KR830001543B1 - Process for preparing cephalosporin antibiotics - Google Patents

Abstract

Cefuroxim esters I(R1 = C1-4 primary or secondary alkyl; R2 = C1-6 primary of secondary alkyl) were prepd. by the reaction of cefuroxim K salf with R2CHBrO2CR1 and the acylation of III with (Z)-2-(fur-2-y1)-2-methoxyimino-acetic acid. Thus, 4.57g cefuroxim was stirred with 760mg K2CO3 and 25ml N,N-dimethylformamide followed by the addn. of AcOCH2Br to give (R and S)-1-acetoxyethyl(6R,7R)-3-carbamoyloxymethyl-7-≮(Z)-2-(fur-2-y1)-2-methoxyiminoacetamido≉ceph-3-em-4-carboxylated. I are useful as antibiotics and are more easily absorbed after oral administration than cefuroxim.

Description

Method for preparing cephalosporin antibiotic

(6R, 7R) -3-carbamoyloxy-methyl-7-[(Z) -2- (fur-2-yl) -2 of formula (I), useful as an antibiotic for oral administration -Methoxyiminoacet-amido]-ceph-3-em-4-carboxylic acid (ie, a thin isomer; generic name cefuroxime) relates to a process for preparing a biologically acceptable ester derivative.

In the above formula,

R ¹ is a primary or secondary alkyl group having 1 to 4 carbon atoms,

R ² is a C1-6 primary or secondary alkyl group,

Provided that at least one of R ¹ and R ² is methyl and an asterisk represents an absent carbon atom.

As described in British Patent No. 145249, cepuroxime is an effective broad spectrum antibiotic characterized by a wide range of Gram-positive and Gram-negative microorganisms, a characteristic of which is the β produced by some Gram-negative microorganisms. It is promoted by the very high stability of this compound against lactamase. In addition, the compound is stable in the body because it is resistant to the action of mammalian esterases, and shows high serum concentrations in parenteral administration (eg in the form of sodium salts) to humans and animals, while having low levels of serum binding.

Cefuroxime and its salts, such as alkali metal salts such as sodium salt, have been used mainly as antibiotics for injection because they are hardly absorbed from the gastrointestinal tract and are present in low concentrations only in serum and urine upon oral administration. Therefore, the development of cefuroxime derivatives that are absorbed through the gastrointestinal tract during oral administration and showing excellent antimicrobial activity can further increase the therapeutic titer of cefuroxime, and therefore, intensive studies on the possible activities of oral administration of various cefuroxime derivatives are performed. It is becoming.

It is known that the effect of oral administration of penicillin antibiotics such as ampicillin can be improved by converting the carboxy group present in the 3-position of the penum nucleus into an esterified carboxy group; In addition, it has been proposed that the activity of oral administration of cephalosporin antibiotics can be increased by esterification in a similar manner.

It is believed that the presence of a suitable esterification group promotes gastrointestinal uptake of the compound, which is hydrolyzed by enzymes present in serum and body tissues to produce parent acid with antimicrobial activity. The ester should be stable enough to reach the absorption site without major degradation in the stomach area, etc. On the other hand, it should be easily hydrolyzed by the esterase to form a parent acid having antimicrobial activity in a short time. Therefore, it is very important to select which property of the esterification group.

In selecting a particular esterification group to enhance the oral administration of β-lactam antibiotics, this choice depends on which β-lactam compound is applied. That is, for example, esterified groups that are found to be effective in increasing the activity of orally administered penicillin antibiotics do not necessarily have the same effect on cephalosporin-based antibiotics. As an example in this case, mention may be made of pivaloyloxymethyl ester. That is, for example, the pivaloyloxymethyl ester of ampicillin is known to improve oral absorption of ampicillin. However, cefuroxime's pivaloyloxymethyl ester has little effect upon oral administration, since the ester is not absorbed from the gastrointestinal tract or, if absorbed, is hardly hydrolyzed by the esterase to produce an acid with antimicrobial activity. Because you can't.

The ester of cefuroxime of the present invention may be represented by the following general formula (I), and these sulfides have very useful properties as antibiotics for oral administration.

