KR830001902B1 - Manufacturing method of waste nisilane derivative - Google Patents

Abstract

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Description

Manufacturing method of waste nisilane derivative

The accompanying drawings are graphs showing that the concentrations of mesyline and β-lactamase inhibitors simultaneously increase upon administration of VD-1825, HCI.

The present invention relates to a process for the preparation of novel β-lactam compounds comprising salts of pharmaceutically acceptable non-toxic acids.

The compounds of the present invention are antibiotics useful for the treatment of human and livestock diseases and are represented by the following general formula (1).

In general, "lower alkyl" refers to a C ₁ -C ₆ straight or branched chain alkyl group, aryl refers to a monocycle or a bicyclic, carbocycle group and acylamino refers to a group present in the side chains of known penicillins.

Of particular interest is that R ₁ is piperidyl-1, hexahydro-1H-azin-1-yl, hexahydro-1 (2H) -azosin-1-yl, octahydro-1H-azonin-1- 1, 2-methyl-hexahydro-1H-azin-1-yl, 3-methyl-hexaside-1-1H-azin-1-yl, 4-methyl-hexahydro-1H-azin-1-yl, 2,6-dimethylpiperidyl-1, cis-3-azabicyclo [3. 3. 0] octyl-3, or cis-8-azabicyclo [4. 3. 0] -nonyl-8, wherein R ₂ represents hydrogen, methyl, ethyl, phenyl, or benzyl.

The presence of one or more chiral centers in the R ₁ and ester moieties (indicated by an asterisk) can result in several disateromer forms of the compound of formula (1). The present invention encompasses the preparation of all possible diastereomeric forms of the compounds of formula (1) and mixtures thereof.

As described above, the present invention provides esters of general formula (1) and pharmaceutically acceptable nontoxic acids such as hydrochloric acid, bromic acid, hydrofluoric acid, phosphoric acid, sulfuric acid, nitric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid And salts with acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, pamoic acid, and p- (di-propylsulfamil) benzoic acid (propenside). Salts with acidic antibiotics are also within the scope of this alias. In some cases, it is desirable to use salts that are soluble, while for other purposes it is appropriate to use salts which are only slightly soluble, for example in order to obtain a sustained effect. In particular, the sustaining effect can be achieved by using a salt with a probenside that blocks the tubule excretion of the β-lactam compound.

6-amidinophenylanic acid is known as a useful antibiotic which shows a particularly good effect against many Gram-negative bacteria. However, they are mainly used by parenteral administration because of insufficient absorption during oral administration. As oral administration, esters of the compounds which are readily hydrolyzed, such as acyloxyalkyl esters of these compounds, are used, in contrast to free acids which are readily absorbed from the gastrointestinal tract. Such esters may be alkanoyloxyalkylesters, but may also include bis-esters of 6-amidinophenicsilane acid and aldehyde hydrate. These latter compounds are described in DOS2716 172 (German Patent Application).

In clinical treatment of bacterial infections, it is a serious problem that β-lactamase-producing bacteria are frequently increased. These enzymes inactivate most β-lactam antibiotics, and it is well known that β-lactamase from gram-positive and gram-negative bacteria contributes significantly to bacterial resistance to β-lactam antibiotics.

Several naturally occurring β-lactamase inhibitors have been described, including crabranic and olibanic acids. Recently, a number of semisynthetic β-lactam compounds such as 6β- such as phenylsilic acid 1,1-dioxide, 6α-chlorophenicylic acid 1,1-dioxide, a series of cravranic acid derivatives, 6β-bromophenicsilane acid It is found that halopenisilane acid, methicillin sulfone and quinacillin sulfone have similar biological properties. All but a few of these compounds show only mild antimicrobial activity against most Gram-positive and Gram-negative microorganisms, but are potent inhibitors of a wide range of β-lactamases. When combined with selected penicillins and cephalosporins, these compounds act cooperatively against a variety of β-lactamase producing bacteria because they protect penicillins and cephalosporins against inactivation.

As described above, the present invention particularly provides a novel compound which exhibits strong antibacterial activity in vivo and is intended for enteral administration. The beneficial effect on β-lactamase producing bacteria is achieved because the compound contains the same moiety as that of the high antibacterial activity of 6-amidinophenicylanic acid and that of the effective β-lactamase inhibitor. However, both prerequisites are necessary to exploit the characteristics of these novel compounds. They must be able to be absorbed from the gastrointestinal tract and be hydrolyzed liberally with amidinophenicsilane acid and β-lactamase inhibitors during or after absorption. Since all these requirements are fulfilled, the present compounds are useful surrogates of both amidinophenicylanic acid and β-lactamase inhibitors.

Thus, studies on animals and humans have shown that the novel compounds are readily absorbed from the gastrointestinal tract. During or after absorption, these compounds are hydrolyzed with equimolar amounts of the two components in question, 6-amidinophenic acid and β-lactamase inhibitors, while at the same time placing the blood and tissue concentrations of the two components. Therefore 6-amidinophenic silane acid is protected in the most effective way against inactivation by β-lactamase.

Effective absorption and in vivo hydrolysis of the compounds of the present invention is one of the novel compounds, namely 1,1-dioxophenicilanoyl-oxymethyl 6-1 (hexedro-1H azepine 1-al) -methyleneamino]- It has been studied in humans orally administered with hydrochloride of penicillate (hereinafter referred to as VD-1825).

For comparison, or for the same group, respectively, for meslynamin [6-[(hexahydro-1H-azin-1-yl) -methyleneamino] penicylic acid], fibmesinyl hydrochloride, And orally effective pivaloyloxymethylester of potassium penicillate 1,1-dioxide. The results of these studies are summarized in Tables 1 and 2.

TABLE 1

Serum concentrations and urinary excretion of mesylinin in volunteers on an empty stomach after oral administration of the following compounds.

A. 100 mg fibmesilinyl hydrochloride as a tablet

B. 128 mg of VD-1825X) hydrochloride as an aqueous solution (corresponding to 100 mg of fibmesilinyl hydrochloride).

X) VD-1825 is 1,1-dioxophenicilanoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] peniclanate.

X) no sample

TABLE 2

Urinary excretion of peniclanic acid 1,1-dioxide in fasting volunteers following oral administration of

A. 60 mg of potassium penisilaneate 1,1-dioxide in aqueous solution (answer 52 mg of penicsilane 1,1-acid dioxide).

B. 128 mg of VD-1825 hydrochloride in aqueous solution (equivalent to 49.0 mg of 1,1-dioxide)

As can be seen from Table 1, oral administration of VD-1825 yields serum concentrations of methylinam and finite as obtained after equimolar fibmesillin administration. In addition, as can be seen from Table 1, the mesilein urine recovery after the administration of VD-1825 is similar to the urine recovery after the administration of fibmesilin.

As shown in Table 2, only 4.3% of peniclanic acid 1,1-dioxide was excreted in urine after oral administration of the corresponding potassium salt. In contrast, 77% of peniclanic acid 1,1-dioxide was recovered from urine when an animal dose of VD-1825 was administered. Thus, VD-1825 absorption was also effective. Effective absorption and in vivo hydrolysis of the compounds of the present invention are described by studying in 8 healthy fasting humans orally administered VD-1825, HCI 260 mg (corresponding to feb mesilin HCI 200 mg) as capsules. After administration, the serum concentrations of mesylinam and peniclanic acid 1,1-dioxide were measured and the results are shown in FIG. The dashed line indicates the serum concentration of peniclanic acid 1,1-dioxide and the solid line indicates the serum concentration of mesylinin. Administration of VD-1825 and HCI raises the concentrations of meslynam and β-lactamase inhibitors simultaneously, and because they are present in approximately the same molar ratio at all times inhibiting β-lactamase, the mesilinine molecule against the effects of β-lactamase Can be effectively protected.

