KR970001164B1 - Cephalosporin antibiotics and preparation method thereof - Google Patents

Abstract

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Description

Cephalosporin antibiotics and preparation method thereof

The present invention relates to a cephalosporin compound and a preparation method thereof. More specifically, it shows a wide range of antimicrobial activity, in particular, the cephalosporin compound represented by the following general formula (I) useful as an antibiotic, showing excellent activity against Gram-negative bacteria, including Pseudomonas strain and Enterobacter cloake P99, and a preparation method thereof It is about.

In general formula (I), Q is nitrogen or CH, and P is N-methyl-bis (2-hydroxy) as acyclic amine or heterocyclic amine having one nitrogen and one or two hydroxyl groups at the same time. Ethyl) amine, racemic-3,4-trans-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, (2R, 4R) -3,4-trans-dihydroxy-1-methylpyrrolidine, meso-3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy-1-methyl -2-pyrrolidinemethanol, 3,4-cis-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy-1-methylpiperidine, or tropin.

Belgian patent No. 876,538 describes ceftazidime represented by the following structural formula (A) after the introduction of a methyl group containing a quaternary ammonium salt at the 3-position of cephalosporin, ie a pyridiniomethyl group. Compounds of this family are characterized by high antibacterial activity and very stable to beta lactamase. In light of the development of this compound, attempts have been made to develop antibiotics with improved antimicrobial activity, represented by the following formula (B): cepirome (Cefpirome, Drug Future 13, 369-371, 1988) and formula (C) Compounds such as cefepime (German Patent No. 3,307,550) have been developed.

On the other hand, according to the Republic of Korea Patent Publication No. 87-1986 (application date: October 24, 1987), similar to having a dihydroxy group in the 3-position of the present invention, this document has a 1-methyl in 3-position Although cephalosporin compounds containing pyrrolidioniomethyl groups and several substituents at the 7-position have been introduced, the present invention exhibits a significant antimicrobial activity as described below in the antimicrobial activity.

The present inventors have been studying to develop cephalosporin antibiotics having excellent antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria, and have an ammoniomethyl group substituted with a hydroxyl group at the 3 position and an aminothiazole group at the 7-β position. And cephalosporin compounds having aminothiadiazole groups exhibit not only a wide range of antibacterial effects, but also excellent antimicrobial activity against Gram-negative bacteria, including Pseudomonas strains and Enterobacter cloak P99.

Hereinafter, the present invention will be described.

The cephalosporin compound of the general formula (I) of the present invention is 7-amino-3- (iodomethyl) -3-cepem-4-carboxylic acid represented by the general formula (II) (hereinafter iodomethyl Tere amine represented by the following general formula (III) and 2- (2-aminothiazol-4yl)-(Z) -2-methoxyiminoacetic acid benzo represented by the following general formula (III) Thiazolyl-2-thio ester (Q = CH, hereinafter referred to as aminothiazole), or 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxy It can be prepared by substitution and condensation reaction with minoacetic acid benzothiazolyl-2-thio ester (Q = N, hereinafter referred to as aminothiazole).

In the general formulas (III) and (IV), P and Q are the same as P and Q in the general formula (I).

Hereinafter, the present invention will be described in more detail.

The iodomethyl cefem of the general formula (II), which is a starting material of the present invention, is a known compound and is prepared according to the following reaction formula (Japanese Patent No. 126,492, 1982). That is, it can be manufactured easily by reacting 7-ACA of general formula (V) with trifluoromethanesulfonic acid and sodium iodide.

P in the compound of formula (III) used in the present invention is racemic-3,4-trans-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy-1 -Methylpyrrolidine, (3R, 4R) -3,4-dihydroxy-1-methylpyrrolidine, meso-3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R)- The compound which is 4-hydroxy-1-methyl-2-pyrrolidinemethanol is a novel substance, and its preparation method is described in detail in the following preparation example.

The cephalosporin compound of formula (I) is mixed with iodomethyl cefem of formula (II) and 1-10 equivalents of a tertiary amine derivative represented by formula (III) using a polar organic solvent, After reacting at 25 ^° C. for 1 to 12 hours, preferably 1 to 2 hours, and then separating the resulting intermediate, 1-3 equivalents, preferably 1.2 equivalents of amino of general formula (IV) After reacting with thiazole or aminothiadiazole for 2 to 12 hours, the reaction product is separated and purified using silica gel column chromatography, followed by freeze-drying. At this time, it is preferable to use N, N-dimethylformamide (DMF) as the polar organic solvent.

