JPS59161383A - Manufacture of 6-beta-brompenicillanic acid derivative as beta-lactamase inhibitor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a series of 6-β-bromopenicillanic acids and their composition, and these compounds
It is a potent inhibitor of lactam degradation and enhances the effectiveness of β-lactam antibiotics.

A well-known and widely used class of anti-orchidicides is the so-called β-lactam antibiotics. These compounds are characterized by having a 2-azetidinone (β-lactam) ring attached to a thiazolidine or dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are commonly referred to generically as penicillins, while when the nucleus contains a dihydronaazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins used in clinical practice are Hensylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), amvicillin and carbenicillin. Typical examples of commonly used cephalosborins are cephalothin, cephalegicin and cefazolin.

However, despite the general and widespread adoption of beta-lactam antibiotics as a beneficial chemotherapy, the acid compounds of these groups have been criticized by some organisms for their vulgarity. This is happening. In many instances, this resistance of specialized microorganisms to a given β-lactam antibiotic
It is thought that this is the result of microorganisms producing β-lactam fraction. The latter proboscis is an enzyme that cleaves the β-lactum ring of penicillins and cephalosporins to render them devoid of antibacterial activity. However, some substances have the ability to inhibit β-lactam degrading enzymes as well, and β-lactam degrading enzymes are used in combination with penicillin or cephalosporin. Alternatively, the antibacterial efficacy of the glaze against microorganisms can be increased or enhanced. In the combination of a β-lactam decomposition inhibitor and a β-lactam antibiotic, the antibacterial effect is considered to increase if the anti-pulmonary activity is greater than the sum of the antibacterial activities of the ingredients. It will be done.

6-substituted penicillanes and certain esters are produced via 6-diazopenicillanic acid (Helv,
Chim, Acta, 50.1327 (1967)), but the direction of the substituent is the α-position. 6-α-Hydroxypenicillane is also prepared from 6-diacibenicilanic acid and its esters (J, Org.

Chem, 39.1444 (1974)).

6-α-penzyloxypenine lanic acid methyl ester was prepared by Manhas et al. (J, Heterocycle, Chen
.

15, 601 (1978)).

Certain 6,6-dihalo- and 6-valopenicillane preparations are described by Harrision et al. (J. Chem. Soc.).

1772 (1977)).

A 6-α-epimer is described on each side of the monosubstituted penicillanic acid.

More recently, Loosemore et al.
m. 43, 3611 (1978), when 6-α-bromopenicillanic acid was treated with a base to epimerize a part of the compound, 6-α- and 6-β-bromopenicillane (1
2%) of the mixture. Similar mixtures are β
- Hydrogenation of 6,6-dipromobensilane, in which about 30% of the epimer is said to be present. 6-α
- It is reported that the amount of β-lactam degrading enzyme in the mixture of Ayo and 6-β-bromopenicillanic acid was related to the amount of 6-β-bromopenicillanic acid in the mixed proboscis.
t, etc. (Proc, Natl, Acad, Sci, 75
, 4145 (1978)).

This finding of Pratt et al.
r et al. (Biochem. J, 177, 365 (197
9)) with 5% 6-β-bromopenicillanic acid and 95
It has been established from evidence that mixtures of %6-α-bromopenicillanic acid inhibit the fermentation of β-lactam molecules, while the α-epimer alone is essentially adulterated.

U.S. Pat. No. 4,093,625 claims a process for the preparation of 6-β-mercaptopenicillanic acid and its derivatives as antibacterial agents.

Cartwright et al. (Natortre278.36
0 (1979)), the 6α-chloropenicillane version is β-
It has been reported that although the inhibitory activity of Rakukum-degrading fermentation filament is low, the corresponding sulfone is a very good inhibitor.

Roets et al. (J. Chem, Sac, (Perkin
I] 704 (1976) identified the benzyl ester of 6β-chloropenicillan as a by-product of the process of treating the product with hydrochloric acid.

John's disease (J, Chem, Soc, Chem,
Uomn.

345 (1979)) reported a method for producing 6β-bromopenicillane parent hensyl ester from benzyl ester of 6,6-dipromopenicillane using a tin hydrogenation reduction method.

The compound of the present invention is a compound represented by the following formula, which is substantially free of 6-α-bromo epimer, or a suitable base salt thereof.

Also disclosed is a bile composition for the treatment of bacterial infections in mammals, which comprises a pharmaceutically suitable carrier, a β-lactum antibiotic and a compound of the formula: 6 -α-bromo epimers or their pharmacologically suitable base salts are included.

A compound of the formula (wherein X is chloro, bromo or iodo, and R10 is a conventional penicillin carboxy protecting group) of the present invention is reacted with an organotin monohydride at about 0-110°C, and the R19 group is leave

A critical step is to use an organotin hydride of the general formula: HSnR16R17R18, where R16, R17 and R18 are each alkyl, phenyl or henzyl of 1 to 5 carbon atoms.

