s, 1H; 3-H), 4.74 (s, 1H; 5-H), 5.22 (s, 1H; CHNH ₂ ), 5.3-5.7 (m, 4-H; 5-H and 6-H), 5.92 (bs, 2H; OCH ₂ O), and 7.49 (s, 5H; arom. CH) ppm.

Example 16

6β-Chlorophenylanoyloxymethyl 6- (D-α-α-amino-α-phenylacetamido) -phenylanate hydrochloride

The desired compound was obtained as a colorless foam according to the method described in Example 12 except for replacing iodomethyl 6β-chlorophenicylate in place of iodomethyl 6β-bromophenicylanate.

Example 17

Clavlanoyloxymethyl 6- (D-α-amino-α-phenylacetamido) phenylanate hydrochloride

A. Iodomethyl 6- (D-α-amido-α-phenylacetamido) phenylanate

To a solution of chloromethyl 6- (D-α-azido-α-phenyl-acet amido) penicilanate (1.32 g, 3 mmol) in acetone (25 ml) was added sodium iodide (1.80 g, 12 mmol) and the mixture was Stir at room temperature for 18 hours. The precipitate was filtered off and the filtrate was evaporated in vacuo. The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue was extracted with ethyl acetate (25 ml) and the extract was concentrated to about 3 ml and column chromatography on silica gel using hexane-ethyl acetate 1: 1 as eluent. The oil containing the scavenging compound was combined and evaporated in vacuo to yield the scavenging compound as a yellowish oil.

NMR spectrum (CDCl ₃ ) is δ = 1.58 (s, 3H, 2-CH ₃ ), 1.67 (s, 3H; 2-CH ₃ ), 4.47 (s, 1H; CHN ₃ ), 5.52-5.82 (m, 2H 5-H and 6H), 6.00 (ABq, 2H; OCH ₃ J), 7.4 (s, 5H; arom. CH), and 7.0-7.4 (m, 1H; CONH) ppm.

TMS was used as internal reference.

B. clavlynoyloxymethyl 6- (D-α-azido-α-phenylacetamido) -penicylanate

Lithium cleavate (90 mg) in a solution of iodomethyl 6- (D-α-azido-α-phenylacetamido) pheniclanate (378 mg, 0.73 mmol) in hexylmethylosporic acid triamide (3.ml) , 0.44 mmol) was added and the mixture was stirred at rt for 1 h. The mixture was diluted with ethyl acetate (90 ml) and washed with water (3 x 20 ml) and then with saturated aqueous sodium chloride (10 ml), dried and evaporated in vacuo. The yellow oil thus obtained was purified by column chromatography on silica gel using hexane-ethyl acetate 1: 4 as the eluent to obtain the desired compound as a slightly yellowish bubble.

NMR spectrum (CDCl ₃ ) is δ = 1.51 (s, 3H, 2-CH ₃ ), 1.64 (s, 3H; 2-CH ₃ ), 3.11 (d, J = 17 Hz, 1H; 6-H), 3.51 ( dd, J ₁ = 17 Hz, J ₂ = 3 Hz, 1H; 6-H), 4.25 (d, J = 7 Hz, 2H; CH ₂ OH), 4.51 (s, 1H; 3-H), 4.92 (m, 1H ; CH), 5.13 (s, 1H; 5-H), 5.13 (s, 1H; 3-H), 5.5-5.8 (m, 3H; 5-H, 6-H, and CHN ₃ ) 5.89 (ABq, 2H OCH ₂ O), 7.16 (d, J = 8.5 Hz, 1H; CONH), and 7.41 (m, 5H; arom. CH) ppm. TMS was used as internal reference.

C. Clavlanoyloxymethyl 6- (D-α-amino-α-phenylamideamido) -penicylanate hydrochloride

A solution of clavlanoyloxymethyl 6- (D-α-azido-α-phenyl-acetamido) phenylanate (130 mg, 0.22 mmol) in ethyl acetate (20 ml) was mixed with a gas inlet and a glass-caramel mixture. Injected into three necked flasks equipped with electrodes and burettes. 10% palladium supported on water (20 ml) and carbon catalyst (130 mg) was added and the system was clarified with nitrogen. At the end of acid consumption the flask was purged with nitrogen and the catalyst was filtered off. The aqueous layer was separated, filtered and lyophilized to give the desired compound as a colorless powder.

NMR spectrum [(CD ₃ ) SO] is δ = 1.30 (s, 3H, 2-CH ₃ ), 1.44 (s, 3H; 2-CH ₃ ), 3.12 (d, J = 17Hz, 1H; 6-H) , 3.65 (dd, J ₁ = 17 Hz, J ₂ = 3 Hz, 1H; 6-H), 4.00 (m, 2H; CH ₂ OH), 4.42 (s, 1H; 3-H), 4.75 (m, 1H; -CH =), 5.15 (bs, 1H; 3-H), 5.40-5.75 (m, 3H; 5-H, 6-H, and CHNH ₂ ), 5.85 (ABq, 2H; OCH ₂ O), 7.50 ( m, 5H; arom. CH), and 9.45 (d, J = 7 Hz, 1H; CONH) ppm and TMS was used as internal reference.