Meanwhile, the cephalosporin compounds prepared in the present invention show high antibacterial activity against a wide range of strains including Gram-positive bacteria and Gram-negative bacteria. The usefulness was evaluated by investigating the minimum inhibitory concentration (MIC) using ceftazidime, a known compound, as a comparative substance. The minimum inhibitory concentration was investigated by the agar dilution method in Mueller-Hinton Agar. The strains of 5 × 10 ⁴ cfu were incubated at 37 ° C for 24 hours, and the results are shown in Tables 1 and 2. Indicated.

More specifically, in Korean Patent Publication No. 87-1986 (filed date: October 24, 1987), there is a 1-methylpyrrolidiomethyl group in 3-position and several substituents in 7-position. Although not directly comparable, according to Table 3 of the patent publication, these compounds exhibit MIC values of 32 µg or more against Enterobacter cloacae bacteria (9th strain) resistant to cephatadimide. However, the compounds of the present invention have a MIC value of 1.56 to 6.25 µg, unlike the above patent publications, which indicates that the present invention has an antimicrobial activity of 5 to 20 times superior to the above patent publications (Table 1 and Table of the Invention). 2, paragraph 19). Meanwhile, in relation to S. aureus, Table 4 of the patent publication shows a MIC value of 14-33 μg (Ceftazidim: 12 μg), whereas the compounds of the present invention exhibit a MIC value of 1.563 to 12.5 μg. It can be seen that the invention has an antimicrobial activity of 1.12 to 21 times superior to the patent publication (see paragraphs 4-6 of Table 1 and Table 2 of the present invention). In summary, in the Enterobacter cloacae and S. aureus bacteria, the present invention containing the dihydroxy group of the present invention is 2.5 to 21 times higher than the patent publication containing 1-methylpyrrolidiniomethyl group. Because it shows an excellent antibacterial activity of antimicrobial activity or can be said to be excellent.

Compound of the Invention

I-a:

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [N-methyl-N, N-bis (2-hydroxyethyl ) Aminoo] methyl-3-cepem-4-carboxylate

I-b:

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-dihydroxy-1-methylpyrroli Dinio) methyl-3-cepem-4-carboxylate

I-c:

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(3S, 4S) -3,4-dihydroxy-1 -Methylpyrrolidinio] -methyl-3-cepem-4-carboxylate

I-d:

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(3R, 4R) -3,4-dihydroxy-1 -Methylpyrrolidinio] methyl-3-cepem-4-carboxylate

I-e:

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(meso-3,4-dihydroxy-1-methylpi Lolidinio) methyl-3-cepem-4-carboxylate

I-f:

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(4R) -hydroxy- (2R) -hydroxymethyl- 1-methylpyrrolidinio] methyl-3-cepem-4-carboxylate

I-g:

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(3,4-trans-dihydroxy-1-methylpipepe Lidinio) methyl-3-cepem-4-carboxylate

I-h:

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3,4-cis-dihydroxy-1-methylpyreridi Nio) methyl-3-cepem-4-carboxylate

I-i:

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-trophinimethyl-3-cepem-4-carboxylate

I-j:

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [N-methyl-N, N -Bis (2-hydroxyethyl) amminio] methyl-3-cepem-4-carboxylate

I-k:

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-di Hydroxy-1-methylpyrrolidinio) methyl-3-cepem-4-carboxylate

I-l:

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-[(3S, 4S) -3 , 4-dihydroxy-1-methylpyrrolidinio] methyl-3-cepem-4-carboxylate

I-m:

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-[(3R, 4R) -3 , 4-Dihyl-1-methylpyrrolidinio] methyl-3-cepem-4-carboxylate

I-n:

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [mezo-3,4-di Hydroxy-1-methylpyrrolidinio) methyl-3-cepem-4-carboxylate

I-o:

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-[(4R) -hydroxy- (2S) -hydroxymethyl-1-methylpyrrolidinio] methyl-3-cepem-4-carboxylate

I-p:

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-di Hydroxy-1-methylpiperidinio) methyl-3-cepem-4-carboxylate

I-q:

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3,4-cis-di Hydroxy-1-methylpiperidinio) methyl-3-cepem-4-carboxylate

I-r:

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-trophinimethyl-3-cepem- 4-carboxylate

Control Compound:

As can be seen from Table 1 and Table 2, the cephalosporin compounds of the present invention all exhibit a broad and excellent antimicrobial activity. In particular, the minimum inhibitory concentration of cytotagemide, a control agent widely known as a broad-spectrum antibiotic, against Enterobacter cloacae P99, a strain resistant to cephalosporin antibiotics, is at least 100 µg / ml. The compounds exhibited a minimum inhibitory concentration of 1.563∼6.25µg / ml, which showed 16 times more antibacterial activity than ceftazidime, and also showed excellent antibacterial activity against other standard strains including Pseudomonas aeruginosa (Pseudomonas). This suggests that the compounds of the present invention are more extensive and useful than ceftazidime used as a control agent. In addition, Ij-Is cephalosporin compounds substituted with aminothiazole derivatives (IV) in which the C-7 position is Q = N are Pseudomonas aeruginosa, a strain that is resistant to cephalosporin antibiotics as compared to the control drug ceftazidime. The antimicrobial activity against is almost equal or about twice as good.

The following examples will illustrate the invention in more detail and refer to the method for the preparation of acyclic amine or heterocyclic amine derivatives of general formula (III).

Production Example

Preparation Example 1

Synthesis of (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol

To a solution in which trans-4-hydroxy-L-proline (2.5 g, 19 mmol) was suspended in tetrahydrofuran (25 ml), BF ₃ Et ₂ O (2.35 ml, 19 mmol) was added dropwise at 15-25 ^° C. . While the mixture was refluxed, borane dimethyl sulfide (18 ml, 190 mmol) was added for 10 minutes and then refluxed for 24 hours. The reaction mixture was cooled to 0 ^° C., methanol (20 ml) was added slowly, and the reaction solution was concentrated to add 6N sodium hydroxide solution (20 ml) to the residue, which was refluxed for 4 hours. The reaction solution was cooled to 15-25 ^° C., the insoluble material was filtered off, and the filtrate was evaporated. Ethanol (50 ml) was added to the resulting residue, followed by vigorous stirring for 30 minutes, followed by filtration to remove insoluble matters. The filtrate was concentrated, isopropanol (100 ml) was added and the insoluble material was again filtered off. The filtrate was concentrated and 35% formaldehyde solution (5 ml) and formic acid (15 ml) were added and refluxed for 16 hours. After the reaction mixture was concentrated, methanol (20 ml) and anhydrous sodium carbonate (5 g) were added thereto, and the mixture was stirred at 15-25 ° C. for 1 hour. The reaction mixture was filtered and methylene chloride (20 ml) was added to the residue obtained by concentrating the filtrate, and the insoluble material was again filtered off. The filtrate was concentrated and then vacuum distilled (200-220 ° C./1 mmHg) to obtain the title compound (950 mg, 30%).

¹ H NMR (CDCl ₃ ) δ: 5.14 (2H, br s), 4.25 (1H, m), 3.55 (1H, dd, J = 11.6Hz, 3.9Hz), 3.41 (1H, dd, J = 11.6Hz , 3.9 Hz), 3.28 (1H, m), 2.75 (1H, m), 2.37 (3H, s), 2. 30 (1H, m), 1.72-1.99 (2H, m).

[α] =-34 ^o (c 0.1, MeOH)

Preparation Example 2

Synthesis of 3,4-trans-dihydroxy-1-methylpyrrolidine (racemic mixture)

0 ^° C. in a solution of racemic-3,4-trans-diacetoxy-1-methylpyrrolidine (1.5 g, 6.54 mmol) suspended in LiAlH4 (1.24 g, 32.72 mmol) in tetrahydrofuran (60 ml). It was added slowly at the temperature of. The reaction mixture was refluxed for 24 hours, then cooled to 0 ^° C. and ethyl acetate (2 ml), ethanol (15 ml) and water (10 ml) were added in turn with vigorous stirring. The reaction was stirred at 15-25 ^° C. for 30 minutes, then filtered and washed with chloroform-ethanol (1: 1) mixed solution (20 ml × 3). The combined filtrates were concentrated and then vacuum distilled (1 mmHg) to obtain the title compound (427 mg, 57%) as a white solid by recrystallization from chloroform and ethyl acetate.

