JPS5953276B2 - Method for producing new cephalosporin derivatives - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (1) (I) R-Co-(NHCO)m
-OH), a 5- to 6-membered heterocyclic group containing an oxygen atom, a sulfur atom, or 1 to 2 nitrogen atoms (or its N-oxide) which may have a lower alkyl group, m is o or 1
means.

7-acylaminocephalosupofuric acid derivatives or salts thereof represented by the general formula (n) H, S-
Co)n+Y01) (wherein, X represents an oxygen atom, a sulfur atom, an imino group or a single bond, A represents a lower alkylene group, Y represents a carboxy group or a sulfo group, and n represents o or 1).

The present invention relates to a method for producing a new cephalosporin derivative represented by the general formula (), which comprises reacting a thiadiazolyl derivative represented by the formula (hereinafter the same applies) or an alkali metal substituted product of the hydrogen of the mercapto group thereof.

The R-CO-(NHCO)m group in the general formula of the starting material (1) and target material (1) in the method of the present invention is a 4-oxo-4H-thiopyran-13-ylcarbonyl group, 2,4-
dihydroxypyrimidin-5-ylcarbonyl group, 3-
Hydroxypyridazin-4-ylcarbonyl group, 2-oxoimidazoline-1-. ylcarbonyl group, pyridine, N-oxide-2-ylcarbonyl group, 4-hydroxynicotinoyl group, 2-furoylcarbamoyl group, and 3
-Hydroxy-1,2,5-thiadiazolyl-4-ylcarbonyl group, etc. Also, examples of the lower alkylene group represented by A in compounds 1) and (self) include methylene group, ethylene group, and propylene group. , butylene group, etc. Therefore, specific examples of the compound () include (5-mercapto-1,3,4-thiadiazole-2
-yl)succinamic acid, (5-mercapto-1,3
, 4-thiadiazole-2-yl)thioacetic acid, 3-(5
-mercapto-1,3,4-thiadiazole-2-yl)propionic acid, 3-(5-mercapto-1,3,4-
Examples include thiadiazol-2-ylthio]propionic acid (5-mercaptoni-1,3,4-thiadiazole)-2-monoacetic acid.

In addition, salts of the starting material (1) include alkali metal salts, ammonium salts, etc., as well as salts with organic bases such as cyclohexylamine, triethylamine, etc.
Examples of the alkali metal substituted product for the hydrogen of the mercapto group of the compound (1) include compounds in which hydrogen is substituted with sodium, potassium, etc. To carry out the present invention, a thiadiazolyl derivative is used as the starting material (1) or a salt thereof. l) or an alkali metal substituted product of the hydrogen of the mercapto group may be reacted.

This reaction is usually carried out in an organic solvent that does not participate in the reaction, such as acetone, ether, chloroform, nitrobenzene, dimethylsulfoxide, dimethylformamide, methanol, or ethanol, or in water or a mixed solvent thereof. In addition, this reaction is preferably carried out under neutral or slightly alkaline conditions, and when the starting material (1) is used in a free state, alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, trialkylamine, etc. Preferably, the reaction is carried out in the presence of a base. Although the reaction temperature is not particularly limited, it is usually carried out at room temperature or under elevated temperature. The target product thus obtained is isolated and purified by conventional chemical operations. Further, the desired product (self) can be converted into a salt with a base such as an alkali metal salt, an ammonium salt, triethylamine, or synchlohexylamine by a conventional method.

All of the target products obtained by the present invention are new products and are useful compounds that have excellent antibacterial activity against Gram-negative and Gram-positive bacteria, especially against Pseudomonas aeruginosa and Pseudomonas aeruginosa. be. The antibacterial activity (minimum effective inhibitory concentration) of the compounds of the present invention is determined below using the known 7-{α-(1H-tetrazol-1-yl)acetamide}-3-(5-methyl-1,3,4-
A comparison is shown with thiadiazol-2-yl)-thiomethyl-Δ3-cephem-4-carboxylic acid (generic name: cefazolin).

Example 1 7-[D-α-(4-oxo-4H-thiopyran-3-
ylcarboxamide)-α-phenylacetamide] Sodium cephalosboranate 820 and (5-mercapto-1,3,4-thiadiazol-2-yl)succinamic acid 35077V were suspended in 50a of water, and 10%
Sodium hydrogen carbonate aqueous solution 3! ! Add 11 and stir for 23 hours while heating to 55°C.

After the reaction, the insoluble matter generated from the reaction solution was filtered out, and 1
Add N-hydrochloric acid to adjust the pH to 2. The deposited precipitate is collected in a furnace, thoroughly washed with water, then with ether, and dried under reduced pressure over phosphorus pentoxide. Dimethyl sulfoxide 1
2a of sodium 2-ethylhexanoate dissolved in
Add 0.9111% n-1 butanol solution and stir for 5 minutes. Add ethyl acetate 120a to the reaction solution,
Stir for 10 minutes. The deposited precipitate was collected, thoroughly washed with ethyl acetate and then ether, and dried under reduced pressure over phosphorus pentoxide to give 71[D-α-(4-oxo-4H-thiopyran-13-ylcarboxamide)-α]. -phenylacetamide]-3-{5-(3-carboxypropionylamino)-1,3,4-thiadiazole-2-. 480 of the disodium salt of yl}thiomethyl-Δ3-cephem-4-carboxylic acid is obtained. Example 2 7-[D-α-(3-hydroxypyridazin-4-ylcarboxamide)-α-phenylacetamide] sodium cephalosboranate 400 and (5-mercapto-1,3,4-thiadiazol-2-yl) ) Suspend 170 succinamic acid in 25 a of water, add 1.5 a 10% aqueous sodium bicarbonate solution! Add ILe and stir while heating to 60°C for 20 hours.