By using the compounds of the present invention, the antimicrobial spectrum of the 6-amidinophenylanic acid in question is broadly extended as the β-lactamase producing strain is sensitive to treatment. Such β-lactamase-producing strains frequently increase and become a problem that is lost in clinical treatment. For this purpose the compounds of the invention are extremely valuable.

The compounds of the present invention have significant advantages over more than just a combination of therapeutically hydrolyzed amidinophenicsilane acids and β-lactamase inhibitors.

For example, poorly or irregularly absorbed from a number of β-lactamase inhibitors (see Table 2) gastrointestinal tract, including peniclanic acid, 1,1-dioxide. In addition, many amidinophenic silanes, including mesilinam, are incompletely absorbed upon oral administration. In addition, varying the absorption ratio of various amidinophenic silane and β-lactamase inhibitors, respectively, in most cases leads to a situation in which the two drugs are not present at the same time or at the optimum ratio.

Easily hydrolyzable esters of amidinophenicsilane acid and β-lactamase inhibitors absorb better than the corresponding free acid from the gastrointestinal tract. However, hydrolysis of such esters in an organism, when the esters hydrolyze, forms inactive byproducts, which are undesirable, although these byproducts are relatively non-toxic, exposing the gas to unnecessary metabolites. Another drawback of using a combination of readily hydrolyzable esters of amidinophenicsilane acid derivatives and β-lactamase inhibitors is that the ester moiety increases the molecular weight of these compounds, i.e. 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, absorption of these esters does not occur at the same time, even when administered to a patient at the same time. For example, the pivaloyloxymethylester of mesylinam is absorbed very rapidly, while the slightly soluble pivaloyloxymethylester of the β-lactamase inhibitor peniclanic acid 1,1-dioxide is absorbed very slowly.

All these drawbacks are overcome by using the compounds of the present invention. It has been found that the co-operation in time between different β-lactamase inhibitors and various amidinophenicsilane acid derivatives is particularly pronounced when the ratio between the two components is between 3: 1 and 1: 3. Since various amidinophenicsilane acid derivatives have slightly different biological half-lives and distribution properties, the ratio between the free components of this novel compound in organs and tissues may vary slightly but is usually within the preferred ranges described above.

Therefore, this invention is comprised by the method of manufacturing the compound of this invention, and its salt. According to one method, the compound of formula (5) is represented by the formula AM (A is a cation such as M as described above, M is Na ⁺ , K ⁺ , ammonium ion tri- or tetraalkylammonium ion, such as tetrabutylammonium ion React with the compound of).

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

In addition, the compound of the general formula (1) may be prepared according to the method of obtaining the intermediate of the following general formula (7) by reacting the compound of the general formula A-M with the compound of the general formula (6) as one step.

The reaction is carried out in the same manner as described for the preparation of known compounds of general formula (5) and is usually carried out at 0-60 ° C. in a suitable solvent such as dimethylformamide, ethyl acetate, dichloromethane, acetone or hexamethylphosphoric acid triamide. Happens.

As a second step, an intermediate of formula (7) is reacted with an amidinophenicsilane acid derivative of formula (8) to prepare an ester of formula (1).

Wherein R ₁ and M are as described above.

In general formula (7), X can be substituted by a better living group as needed.

The above-mentioned conversion is usually carried out at 0-60 ° C. under the above-mentioned conditions in an inert organic solvent such as, for example, dimethylformamide, ethyl acetate, dichloromethane, acetone, or hexamethylphosphoric acid triamide.

Another example of this method is to prepare a compound of formula (10) by reacting a compound of formula (AM) with an amino protective derivative thereof, such as the 6-aminophenylsilane ester or trialkylsilyl derivative of formula (9) It is composed of one step method.

Wherein R ₂ , A, and X are as described above.

The reaction is carried out at a suitable organic solvent such as, for example, dimethylformamide and at a temperature of 0-30 占 폚.

Alternatively, the intermediate 6-silveraminophenic acid of formula (10) or a salt or amino protecting derivative thereof may be prepared by reacting with a compound of formula (7).

As a second step, an ester of formula (1) is prepared by reacting a compound of formula (10) or a trialkylsilyl derivative thereof with a reactive derivative of amide or thioamide of formula (11).

R ₁ -CH = Z (11)

Food,

Examples of reactive derivatives of the compound of formula (11) include compounds of non-limiting form such as iminium chloride, iminium ether, thioether, amide acetal.

The reaction with the reactive derivatives described above is well known to those skilled in the art of making amidinophenicsilane acid derivatives.

In another example of this method, the compound of formula (1) is prepared by reacting a compound of formula (10) or a trialkylsilyl derivative thereof with a compound of formula (12).

The hydrogen atom of the 6-amino group of formula (10) is substituted by a group of R ₇ -Z-CH =. Addition of an amine of the general formula R ₁ -H to the reaction mixture without separation of the reaction product affords the compound of formula (1).

The reaction is preferably carried out at room temperature or lower in diethyl ether, tetrahydrofuran, ethyl acetate or benbene and in a solventless solvent. The first part of the reaction proceeds rapidly and the amine R ₁ -H is added and the reaction mixture is left at room temperature or lower until the reaction is complete.

Intermediates of formulas (7) and (10) are novel compounds.

Starting materials of the general formulas (5), (6), (8), (9), (11) and (12) are known and can be prepared by methods analogous to those used in the preparation of similar known compounds. have.

Most of the starting materials of the general formula AM or the corresponding acid are known compounds. The novel compound is an acid or salt corresponding to group A of formula (2) wherein R ₄ is an acylamino group. The latter compound is penicillin sulfone, which can be produced by a known method.

The compound of formula (1) can be purified and separated by conventional methods and can be obtained in free state or in the form of a salt.

In some cases the compounds can be obtained as diastereomer mixtures which can be separated by known methods, for example by chromatography, if necessary.

The compounds of the present invention are useful in the treatment of infectious diseases in humans and animals and can be used as pharmaceutical compositions that can be used for enteral, parenteral or topical administration.

Such a composition contains, as an active ingredient, at least one selected from the group consisting of the compound of formula (1) or a salt thereof and a pharmaceutical carrier and / or diluent of solid or liquid.

In the above-mentioned composition, the ratio of the therapeutically effective material to the carrier material varies between 1-95% by weight.

The composition may be in various pharmaceutical dosage forms such as tablets, pills, dragees, suppositories, capsules, sustained release, suspensions, and the like, which contain a compound of formula (1) or a nontoxic salt thereof mixed with a carrier and / or diluent. .

Pharmaceutically acceptable non-toxic, organic or inorganic, solid or liquid carriers and / or diluents for drugs can be used to prepare the compositions containing a compound of the present invention. Gelatin, lactose, starch, magnesium stearate, talc, plant and animal fats and oils, gums, polyalkylene glycols, buffers or other known carriers, adjuvants and / or diluents are all suitable.

Moreover, the composition may contain a therapeutically effective ingredient which can be appropriately administered with the compound of the present invention in the treatment of infectious diseases such as antibacterial agents, antitussives, pain relief agents, probenesidide and the like. Particularly suitable are antibacterial agents such as penicillin or cephalosporin which cooperate with one or both of the active ingredients formed by in vivo hydrolysis of the compounds of the present invention.

The compound of formula (1) can be used as it is or in the form of a salt. Although the compound is only slightly water soluble as it is, many salts, such as hydrochloride, readily dissolve in water.

As mentioned above, the compounds of the present invention may be formulated in pharmaceutical dosage forms comprising suspensions or non-aqueous ointments. Pharmaceutical formulations for oral treatment may be in the form of suspensions of one of the compounds of the invention and now contain 10-100 mg per ml of excipient.

The compounds of the present invention are administered in such dosages in which desired activity is achieved at the same time without side effects. In the treatment of humans, the compound of the present invention is conveniently administered in the dosage unit of a composition containing 50 to 2500 mg, up to 100 mg, preferably 100 to 1000 mg, calculated as a compound of formula (1). .