The next feature of this process is that R10 is a conventional penicillin carboxy protecting group using a compound selected from the following: a) -PR2R3 (wherein R2 and R3 are each from 1 to 3
alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or phenyl).

b) 3.5-di-t-butyl-4-hydroxybenzyl, c) -CH2-F (wherein Y is -C(O)R4, where R4 is phenyl or alkyl of 1 to 3 carbon atoms, c) or carboalkoxy of 2 to 4 carbon atoms) d) -N=CHR5 (wherein R3 is phenyl or alkyl of 1 to 3 carbon atoms) e) -CH(COCH3)CO2R5 (wherein R6 is 1 to alkyl of 4 carbon atoms) f) -CR7R8R9 (wherein R7 and R3 are each hydrogen, phenyl or methyl, and R9 is phenyl, 4
-Methoxyphenyl or methyl. However, when R7 and R8 are each methyl, R9 is methyl. ) g) -Si(CH3)3 and -Si(CH3)2t-
C4H9:h)-SnR10R17R18 (R16 in the formula
, R17 and R18 are each alkyl of 1 to 5 carbon atoms, phenyl or benzyl) A particularly preferred process is where R19 is the penicillin carboxy protecting group -SnR10R16R17R18 (wherein R18
, R17 and R18 are n-butyl. The key group is removed by hydrolysis. A particularly preferred process is that R2O is a conventional penicillin carboxy protective
(CH3)3. X is bromo, chloro and X is iodine,
In the step where the organotin monohydride is tri-n-butyl hydride, the migrating group is removed by the hydrolytic group. Similarly, a particularly preferred process is such that R10 is a conventional penicillin carboxy protecting group -CR7R8R9 (wherein R7 and R8 are each hydrogen atom, R9 is 4-methoxyphenyl, and the organotin monoaqueous compound is tri-n-butyltin hydride. That is,
The retaining group is removed by hydrolysis.

The unprocessed 6-α corresponding to 6-p-brompenicillanic acid
- It is unique in that a 6β-bromopenicillane containing at least 75% β-epimer is used, considering the method of synthesizing the epimer virtually free of gold. In many cases, the required β-epimer mass can be as high as 99.5%.

Since the α-epimer is essentially inactive as a inhibitor of β-lactam degrading enzymes, it is essential to utilize the β-epimer content of the compound as high as possible. Compounds containing α-epimers inhibit β-lactamase and must be used in large doses to make β-lactam antibiotics effective. Large doses of these substances cause chemotaxis in the lactating host.

The biologically active compounds of the present invention are synthesized by the steps depicted in the following formula.

(In the formula, X, R10, R16, R17, and R18 are as described above in Ashishiro.) In part, the reduction can be easily carried out without using a solvent, or if the solvent is The reaction can be carried out in a hot medium if there is a reaction-inert cat that absorbs the reactants to some extent without reacting with the proboscis or product all at once. When a solvent is used, the solvent is an aprotic solvent. It is desirable to do so without mixing with water and with the reaction temperature matching the boiling and freezing points. The solvent or admixture includes aromatic solvents such as benzene or toluene.

When carrying out the above-mentioned reactions in situ, the reactants are mixed into the pre-metal and heated to the described reaction temperature.

The molar ratio of the starting penicillanic acid diform to the organotin monohydride is not critical for the scope of the claims. A small excess of tin hydride, up to a 10% excess, is used to help complete the reaction, which is sufficient to obtain the desired product in its pure form.

The reaction time essentially depends on the concentration, the degree of reaction and the reactivity of the starting reagents. For non-processing, if there is no bath table, 60~
The reaction temperature is 100°C.

At this temperature, the reaction usually takes 5 to 8 hours to complete. When a hot medium is used, the reaction temperature is 80-100° C., and it takes 4-6 hours to complete the reaction.

The reaction time and reaction temperature can be significantly reduced by carrying out this step under ultraviolet gland irradiation. The reaction under these conditions is initiated with a free radical inducing agent such as azobisin butyronitrile and carried out under cold conditions such that the temperature is maintained at about 15-25°C. The reaction time under these conditions is about 15 minutes to several hours.

The reaction temperature is a temperature that allows the reaction to proceed at a normal rate without causing heat dissipation that would result in the formation of heat exchangers or heat exchangers. Therefore, a masterpiece is produced at 0 to 100°C.

Since the oil as a reagent to be added is not critical, it is not desirable to add aged tin monohydrogen to the 6,6-disubstituted penicillane solution. When a 6,6-cyhalopenicilane derivative is used in this method, two dehalogenation reactions are minimized.

In the compound proboscis of the above-mentioned formula, the substituent bond to the dinuclear penicillane imaginary nucleus indicates that the substituent is below the plane of the proboscis, and this is said to be in α-memory. A real diagonal bond saturated with the core indicates that the Yoshimata group is bonded on a plane, and is called a β-configuration. The wavy line is intended to capture two epimers or even a mixture thereof.

The bamboo monohydrogenase used as a reagent in this step is prepared by methods known to those skilled in the art. Commercially available reagents that are labor-intensive are available from Hayashi Temple (J.

Organametal, Chem, 10.81 (19
67)).

The first of the penicillin protecting groups is a phosphine ester. According to the process of Nishimushi Patent Publication No. 2,218,209, a suitable 6β-hydroxymethyl or 6,6-displaced penicillanic acid is prepared as a triethylamine salt and reacted with dialkyl or dialkoxy-chlorophosphine. Let me. Generate the desired source reagent from the non-process.