In the above formula,

R ¹ is a primary or secondary alkyl group of 1 to 4 carbon atoms,

R ² is a secondary or secondary alkyl group of 1 to 6 carbon atoms,

Provided that at least one of R ¹ and R ² is methyl and an asterisk represents an absent carbon atom.

Individual diastereomers and mixtures thereof are also included in the present invention.

Examples of the compound of formula (I) include a compound in which R ¹ is a methyl group, R ² is an alkyl group having 2 to 4 carbon atoms, and R ² is a methyl group and R ¹ is a primary or secondary alkyl group having 1 to 4 carbon atoms. Phosphorus compounds are included.

The ester of general formula (I) has a low antimicrobial activity in comparison with cepuroxime in vitro, which confirms the stability of the ester, indicating that most of the ester remains unchanged through in vitro testing. As it is, safety is excellent.

On the other hand, this ester is very easily hydrolyzed by esterases to produce cefuroxime, as evidenced by in vitro tests with esterases derived from rat livers, human livers and serum.

In vivo studies in rats show that the absorption of cepuroxime is markedly demonstrated by oral administration of the ester of formula (I), as evidenced by higher serum concentrations and increased urinary recovery than did oral administration of cepuroxime itself. It is confirmed to increase.

Among the compounds of general formula (I), the absorption of cefuroxime is excellent, especially in the following cases:

1-acetoxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -sep-3- M-4-carboxylate;

1-propionyloxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -sef-3 -M-4-carboxylates;

1-butyryloxymethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -sef-3 -M-4-carboxylates;

1-isovaleryloxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -sefe- 3-m-4-carboxylate;

1-acetoxybutyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -sef-3- M-4-carboxylate;

1-acetoxybutyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -sep-3- M-4-carboxylate; And

1-acetoxypropyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -cep-3- M-4-carboxylate.

The first compound described above is particularly preferred because it exhibits particularly high sepuroxime uptake as seen in vivo tests for mice, mice and dogs.

The compound of formula (I) of the present invention reacts cefuroxime or a salt thereof (e.g., an alkali metal salt such as sodium or potassium salt or an onium salt such as ammonium salt such as quaternary ammonium salt) with haloester of formula (II) Can be prepared.

In the above formula

R ¹ , R ² and asterisk have the same definitions as described above,

X is a halogen such as chlorine, bromine or iodine.

This reaction is conveniently carried out with an inert organic solvent (e.g., N, N-dimethylformamide or N, N-disubstituted amides such as N, dimethylacetamide, ketones such as acetone, sulfoxides such as dimethylsulfoxide, Nitrile such as acetonitrile, or hexamethylphosphoric triamide) in a solution in the range of -50 ° to + 150 ° C, for example -10 ° to + 50 ° C, conveniently 0 ° C to room temperature. When reacting in a nitrile solvent using cefuroxime salts, for example potassium salt as starting material, if necessary, crown ethers such as 18-crown-6

The use of a compound of formula (II), wherein X is bromine or iodine, with potassium carbonate as a base, has been found to be advantageous, under these conditions, to minimize the production of cefe-2-M ester product. The cefuroxime and the base are convenient to use in approximately equal amounts, for example, about 0.5 mole of a diacid group such as potassium carbonate is used per mole of cefuroxime. Haloester (II) is conveniently used in slightly excess amounts, for example 1 to 1.5 moles per mole of cefuroxime.

This process involves the conversion of the polar acid or salt starting material to the neutral ester product, so that the progress of the reaction can be easily monitored by t.c.c.

The ester of general formula (I) may also contain a compound of general formula (III) or an acid addition salt or N-silyl derivative thereof (Z) -2 (fur-2-yl) -2-methoxyiminoacetic acid or Derivatives can be prepared, for example, by acylating by the method described in the above mentioned British Patent No. 153049.

In the above formula,

R ¹ and R ² have the same definition as described above.

The compound of formula (I) may be conveniently prepared by acylating the compound of formula (III) with an acylating agent, including acid halides, especially acid chlorides or bromide. Such acylation can be carried out at temperatures of -50 to + 50 ° C, preferably -20 to + 30 ° C, and can be carried out in an aqueous or non-aqueous medium.