A “dosage unit” is administration to a patient and can be easily handled as a physically stable unit dose containing the active substance or a mixture of the active substance and a solid or liquid pharmaceutical diluent, carrier, solvent and / or adjuvant. Means a single capacity that can be packaged.

In dosage unit form, the compounds of the present invention may be administered at appropriate intervals, but once or more per day, depending on the condition of the patient or upon the prescription of a practitioner.

Therefore, the daily dose is preferably 0.25-15 g of the compound of formula (1) or the same amount thereof, and it may be convenient to divide it into several single doses.

In the continuing treatment of patients suffering from infectious diseases, the economy or capsule is a suitable pharmaceutical form, and sustained-release forms are suitable as necessary.

In animals, the above-mentioned pharmaceutical composition is also preferably used in the form of a dosage unit containing 50 mg-25 g of the compound of formula (1) or a significant amount thereof.

In the treatment of mammary diseases, in particular bovine mastitis, the antimicrobial agent can be administered in liquid or semi-liquid form, such as ointment, or in the mammary gland with water-insoluble and oil-insoluble binders in the form of granules.

The compound of formula (1) is typically administered to an adult patient in an amount of 3-200 mg / kg of patient weight per day, equivalent to 0.25-15 g per day, or in the form of the same amount of salt.

In the treatment of patients, the compounds of the present invention may be administered alone or in combination with other therapeutically effective compounds such as probebenid to help combat bacterial infection. Such combination therapy can be made as a formulation containing many or all therapeutically effective compounds, and these compounds can be administered in separate formulations, and these compounds can be administered simultaneously or at appropriate intervals.

In the treatment of patients, the daily dose may be administered temporarily, or dividedly, such as twice, three or four times daily.

Hereinafter, a method for preparing a new starting material and an intermediate material will be described in detail based on the preparation examples.

[Production Example 1]

6α-bromophenic silane acid 1,1-dioxide

Potassium 6α-bromopheni silaneate (1.91 g, 6 mmol) dissolved in water (25 ml) in a stirring solution of potassium permanganate (1.90 g, 12 mmol) dissolved in water (35 ml) and acetic acid (1.36 ml, 24 mmol) The cooling solution was added dropwise at 0-5 ° C. After the addition was complete (about 15 minutes), the mixture was stirred at low temperature for 20 minutes. The cool-bath was removed and excess sodium pyrosulphite (1.52 g, 8 mmol) was added to the mixture to remove excess oxidant. Precipitated manganese oxide was filtered off and solid sodium chloride (20 g) and ethyl acetate (50 ml) were added to the filtrate (about 60 ml). 4N hydrochloric acid was added with stirring to adjust the pH of the mixture to 1.5, and then the organic phase was separated. The aqueous phase was reextracted with ethyl acetate (25ml), and the organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried and evaporated in vacuo. Thus, the obtained amorphous residue was determined from ether-diisopropyl ether to give 6α-bromophenic silane 1,1-dioxide (melting point: 124-127 ° C).

The crystalline potassium salt of the compound described above was dissolved in acetone (12 ml) in 6 M-bromophenic silane 1,1-dioxide (0.94 g, 3 mmol) in 1 M potassium 2-ethylhexahexane in acetone (3.6 ml). Eight was added to obtain.

NMR spectra of potassium 6α-bramophenisilaneate 1,1-dioxide (CD ₃ OD) were δ = 1.48 (s, 3H; 2-C H 3), 1.59 (s, 3H; 2-C H 3), Signals were seen at 4.48 (s, 1H; 3- H ), 5.10 (d, J = 2 Hz, 1H; 6-H), 5.35 (d, J = 2 Hz, 1H; 5- H ) ppm. Tetramethylsilane was used as internal standard.

[Production Example 2]

6α-chlorophenicylanic acid 1,1-dioxide

As a result of using potassium 6α-chlorophenylsilaneate instead of potassium 6α-bromophenicsilaneate in the process of Preparation Example 1, 6α-chlorophenicsilane 1,1-acid dioxide was obtained as crystals from diisopropyl ether (melting point: 134-137 ° C.).

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

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

[Manufacture example 3]

Chloromethyl penicsilaneate 1,1-dioxide

To a solution of peniclanic acid 1,1-dioxide (1.17 g, 5 mmol) dissolved in dimethylformamide (7.5 ml) was added triethylamine (0.98 ml, 7 mmol) and chloroiomethane (2.18 ml, 30 mmol), The mixture was stirred at room temperature for 4 hours. After dilution with ethyl acetate (30 ml), the mixture was washed with water (3 x 10 ml), then with saturated aqueous sodium chloride solution (5 ml), dried and evaporated in vacuo to afford the desired compound as a yellow oil.

This was determined from ether-petroleum ether (melting point: 94-96 ° C.).

NMR spectrum (CDCl ₃ ) is δ = 1.47 (s, 3H; 2-C H ₃ ), 1.66 (s, 3H; 2-C H ₃ ), 3.53 (d, J = 3Hz, 2H; 6α- H and 6β -H ), 4.46 (s, 1H; 3- H ), 4.68 (t, J = 3Hz, 1H; 5- H ) and 5.85 (ABq, J = 6Hz, 2H; OC H ₂ Cl) ppm . Tetramethylsilane was used as internal standard.

[Production Example 4]

1-chloromethyl penicsilaneate 1,1-dioxide

According to the process of Preparation Example 3, 1-chloro-1-iodineethane was used instead of clododomethane and the reaction time was increased up to 16 hours. As a result, crude 1-chloroethylphenysilaneate 1,1-dioxide was yellow. Obtained as an oil. It can be purified by dry column chromatography on silica gel (ethyl acetate-petroleum, 7: 3).

Production Example 5

Chloromethyl 6α-bromophenisilaneate 1,1-dioxide

As a result of using 6α-bromophenicsilane 1,1-acid dioxide instead of peniclanic acid 1,1-dioxide in the process of Preparation Example 3, chloromethyl 6α-bromo penicsilaneate 1,1-dioxide was obtained as a yellow oil. lost.

NMR spectrum (CDCl ₃ ) is δ = 1.48 (s, 3H; 2-C H ₃ ), 1.64 (s, 3H; 2-C H ₃ ), 4.46 (s, 1H; 3- H ), 4.71 (d, Signals were seen at J-1.5 Hz, 1 H; 6- H ), and 5.17 (d, J = 1.5 Hz, 1H; 5- H ) and 5.80 (ABq, J = 6 Hz, 2H; OC H ₂ Cl) ppm. Tetramethylsilane (TMS) was used as internal standard.

[Manufacture example 6]

Chloromethyl 6β-bromophenisilaneate

In the process of Preparation Example 3, potassium 6β-bromophenicsilaneate was used instead of peniclanic acid 1,1-dioxide and triethylamine, thereby obtaining chloromethyl 6β-bromophenicsilaneate as a viscous oil.

[Manufacture example 7]

Chloromethyl clavranate

According to the process of Preparation Example 3, chloromethyl clavranate was obtained when sodium clavranate was used instead of peniclanic acid 1,1-dioxide and triethylamine.

[Manufacture example 8]

Chloromethyl penicsilaneate 1,1-dioxide

Bischloromethylsulfate (1.6 g) was added to a suspension of potassium penicsilaneate 1,1-dioxide (1.08 g) suspended in dimethylformamide (12 ml), and the mixture was stirred at room temperature for 45 minutes. After dilution with ethyl acetate (50 ml), the mixture was washed with water, then with an aqueous sodium bicarbonate solution, dried and evaporated in vacuo to give an oil. The oil was purified by chromatography on silica gel to give the same desired compound as the compound described in Preparation Example 3.