When the reaction between the reagent and the halogenated reagent or organotin monohydric complex occurs, by adding water, the reaction mixture is separated from 6-β-frompenicillic acid to form this product.

The second reservoir is 3,5-di-tert-butyl-4-hydroxybenzyl ester. It is easily synthesized from the essential 6.beta.-hydroxymethyl or 6,6-disubstituted penicillane according to the procedure of West German Special Edition Dekai No. 2.033.493. For the treatment, the aforementioned penicillanic acid was reacted with ethyl chloroformate in the form of triethylamine, and the obtained 3,5-di-t-butyl-4-
Contains a substance that may react slightly with hydroxybenzyl alcohol. Due to the reaction between the starting reagent and the halogenated reagent or the Arikari tin monochloride, the pH
The protecting group is removed by hydrohydration at a temperature of 8.0.

A third type of protecting group suitable in the process of the invention is R
This is a thread in which 10 is -CH2Y (in the formula, Y is as defined previously). These 6β-hydroxymethyl and 6
, 6-disorted penicillanic acid esters can be prepared by alkylating the corresponding triethylamine penicillanate with a suitable halide [Acta, Ch.
See Em, Scand, 21.2210 (1967)]
. Following the subsequent reaction of the aforementioned reagents with the halogenating reagent lubrication or tin monohydride, the preservative group is liberated, preferably together with potassium thiophene oxide.

The strain groups of type 4 in this series where R10 is -N=CHR5 (where R5 is as defined previously) [J, Chem, Soc, 1917 (1971C)]
6β-hydroxymethyl or (6,
Incorporated into 6-disubstituted beninolanic acid. It is then suggested that the mixed anhydride produced from the necessary 6.beta.-hydroxymethyl acid 6,6-didiconverted penicillane and chloro ether be reacted with the appropriate altehyde oxime.

Following the reaction of the 6-hydroquinemethyl compound with a halogenating reagent or the 6β-hydroxymethyl compound with a tin hydride in this step, 6-β-substituted benicillanic acid is recovered by treatment with potassium thiophenoxide. The base is decapitated.

A fifth type of monomer group is an ester derived from acetocarbonate. The introduction of this type of binding group into the penicillin binding group has been described by Ishimaru et al. [Cb
emjstry Letters, 1313 Ayo and 13
17 (1977)]. Then 6β
-Hydroxymethyl or the sodium salt of 6,6-disubstituted penicillanic acid can be treated with the appropriate alkyl α-haloacetoacetate. The protective layer is removed from the 6-β-penicillanic acid derivative by treating the substrate with a halogenating reagent or an aqueous solution of sodium nitrate.

A sixth type of calibration balance can be produced in a number of ways with the group R10 being -CR7R8R9. These deceptions have already been demonstrated in the chemical literature. Photosynthesis method uses 6-β-
Using aminopenicillanic acid esters as starting materials, for example Cama et al. (J. Am.

Cgen. Soc, 94.1408 (1972) and Harrison et al.
kin I), 1772 (1976)) by Bunshu,
This includes substituting the 6-amine moiety with a 6-diazo convex. When a penicillin protective group is reacted with a 6,6-di-substituted hemylamine bonded with a 3-carboxy group with an organotin monohydric complex in a conventional manner, the protective group is released. If two or more of the substituents R7, R8 and R9 are phenyl, or if R9 is 4-methoxyphenyl or R1, R8 and R9 are each methyl, the conservative group can be removed by treatment with trifluoroacetic acid. Will be detached. This mode of elimination is consistent with all possible substituents in the 6-β-position. When R7 or R6 is methyl, R7 and R8 are hydrogen and R9 is phenyl, the guarantee group is removed by treatment with trimethylsilyl iodide [Jung et al. Am, Chern,
Soc. 99.968 (1977)] In any case, these groups can be dissociated by icing if the 6-β-substituted group is not a halogen or alkylthio moiety.

The required 6β-hydroxymethylpenicillanate can be produced by reacting the corresponding 6β-hydroxymethylpenicillane QC2 with a suitable alcohol as an active compound, or by reacting the 6β-hydroxymethylpenicillane QC2 with a suitable alcohol, or by converting the salt with an R7R8R8C-halide. It can be made central by becoming. 6β
-Hydroxymethylpenicillane liquid salt is treated with a suitable halogenating agent and decapitated into a protecting group as indicated above.

The seventh type of ridge retention group is trimethylsilyl or dimethyl-t-bunarsilyl ester, which is 6,6-
Reaction of triethylamine of diconverted penicillane lily with appropriate silyl chloride [Reference Ann, 673.166 (1)
964)] to generate it there. 6 attached with a protecting group,
After reacting the 6-disubstituted penicillanic acid with the organotin monowater complex, the protecting group is removed by water hydrolysis.

The eighth type of protecting group envisaged by the present invention and already rotated is R10-SnR10R17R18, and R1
6, R17 and R15 are as previously defined.

In addition, to prepare the ester, 1 mol of bis-tin-oxide is added to 2 mol of Yushin's 6,6-disubstituted penicillane [Cher, Ind. 1025 (1976)]. At the completion of the process, the anchoring group is removed by water hydrolysis.