Example 18

Clavlanoyloxymethyl 6- [D-α-amino-α- (p-hydroxyphenyl) acetamido] -phenylanate hydrochloride

A. Chloromethyl 6- [N-benzyloxycarbonyl-D-α-amino-α- (D-hydroxyphenyl) acetamido] penicilanate

Potassium 6- [N-benzyloxycarbonyl-D-α-amino-α- (p-hydroxyphenyl) acetamido] phenylanate (2.46 g, 5 mmol) in N, N-dimethylformamide (25 ml) Chloroiodomethane (2.18 ml) and 30 mmol were added to the suspension, and the mixture was stirred at room temperature for 3 hours. After dilution with ethyl acetate (100 ml), the mixture was washed with water (4 x 25 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel (using ethyl acetate / hexane 1: 1 as eluent) to afford the desired compound as a yellowish oil.

B. clavlanoyloxymethyl 6- [D-αamino-α- (p-hydroxyphenyl) -acetimido] phenylsilanate hydrochloride

Chloromethyl 6- [N-benzyloxy-carbonyl-D-α-amino-α- (p-hydroxy) instead of chloromethyl 6- (D-α-azido-α-phenylacetamido) phenylanate Phenyl) acetamido] Except for using penicilanate, the desired compound was obtained as a colorless lyophilized powder according to the method described in Examples 17A, 17B and 17C.

IR spectra (KBr) showed strong bands at 1775 and 1690 cm ⁻¹ .

Example 19

1, 1-dioxophenysilane oyloxymethyl 6- (D, L-α-carboxy-α-phenylacetamido) penicilanate sodium salt

A. 1, 1-dioxophenicylanoyloxymethyl 6- (D, L-α-benzyloxy carbonyl-α-phenylacetamido) phenylanate

Iodomethyl penicila in a suspension of sodium 6- (D, L-α-benzyloxy-α-carbonylphenylacetamido) pheniclanate (0.98 g, 2 mmol) in N, N-dimethylformamide (10 ml) Nate 1, 1-dioxide (0.75 g, 2 mmol) was added and the mixture was stirred for 30 minutes at room temperature. Ethyl acetate (50 ml) was added and the mixture was extracted with saturated aqueous calcium chloride (3 x 12 ml), dried and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel using hexane-ethyl acetate 1: 1 as eluent to afford the desired compound as a yellowish oil.

NMR spectrum (CDC1 ₃ ) is δ = 1.4-1.6 (m, 12H; 2-CH ₃ ), 3.46 (m, 2H; 5-H), 4.4-4.5 (m, 2H; 3-H and CHCO), 4.56 -4.65 (m, 2H; 3-H and 5-H), 5.19 (s, 2H; phCH ₂ O), 5.4-5.75 (m, 2H; 5-H and 6-H), 5.9 (ABq, 2H; OCH ₂ O), 7.3 (s, 5H; arom. CH), 7.35 (s, 5H; arom. CH), and 7.5-7.95 (m, 1H, CONH) ppm and TMS as internal standard Used.

B. 1, 1-dioxophenicylanoyloxymethyl 6- (D, L-α-carboxyl-α-phenylacetamido) penicillane sodium salt

(1.0 g, 1.4 mmol) in a solution of 1,1-dioxophenicylanoyloxymethyl 6- (D, L-α-benzyloxycarbonyl-α-phenylacetamido) peniclanate in ethyl acetate (25 ml) 10% palladium supported on water (25 ml) and carbon catalyst (1.0 g) were added and the pH value of the mixture was adjusted to 7.0. The mixture was stirred through a mixture of hydrogen and the pH was adjusted to 7.0 by adding 0.1N aqueous sodium hydroxide. At the end of consumption of the base (after about 1 hour), the catalyst was filtered off, the aqueous phase was separated, filtered and lyophilized to afford the desired compound as a colorless powder.

NMR-spectrum (D ₂ O) is δ = 1.47 (s, 3H, 2-CH ₃ ), 1.53 (s, 3H; 2-CH ₃ ), 1.63 (s, 6H; 2-CH ₃ ), 3.55 (m , 2H; 6-H, 4.12 (s, 1H; 3-H), 4.17 (s, 1H; 3-H), 4.70 (s, 1H; CHCO), 5.00 cm, 1H; 5-H), 5.4- 5.7 cm, 2 H; 5-H; 6-H), 6.00 (bs, 2H; OCH ₂ O), 7.42 (s, 5H; arom. CH) ppm and TMS was used as internal reference material.