[Manufacture example 9]

Chloromethyl 6α-chlorophenicylanate 1,1-dioxide

In the process of Preparation Example 3, 6α-chlorophenicylic acid 1,1-dioxide was used instead of peniclanic acid 1,1-dioxide. As a result, chloromethyl 6α-chlorophenisilaneate and 1,1-dioxide were used as viscous oil. Obtained.

NMR spectrum (CDCl ₃ ) is δ = 1.48 (s, 3H; 2-C H ₃ ), 1.64 (s, 3H; 2-C H ₃ ), 4.47 (s, 1H; 3- H ), 4.68 (d, Signals were seen at J-1.5 Hz, 1H; 6- H ), and 5.17 (d, J = 1.5 Hz, 1H; 5- H ) and 5.81 (ABq, J = 6Hz, 2H; OC H ₂ Cl) ppm. TMS was used as internal standard.

[Production Example 10]

Iodinemethyl penicsilaneate 1,1-dioxide

Sodium iodide (9 g) was added to a solution of chloromethyl penicsilaneate 1,1-dioxide (5.6 g, 20 mmol) dissolved in acetone (45 ml), and the mixture was stirred 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 off and the filtrate was evaporated under reduced pressure.

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

[Production Example 11]

6β-aminophenicylanic acid 1,1-dioxide hydrate

A. 6β-benzyloxycarbonylamino peniclanic acid 1,1-dioxide

: +146.9°(C=1, 96% C₂H₅OH).Potassium permanganate in water (915 ml) slowly at 0 ° C. (about 45 minutes) in a stirred solution of 6β-benzyloxycarbonylamino-phenic acid (63.5 g) and potassium hydrogencarbonate (18.1 g) dissolved in water (1125 ml). (38 g) was added to the solution. Dilute sulfuric acid was added during oxidation to keep the reaction mixture at pH 6.5. The insoluble material was filtered off and the filtrate was extracted with ethyl ether. The aqueous layer obtained was filtered again, and then ethyl acetate (600 ml) was added to make the pH 2.5 while stirring. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 300 ml). After drying, the ethyl acetate extracts were collected and evaporated in vacuo. The residue was recrystallized from ethyl acetate (250 ml) -petroleum ether (500 ml) to give pure compound. Melting point: 153-154 ° C,

: + 146.9 ° (C = 1, 96% C ₂ H ₅ OH).

B. 6β-amifenicylate acid 1,1-dioxide hydrate

: +252.9°(C=1, 디메틸포름아미드).A filtered solution of 6β-benzyloxycarbonylamino peniclanic acid 1,1-dioxide (15.3 g) and potassium hydrogen carbonate (4 g) dissolved in water (160 ml) was 10% Pd / for 4 hours at slightly elevated pressure. Hydrogenated on BaSO ₄ (5 g). After filtration and extraction with ethyl ether (100 ml), the pH of the cooling water solution was adjusted to 2.5. The precipitate thus formed was filtered off, washed with water and dried with air. Recrystallization from dimethylformamide-water gave pure monohydrate. Melting Point: 199-200 ℃ (Decomposition)

: + 252.9 ° (C = 1, dimethylformamide).

[Manufacture example 12]

Chloromethyl 1,1-dioxophenicsilaneate

Of potassium 1,1-dioxopheny silaneate (2.7 g, 10 mmol), potassium bicarbonate (6.0 g, 60 mmol) and tetra butylammonium hydrogen sulfate (0.34 g, 1 mmol) in water (10 ml) and dichloromethane (15 ml) Chloromethyl chlorosulfate (1.5 ml) was added to the mixture. After stirring at 30 ° C. for 1 hour, the mixture was filtered, the organic layer was separated and dried (sodium sulfate). After dilution with propanol-2- (25 ml), the solution was concentrated to about 10 ml in vacuo and then left at 5 ° C. for 1 hour. The crystals were filtered off, washed with cold propanol-2 and dried in vacuo to yield the title compound as colorless crystals. Melting point: 94-46 ° C.

[Production Example 13]

1-chloroethyl 1,1-dioxophenicylanate

1-chloro-1-iodine in a mixture of potassium 1,1-dioxophenicylanate (40.7 g, 0,15 mol), silver nitrate (25.5 g, 0.15 mol), and silver oxide (7.5 g) in acetonitrile (750 ml) Ethane (42 ml) was added. After stirring for 48 hours at room temperature, the silver salt was filtered off and dried in vacuo. The residue was dissolved in ethyl acetate (200 ml) and the solution was washed with saturated aqueous sodium chloride solution, filtered, dried and evaporated in vacuo.

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

Production Example 14

1-iodineethyl 1,1-dioxophenicsilaneate

Sodium iodide (30 g, 0.2 mol) was added to a solution of 1-chloroethyl 1,1-dioxophenicsilaneate (30 g to 0.1 mol) dissolved in acetone (100 ml), and the mixture was stirred at room temperature for 3 days. Aqueous sodium thiosulfate was added and then the acetone was removed in vacuo. The separated oil was dissolved in ethyl acetate and the solution was washed with water, dried and then evaporated in vacuo. The remaining oil was chromatographed on silica gel (hexane-ethyl acetate, 3: 1), and microcrystalline analysis of iodine determined the determination of 1-iodine ethyl and 1-chloroethyl ester of diastereomer containing 40% of iodine compound. An acid mixture (melting point: 134-136 ° C.) was obtained.

[Production Example 15]

Chloromethyl 6β-bromo phenylsilaneate

Tetrabutyl ammonium hydrogen sulfate (0.10 g, in a stirring solution of potassium 6β-bromophenisilaneate (0.96 g, 3 mmol) and potassium bicarbonate (1.80 g, 18 mmol) dissolved in water (9 ml) and ethyl acetate (9 ml). 0.3 mmol) was added, followed by chloromethyl chlorosulfonate (0.45 ml, 4.5 mmol), and the mixture was stirred at room temperature for 1.5 hours.

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 × 5ml), dried and concentrated to about 5ml under reduced pressure. The concentrate was subjected to dry column chromatography on silica gel (petroleum ether-ethyl acetate, 9: 1) to give pure chloromethyl 6β-bromophenisilaneate almost as colorless oil.

NMR spectrum (CDCl ₃ ) is δ = 1.54 (s, 3H; 2-C H ₃ ), 1.70 (s, 3H; 2-C H ₃ ), 4.54 (s, 1H; 3- H ), 5.35 and 5.59 ( Signals were seen at 2d, J-4Hz, 2H; 5- H and 6- H ), and 5.77 (ABq, J = 5Hz, 2H; OC H ₂ Cl) ppm. Tetramethylsilane was used as internal standard.

[Production Example 16]

Iodinemethyl 6β-bromophenisilaneate

To a solution of chloromethyl 6β-bromophenisilaneate (0.82 g, 2.5 mmol) dissolved in acetone (5 ml) was added solid sodium iodide (0.75 g, 5.0 mmol) and protected from light, and then the mixture was allowed to stand at room temperature for 24 hours. Stir for hours.

After filtration with precipitated sodium chloride and washing with acetone (2 x 1 ml), the filtrate was evaporated in vacuo to give an oil residue, which was dissolved in ethyl acetate (20 ml). The resulting solution was washed with water (3 × 10 ml), dried (MgSO ₄ ), concentrated to about 5 ml under reduced pressure and column chromatography on silica gel using petroleum ether-ethyl acetate (9: 1) as eluent. . Fractions containing pure subject compound as shown by thin layer chromatography (TLC) were combined and vacuum evaporated to obtain iodinemethyl 6β-bromophenicsilaneate as a weak yellow oil.

The spectra were δ = 1.55 (s, 3H; 2-C H ₃ ), 1.69 (s, 3H; 2-C H 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; OC H ₂ l) ppm. Tetramethylsilane was used as internal standard.