A penicillin carboxylic group that is particularly useful in the synthesis of compounds of Formula II is trichloroethyl.

This group is introduced into the carboxy group of the appropriate 6,6-dicyclic penicillane using a procedure as described in German Patent Application No. 1,937,962. The disubstituted benisolanic acid trichloroethyl ester is converted into 6-halo-6-alkylthiopenicillanic acid trichloroethyl ester or sulfoxide by the treatment described below, and then treated with an organotin monoaqueous compound. Thus, 6-β-alkylthiopenicillanic acid tritaloloethyl ester or sulfoxide is produced.

By removing the trichloroethyl moiety, which is a holding thread, formula II
Obtaining the compound (wherein R11 is hydrogen) is coupled by treatment with zinc dust in a buffer.

Compounds of formula II form salts with compatible basic reagents. Such a fence is considered to be within the scope of the present invention. They may be prepared by standard techniques such as contacting the acidic and clogging components, usually in a 1 molar ratio, in an aqueous solution, either a non-Mizutani or a partially aqueous medium. The reaction product is filtered,
A precipitate is generated in a non-aqueous medium and recovered by filtration, distillation of a hot medium, or, in the case of a water bath liquid, by freeze-drying as appropriate.

Suitable basic reagents used for the formation of salts belong to both organic and inorganic types, including ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, halides and alkoxides, as well as alkali Contains earth metal hydroxides, carbonates, hydrides and alkoxides.

Typical examples of such base threads are the basic amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, diethylamine, morpholine, pyrrolidine and piperidine. 26-amine shellfish, triethylamine, N-enalbiberidine, N-methylmorpholine and 1,5-
Diazabicyfuro[1,3,0]non-5-ene pestle 3
grade amines, hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide,
Alkoxides such as sodium ethoxide and potassium ethoxide, hydrides such as scaled calcium and sodium hydride, carbonated salts such as potassium carbonate and sodium carbonate, sodium bicarbonate salts and charcoal water. There are carbonated water salts such as potassium salts, and alkali metal salts of long chain fatty acids such as sodium 2-ethylhexanoate.

Preferred salts of compounds of formula II are the sodium, potassium and triethylamine salts.

As previously reported, the compound of formula
It is a potent inhibitor of lactam-degrading enzymes and is therefore a potent inhibitor of β-lactam antibiotics (penicillins and cephalosporins) against many microorganisms, especially β-lactam-degrading enzymes. It has antibacterial effect. The manner in which the compound of formula II enhances the efficacy of A-Rakum antibiotics was evaluated with respect to the minimum elemental concentration (MIC) of a given antibiotic alone and the MIC value of the compound of formula II alone was determined. can be done. These minimum inhibitory concentrations are relative to the minimum inhibitory concentrations obtained by combining the antibiotic and the compound of Formula II. If the antibacterial activity of this combination is sufficiently greater than that expected from the antibacterial activity of the individual compounds, this is considered to consist of enhanced activity. The MIC direct of the combination is Barry and Sabath [■Manual of Clini
cal Acrobiology”Lenetle,
, edited by Sparcing and Trant,
2nd edition, 1974, American, Society
for Microbi-otogy].

Compound II enhances the antibacterial efficacy of β-lactam antibiotics in the terminal organism. In other words, these compounds have the effect of reducing the effectiveness of antibiotics that are safe to protect mice due to the appearance of lethal compounds in the production phase of certain β-lactamases.

The ability of the compound proboscis of formula II to enhance the effectiveness of beta-lactam anti-inflammatory agents against beta-lactam-degrading enzyme-induced closure makes beta
- When administered simultaneously with lactam raw shellfish substances, these compounds have a mild effect. For the treatment of fungal infections, the compound of formula II
- Both test samples are administered at the same time as they can be mixed together with lactam antibiotics. Alternatively, the compound of formula II can be administered as a separate agent during treatment with a β-lactam antibiotic. In some instances, it may be advantageous to pre-medicate a subject with a compound of Formula II prior to initiating initial treatment with a beta-lactam antibiotic.

When the compound of formula II is used to enhance the efficacy of β-lactam antibiotics, it is preferably administered in the form of a pharmaceutical carrier or diluent.

A pharmaceutically suitable carrier, a β-lactam antibiotic and a
Pharmaceutical compositions containing a compound of I will normally contain from about 5 to about 80% by weight of a pharmaceutically suitable carrier.

When using compounds of formula II in combination with other β-lactam antibiotics. The compounds may be administered orally or parenterally, ie, intramuscularly, subcutaneously, or intraperitoneally. Although the prescribing physician ultimately determines the dosage to be used in a subject, the ratio of the daily dosage of the compound of formula II to the beta-lactam antibiotic is usually within the range of 1:3 to 3. : The range is 1.

Additionally, when the compound of Formula II is used in combination with other β-lactam antibiotics, the daily oral dosage of each component is typically between 10 and about 200 mg/yg body weight. and the daily parenteral dosage of each component is from the normal line 10 to about 400.
mg/km body weight. However, these numbers are only examples; in some cases it may be necessary to use dosages outside these limits.