mp: 93-95 ^o C

¹ H NMR (CDCl ₃ ) δ: 4.79 (2H, br s), 4.10 (2H, m), 2.94 (2H, dd, J = 10Hz, 6Hz), 2.47 (2H, dd, J = 10Hz, 4Hz), 2.32 (3H, s)

Preparation Example 3

Synthesis of (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine

The title compound was obtained in the same manner as in the Preparation Example 2 using (3R, 4R) -3,4-diacetoxy-1-methylpyrrolidine.

mp: 93-95 ^o C

[α] = + 28 ^o (c 0.05, MeOH)

Preparation Example 4

Synthesis of (3S, 4R) -3,4-dihydroxy-1-methylpyrrolidine

(3S, 4S) -3,4-Diacetoxy-1-methylpyrrolidine was used to obtain the title compound in the same manner as in Preparation Example 2.

mp: 93-95 ^o C

[a] = -28 (c 0.6, MeOH)

Preparation Example 5

Synthesis of 1-benzyloxycarbonyl-3-pyrroline

3-pyrroline (2g, 65%, 18,8 mmol) and anhydrous sodium carbonate (15.33g, 144.6 mmol) in methylene chloride (30ml) was added benzyl chloroformate was suspended and cooled to 0 ^o C to the formate (7.4g, 43.4 mmol) was added slowly. After stirring for 20 minutes, the reaction temperature was raised to 20 ^o C and stirred for 2 hours. The reaction solution was washed with cooling water (30 ml) and saturated brine (20 ml) in that order, and dried over anhydrous magnesium sulfate and evaporated to give a residue obtained by silica gel column chromatography to obtain the title compound (3 g, 78%).

Preparation Example 6

Synthesis of Meso-1-benzyloxycarbonyl-3,4-dihydroxypyrrolidine

A solution of N-methylmorpholine monohydrate (479 mg, 3.54 mmol) in distilled water (15 ml) and acetone (7 ml) was added to a solution of osmium tetraoxide and the compound synthesized in Preparation Example 3 (600 mg, 2.95 mmol) and stirred overnight. It was. Sodium hydrosulfide (0.1 g) and florisil (2 g) were added to the reaction mixture and stirred for 30 minutes. The reaction solution was filtered and the filtrate washed with acetone (10ml × 2) was concentrated to remove acetone. The resulting aqueous solution was saturated with salt, extracted with chloroform (10 ml × 4), dried over anhydrous magnesium sulfate and evaporated to obtain a residue obtained by silica gel column chromatography to obtain the title compound (586 mg, 83.7%).

¹ H NMR (CDCl ₃ ) δ: 7.36 (5H, s), 5.13 (2H, s), 4.25 (2H, m), 3.65 (2H, dd, J = 11Hz, 5Hz), 3.44 (2H, dd, J = 11 Hz, 3 Hz)

Preparation Example 7

Synthesis of Meso-3,4-dihydroxy-1-methylpyrrolidine

Compound (270 mg, 1.14 mmol) synthesized in Preparation Example 4 was dissolved in 95% ethanol solution, 10% Pd / C (27 mg) was added, and stirred under hydrogen atmosphere (1 atm) for 6 hours. The reaction solution was filtered and concentrated to give a product obtained by adding 35% formaldehyde solution (4.5 ml) and formic acid (5.5 ml) and refluxing for 24 hours. The reaction mixture was concentrated and methanol (20 ml) and anhydrous potassium carbonate (2 g) were added and stirred for 1 hour. Chloroform (10 ml) was added to the residue obtained by filtration and concentration. The insoluble substance was filtered off and the filtrate was concentrated to give the title compound (107 mg, 82%).

¹ H NMR (CDCl ₃ ) δ: 4.17 (2H, m), 2.67 (4H, m), 2.30 (3H, m).

Preparation Example 8

Synthesis of 1-benzeneoxycarbonyl-1,2,3,6-tetrahydropyridine

1,2,3,6-tetrahydropyridine (1.5 g, 18 mmol) was carried out in the same manner as in Production Example 3 to obtain the title compound (1.85 g, 47%).