Acylation with acid halides may include acid-binding agents (e.g., tertiary amines such as triethylamine or dimethylaniline, inorganic bases such as calcium carbonate or sodium bicarbonate), which serve to remove the hydrogen halides produced in the acylation reaction; Or oxirane, preferably lower-1,2-alkyleneoxide, such as ethylene oxide or propylene oxide).

The free acid itself can also be used as the acylating agent. In this case, acylation may include carbonyl compounds such as carbodiimide such as N, N'-dicyclohexylcarbodiimide, and carbonyldiimidazole; It is preferably carried out in the presence of an isoxazolinium salt such as N-ethyl-5-phenylisoxazolinium-3 'sulfonate or n-t-butyl-5-methylisoxazolinium perchlorate. The condensation reaction is preferably carried out in anhydrous reaction medium such as methylene-chloride, dimethylformamide or acetonitrile.

Acylation may also be carried out using other amide-forming derivatives of the free acid, such as, for example, symmetric anhydrides or mixed anhydrides with pivalic acid, or may be formed with haloformates such as lower alkyl haloformates. have. Mixed or symmetric anhydrides may be produced directly. For example, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline can be used to produce mixed anhydrides, which can also be used as phosphoric acids (phosphoric or phosphorous), sulfuric acid or aliphatic or It may also be produced using aromatic sulfonic acids such as p-toluenesulfonic acid.

The starting materials of general formula (III) described above can be prepared by conventional methods, for example using the methods described in US Pat. Nos. 3,905,963 and 1,041,985 and 1,350,772.

If the desired ester product is severely contaminated with the corresponding Cef-2-M isomer, the product is oxidized (eg, treated with metaperiodic acid, peracetic acid, monoper-phthalic acid or m-chloroperbenzoic acid, Treatment with t-butylhypo-chlorite in the presence of a weak base such as pyridine) yields cef-3-em-1-oxide esters, which are then reduced (e.g., with acetyl chloride and potassium iodide) to almost pure ceph-3- Emesters can be obtained.

Individual diastereomers can be separated by recrystallization of the isomeric mixture.

Esters of formula (I) may be formulated into compositions for oral administration by conventional methods, together with the required pharmaceutical carriers or excipients. The composition is conveniently prepared in tablets, capsules or sachets, advantageously in unit dosage form, and may contain conventional excipients such as binders, fillers, suspending agents, disintegrating agents and wetting agents. Peeling can be carried out in conventional manner for tablets. The active compounds may also be formulated in rectal compositions such as suppositories or retention enemas.

The composition may contain at least 0.1% of active ingredient (I), depending on the method of administration, for example 0.1 to 99%, conveniently 10 to 60%. Dosage unit compositions conveniently contain 50 to 500 mg of the active ingredient, calculated on the basis of septum. The dose used in the treatment of an adult patient, of course, the exact dose depends on the frequency of administration, but is typically in the range of 500 to 5000 mg per day, calculated for example by septums, for example 1500 mg per day.

The following examples illustrate the invention in detail. All temperatures are 0 degreeC. Melting point is measured by capillary method and not corrected.

는 여기에서, x는 가열율(1분당 ℃로 표시)이며, y는 주입온도이다〕 메틀러(Mettler) 장치로 측정한 것이다. 실시예 5에서, 사용된 탄산칼륨은 진공중 120°에서 건조하여 미세하게 분쇄한 것이다. 사용된 N, N-디메틸포름아미드는 건조하여 산성 알루미나를 통과시켜 정제한 것이다.

Where x is the heating rate (expressed in degrees Celsius per minute) and y is the injection temperature] measured by a Mettler apparatus. In Example 5, the potassium carbonate used was finely ground by drying at 120 ° in vacuum. N, N-dimethylformamide used was dried and purified by passing through acidic alumina.

HPLC refers to "high pressure liquid chromatography". Detection is performed with ultraviolet light at 276 nm. The state peak area is measured at this wavelength (λ max of the target compound appears at 276 to 277 nm).