Typical beta-lactam antibiotics for co-administration with compounds of Formula II are: 5-(2-phenylacetamido)penicillanic acid, 6-(2-phenoxyacetamito)penicillanic acid, 6- (2-phenylbrobionamito)penicillanic acid, 6-(2-carboxy-2-phenylacetamido)penicillanic acid, noenyl)-EPJJ-penicillane, 6-(2-7enylacetamido)penicillane acetogisimethyl, 6 -(2-phenylacetamido)penicillane Y1-(
6-(p-2-amino-2-phenyladamide) penicillane cai-(
Ethoxycarnyloxy) enanope 6-J) -2-amino-2-4-hydroxyphenyladamido)penicilane S- (ethoxycarbonyloxy)ethyl, 3-phthalidyl 6-(2-phenylaceamido)penicillanate, ( D2-amino-2-phenylacetamidopenicillane 3-phthalidyl, 6-(1)-2-amino-2-[4-hydroxyphenylacetamido)-penicillane-3-phthalidyl, 6-(2-phenogysilyl sulfonyl- 2-phenylacetamido)penicillanic acid, 6-(2-)ruyloxycarbonyl-2-phenylacetamido)penicillanic acid, 6-(2-[5-indanylboxycarbonyl"-2-
phenylacetamido)penicillanic acid, b-(2-noenoxycarbonyl-2-[3-thenyl]acetamide)penicillane-16(2-ruyloxycarbonyl-2-3-thenyl]acetamide)penicillane, 6-(2- [5-indanyloxycarbonyl]-2-
3-chenyl]acetamido)penicillanic acid, 6-(2,2-dimethyl-5-oxo-4-phenyl-
1-imidazolidinino)penicillane 7-(2-C2-chenyl]acetamic)cephalosporanic acid, 7-(2-11-tetrasolyl)acetamido-3-(
2-1,5-Methyl-1,3,4-thiadianlyl]thiomethyl)-3-desacetoxymethercephalosboranic acid, 7-(ρ-2-formyloxy2-phenylacetamide)-3-(5- 11-Notyltetrazolyl (thiomethyl)-3-desacetoxymethylcephalosborane, 7-(D-2-amino-2-phenylacetamido)desacetoxychaphalosborane, 7-alphamethoxy-7-(2 -42-chenyl]acetamide)-3
-carbamoyloxymethyl-3-desacetoxy-methylcephalosporanic acid, 7-(2-one anoacetamido)cephalosporanic acid, 7-(7-2-hydroxy-2-enylacetamide)
3-3-(5-11-methyltetrasolylnaomethyl)
-3-descetoxymethylphalosphoran, 7-(2-amino-2-14-hydroxyphenylacetamido)desacetoxycephalosborane: 7-(2-L-1-pyridylnaoacetamido)cephalosporan; 1 7-2-amino-2,4-cyclohequinadienyl]acetofumidonecephalosporanic acid, 7-(2-amino-2-phenylacetamido)cephalosporanic acid, 7-l-(-)-alpha-(4-ethyl -2,3-dios)-1-biperazinecarboquinoad)-alpha=
(11-hydroxyphenyl-)acetamide]-3-
L(1-methyl-1,2,3,4-tetrasol-5-
Irunthiomethyl, J-3-cephem-4-carbonier, 7-D-2-amino-2-phenyladamide)-3-
Chloro-3-cephem-4-carvone, 7-12-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamidorosephalosporan, [6R,7-3-carbamoyloxymethyl-7( 2Z
)-2-methoxyimino(flu-2-acetamido-cephem-4-carboxylate 7-42-(2-aminothiazol-4-yl)acetamide" 3-[2-dimethylaminoethyl-1H-tetrazol-5- [yl]thio)methyl]cephemu 4-carboxylic acid, and its salt suitable for mulberry fields.

As appreciated by experts in this field, some of the β-lactam compounds mentioned above are suitable for oral or parenteral administration, while others can be administered by the parenteral route. It is effective only when

When Formula II is used simultaneously (ie, mixed together) with a β-lactam antibiotic that is effective only for parenteral administration, a silk combination dosage form suitable for parenteral administration is required. Formula II is
When used in combination with orally or parenterally effective β-lactam antibiotics, combinations suitable for either oral or parenteral administration may be used. Can be quasi-secondary. Additionally, formulations of Formula II compounds can be administered orally, while the beta-lactam antibiotic can be administered parenterally at intervening intervals. The compound formulation of formula II can then be co-administered parenterally while the beta-lactam antibiotic can be administered orally.

The following examples are provided for further illustrative purposes only. Nuclear magnetic resonance spectrum (NAR) is 60 mechahertz (MHz)
), deuterated chloroform (CDCl2), deuterated dimethyl sulfoxide (DMSO-d5), or deuterated water (D2O), or other solvents as described. The peak positions are then expressed in parts per million (ppn) downfield from butramethylsilane or 2,2-dimethyl-2-silapentane-5-sulfonic acid sodium salt. The following distinctive abbreviations are used for peak types: S, singlet; d, goblet; t, triplet (
3 stationary pictures); q, quartenote (4 city lines); m, multi-bullet (multiple lines).

Example 1 6-β-bromopenicillanic acid A mixture of 5.0 g of 6-dipromopenicillanic acid, 1.54 ml of triethylamine, and 100 ml of benzene was stirred under nitrogen freezing until a solution was obtained.