¹ H NMR (CDCl ₃ ) δ: 7.33 (5H, s), 5.17 (2H, m), 5.17 (2H, m), 3.97 (2H, m), 3. 53 (2H, t, J = 6 Hz), 2.10 (2H, m).

Preparation Example 9

Synthesis of 1-benzeneoxycarbonyl-3,4-cis-dihydroxypiperidine

Compound (400 mg, 1,84 mmol) synthesized in Preparation Example 6 was subjected to the same procedure as in Preparation Example 4 to obtain the title compound (412 mg, 89%) (racemic mixture).

¹ H NMR (CDCl ₃ ) δ: 7.30 (5H, s), 5.10 (2H, s), 3.41-4.10 (6H, m), 1.68 (2H, m)

Preparation Example 10

Synthesis of 3,4-cis-dihydroxy-1-methylpiperidine

The compound (500 mg, 1,84 mmol) synthesized in Preparation Example 7 was subjected to the same method as in Preparation Example 5, to obtain the title compound (109 mg, 47%) (racemic mixture).

¹ H NMR (CDCl ₃ ) δ: 3.70 (2H, m), 2.23 to 2.57 (4H, m), 2.02 (3H, s), 1.63 (2 H, m)

Preparation Example 11

Synthesis of 1-benzyloxycarbonyl-3,4-trans-dihydroxypyridine

35% hydrogen peroxide solution (2 ml) was added dropwise to formic acid (5 ml) at 0 ^° C. and stirred for 10 minutes. To the above solution was added the compound synthesized in Preparation Example 6 (600mg, 2.76mmol) and the temperature was raised to 25 ℃ and stirred for 24 hours. The reaction mixture was concentrated and stirred for 2 minutes with 2N aqueous sodium hydroxide solution (10ml), and then extracted with chloroform (10ml × 2). The chloroform solution was evaporated to dryness with anhydrous magnesium sulfate and purified by silica gel column chromatography to obtain the title compound (403 mg, 58%) (racemic mixture).

Preparation Example 12

Synthesis of trans-3,4-dihydroxy-1-methylpiperidine

The compound synthesized in Preparation Example 9 (403 mg, 1.60 mmol) was obtained in the same manner as in Preparation Example 5, to obtain the title compound (174 mg, 83%) (racemic mixture).

¹ H NMR (CDCl ₃ ) δ: 3.2 to 3.5 (2H, m), 2.7 to 3.1 (4H, m), 2.2 (3H, s), 1.8 to 2.1 (2H, m).

Example 1

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [N-methyl-N, N-bis (2-hydroxyethyl ) Aminoo] Methyl-3-cepem-4-carboxylate (Ia) Preparation

Iodomethylcefem (II, 100mg, 0.29mmol) and N-methyldiethanolamine (104mg, 0.87mmol) were added to N, N-dimethylformamide (4ml) and stirred at 20-25 ^° C for 3 hours. . Aminothiazole (IV, Ⅹ = CH, 120 mg, 0.34 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was purified by silica gel column chromatography (CH ₃ CN / H ₂ O = 5: 1) to afford the title compound (22 mg, 14.7%).

¹ H NMR (D ₂ O) δ: 7.07 (1H, s), 5.92 (1H, d, J = 4.9Hz), 5.41 (1H, d, J = 4.9Hz), 4.23,4.93 (ABq, J = 13.8 Hz), 4.04 (3H, s), 3.19 (3H, s), IR (KBr): 3358, 1769,16 14, 1537cm ^-1

Example 2

7-[(Z) -2-95-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [N-methyl-N, N- Preparation of Bis (2-hydroxyethyl) amminio] methyl-3-cepem-4-carboxylate (Ij)

Iodomethylcefem (II, 100mg, 0.29mmol) and N-methyldiethanolamine (104mg, 0.87mmol) were added to N, N-dimethylformamide (4ml) and stirred at 20-25 ° C for 3 hours. Aminothiazole (IV, X = N, 60 mg, 0.17 mmol) was added to the reaction mixture, which was then stirred for 18 hours and purified by silica gel column chromatography (CH ₃ CN / H ₂ O = 5: 1) to obtain the title compound (10 mg). , 10%).