N.m.r. for the product of Examples 1-7. The spectral results are described in Table 1 below, indicating that the compound is obtained in about a 1: 1 mixture of R and S isomers.

Preparation Example 1

(R, S) 1-bromoethyl propionate

To propionyl bromide (3.18 g, 23.2 mmol) acetaldehyde (1.7 ml, 1.34 g, 30.5 mmol) is added dropwise with stirring (0-5 ° C.). The mixture is warmed to room temperature (about 20 ° C.) over 1 hour. The product was distilled off to give the title ester (2.7 g), which was a liquid with a boiling point of 41 to 500/15 mm, which showed characteristic nmr (CDCl ₃ ) and infrared (CHBr ₃ ) spectra.

Production Example 2

(R, S) 1-bromoethyl n-butyrate

To n-butyryl bromide (2.09 g, 13.8 mmol) is added dropwise acetaldehyde (2 ml) with stirring at 0-10 ° C. After the initial reaction, the mixture is stored at about 4 ° for 2 days. The product was distilled to yield the title ester (1.87 g), which was a liquid having a boiling point of 63 to 65 ° C./14 mm, which showed characteristic nmr (CDCl ₃ ) and infrared (CHBr ₃ ) spectra.

Preparation Example 3

(R, S) 1-bromoethyl 3-methylbutyrate

To 3-methylbutyryl bromide (5.33 g, 32 mmol) is added dropwise acetaldehyde (2.3 ml, 1.8 g, 41 mmol) with stirring at 0 ° C. The mixture is warmed to room temperature (about 20 ° C.) over 30 minutes.

The title ester is separated by distillation into two fractions (2.99 g and 1.64 g) having boiling points of 60 to 70 ° C./25 mm and 70 to 75 ° / 25 mm, respectively. Both fractions show characteristic nmr (CDCl ₃ ) spectra. nmr shows that the second fraction is purer.

Production Example 4

(R, S) 1-Bromo-n-butyl acetate

To chilled (about 0 ° C.) acetyl bromide (1.49 ml, 20 mmol) n-butyraldehyde (1.76 ml, 20 mmol) is added. The reaction mixture is warmed to room temperature over 1 hour to give a light brown solution. Distillation in vacuo affords two fractions:

(Iii) boiling point 60 to 70 ° C./27 mm (0.78 g)

(Ii) boiling point 70 to 80 ° C./27 mm (1.64 g)

Fraction (ii) contains the title ester, which shows characteristic nmr (CDCl ₃ ) and infrared (CHBr ₃ ) spectra.

Production Example 5

(R, S) 1-bromopropyl acetate

Acetyl bromide (1.5 ml, 20 mmol) and propionaldehyde (2.2 ml, 31 mmol) are used and the mixture is prepared in a similar manner as in Preparation Example 4, except that the mixture is reacted at about 5 ° overnight.

The title ester (1.56 g) is separated into a liquid having a boiling point of 50 to 60 ° C./20 mm showing a characteristic nmr (CDCl ₃ ) spectrum.

Example 1

(R and S) -1-acetoxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido Chef-3-M-4-carboxylate

Potassium carbonate (760 mg, 5.5 mmol) was added to (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl)-in N, N-dimethylformamide (25 ml). 2-methoxyimino acetamido] sef-3-m-4-carboxylic acid (4.57 g, 11 mmol) was added and the mixture was stirred at about 20 ° C. for 25 minutes. To the reaction is added 1-bromo-ethylacetate (1.8 g, 11 mmol) in N, N-dimethylformamide (5 ml) and the reaction mixture is stirred at about 20 ° C. for 40 minutes. The reaction mixture is poured into excess 2N hydrochloric acid and treated and extracted three times with ethyl acetate. 2N combined organic extract

The resulting precipitate is filtered off and dried to give the title compound (780 mg).

The mother liquor is evaporated to give a foamy material which is dissolved in ethyl acetate and precipitated with di-isopropylether to give an additional amount of the title compound (1.21 g). This sample is dried for 2 days at 22 ° under vacuum to remove di-isopropyl ether. The physical constants of the secondary obtained of the title compound are as follows.