[Production Example 17]

Chloromethyl 1,1-dioxo-6β- (2,6-dimethoxy benzamido) peniclanate

Chloromethyl chlorosulfate (1.81 ml, 18 mmol) was added to 1,1-dioxo-6β- (2,6-dimethoxy benzamido) peniclanic acid in water (15 ml) and dichloromethane (15 ml) for 20 minutes at room temperature. (Methicillin sulfone, 6.2 g, 15 mmol), potassium hydrogen carbonate (8.7 g, 87 mmol) and tetrabutyl ammonium hydrogen sulfate (0.51 g, 1.5 mmol) were added.

+195°(C=1, CHCl₃).After stirring for 15 minutes, the organic phase was separated, dried and evaporated in vacuo to give an oil which was determined from 96% ethanol to give colorless crystals. Melting point: 142-143 ° C. (decomposition). The sample was recrystallized twice from acetone-water as analytical sample. Melting Point: 154-155 ° C (Decomposition),

+ 195 ° (C = 1, CHCl ₃ ).

[Production Example 18]

Iodinemethyl 1,1-dioxo-6β- (2,6--dimethoxy benzamido) peniclanate

Sodium iodide (3 g, 20 mmol) was added to a solution of chloromethyl 1,1-dioxo-6β- (2,6-dimethoxybenzamido) phenylanate (2.31 g, 5 mmol) in acetone (10 ml) and the mixture was It was stirred overnight at room temperature. Water was added to precipitate the subject compound as crystals, which were collected by filtration and dried in vacuo. Melting point: 153-156 ° C. (decomposition).

: +179℃(C=1, CHCl₃).The product was dissolved in a mixture of acetone and 96% ethanol and the acetone was removed in vacuo resulting in crystallization of the desired compound. As a result of repeating this process, the melting point rose to 169-170 ° C (decomposition).

: + 179 ° C. (C = 1, CHCl ₃ ).

[Production Example 19]

Chloromethyl 1,1-dioxo-6α-chlorophenicylanate

+210°(C=0.5, CHCl₃).The use of potassium 1,1-dioxo-6-chloro penicylanate in place of potassium 6β-bromophenicylanate according to the process of Preparation Example 15 resulted in the subject compound as colorless crystals from ethyr-diisopropyl ethyr. Obtained. Melting point: 111-113 ° C,

+ 210 ° (C = 0.5, CHCl ₃ ).

[Production Example 20]

Iodinemethyl 1,1-dioxo-6α-chlorophenylsilaneate

According to the process of Preparation Example 16, chloromethyl 1,1-dioxo-6α-chlorophenicylanate was used instead of chloromethyl 6β-brocophenylsilaneate to obtain the title compound as a colorless foam.

NMR spectrum (CDCl ₃ ) is δ = 1.49 (s, 3H; 2-C H ₃ ), 1.62 (s, 3H; 2-C H 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 = 5Hz, 2H; OC H ₂ l) ppm. Tetramethylsilane was used as internal standard.

[Production Example 21]

Chloromethyl 1,1-dioxo-6α-bromophenisilaneate

The use of potassium 1,1-dioxo-6α-bromophenicylanate in place of potassium 6β-bromophenicylanate according to the process of Preparation Example 15 resulted in the subject compound as colorless crystals from ether-diisopropyl ether. Obtained.

+185℃(C=0.5, CHCl₃).Melting point: 92-93 ℃,

+ 185 ° C. (C = 0.5, CHCl ₃ ).

[Production Example 22]

Iodinemethyl 1,1-dioxo-6α-bromophenicylanate

According to the process of Preparation Example 16, chloromethyl 1,1-dioxo-6α-bromophenisilaneate was used instead of chloromethyl 6β-bromophenicsilaneate to obtain the title compound as a colorless foam. This was not crystallized.

NMR spectrum (CDCl ₃ ) is δ = 1.49 (s, 3H; 2-C H ₃ ), 1.63 (s, 3H; 2-C H 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 = 5Hz, 2H; OC H ₂ l) ppm. Tetramethylsilane was used as internal standard.

[Manufacture example 23]

Chloromethyl 6β-iodinephenylate

According to the process of Preparation Example 15, using potassium 6β-iodinephenylanate instead of potassium 6β-bromophenylsilaneate, the subject compound was obtained as a weak yellow oil.

NMR spectrum (CDCl ₃ ) is δ = 1.52 (s, 3H; 2-C H ₃ ), 1.71 (s, 3H; 2-C H ₃ ), 4.55 (s, 1H; 3 H ), 5.40 and 5.63 (2d , J = 3.5Hz, 2H; 2- H and 6- H ), and 5.78 (ABq, J = 5.5Hz, 2H; OC H ₂ l) ppm. Tetramethylsilane was used as internal standard.

[Manufacture example 24]

Iodinemethyl 6β-iodine peniclanate

Using the chloromethyl 6β-bromophenisilaneate instead of chloromethyl 6β-bromophenylsilaneate according to the process of Preparation Example 16, the subject compound was obtained as a yellow oil.

NMR spectrum (CDCl ₃ ) is δ = 1.53 (s, 2H; 2-C H ₃ ), 1.70 (s, 3H; 2-C H ₃ ), 4.53 (s, 1H; 2 H ), 5.39 and 5.61 (2d , J = 3.5Hz, 2H; 5- H and 6-H), and 6.00 (ABq, J = 5.5Hz, 2H; OC H ₂ l) ppm. Tetramethylsilane was used as internal standard.

Production Example 25

Chloromethyl 6β-chlorophenicylanate

According to the process of Preparation Example 15, using potassium 6β-chlorophenicylate in place of potassium 6β-bromophenicylanate, the subject compound was obtained as a colorless oil.

NMR spectrum (CDCl ₃ ) is δ = 1.53 (s, 3H; 2-C H ₃ ), 1.69 (s, 3H; 2-C H 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; OC H 2 l) ppm the signal is shown in. Tetramethylsilane was used as internal standard.

Production Example 26

Iodinemethyl 6β-chlorophenicylanate

Using the chloromethyl 6β-chlorophenicylate instead of chloromethyl 6β-bromophenicylanate according to the process of Preparation Example 16, the subject compound was obtained as a weak yellow oil.

NMR spectrum (CDCl ₃ ) is δ = 1.52 (s, 3H; 2-C H ₃ ), 1.69 (s, 3H; 2-C H 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; OC H 2 l) ppm the signal is shown in. Tetramethylsilane was used as internal standard.

[Production Example 27]

Chloromethyl 6β-bromophenisilaneate

A. Chloromethyl 6,6-dibromophenicylanate

: +206°(C=0.5, CHCl₃).According to the process of Preparation Example 15, using potassium 6,6-dibrofenenisilaneate instead of potassium 6β-bromophenisilaneate, the subject compound was obtained as a weak yellow oil. This was recrystallized from ether-di isopropyl ether. Melting point: 105-107 ° C,

: + 206 ° (C = 0.5, CHCl ₃ ).

NMR spectrum (CDCl ₃ ) is δ = 1.54 (s, 3H; 2-C H ₃ ), 1.66 (s, 3H; 2-C H ₃ ), 4.60 (s, 1H; 3 H ), 5.80 (AB4, J = 5 Hz, 2H; OC H ₂ Cl) and 5.83 (s, 1H; 5-H) ppm. Tetramethylsilane was used as internal standard.

B. Chloromethyl 6β-bromophenisilaneate

To a stirring solution of chloromethyl 6,6-dibromophenisilaneate (1.63 g, 4 mmol) in anhydrous benzene (40 ml) was added tri-n-butyline hydride (1.16 g, 4 mmol) under nitrogen at 0 ° C. After stirring for 18 hours at room temperature, the mixture was evaporated in vacuo. The remaining oil was purified by dry column chromatography on silica gel (petroleum ether-ethyl acetate, 85:15) to obtain pure chloromethyl 6β-bromophenicsilaneate as a pale yellow oil.