¹ H NMR (D ₂ O) δ: 5.92 (1H, d, J = 4.9 Hz), 5.41 (1H, d, J = 4.9 Hz), 4.25, 4.93 (ABq, J = 13.8 Hz), 4.11 (3H, s), 3.16 (3H, s), IR (KBr): 3321, 1767,1674, 1617,15 24cm ^-1

Example 3

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-dihydroxy-1-methylpyrroli Preparation of Dinio) methyl-3-cepem-carboxylate (I-b)

The title compound (18%) was obtained in the same manner as in Example 1 using racemic-3,4-trans-dihydroxy-1-methylpyrrolidine synthesized in Preparation Example 2.

¹ H NMR (D ₂ O) δ: 7.02 (1H, s), 5.88 (1H, d, J = 4.8Hz), 5.37 (1H, d, J = 4.8Hz), 4.00 (3H, s), 3.22 ( 3H, s), IR (KBr): 3408, 1769, 1617,1535cm ^-1

Example 4

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-di Preparation of Hydroxy-1-methylpyrrolidinio) methyl-3-cepem-4-carboxylate (Ik)

The title compound (16.6%) was obtained in the same manner as in Example 2 using racemic-3,4-trans-dihydroxy-1-methylpyrrolidine synthesized in Preparation Example 2.

¹ H NMR (D ₂ O) δ: 5.911 (1H, d, J = 4.8 Hz), 5.36 (1H, d, J = 4.8 Hz), 4.00 (3H, s), 3.23 (3H, s), IR ( KBr): 3410, 1769, 1617, 1526cm ^-1

Example 5

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(3S, 4S) -3,4-dihydroxy-1 Preparation of -methylpyrrolidinio] methyl-3-cepem-4-carboxylate (I-c)

The title compound was obtained in the same manner as in Example 1 using (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine synthesized in Preparation Example 2.

¹ H NMR (D ₂ O) δ: 7.04 (1H, s), 5.89 (1H, d, J = 4.7Hz), 5.38 (1H, d, J = 4.7H z), 4.02 (3H, s), 3.24 , 3.27 (3H, two s), IR (KBr): 3320, 1775, 1661, 1615, 1535 cm ^-1

Example 6

7 [(Z) -2 (2-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-[(3S, 4S) -3,4 Preparation of -Dihydroxy-1-methylpyrrolidinio] methyl-3-cepem-4-carboxylate (I-1)

The title compound was obtained in the same manner as in Example 1 using (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine synthesized in Preparation Example 2.

¹ H NMR (D ₂ O) δ: 5.93 (1H, d, J = 4.7Hz), 5.39 (1H, d, J = 4.7Hz), 4.12 (3H, s), 3.25, 3.28 (3H, two s ), IR (KBr): 3322, 1771, 1616, 1524cm ^-1

Example 7

7 [(Z) -2 (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(3R, 4R) -3,4-dihydroxy-1-methyl Preparation of Pyrrolidinio] methyl-3-cepem-4-carboxylate (I-d)

The title compound was obtained in the same manner as in Example 1 using (3R, 4R) -3,4-dihydroxy-1-methylpyrrolidine synthesized in Preparation Example 2.

¹ H NMR (D ₂ O) δ: 7.04 (1H, s), 5.89 (1H, d, J = 4.7Hz), 5.38 (1H, d, J = 4.7Hz), 4.02 (3H, s), 3.24, 3.27 (3H, two s), IR (KBr): 3320, 1775, 1661, 1615, 1535cm ^-1

Example 8

7 [(Z) -2 (2-amino-1,2,4-thiadiazol-3-yl) -2--methoxyiminoacetamido] -3-[(3R, 4R) -3, Preparation of 4-dihydroxy-1-methylpyrrolidinio] methyl-3-cepem-4-carboxylate (Im)

The title compound was obtained in the same manner as in Example 1 using (3R, 4R) -3,4-dihydroxy-1-methylpyrrolidine synthesized in Preparation Example 2.