70°;Melting point

70 °;

[Α] _D 84 ° (C 0.87, DMSO)

355, ε18,120) ;λ max (EtOH) 277 nm (

355, epsilon 18,120;

Trace analysis before drying in vacuo

C ₂₀ H ₂₂ N ₄ O ₁₀ S (510.5)

Found: C46.6; H4.4; N10.95; S6.2%

Theoretic value: C47.1; H4.3; N10.9; S6.3%

Infrared spectra and nmr spectra are as described in Table 1 below.

Example 2

(R and S) -1-propionyloxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxy-iminoacet Amido] chef-3-m-4-carboxylate.

The preparation method was similar to that described in Example 1, in which 1-bromoethylpropionate (1.5 g, 8.3 mmol) was added to potassium (6R, 7R) -3- in N, N-dimethylformamide (25 ml). Carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] sep-3-m-4-carboxylate (3.8 g, 8.3 mmol) The reaction is carried out at about 22 ° for 30 minutes.

The reaction mixture is treated as described in Example 1 to give an oily material which is dissolved in ethyl acetate and precipitated with ether (250 ml). The filtrate is evaporated to give an oily substance which is dissolved in ethyl acetate and added dropwise to di-isopropyl ether. The precipitate is filtered off, washed with di-isopropyl ether and dried to afford the title compound (1.46 g, 2.8 mmol).

81°;Melting point

81 °;

[Α] _D + 66 ° (C 1.2, DMSO);

362, ε18,985)λ max (E ± OH) 276.5 nm (

362, ε18,985)

Infrared and nmr spectral data are as described in Table 1 below.

Example 3

(R and S) -1-Butylyloxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -3-methoxy-iminoacet Amido] chef-3-m-4-carboxylate.

Potassium (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2-fur-2-yl) -2-methoxyiminoacetamido in N, N-dimethylformamide (12 ml) A solution of cef-3-m-4-carboxylate (1.025 g, 2.22 mmol) was dissolved in 1-bromoethylbutyrate (649 mg, 3,33 mmol in N, N-dimethylformamide (2 ml) for 30 minutes at room temperature. ).

The reaction mixture is then treated as described in Example 1 to give a pale yellow foamy material (964 mg) after drying (on magnesium sulfate) and evaporating. The foamed material was triturated with cyclohexane (80 ml) and the resulting solid was filtered, washed with cyclohexane (2 x 20 ml) and dried in vacuo to yield the title compound (711 mg) as an off-white solid:

84°;Melting point

84 °;

[Α] _D + 36 ° (C 1.13, DMSO);

350, ε18,850);λ max (E ± OH) 276.5 nm (

350, epsilon 18,850;

Elemental analysis: C ₂₂ H ₂₆ N ₄ O ₁₀ S (538.5)

Found: C 48.8; H 5.0; N 10.1; S 5.5%

This theory: C 49.1; H 4.9; N 10.4; S 5.95%

Infrared and nmr spectral data are as described in Table 1 below.

Example 4 (a)

(R and S) -1-Isovaleryloxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacet Amido] sef-3-m-4-carboxylate and (R and S) -1-isovaleryloxyethyl (4R, 6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2 -(Fur-2-yl) -2-methoxyiminoacetamido] sef-2-m-4-carboxylate.

1-Bromoethyl-3-methylbutyrate (2.38 g, 11.4 mmol) was added potassium (6R, 7R) -3-carbamoyloxymethyl- in N, N-dimethylformamide (50 ml) for 35 minutes at about 22 °. To a stirred solution of 7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -cep-3-m-4-carboxylate (4.2 g, 9.1 mmol) Add.

The reaction mixture is then treated in a similar manner to that described in Example 1 and the product (2.15 g) is precipitated with di-isopropylether. nmr spectrum (DMSO-d ₆ ) shows that the product is about 1: 1 mixture of the two title compounds.

(b) (R and S) -7-Isovaleryloxyethyl (1S, 6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2- Methoxyiminoacetamido] -cep-3-m-4-carboxylate-1-oxide.