The solution was cooled to 0-5C for 2-3 minutes and 1.78 ml of trimethylsilyl chloride was added. The reaction mixture was heated to 0-5°C.
, 2-3 minutes, then stirred at 50C for 35 minutes. The cooled reaction mixture was filtered and the filtrate was cooled to 0-5°C. Add a little azobisinbuteronitrile and hydrogenate tri=n-
3.68 ml of butyl powder was added. The reaction flask was irradiated with ultraviolet light for 13 minutes.

The reaction mixture was then stirred for 1.75 hours at about 25°C.

The reaction mixture was again irradiated with pure ultraviolet light for 15 minutes and then continued to stir for 2.5 hours. At this point a further small amount of azobisisobutyronitrile is added and then tri-n-butyltin hydride 0
．． 5 ml was added and the mixture was irradiated for 30 minutes.

The solvent was then removed by vacuum distillation and 5% sodium bicarbonate solution and diethyl ether were added to the residue.

This bilayer system was vigorously immersed for 10 minutes. Then the pH was adjusted to 2.0. The ether layer is transferred, dried and vacuum distilled to yield 2.38 g of oil. This oil was converted to the sodium salt with sodium carbonate and the solution was lyophilized. It is 6-β-bromopenicillanic acid sodium salt and contains a small amount of the α-isomer.

Sodium 9 was purified by chromatography on Sephadex LH-20.

The nuclear magnetic resonance spectrum of this product showed the following dimethyl. 5.56 (s, 2H), 4.25 (s, 1H),
1.60 (s, 3H) and 1.50 (s, 3H) pp
m Example 2 6-B-bromopenicillanic acid 1000 g of 6,6-dibromopenicillanic acid and 390 ml of triethylamine are added to 4000 ml of dry toluene, and the slurry is slowly cooled to 20-25°C. Trimethylchlorosilane (855 ml) at 10
The reaction mixture was allowed to warm up to 25C. Triethylamine hydrochloride was filtered off, and the solid was washed with 1.75 liters of toluene. The filtrate and the filtrate were put together in a flask, and a solution of 783 ml of tri-n-butynotin hydride in 1000 ml of toluene was added at 18-2
Add at a rapid rate of 0ml/min. When the intensification was completed, the reaction mixture was allowed to stir for 1 hour and then placed in 7 liters of saturated hydrogen sodium trirum solution to stop the reaction.

Separate each layer and remove the special layer with 3 saturated sodium bicarbonate.
Extracted with l. The aqueous layer and extract were combined, treated with 5 liters of ethyl acetate, and adjusted to pH 1.5 using 12N hydrochloric acid.
Adjusted to 5. The ethyl acetate was separated and the aqueous layer was extracted with 2.5 liters of ethyl acetate.

Both ethyl acetate layers and extracts were combined, dried over sodium sulfate, and treated with 2.26 liters of an intoxicated ethyl solution containing sodium 2-ethylhexanoate. The sodium moth precipitate was left overnight at 8-10°C, filtered and dried to yield 391.5 g of crystalline material.

Add sodium salt (380 g) to 1.9 liters of deionized water.
Dissolve at 8C and add 6N hydrochloric acid to adjust the pH to 1.5.
I made it. After stirring in a cold place (3-5C) for 1 hour, the precipitate of the evacuated acid was poured into a bowl, and the mixture was poured with 500 ml of cold water. 100 ml of water was added to 2 liters of Sochi ethyl solution of evacuated acid at 8° C., and the pH was adjusted to 1.5 with 6N hydrochloric acid. The promising layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and extracted powder were treated with activated carbon and dried over magnesium carbide. The ethyl acetate layer is stirred and a solution of about 1 equivalent of sodium 2-ethylhexanoate in 311 ml of ethyl acetate is added. After stirring for 1.25 hours, the precipitated solid was filtered and dried to give 262 g of 6-β-bromoveninlan and acid sodium salt.
I got it.

To purify this compound, the above sodium salt was dissolved in 1300 ml of deionized water and the pH was adjusted to 1.8 at 6-8°C. The precipitated solids were stirred at 6-8°C for 1.5 hours. It was then filtered and washed with 300 ml of water.

This pre-acid was treated with 2 liters of ethyl acetate and 200 ml of water, and the pH was adjusted to 1.35-1.40 with 6N hydrochloric acid. The organic layer was removed and treated with magnesium sulfate. 802 ml of ethyl acetate containing an equivalent amount of sodium 2-ethylhexanoate was added to the filtrate. The precipitated natrirum salt was stirred at room temperature for 1 hour, filtered, and dried to obtain 227 g of the desired crystalline sodium salt.

A 40.0 g sample of the above sodium salt was added to 200 ml of water and the resulting solution was adjusted to pH using 6N hydrochloric acid at water bath temperature.
Adjusted to 1.6. The precipitated free acid was filtered and dissolved in water for 2 hours.
I kneaded it again. After vacuum recording at room temperature overnight, 34.05 g of the desired crystalline compound was obtained.

Melting point: 190-195°C (decomposition point).