¹ H NMR (D ₂ O) δ: 5.89 (1H, d, J = 4.7 Hz), 5.36 (1H, d, J = 4.7 Hz), 5.36 (1H,, d, J = 4.7 Hz), 4.09 (3H , s), 3.24 (3H, s), IR (KBr): 3322, 1771, 1616, 1524cm ^-1

Example 9

7 [(Z) -2 (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (meso-3,4-dihydroxy-1-methylpyrrolidinio Preparation of Methyl-3-cepem-4-carboxylate (I-e)

The title compound (20%) was obtained in the same manner as in Example 1 using meso-3,4-dihydroxy-1-methylpyrrolidine synthesized in Preparation Example 5.

¹ H NMR (D ₂ O) δ: 7.04 (1H, s), 5.90 (1H, d, J = 4.8Hz), 5.39 (1H, d, J = 4.8Hz), 4.02 (3H, s), 3.12 ( 3H, s), IR (KBr): 3455, 1769, 1615, 1535cm ^-1

Example 10

7 [(Z) -2 (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (meso-3,4-dihydroxy Preparation of -1-methylpyrrolidinio) methyl-3-cepem-4-carboxylate (In)

The title compound (7%) was obtained in the same manner as in Example 2 using meso-3,4-dihydroxy-1-methylpyrrolidine synthesized in Preparation Example 5.

¹ H NMR (D ₂ O) δ: 5.90 (1H, d, J = 4.7 Hz), 5.38 (1H, d, J = 4.7 Hz), 4.10 (3H, s), 3.27 (3H, s), IR ( KBr): 3345, 1771, 1613, 1528 cm ^-1

Example 11

7 [(Z) -2- (2 aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(4R) -hydroxy- (2R) -hydroxymethyl-1- Preparation of Methylpyrrolidinio] methyl-3-cepem-4-carboxylate (I-f)

Using the (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol synthesized in Preparation Example 1 to give the title compound (16%) in the same manner as in Example 1.

¹ H NMR (D ₂ O) δ: 7.02 (1H, s), 5.87 (1H, d, J = 4.7Hz), 5.38 (1H, d, J = 4.7Hz), 4.00 (3H, s), .17 (3H, s), IR (KBr): 3320, 1771, 1617, 1535cm ^-1

Example 12

7 [(Z) -2 (2-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-[(4R) -hydroxy- (2S ) -Hydroxymethyl-1-methylpyrrolidinio] methyl-3-cepem-4-carboxylate (Io)

Using the (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol synthesized in Preparation Example 1 to obtain the title compound (10%) in the same manner as in Example 2.

¹ H NMR (D ₂ O) δ: 5.92 (1H, d, J = 4.9Hz), 5.40 (1H, d, J = 4.9Hz), 4.11 (3H, s), 3.19 (3H, s), IR ( KBr): 3364, 1769, 1617, 1537cm ^-1

Example 13

7 [(Z) -2 (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3,4-cis-dihydroxy-1-methylpyrrolidinio Preparation of Methyl-3-cepem-4-carboxylate (Ig)

The title compound (13.7%) was obtained in the same manner as in Example 1 using 3,4-cis-dihydroxy-1-methylpyrrolidine synthesized in Preparation Example 8.

¹ H NMR (D ₂ O) δ: 7.01 (1H, s), 5.87 (1H, d, J = 4.7Hz), 5.37 (1H, d, J = 4.7Hz), 3.99 (3H, s), 3.06, 3.19 (3H, two s), 2.10 (2H, m), IR (KBr): 3322, 1771, 1618, 1537cm ^-1

Example 14

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3,4-cis-di Preparation of Hydroxy-1-methylpiperidinio) methyl-3-cepem-4-carboxylate (Ip)

The title compound (20.9%) was obtained in the same manner as in Example 2 using 3,4-cis-dihydroxy-1-methylpyrrolidine synthesized in Preparation Example 8.

¹ H NMR (D ₂ O) δ: 5.91 (1H, d, J = 4.9Hz), 5.40 (1H, d, J = 4.9Hz), 4.07 (3H, s), 3.35, 3.98 (2H, ABq, J = 13.3 Hz), 3.19 (3H, two s), 2.10 (2H, m), IR (KBr): 3320, 1771, 1617, 1524 cm ^-1

Example 15

7 [(Z) -2 (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-dihydroxy-1-methylpyrrolidinio Preparation of Methyl-3-cepem-4-carboxylate (Ih)

The title compound (20%) was obtained in the same manner as in Example 1 using 3,4-trans-dihydroxy-1-methylpiperidine synthesized in Preparation Example 10.