A solution of a mixture (2.0 g) of the ester produced in Example 4 (a) in dichloromethane (50 ml) is treated with m-chloroperbenzoic acid (1.0 g, 5.7 mmol) at about 22 ° for 40 minutes.

The solvent is evaporated in vacuo and the residue is triturated with ether to give the title compound (1.8 g) which is a solid:

167.5°;Melting point

167.5 °;

[Α] _D + 52 ° (C 0.5, DMSO);

Elemental analysis: C ₂₃ H ₂₈ N ₄ O ₁₁ S (568.5)

Found: C 47.1; H 4.7; N 10.05; S 5.8%

This theory: C 48.6; H 4.95; N 9.85; S 5.65%

(C) (R and S) -1-Isovaleryloxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxy Iminoacetamido] chef-3-m-4-carboxylate.

(R and S) -1-Isovaleryloxyethyl (1S, 6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (pur) in N, N-dimethylformamide (50 ml) -2-yl) -2-methoxyiminoacetamido] -sep-3-m-4-carboxylate-1-oxide (1.67 g, 2.9 mmol) potassium iodide (1.95 g, 11.7 mmol) in a solution And acetyl chloride (460 mg, 5.9 mmol) was added continuously.

The solution is stirred at about 22 ° for 35 minutes and then added dropwise to aqueous sodium metabisulfite solution. The precipitate was filtered off, washed with water and dried over phosphorus pentoxide in vacuo to yield the title compound (1.19 g, 2.1 mmol) as a solid:

92°;Melting point

92 °;

[Α] _D + 24 ° (C 1.9, DMSO);

360, ε19,890);λ max (E ± OH) 276 nm

360, epsilon 19,890;

Elemental analysis: C ₂₃ H ₂₃ N ₄ O ₁₀ S (552.5)

Found: C 48.1; H 4.95; N 10.35; S 6.0%

This launch: C 49.9; H 5.1; N 10.1; S 5.8%

Infrared and nmr spectral data are as described in Table 1 below.

Example 5

(R and S) -1-acetoxybutyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxy-iminoacetami Fig. 3] Ce-3-M-4-carboxylate.

Potassium (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -cep-3-m-4- Carboxylate (1.850 g, 4 mmol) is added to a solution of 1-bromobutyl acetate (780 mg, 4 mmol) in purified N, N-dimethylformamide (10 ml) to form a brown solution and release of heat.

After about 10 minutes, the solids begin to separate, and after 20 minutes the reaction mixture is poured into 2N hydrochloric acid (120 ml) to give a pale yellow solid which is dissolved by addition of ethyl acetate (120 ml).

The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution (120 ml) and brine (60 ml), dried over magnesium sulfate and evaporated to yield a pale yellow foamy substance (1.378 g). The foamed material was triturated with di-isopropyl ether (30 ml) to give a light solid, filtered, washed with an additional amount of di-isopropyl ether and dried in vacuo to give the title compound (1.261 g) as a creamy powder. .

Melting point: 59-68 °;

+54.5°(C 1.0, DMSO);

+ 54.5 ° (C 1.0, DMSO);

333, ε17,930);λ max (E ± OH) 277 nm

333, epsilon 17,930;

Elemental analysis: C ₂₂ H ₂₆ N ₄ O ₁₀ S (538.5)

Found: C 50.1; H 5.5; N 9.4; S 5.1%

This launch: C 49.05; H 4.85; N 10.4; S 5.95%

nmr and infrared spectral data are as described in Table 1 below.

Example 6

(R and S) -1-acetoxypropyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido Chef-3-m-4-carboxylate.

Potassium (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetami in N, N-dimethylformamide (50 ml) A solution of cef-3-em-4-carboxylate (3.7 g, 8 mmol) is stirred with 1-bromopropyl acetate (1.45 g, 8 mmol) at about 22 ° for 45 minutes. The crude product was treated in a similar manner to that described in Example 5 except for purification by precipitation from ethylacetate solution with di-isopropyl ether and drying in vacuo to afford the title compound (920 mg).