The NMR spectrum of the product was consistent with the compound described in Preparation Example 15.

Production Example 28

Bromomethyl 1,1-dioxophenicsilaneate

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

NMR spectrum (CDCl ₃ ) is δ = 1.49 (s, 3H; 2-C H ₃ ), 1.64 (s, 3H; 2-C H ₃ ), 3.52 (m, 2H; 6-H), 4.47 (s, Signals were seen at 1H; 3- H ), 4.75 (m, 1H; 5- H ), and 5.98 (ABq, J = 4.5 Hz, 2H; OC H ₂ Br) ppm. TMS was used as internal standard.

Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1

1,1-dioxophenicilanoyloxymethyl 3-[(hexahydro-1H-azin-1-yl) -methyleneamino] phenylanate hydrochloride

Potassium penisilaneate 1,1- in a solution of chloromethyl 6-[(hexahydro-1H-azin-1-yl) methyleneamino] pheniclanate (1.87 g, 5 mmol) dissolved in dimethylformamide (25 ml). Dioxide (1.36 g, 5 mmol) was added and the mixture was stirred at room temperature for 48 hours. Ethyl acetate (75 ml) was added and the mixture was washed with water (4 × 25 ml) to remove dimethylformamide. The remaining organic phase was dried and then decolorized with stirring with charcoal. After filtration to remove charcoal, the filtrate was concentrated to about 30 ml, water (25 ml) was added, and the mixture was adjusted to 2.6 by adding 4N hydrochloric acid while stirring the pH. The aqueous phase was separated and lyophilized to give the desired compound as an amorphous powder.

NMR spectra (D ₂ O) are δ = 1.48 and 1.55 (2s, 6H; C (CH ₃ ) ₂ ), 1.60 and 1.72 (2s, 6H; C (CH ₃ ) ₂ ), 1.68 (b, 8H; CH ₂ CH ₂ CH ₂ ), 3.65 (m, 6H; CH ₂ NCH ₂ , 6α-H and 6β-H), 4.68 (s, 1H; 3-H), 4.75 (s, 1H; 3-H), 5.08 ( dd, J ¹ = 4 Hz, J ² = 2 Hz, 1H; 5-H), 5.56 (d, J = 4Hz, 1H; 6-H), 5.68 (d, J = 4Hz, 1H; 5-H), 6.02 Signals were seen at (s, 2H; OCH ₂ O), and 8.03 (s, 1H; N-CH = N) ppm. Tetramethylsilane was used as external standard.

Isopropanol was added to the solution of the above-mentioned product (0.5 g) in which methanol (1.5 ml) was dissolved until turbidity occurred, and scratched to crystallize. After being left in the freezer for 24 hours, the crystals were filtered off, washed with isopropanol and dried in vacuo to yield the title compound as a colorless crystalline product. Melting point unclear (gradual decomposition above 120 ° C).

IR-spectrum (KBr) showed bands at V = 1690 and 1790 (wide) cm ⁻¹ .

Example 2

1,1-dioxophenicilanoyloxymethyl 6- [9hexahydro-1-azin-1-yl) methyleneamino] peniclanate hydrochloride

6-[(hexahydro-1H-azin-1-yl) -methyleneamino] peniclanic acid (1.63) in which chloromethyl penicsilaneate 1,1-dioxide (1.41 g 5 mmol) was dissolved in dimethylformamide (25 ml). g, 5 mmol) and triethylamine (0.7 ml, 5 mmol) were added and the mixture was stirred at ambient temperature for 16 hours. After dilution with ethyl acetate (75 ml), the mixture was washed with water (4 x 20 ml), the remaining organic phase was dried and decolorized with charcoal. Charcoal was filtered off and water (35 ml) was added to the filtrate. 2N hydrochloric acid was added while stirring to adjust the pH of the mixture to 2.8. The aqueous phase was separated and lyophilized to afford the same amorphous compound as obtained in Example 1.

Example 3-11

According to the process of Example 2, instead of 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] phenic acid, the result of using amidino phenylsilane acid shown in Table 1 below The corresponding compound of 1) was obtained.

TABLE 1

Example 12

1- (1,1-dioxophenicilanoyloxy) ethyl 6-[(hexahydro-1H-azin-1-yl) methyleneamino] phenylanate hydrochloride

Example 1- (1,1-dioxophenylananoyloxy) ethyl 6- as a result of using 1-chloroethyl penicsilaneate 1,1-dioxide instead of chloromethyl penicsilaneate 1,1-dioxide according to the process of Example 2 [(Hexahydro-1H-azin-1-yl) -methyleneamino] peniclanate hydrochloride was obtained as a colorless foam.

Example 13

1,1-Dioxo penicilanoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) -methylamino] peniclanate hydrochloride

6-[(hexahydro-1H-azin-1-yl) -methyleneamino] peniclanic acid (5.85 g, 18 mmol) and tetrabutylammonium hydrogen sulfate (6.12 g) in dichloromethane (35 ml) and water (35 ml) , 18 mmol) was added with stirring to 2N aqueous sodium hydroxide (18 ml). The organic layer was separated, the aqueous phase was reextracted with dichloromethane (15ml), the dichloromethane extracts were combined, dried (MgSO ₄ ) and evaporated in vacuo. The colorless oil thus obtained was dissolved in ethyl acetate (100 ml) and the resulting solution was concentrated to about half the capacity under reduced pressure. To the concentrate was partially added a solution of 1, 1-dioxide (5.6 g, 15 mmol) of iodinemethyl penicsilaneate and the mixture was stirred at room temperature for 10 minutes. The precipitated tetrabutyl ammonium iodine was spared, and water (17 ml) was added to the filtrate, and the pH of the stirred mixture was adjusted to 3.0 with 5 N IN hydrochloric acid. The aqueous phase was separated and the pH was adjusted to 7.2 by addition of 0.5 M aqueous sodium hydrogen carbonate while stirring under a layer of ethyl acetate (50 ml). After separating the organic layer, water (50ml) was added and the pH of the stirred mixture was adjusted to 3.0 with 1N hydrochloric acid. The aqueous phase was separated and lyophilized to yield the title compound as a colorless amorphous powder.

A solution of the aforementioned product (5 g) in ethanol (15 ml) was diluted with isopropanol (about 20 ml) until turbidity occurred. After stirring at room temperature for about 1 hour a large crystalline precipitate was formed. The mixture was diluted slowly with isopropanol (40 ml) and then left at 5 ° C. for 3 hours. The precipitate was filtered off, washed with isopropanol, washed with ether and dried in vacuo to give 1,1-dioxophenicilanoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) methyleneamino] peniclanate Was obtained as colorless crystals. Unclear melting point (decompose slowly above 120 ℃). This was the same as the product described in Example 1.

Example 14

Clabranoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] phenylanate hydrochloride

According to the process of Example 1, sodium clavranate was used in place of potassium peniclanate 1 and 1-dioxide, and the reaction time was reduced to 16 hours, whereby a desired compound was obtained as a yellow foam.

Example 15

1,1-Dioxo-6α-chlorophenicilanoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) methyleneamino] phenylanate hydrochloride

According to the process of Example 2, chloromethyl 6α-chlorophenisilaneate 1, 1-dioxide was used instead of chloromethyl penicsilaneate 1, 1-dioxide to obtain the title compound as a yellow powder.

Example 16

6β-bromophenicilanoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) methyleneamino] phenylanate hydrochloride

According to the process of Example 2, chloromethyl 6β-bromopheni silaneate was used instead of chloromethyl penicsilaneate 1, 1-dioxide to obtain the desired compound as an amorphous powder.