Example 20

1, 1-dioxophenicylanyloxymethyl 6β-aminophenicylanate hydrochloride

A. Tetrabutyl Ammonium 6β-Aminophenicylanate

To a stirred and ice-cold mixture of 6β-aminophenicylic acid (4.32 g, 20 mmol), tetrabutyl ammonium hydrogen sulfate (6.8 g, 20 mmol), dichloromethane (50 ml), and water (20 ml) in water (3.5 ml) A solution of sodium hydroxide (1.60 g, 40 mmol) was added slowly. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 25 ml). The combined organic layer was dried and evaporated in vacuo to leave the desired compound as a viscous oil.

IR spectrum (CHC1 ₃ ) showed strong bands at 1760 and 1610 cm ⁻¹ .

B. 1, 1-dioxophenicsilane oiloxyketyl 6β-aminophenicilanate hydrochloride

LH20상에서 컬럼크로마토그래피하여 정제하였다. 정제된 생성물을 에틸아세테이트(25ml)중에 용해시키고, 물(25ml)를 가하여, 2N염산을 가하여 혼합물을 pH값을 2.0으로 조절하였다.A solution of iodomethyl penicilanate, 1, 1-dioxide (3.73 g, 10 mmol) in ethyl acetate (25 ml) to a solution of tetrabutyl ammonium 6β-aminophenicilanate (5.1 g, 11 mmol) in ethyl acetate (25 ml) Was added. After stirring for 15 min at room temperature the precipitate was filtered off and the filtrate was evaporated in vacuo. Sepadex (5ephadex) using the residue as eluent 65:35 chloroform-hexane

Purification by column chromatography on LH20. The purified product was dissolved in ethyl acetate (25 ml), water (25 ml) was added, and 2N hydrochloric acid was added to adjust the mixture to a pH value of 2.0.

The aqueous phase was separated and lyophilized to afford the desired compound as a colorless powder.

Spectrum (D ₂ O) shows δ = 1.52 (s, 3H; 2-CH ₃ ), 1.60 (s, 3H; 2-CH ₃ ), 1.65 (s, 3H; 2-CH ₃ ), 1.76 (s, 3H ; 2CH ₃ ), 3.52-3.8 (s, 2H; 6-H, 4.78 (s, 1H; 3-H), 4.90 (s, 1H; 3-H), 5.05-5.25 (m, 1H; 5-H ), 5.20 (d, J = 4 Hz, 1H; 6-H), 5.78 (d, J = 4 Hz, 1H; 5-H), and 6.08 (bs, 2H; OCH ₂ O) ppm, TMS Was used as internal reference material.

Example 21

1, 1-dioxophenicylanoyloxymethyl 6- (D-α-amino-α-phenylacetamido) penicilanate hydrochloride

To a stirred suspension of D-α-phenylglycichloride hydrochloride (1.98 g, 10 mmol) in dichloromethane (25 ml) was added sodium hydrogencarbonate (1.68 g, 20 mmol) at 0 ° C., followed by 1, 1-dioxopheny Silanoyloxymethyl 6-aminophenicilanate hydrochloride (3.98 g, 8 mmol) was added. After vigorously stirring at 0 ° C. for 1 h 30 min, the mixture was evaporated in vacuo. The residue was taken up in an ice cold mixture of ethyl acetate (25 ml) and saturated aqueous sodium hydrogen carbonate (25 ml). The organic phase was separated and water (20 ml) was added to adjust the pH of the mixture to 2.5 by addition of 2N hydrochloric acid. The aqueous phase was separated and lyophilized to give an amorphous powder crystallized from ethanol / butanone-2, which gave the same product as described in Example 8.

Example 22

1, 1-dioxophenicylanoyloxymethyl 6- (D-α-amino-α-phenylacetamido) penicilanate hydrochloride

A. Potassium 6- [N- (1-dimethylamino carbonylpropen-2-yl) -D-α-amino-α-phenylacetamido] penicilanate

Triethylammonium 6- [N- (1-dimethyl-aminocarbonylpropen-2-yl) -D-α-amino-α-phenylacetamido] penicilanate in acetone (1 L) (27.3 g, 48 mmol) To 1 M potassium 2-ethylhexanoate in acetone (49 ml) was added dropwise. After stirring for 2 hours at room temperature, the precipitate was filtered off and recrystallized from methanol-isopropanol to obtain an extra-extinction compound having a fusion of 201-203 占 폚 (decomposition).