81°;Melting point

81 °;

[Α] _D + 69 ° (C 0.87, DMSO);

349, ε18,305);λ max (E ± OH) 277 nm

349, epsilon 18,305);

Elemental analysis: C ₂₁ H ₂₄ N ₄ O ₁₀ S (524.5)

Found: C 48.15; H 4.8; N 10.45; S 5.9%

This theory: C 48.1; H 4.6; N 10.7; S 6.1%

nmr and infrared spectral data are as described in Table 1 below.

Example 7

(R and S) -1-acetoxyheptyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxy-iminoacetami Fig. 3] Ce-3-M-4-carboxylate.

(6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido in N, N-dimethylformamide (7 ml) Potassium carbonate (0.21 g) is added to a solution of cef-3-em-4-carboxylic acid (1.27 g) with stirring at 23 °. Most potassium carbonate dissolves within 10 minutes to yield a black solution. 1-Bromoheptyl acetate (0.72 g) is added in solution in N, N-dimethylformamide (1.5 ml). Precipitation begins to form after 15 minutes and after 18 minutes the reaction mixture is poured into 2N hydrochloric acid (75 ml) to give a brown gummy material. It is dissolved by addition of ethyl acetate (75 ml). The organic layer is separated, washed successively with 2N hydrochloric acid (75 ml) and saturated sodium bicarbonate solution (75 ml), dried (MgSO ₄ ) and evaporated in vacuo to give a brown glassy substance (1.01 g). The material was triturated with petroleum ether (boiling point 40-60 °, 3 × 15 ml) to give a pale yellow solid, which was filtered off, washed with petroleum ether (40-60 °) and dried in vacuo to give a pale yellow powder (0.75 g). Obtain the compound:

Melting point: 68 to 71 ° (decomposition);

+46°(C 1.00, DMSO);

+ 46 ° (C 1.00, DMSO);

λ max (EtOH) 276.5 nm (ε 18,154).

nmr and infrared spectral data are as described in Table 1 below.

Example 8

1S-acetoxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -cep-3- M-4-carboxylate (isomer A).

(R and S) -1-acetoxyethyl- (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-meth in methanol (3 ml) Oxyiminoacetamido] -cep-3-m-4-carboxylate (about 1: 1; about 1 g) was cooled to 0 ° and left overnight to obtain crystalline precipitate of isomer A (300 mg) This is confirmed by nmr spectroscopy (DMSO-d ₆ ) to contain essentially one isomer.

The mother liquor is evaporated to dryness in vacuo and the residue is dissolved in ethyl acetate and precipitated with petroleum (40 to 60 °). nmr (DMSO-d ₆ ) indicates that the precipitation consists of a mixture of diastereomers B and A of about 65:35, respectively.

Example 9

1-acetoxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -sep-3- Separation of Diastereomers of M-4-carboxylates (Isomer A and Isomer B).

(R and S) -1-acetoxyethyl- (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2- in methanol (7.5 ml) A solution of methoxyiminoacetamido] -cep-3-m-4-carboxylate (about 1: 1; 5.0 g, 9.8 mmol) was prepared by isomer A (the method described in Example 8) at about 25 °. Inoculated with a sample). The solution is solidified and frozen overnight at 0 °. The solid obtained by filtration (1.7 g) was recrystallized from methanol (30 ml) to give essentially pure isomer A (1.28 g) (fraction 1).

Secondary crystals (110 mg, fraction 2) are obtained from the mother liquor. This shows that isomer A and isomer B are contained in a ratio of about 1: 1 by nmr (DMSO-d ₆ ).

The remaining mother liquor is evaporated to dryness in vacuo, and the remaining rubbery material is dissolved in ethyl acetate and frozen, and the solution is solidified. Ethyl acetate is added thereto to give a total capacity of about 15 ml, and the mixture is heated to reflux. A small amount of undissolved solid is filtered (fraction 3190 mg). It can be seen that Fraction 3 consists essentially of Isomer B by nmr spectroscopy (DMSO-d ₆ ).

Freeze the filtrate and slowly solidify. The resulting solid is filtered off and dried (fraction 4410 mg). Fraction 4 consists essentially of isomer B (about 80% purity) as can be seen by nmr spectroscopy (DMSO-d ₆ ) and HPLC.