Theory clay C8H10NO3SBr:C,84,8;H,
3, 6; N, 5.0 experimental value
:C, 84.4:H, 3,7;N, 5.0[α]D=+
292゜Example 8 6-β-bromopenicillanic acid sulfoxide sodium salt 182 mg of sodium periodopyrate was added to a solution of 255 ng of disodium 6-β-phromopenicillane in 5 ml of water.
The resulting solution was kept stirring at room temperature for 8 hours.

80 ml of ethyl acetate was added to the reaction solution, and 6N hydrochloric acid was added to adjust the pH to 1.3. The ethyl acetate layer was separated, backwashed with saturated brine, and dried over magnesium sulfate. The solvent was removed by vacuum distillation and the residual product was then dissolved in water containing 1 equivalent of sodium bicarbonate salt. This aqueous solution was freeze-dried to obtain 285 mg of the target product as a sodium salt.

Example 4 6-B-bromopenicillanic acid sulfone sodium salt To a solution of 255 mg of 6-β-bromopenicillanic acid sodium salt in 5 nl of water was carefully added a solution of 140 mg of potassium permanganate and 0.11 ml of phosphoric acid in 3 ml of water. was added while maintaining the pB at 6.0-6.4. The reaction mixture was stirred at 0-5C for 15-20 minutes and treated with 50 ml of ethyl acetate.

Adjust the pH to 1.5 with 6N hydrochloric acid and add charcoal sodium 8
I took 80mg little by little. The pH was adjusted to 1.7, and the solution was sprinkled with Suzuzawa enal debris and backwashed with Sowa Shokuhan water. When the solvent was distilled off by distillation, 216 mg of the product was obtained in the form of an oil.

The free particles were suspended in 10 ml of ethyl acetate and added to a solution of 10 ml of water containing 57 mg of sodium carbonate.

The solids were separated and dried to obtain 140 mg of the target compound as a sodium salt.

Example 4 6-B-bromopenicillanic acid sulfone sodium salt 6-
10 ml of bromo-6-iodopenicillanic acid 2.5N sulfur, 6.21 g of iodine bromide and 75 ml of methylene chloride with 2.16 g of limited sodium nitrite.
The bath liquid was cooled to 0 to -5°C, and 4.32 g of 6-β-aminopenicillanic acid was added thereto over 15 minutes. After stirring at -5°C for 20 minutes, a total of 100 ml of 10% sodium carbonate was added, taking care to maintain the temperature of the reaction mixture at 10°C. Each layer was separated and the aqueous layer was extracted with methylene chloride (3×50 ml). The organic layer and the extract were combined, washed with saturated brine, dried with macanine sulfate, and concentrated by vacuum distillation to obtain 5.78 g of the desired intermediate (melting point 145-147°C).

6-bromo-6-iodopenicillanic acid sulfone 4.05 g of 6-bromo-6-iodopenicillanic acid in a 30 ml volume of methylene chloride and 60 ml of water were layered on top.
3N sodium hydroxide was added to bring the pH to 7.0. The aqueous layer was separated, cooled to 5°C, and potassium permanganate 1.9
3 g and 1 ml of 85% phosphoric acid in 80 ml of water.
It dripped for more than a minute. The pH was adjusted to 5.8-6.2 with 8N aqueous sodium dredging, and the temperature was kept at about 5°C, when the addition was completed, 100 nl of ethyl acetate was added and the pH was adjusted to 1.0 with 6N hydrochloric acid. 5. Add 10% sodium hydrogen solution (3%) until the reaction mixture turns pale yellow.
0 ml) was added. The treated layers were separated and the aqueous layer was extracted with ethyl acetate (4X50ml). The organic layer and extract were combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 3.6 g of a substance. Layer points 151-153
C Sodium 6-β-bromopenicillane sulfone 6-bromo-6-iodopenicillane late sulfone 3.36
130 ml of toluene stock solution was kept at 5 DEG C., and 1.09 ml of triethylamine and then 1.3 g of dimethyl-t-butylsilyl chloride were each added in a nitrogen stream. Continue stirring at 5°C for 5 minutes, at 25°C for 60 minutes, and at 45°C for 30 minutes. Then cool the reaction mixture to 25C. The triethylamine hydrochloride was filtered off, and 15 ml of azobisin butyronitrile and 2.04 ml of dibenzylphenyl hydrogenated salt were added to the filtrate. The mixture is maintained at an external temperature of about 20-25°C and irradiated with ultraviolet light for 15 minutes. The solution is distilled off in vacuo, and the residue is dissolved in a 1:1 mixture of tetrahydrofuran and water. The pH was adjusted to 7.0 and tetrahydrofuran was distilled off under reduced pressure. The aqueous layer is treated with 100 ml of ethyl acetate and the pH is read to 1.8 with 6N hydrochloric acid. The solid layer was separated, and the aqueous layer was further extracted with ethyl acetate. Combine the liquid layer and extract, backwash with saline solution, and dry with sodium hydroxide. The organic liquid was then treated with a solution of 2.2 g of 2-ethylhexenoic acid sodium salt in ethyl acetate,
Cook for 1 hour with stirring. The salt of the obtained precipitate is filtered off and dried.