B. 1, 1-dioxophenicylanoyloxymethyl 6- (D-α-amino-α-phenylacetamido) phenylanate hydrochloride

Potassium 6- [N- (1-dimethylaminocarbonylpropen-2-yl) -D-α-amino-α-phenylacetamido] penicilanate in N, N-dimethylformamide (25 ml) g, 11 mmol) was added iodomethyl penicillate 1, 1-dioxide (3.73 g, 10 mmol) and the mixture was stirred at 5 ° C for 30 minutes. After dilution with ethyl acetate (100 ml), the mixture was extracted with water (4 x 25 ml) and saturated aqueous sodium chloride. The organic phase was dried and evaporated in vacuo to half the original capacity. Water (25 ml) was added, and 2N hydrochloric acid was added with stirring to make the pH value of the mixture 2.5.

During hydrolysis this pH value was maintained by adding hydrochloric acid again. At the end of consumption of the acid (after about 30 minutes) the aqueous phase was separated and lyophilized to determine from ethanol / butanone-2 and the compound obtained was the same as described in Example 8.

Example 23

1,1-Dioxo-6β- (2,6-dimethoxybenzamido) peniclanoyloxymethyl 6- (D-α-amido-α-phenylacetamido) phenylsilanate hydrochloride

Sodium 6- (D-α-amido-α-phenylacetamido) penicillate (0.75 g, 2 mmol) was added to iodomethyl 1, 1-dioxo-6β- (2, in dimethylformamide To an ice cold solution of 6-dimethoxybenzamido) penicilanate (1.11 g, 2 mmol). The resulting solution was kept on an ice bath for 30 minutes, diluted with ethyl acetate (40 ml) and washed with water (4 × 10 ml). The pH was adjusted to 2.5 by adding hydrochloric acid while stirring the organic phase with water. The aqueous phase was separated and freeze dried to afford the desired compound as a colorless powder.

NMR spectrum (CD ₃ OD, TMS is used as internal reference material) is δ = 1.47 (s, 3H; 2-CH ₃ ), 1.50 (s, 6H; 2-CH ₂ ), 1.58 (s, 3H; 2- CH ₂ ), 3.83 (s, 6H; OCH ₃ ), 4.50 (s, 1H; 3-H), 4.69 (s, 1H; 3-H), 5.18 (s, 1H; CHNH ₂ ), 5.21 (d, J = 4 Hz, 1H; 5-H), 5.4-5.8 (m, 2H; 5-H and 6-H), 6.00 (m, 2H; OCH ₂ O), 6.27 (d, J = 4 Hz, 1H; 6 -H), 6.72 (d, 2H; arom. 3-H and 5-H), 7.43 (t, 1H; arom. 4-H), and 7.53 (s, 5H, arom. CH) ppm.

Example 24

1- (1,1-Dioxophenylanioyloxy) methyl 6- [D-α-amino-α- (p-hydroxyphenyl) acetamido penicillate hydrochloride

A scavenging compound was obtained as a colorless powder according to the method of Example 10B except for using 1-iodoethyl 1, 1-dioxophenicylanate instead of iodomethyl 1, 1-dioxophenicylanate.

IR spectra (KBr) showed strong bands at 1785, 1690 and 1655 cm ⁻¹ .

Example 25

6β-bromophenisilaneoiloxymethyl 6- [D-α-amino-α- (p-hydroxyphenyl) acetamido] peniclanate hydrochloride

The desired compound was obtained as a slightly yellowish powder using iodomethyl 6β-bromophenicylanate in place of iodomethyl 1, 1-dioxophenicylanate in the method of Example 10B.

The IR spectrum (KBr) showed a strong band at 1790, 1775 alc 1690 cm ⁻¹ .

Example 26

6β-iodophenicylanoyloxymethyl 6- [D-α-amino-α- (p-hydroxyphenyl) acetamido] peniclanate hydrochloride

A scavenging compound was obtained as an amorphous powder according to the method described in Example 10B except for using iodomethyl 6β-iodomethyl 6β-iodophenicilanate in place of iodomethyl 1,1-dioxophenicylanate. .

IR spectra (KBr) showed strong bands at 1790, 1755 and 1685 cm ⁻¹ .

Claims (1)

As described above in the text, the compound of the following general formula (5) is subjected to catalytic hydrogenolysis or hydrolysis according to A and B, or the 6-aminophenic silane ester of the following general formula (11) is A process for preparing a compound of the following general formula (1), comprising reacting with an acid reactive derivative of (12) or reacting an amino penicillin of the following general formula (13) with a compound of the following general formula (8):

Wherein R ₁ is phenyl, 4-hydroxyphenyl, 1, 4-cyclohexadienyl or 3-thienyl group, R ₂ is a primary amino or carboxy group, R ₃ is a hydrogen atom or lower alkyl, aryl Or an aralkyl group, preferably methyl, phenyl or benzyl group, A is a group of β-lactamase inhibitors containing carboxyl groups as well as β-lactam rings, A is bound through a carboxyl group, and B is a formula (5) In azido group, and a protected amino group, or a protected carboxy group, (12) In formula NH _3, Hal ^- is, M is a cation, X is a halogen atom or a similar free radical.