The mother liquor from which fraction 4 is separated is evaporated to dryness, and the resulting solid is triturated with ethyl acetate-ether. The solid obtained is filtered off and dried (fraction 5640 mg). Fraction 5 consists of about 70:30 mixture of isomers B and A, as can be seen by nmr (DMSO-d ₆ ).

Fraction 1 (Isomer A) and Fraction 4 (Isomer B) have the following physical properties:

Isomer A (fraction 1):

191°;Melting Point:

191 °;

[Α] _D + 53 ° (C 0.9, DMSO);

414, ε21,130);λ max (EtOH) 277 nm (

414, epsilon 21,130;

Elemental analysis: C ₂₀ H ₂₂ N ₄ O ₁₀ S (510.5)

Found: C 46.95; H 4.4; N 10.9; S 6.5%

This theory: C 47.1; H 4.3; N 10.9; S 6.3%

HPLC confirms that the purity of the isomer is about 94%.

Isomer B (fraction 4):

129°;Melting point

129 °;

[Α] _D + 11 ° (C 1.2, DMSO);

422, ε22,700);λ max (EtOH) 277 nm (

422, epsilon 22,700;

Elemental analysis: C ₂₀ H ₂₂ N ₄ O ₁₀ S.0.3 mol EtOAc (539.9)

Found: C 46.8; H 4.5; N 10.35; S 5.9%

This launch: C 47.45; H 4.6; N 10.4; S 5.9%

HPLC confirmed that the purity of isomer B was about 80%.

The nmr and infrared spectral data for the two isomers are as described in Table 1 below.

TABLE 1

Physical Properties of the Products of Examples 1-7 and 9

Example A

refine

Furtherance :

1-acetoxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacet-amido] sep-3- M-4-carboxylate (atomized) 326.0 mg

Sodium Starch Glycolate (Primogel) 8.0mg

Microcrystalline cellulose (avicel pH101) 64.0 mg

Magnesium Stearate Total Weight 400.0mg

Manufacturing method

Magnesium stearate is mixed with the active ingredient and compressed directly to produce tablet slugs. The slugs are continuously milled through 12 mesh, 16 mesh and 20 mesh and the granules are mixed with sodium starch glycolate and microcrystalline cellulose. The mixture is tableted on a concave punch so that the tablet weight is 400 mg. Tablets may be film coated by an aqueous or organic solvent method using cellulose derivatives with plasticizers and colorants. Another method of preliminary slugization can be compacted by roller compaction of the active ingredient.

Example B

Powder for Oral Suspensions

Composition (per sachet):

1-acetoxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacet-amido] sep-3- M-4-carboxylate (crushed) 326.0 mg

Lecithin 25mg

Sodium Carboxymethyl Cellulose (Low Viscosity) 90mg

Spray Dried Orange Flavor 150mg

2.2 g per caster suger

Manufacturing method

Lecithin is dissolved in chloroform and ground with the active ingredient (pre-milled using a fluid energy grinder). Chloroform is evaporated and the residual solid is powdered. This is then thoroughly mixed with sodium carboxymethyl cellulose and the fragrance. This mixture is further mixed by adding Kasutter sugar in two steps. It is filled in a sachet of suitable thin layer foil with a suitable weight and heat sealed. The powder is prepared by using about 15 ml of water immediately before administration.

Claims (1)

(6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] sep-3-m-4-carboxylic acid ( That is, Cerroxime) or a salt thereof is reacted with a haloester of the following general formula (II), or a compound of the following general formula (III), or an acid addition salt thereof or an N-silyl derivative thereof is (Z) -2- (fur- A 2-yl) -2-methoxyimino-acetic acid or a reactive derivative thereof, characterized by acylation, to prepare a compound of formula (I)

Wherein, R ¹ is primary or secondary alkyl group having 1 to 4, R ² is a primary or secondary alkyl group having 1 to 6 carbon atoms, with the proviso that, R ¹ and R at least one of the ^two is methyl, X Is halogen.