Example 5 6-B-bromopenicillanic acid A, 6.6-dibromopenicillane dimethoxyphosphine ester 8.58 g of 6.6-dibromopenicillanic acid, 40 ml of methylene chloride, 1.08 g of triethylamine
Add. The solution is then treated with 1.28 g of dimethoxychlorophosphine and left to stir for 30 minutes. The solvent was removed in vacuo and the residue was treated with 125 ml of dry diethyl ether. Filter the insoluble triethylamine hydrochloride and distill off the ether under reduced pressure to obtain the desired intermediate.

B, 6-B-Bromopenicillanic acid 6.6-Dibromopenicillanic acid dimethoxyphosphine ester 4.5g was added to a dry toluene solution of 3.4g of di-n-butylphenyltin aqueous cumulate, obtained. The reaction mixture is left stirring at room temperature for 20 minutes. 150 ml of saturated aqueous sodium bicarbonate solution is added to the reaction mixture and the organic layer is separated and discarded. Furthermore, the aqueous layer was diluted with ethyl acetate (2 x 25 ml
) and carefully adjust the pH to 1.5 with 6N hydrochloric acid. The acidified aqueous layer was extracted with ethyl acetate (8 x 50 ml
), collect the extracts, dry with magnesium sulfate, and concentrate to obtain the desired product.

Example 6 6-B-bromopenicillanic acid sodium salt A,6,6-
Dibromopenicillanic acid tri-n-butyltin ester 6.6-dibromopenicillanic acid 85.9 g toluene 7
29.5 g of bis(tri-n-phthyltin) oxide was added to 00 ml of the slurry and the reaction mixture was heated to reflux. The water that distilled the toluene from the reaction mixture over about 45 minutes was azeotropically distilled off during this time. The remaining solvent was distilled off under vacuum at room temperature to obtain 78.7 g of the desired intermediate.

6-B-bromopenicillanic acid sodium salt 6,6-dibromopenicillanic acid tri-η-butyric acid nister 1.0 g
0.4 ml of tri-n-butyltin hydrogenation solution was added dropwise to the solution with 5 ml of toluene at 55C.

It heated up at 8.5 o'clock. Thereafter, the solvent was distilled off, and the residue was dissolved in 25 ml of chloroform. The chloroform layer was treated with saturated sodium carbonate solution (2 x 50 ml). The water washing solution was dyed, the pH was adjusted to 1.5 with 6N hydrochloric acid, and the product was extracted with ethyl acetate.

The ethyl acetate extracts were combined and dried over sulfated magnesium.
Ethyl acetate containing sodium 2-ethylhexane (1
．． 24 nmol/cc) 1.24 ml was added.

After stirring for 1 hour in the cold, the product was filtered and dried. 114mg
.

Example 7 6-B-bromopenicillanic acid A. Methyl 2-chloroacetoacetate (1.6 ml) was added to a solution of 5.0 g (5.0 g) of 6,6-dibromopenicillanic acid acetoacetic acid sodium salt in dimethylformamide (100 ml), and the resulting reaction mixture was stirred at room temperature. It was stirred overnight. The mixture was poured into 400 ml of ice water and extracted with ethyl acetate.

The solids were separated and washed successively with water, saturated aqueous sodium carbonate solution and saline water. The nucleated grains were then dried over magnesium sulfate and concentrated to give a dark colored substance (5.0g
), which was chromatographed on 300 g of silica gel. Toluene/ethyl acetate (2:1 volume:
The product-containing fraction of the eluate (volume) was dyed and vacuum knitted to obtain 4.0 g of the target product.

B. 6-B-bromopenicillanic acid can A solution of 2.0 g of 6,6-dibromopenicillanic acid acetoacetic acid methyl ester in 140 ml of dry benzene was added to 1.1 ml of tri-n-butyltin hydride in water conditions and hydrogen gas mud.
The resulting reaction mixture was kept stirring at room temperature overnight. The benzene solvent was distilled off in vacuo, the residue was made into a hexane slurry, and the insoluble material was chromatographed using 250 g of silica gel and an eluent of toluene/ethyl acetate (5:1 by volume). Fractions containing the target product were collected and concentrated to dryness under reduced pressure.

Acetone 5 of 3.9 g of 6-β-bromopenicillane triacetate methyl ester (synthesized by the above treatment method)
0ml solution, 2.1g sodium nitrite in 10ml water
Add the solution while stirring. After stirring at room temperature for 3 hours, the solvent was distilled off in vacuo, and the aqueous residue solution was extruded once with ether. The aqueous layer is then acidified to pH 1.5 with 6N hydrochloric acid and purged with ethyl acetate.

The organic layer is dried over magnesium sulfate and concentrated under pressure to obtain the desired product.

Patent applicant: Pfizer, Inc. Representative Patent attorney: Kyozo Yuasa (2 others)

Claims (2)

[Claims] (1) A compound represented by the formula: that does not significantly contain 6-alpha bromo epimer, or a pharmaceutically reasonable base salt thereof. (2) A pharmaceutical carrier, a bakelactam antibiotic, and the following formula. 6-Alphapromevimer is a compound represented by the formula 6-alphapromevimer, or its pharmaceutically suitable base compound for the treatment of bacterial infections in breast milk products.