Example 17

1,1-dioxophenicilanoyloxymethyl 6-[(hexahydro-1 (2H) -azosin-1-yl) methyleneamino] phenysilane chloride

6-[(hexahydro-1- (2H) -azosine-1 instead of 6-[(hexahydro-1H-azin-1-yl) methyleneamino] phenicylic acid according to the process described in Example 13 The subject compound was obtained as a colorless freeze-dried powder as a result of using -yl) -methyleneamino] phenicylic acid.

NMR spectrum (CD ₃ OD, TMS as internal standard) is δ = 1.46 (s, 3H; 2-CH ₃ ), 1.57 (s, 6H; 2-CH ₃ ), 1.74 (s, 3H; 2-CH ₃ ) , 1.5-2.0 (m, 10H; (CH ₂ ) ₅ ), 3.2-3.8 (m, 6H; (CH ₂ ) ₂ N, 6α-H and 6β-H), 4.48 (s, 1H; 3-H) , 4.63 (s, 1H; 3-H), 4.93 (m, 1H; 5-H), 5.53 (d, J = 4 Hz, 1H; 6-H), 5.63 (d, J = 4 Hz, 1H, 5- Peaks were seen at H), 5.97 (s, 2H; OCH ₂ O) and 8.18 (s, 1H; N-CH = N) ppm.

Example 18

1- (1,1-dioxophenicilanoyloxy) ethyl 6-[(hexahydro-1H-azin-1-yl) methyleneamino] phenylanate hydrochloride

In a solution of tetrabutyl ammonium 6-[(hexahydro-1H-azin-1-yl) methyleneamino] peniclanate (4.53 g, 8 mmol) dissolved in ethyl acetate (40 ml), dissolved in ethylene acetate (25 ml). A solution of 1-iodine ethyl 1, 1-dioxo penicsilaneate (8.13 g, 38% purity, 3.09 g, corresponding to 8 mmol) was added thereto. After stirring for 5 minutes at room temperature, the separated tetrabutyl ammonium iodine was filtered and washed with ethyl acetate. From the filtrate the subject compound was converted to 1N hydrochloric acid (CH3.0, 5 ° C.) into an aqueous phase (40 ml) and from the aqueous phase to an aqueous sodium hydrogen carbonate (pH 7.0, 5 ° C.) an organic phase (ethyl acetate, 40 ml). Switched to The organic phase was washed with water and the subject compound was converted back to the aqueous phase as described above. The aqueous phase was lyophilized to afford the title compound as a colorless solid.

NMR spectrum (D ₂ O) is δ = 1.50 (s), 1.61 (s), 1.66 (d, J = 77), 1.73 (s), 1.5-2.0 (m), 3.20-3.85 (m), 4.61 ( s), 1.66 (d, J = 7), 1.73 (s), 1.5-2.0 (m), 3.20-3.85 (m), 4.61 (s), 4.75 (s), 5.10 (m), 5.53 (d, Peaks were seen at J = 4), 5.68 (d, J = 4), 7.05 (q, J = 7), and 8.03 (s).

Example 19

1, 1-dioxo-6- (2, 6-dimethoxy benzamido) phenicilanoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] phenylanate, hydro Chloride

Sodium 6-[(hexahydro-1H-azin-1-yl) methylamino] phenylanate (0.7 g, 2 mmol) dissolved in dimethylformamide (10 ml) Iodine methyl 1, 1-dioxo-6 It was added to an ice-cooling solution of-(2, 6-dimethoxybenzamido) phenylanate (1.11 g, 2 mmol). After stirring at room temperature for 30 minutes, the mixture was diluted with ethyl acetate (40 ml) and washed with water (4 × 10 ml).

Hydrochloric acid was added to the organic phase while stirring with water to pH 3. The aqueous phase was lyophilized to give the title compound as a colorless powder.

NMR spectrum (CD ₃ OD, TMS as internal standard) is δ = 1.47 (s, 3H; 2-CH ₃ ), 1.58 (s, 6H; 2-CH ₃ ), 1.76 (s, 3H; 2-CH ₃ ) , 1.25-2.25 (m, 8H; (CH ₂ ), 3.5-4.0 (m, 4H; (CH ₂ ) ₂ N), 3.83 (s, 6H; OCH ₃ ), 4.67 (s, 1H; 3-H) , 4.70 (s, 1H; 3-H), 5.29 (d, J = 4 Hz, 1H, 5-H), 5.5-5.8 (m, 2H; 5-H and 6-H), 6.03 (m, 2H; OCH ₂ O), 6.25 (b, J = 4 Hz, 1H; 6-H), 6.71 (d, 2H; arom.3-H and 5-H), 7.41 (t, 1H; arom. 4-H), And 8.21 (s, 1H, N-CH = N) ppm.

Example 20

Clabranoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] phenicylanate

Iodinemethyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] phenicsilane in which lithium clabutanate (0.1 g, 0.5 mmol) was dissolved in hexamethylphosphoric acid triamide (3 ml) To a solution of eight (0.23 g, 0.5 mmol). After stirring at room temperature for 90 minutes, the mixture was diluted with ethyl acetate (20 ml) and washed with water (4 × 10 ml). The organic phase was stirred with water (20 ml) and hydrochloric acid was added to adjust the pH to 3.

The aqueous phase is separated off and with ethyl acetate (10 ml). The organic phase was dried and then evaporated to give an oil, which was purified by chromatography on Sephadex LH-20 (8 g). The subject compound was isolated as colorless oil.

NMR spectrum (CDC1 ₃ , TMS as internal standard) is δ = 1.49 (s, 3H; 2-CH ₃ ), 1.65 (s, 3H; 2-CH ₃ ), 1.4-2.0 (m, 8H; (CH ₂ ) 4), 3.11 (d, J = 17 Hz, 1H; 6β-H), 3.48 (dd, J = 17 Hz, 1H; 6α-H), 3.3-3.6 (m, 4H; (CH ₂ ) ₂ N, 4.22 ( d, J = 7 Hz, 2H; CH ₂ OH), 4.41 (s, 1H; 3-H), 4.91 (t, J = 7H, 1H, C = CH), 5.08 (s, 1H; 3H), 5.18 (d, J = 4 Hz, 1H; 6-H), 5.51 (d, J = 4 Hz, 1H; 5-H, 5.68 (d, J = 3 Hz, 1H; 5-H), 5.87 (m, 2H; O -CH ₂ 0), and 7.60 (s, 1H; N-CH = N) ppm.

Example 21

6β-bromophenicilanoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] phenylanate hydrochloride

Iodine methyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] pheniclanate dissolved in potassium 6β-bromophenicylanate (535 mg, 1.68 mmol) in dimethylformamide (15 ml) 6.52 mg, 1.40 mmol). After stirring at room temperature for 30 minutes, the mixture was diluted with ethyl acetate (60 ml) and washed with water (4 × 15 ml). The glass phase was separated and concentrated in vacuo to about 20 ml. Water (15 ml) was added to the concentrate and 0.5 N hydrochloric acid was added to adjust the pH of the stirred mixture to 3. The aqueous phase was separated and then lyophilized to give the title compound as a colorless foam.

NMR spectrum (D ₂ O) is δ = 1.48 (s, 3H; 2-CH ₃ ), 1.51 (s, 3H; 2-CH ₃ ), 1.62 (s, 3H; 2-CH ₃ ), 1.68 (s, 3H; 2-CH ₃ ), 1.4-2.0 (m, 8H; (CH ₂ ) ₄ ), 3.47-3.75 (m, 4H; (CH ₂ ) ₂ N), 4.71 (slH; 3-H) 4.76 (s , 1H; 3-H), 5.46, 5.59, 5.62 and 5.66 (4d, J-4 Hz, 8H; 5-H and 6-H), 5.39 (s, 2H; OCH ₂ O), alc 7.97 (s, 1H N-CH = N) ppm showed a signal.