¹ H NMR (D ₂ O) δ: 7.04 (1H, s), 5.90 (1H, d, J = 4.8Hz), 5.40 (1H, d, J = 4.8Hz), 4.02 (3H, s), 3.13, 3.19 (3H, two s), IR (KBr): 3387, 1771, 1615, 1526cm ^-1

Example 16

7 [(Z) -2 (2-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-dihydroxy Preparation of -1-methylpiperidinio] methyl-3-cepem-4-carboxylate (I-q)

Using the 3,4-trans-dihydroxy-1-methylpiperidine synthesized in Preparation Example 10 to obtain the title compound (9%) in the same manner as in Example 2.

¹ H NMR (D ₂ O) δ: 5.94 (1H, d, J = 4.9Hz), 5.41 (1H, d, J = 4.9Hz), 4.10 (3H, s), 3.19 (3H, s), IR ( KBr): 3312, 1773, 1615, 1534 cm ^-1

Example 17

Preparation of 7 [(Z) -2 (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-trophinimethyl-3-cepem-4-carboxylate (I-i)

Tropin was used to obtain the title compound (13.7%) in the same manner as in Example 1.

¹ H NMR (D ₂ O) δ: 7.02 (1H, s), 5.87 (1H, d, J = 4.8 Hz), 5.35 (1H, d, J = 4.8 Hz), 4.00 (3H, s), 2.93, 3.00 (3H, two s), IR (KBr): 3368, 1765, 1617, 1534 cm ^-1

Example 18

7 [(Z) -2 (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-trophinimethyl-3-cepem-4- Preparation of Carboxylate (I-r)

Tropin was used to obtain the title compound (18.4%) in the same manner as in Example 2.

¹ H NMR (D ₂ O) δ: 5.89 (1H, d, J = 4.6Hz), 5.36 (1H, d, J = 4.6Hz), 4.09 (3H, s), 2.92, 3.00 (3H, two s ), IR (KBr): 3412, 1773, 1672, 1617, 1526 ^-1

Tropin was used to obtain the title compound (18.4%) in the same manner as in Example 2.

¹ H NMR (D ₂ O) δ: 5.89 (1H, d, J = 4.6Hz), 5.36 (1H, d, J = 4.6Hz), 4.09 (3H, s), 2.92, 3.00 (3H, two s ), IR (KBr): 3412, 1773, 1672, 1617,1526cm ^-1

Claims (4)

The cephalosporin compound represented by the following general formula (I). Wherein Q is nitrogen or CH and P is acyclic amine or heterocyclic amine having one nitrogen and at the same time having one or two hydroxyl groups N-methyl-bis (2-hydroxyethyl) amine Mic-3,4-trans-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, (3R, 4R) -3,4- Dihydroxy-1-methylpyrrolidine, meso-3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol, 3,4-cis-dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy-1-methylpiperidine, or tropin. The intermediate formed by reacting iodomethylcefe represented by formula (II) with acyclic amine or heterocyclic amine of formula (III) in the presence of a solvent at 20-25 ° C. is continuously represented by formula (IV). A method for producing a cephalosporin compound represented by the general formula (I), which is reacted with a compound. Wherein Q is nitrogen or CH, and P is N-methyl-bis (2-hydroxyethyl) amine as acyclic amine or heterocyclic amine having one nitrogen and at the same time having one or two hydroxyl groups, Racemic-3,4-trans-dihydroxy-1-methylpyrrolidine, (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine, (3R, 4R) -3,4 -Dihydroxy-1-methylpyrrolidine, meso-3,4-dihydroxy-1-methylpyrrolidine, (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol , 3,4-cis dihydroxy-1-methylpiperidine, 3,4-trans-dihydroxy-1-methylpiperidine, or tropin. The general formula (I) according to claim 2, wherein the acyclic amine or heterocyclic amine derivative of general formula (III) is added in an amount of 1-10 equivalents to the iodomethyl cefem of general formula (II). Method for producing a cephalosporin compound. The process for producing the cephalosporin compound of formula (I) according to claim 2, wherein N, N-dimethylformamide is used as a solvent.