Example 22

6β-iodinephenylananoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] phenylanate hydrochloride

Potassium 6β-iodine peniclanate was used in place of potassium 6β-bromophenicsilaneate according to the process described in Example 21, whereby the subject compound was obtained as a colorless powder. The IR spectrum (KBr) showed strong bands at 1780 and 1680 cm ⁻¹ .

Example 23

1, 1-dioxophenicilanoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] peniclanate hydrochloride

A. Tetrabutylammonium 6β-aminophenicylanate

To a stirred ice-cooled mixture of 6β-aminophenicylic acid (4.32 g, 20 mmol), tetrabutylammonium hydrogen sulfate (6.8 g, 20 mmol), dichloromethane (50 ml) and water (20, l), water (3.5 A solution of sodium hydroxide (1.60 g, 40 mmol;) dissolved in ml) was slowly added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 × 25 ml). The organic layers were combined, dried and evaporated in vacuo to give the desired compound as a gum oil. IR spectrum (CHCl ₃ ) showed strong bands at 1760 and 1610 cm ⁻¹ .

-아미노페니실란에이트하이드로클로라이드B. 1, 1-dioxophenylsilanoyloxymethyl 6

-Aminophenicsilaneate hydrochloride

-아미노페니실란에이트(5.1g, 11mmol)의 용액에, 에틸아세테이트(25ml)에 용해시킨 요오드메틸 페니실란에이트 1, 1-디옥사이드(3.73g, 10mmol)의 용액을 가했다. 상온에서 15분동안 교반한 후 침전물을 여별한 다음, 여액을 진공증발시켰다. 잔사를 용리제로써 클로로포름-헥산(65 : 35)을 사용하여 세파덱스

에서 컬럼 크로마토그래피하여 정제하였다. 정제도니 생성물을 에틸아세테이트(25ml)에 용해시키고 물(25ml)을 가한 다음 2N염산을 가하여 혼합물의 pH를 2.0으로 조절하였다. 수성상을 분리하고 동결 건조시킨 결과 주제 화합물이 무색분말로써 얻어졌다.Tetrabutylammonium 6 dissolved in ethyl acetate (25 ml)

To a solution of aminophenicsilaneate (5.1 g, 11 mmol) was added a solution of iodine methyl penicsilaneate 1, 1-dioxide (3.73 g, 10 mmol) dissolved in ethyl acetate (25 ml). After stirring for 15 minutes at room temperature, the precipitate was filtered and the filtrate was evaporated in vacuo. Separate the residue using chloroform-hexane (65:35) as eluent.

Purified by column chromatography at. The purified product was dissolved in ethyl acetate (25 ml), water (25 ml) was added, and then 2N hydrochloric acid was added to adjust the pH of the mixture to 2.0. The aqueous phase was separated and lyophilized to yield the title compound as a colorless powder.

NMR spectrum (D ₂ O) is 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; 2-CH 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 ; Signals at 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 an external standard.

-아미노페니실란에이트C. 1, 1-dioxophenylsilanoyloxymethyl 6

Aminophenicsilaneate

The hydrochloride obtained according to Example 23B was dissolved in water and then cooled in an ice bath. Ethyl acetate was added, followed by addition of saturated aqueous sodium hydrogen carbonate solution with stirring until the pH of the aqueous phase was about 7. The organic phase was separated, dried and evaporated in vacuo to afford the desired compound as a yellow oil.

D. 1, 1-dioxophenicilanoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] phenylanate hydrochloride

-아미노페니실란에이트(4.15g) 및 N, N-디이소프로필에틸아민(1.80ml)의 얼음-냉각용액을 가한다음 반응 혼합물을 약 0℃에서 진공에서 서서히 증발시켰다. 약 3시간 후 모든 용매를 증발제거하였다. 잔사를 디에틸에테르(3×100ml)로 추출한 다음, 디에틸에테르 추출물을 건조시키고 목탄으로 처리하였다. 물(100ml)을 가한 다음, 2N염산을 가하여 pH를 2.5로 조절하고 수성상을 동결 건조시킨 결과, 소기의 화합물이 무정형 분말로써 얻어졌다. 이것은 실시예 1에 기술한 화합물과 일치하였다.Triethyloxonium tetrapuloroborate (1.90 g) was added to an ice-cooling solution of 1-thioformyl-hexamethylene-imine (1.43 g) dissolved in anhydrous dichloromethane (20 ml). The solution was stirred for half an hour at room temperature and then cooled again in an ice bath. 1, 1-dioxophenicylalanyloxymethyl 6 dissolved in anhydrous dichloromethane (20 ml)

Aqueous cooling solution of aminophenicylanate (4.15 g) and N, N-diisopropylethylamine (1.80 ml) was added and the reaction mixture was slowly evaporated in vacuo at about 0 ° C. After about 3 hours all solvents were evaporated off. The residue was extracted with diethyl ether (3 x 100 ml), then the diethyl ether extract was dried and treated with charcoal. Water (100 ml) was added, then 2N hydrochloric acid was added to adjust the pH to 2.5 and the aqueous phase was lyophilized to afford the desired compound as an amorphous powder. This is consistent with the compound described in Example 1.

Example 24

1, 1-dioxophenicilanoyloxymethyl 6-[(hexahydro-1H-azin-1-yl) -methyleneamino] phenylanate hydrochloride

-아미노페니실란에이트(4.15g) 및 트리에틸아민(3.2ml)의 용액에, 무수의 알코올이 없는 클로로포름(10ml)중의 1-클로로메틸렌-헥사메틸렌이미늄 클로라이드(2.0g)를 약 -20℃에서 적가하였다. -20℃에서 반시간동안 방치한 후 15분내에 온도를 0℃까지 상승시켰다. 용액을 진공증발시키고 잔사를 에틸에테르(150ml)와 함께 교반한 다음, 용해하지 않은 트리에틸아민 하이드로클로라이드를 여별하였다. 물(50ml)을 가한 다음, 2N염산을 가하여, 혼합물의 pH를 2.5로 조절하였다. 수성상을 분리하여 동결건조시킨 결과, 소기의 화합물이 무정형 분말로 얻어졌다. 이것은 실시예 1에 기술한 화합물과 일치하였다.1,1-dioxophenicilanoyloxymethyl 6 dissolved in anhydrous alcohol-free chloroform (25 ml)

To a solution of aminophenicylanate (4.15 g) and triethylamine (3.2 ml), 1-chloromethylene-hexamethyleneimide chloride (2.0 g) in chloroform (10 ml) free of anhydrous alcohol was about -20 ° C. Dropped at The temperature was raised to 0 ° C. within 15 minutes after being left at −20 ° C. for half an hour. The solution was evaporated in vacuo and the residue was stirred with ethyl ether (150 ml) and then undissolved triethylamine hydrochloride was filtered off. Water (50 ml) was added, followed by 2N hydrochloric acid to adjust the pH of the mixture to 2.5. The aqueous phase was separated and lyophilized to afford the desired compound as an amorphous powder. This is consistent with the compound described in Example 1.

Claims (1)

As described above in the text, the compound of formula (5) is reacted with a compound of formula AM (M is a cation, A is as described later), or the compound of formula (8) React with a compound of formula (7), or react a compound of formula (10) or a trialkylsilyl derivative thereof with a reactive derivative of amide or thioamide of formula (11) ) Is reacted with a compound of formula (12), and then an amine of formula R ₁ -H is added to the reaction mixture without isolating the reaction product to prepare a compound of formula (1).

Wherein R 1 represents a 5-10 membered azacycloalkyl or azabicyclo alkyl residue attached via a nitrogen atom and is optionally substituted by one or two identical or different lower alkyl groups. R2 represents a hydrogen atom, a lower alkyl, an aryl or an aralkyl group, A represents a group of β-lactamase including a carboxy group as well as a β-lactam ring and is attached via a carboxy group. X represents a living group such as a halogen atom, Z represents oxygen or sulfur, and R ₇ represents a lower alkyl or benzyl group.

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