After the reaction, the insoluble matter generated from the reaction solution is filtered out, and 1
Add N-hydrochloric acid to adjust the pH to 2. The precipitated filtrate is filtered out, thoroughly washed with water, thoroughly washed with 25 ml of a methanol-ether mixture (volume ratio 1:5), then with ether, and dried under reduced pressure over phosphorus pentoxide. This was dissolved in 4 ml of dimethyl sulfoxide, 0.5 a of a 30% n-butanol solution of sodium U2-ethylhexanoate was added, and the mixture was stirred for 5 minutes.

Add 50 ml of ethyl acetate to the reaction solution and stir for 10 minutes. The deposited precipitate was filtered, thoroughly washed with ethyl acetate and then ether, and dried under reduced pressure over phosphorus pentoxide to give 71 [D
-α-(3-hydroxypyridazin-4-ylcarboxamide)-α-phenylacetamide]-3-{5-(
260 my of the disodium salt of 3-carboxypropionylamino)-1,3,4-thiadiazol-2-yl}thiomethyl-Δ3-cephem-4-carboxylic acid is obtained.
Nuclear magnetic resonance spectrum (D2O) Example 3 7-[D-α-(2,4-dihydroxypyrimidine-5
-ylcarboxamide)-α-phenylacetamide]
Sodium cephalosporanate 400mf1 and (5-
mercapto-1,3,4-thiadiazol-2-yl)
Suspend 170 liters of succinamic acid in 251 liters of water,
Add 1.5i1Le of 10% aqueous sodium bicarbonate solution and stir for 22 hours while heating to 55°C.

After the reaction, insoluble matter generated from the reaction solution is removed, and 1N monohydrochloric acid is added to the resulting solution to adjust the pH to 2. After collecting the deposited precipitate and thoroughly washing it with water, washing it with ether and drying it under reduced pressure over phosphorus pentoxide, this product was treated in the same manner as in Example 2 to obtain 71 [
D-α-(2,4-dihydroxypyrimidine-5-carboxamide)-α-phenylacetamide]-3-{5
-(3-carboxypropionylamino)-1,3,4
-Thiadiazolyl-2-inoqthiomethyl-Δ3-cephem-4-carboxylic acid sodium salt 2201!11
Get 1. Example 4 Water: $12-71[D-α-(4-hydroxynicotinoylamide)-α-phenylacetamidocephalosporanate sodium 500%] (5-mercapto-1
,3,4-thiadiazol-2-yl)thioacetic acid 209
Add mv and 203 w of sodium hydrogen carbonate, and stir at 55°C for 22 hours.

Next, the reaction solution was adjusted to pH about 2 with 1N monohydrochloric acid under ice-cooling, and the resulting white precipitate was collected by filtration, thoroughly washed with water, washed with ether, and dried to give 7-[D-α-(4-hydroxynicotinoyl)]. amide)-α-phenylacetamide]-3-(5
-Carboxymethylthio-1,3,4-thiadiazol-12-yl)thiomethyl-Δ3-cephem-4-carboxylic acid (400 W) is obtained. Water 44! ! Ll, inside 71 [D-
α-(4-hydroxynicotinoylamide)-α-phenylacetamide]-sodium cephalosporanate 7
00119, 3-(5-mercapto-1,3,4-thiadiazol-12-ylthio)propionic acid 312 blue and sodium bicarbonate 2831 are added and stirred at 55°C for 22 hours.

Thereafter, the same treatment as in Example 4 was carried out to obtain 7-[D-α-(4-hydroxynicotinoylamide)-α-phenylacetamide]-3-(5-carboxyethylthio-1,3,4
-thiadiazol-2-yl)thiomethyl-Δ3-cephem-4-carboxylic acid 520Wi was obtained. Melting point ~2
50°C (decomposition) Infrared absorption spectrum Example 6 In water 40-71 [D-α-(4-hydroxynicotinoylamide)-α-phenylacetamide]-sodium cephalosporanate 615171fi, 3-(5-mercapto -1,3,4-thiadiazole-2-yl)thiopropionic acid 235 and sodium bicarbonate 218
Add Soku and stir at 55℃.

Thereafter, the same treatment as in Example 4 was carried out to obtain 7-[D-α-(4-
Hydroxynicotinoyl, 1α-phenylacetamide]-3-(5-carboxyethyl-1,3,
4-Thiadiazo i) V. -2-yl)thiomethyl-ΔS
-Cefem-4; Carboxylic acid 450 blue was obtained. 71 [D
-α-(Pyridine N-oxide-2-ylcarboxamide)-α-phenylacetamide] sodium cephalosporanate in a solution of 400 mv of water 25a at room temperature (
5-Mercapto-1,3,4-thiadiazole-2-yl)thioacetic acid. 190~ is added, and then a saturated aqueous sodium hydrogen carbonate solution is added to obtain a solution with a pH of 6.8~7.2.

This solution was stirred at 55-60°C for 26 hours, and adjusted to pH 2.0 with dilute hydrochloric acid. When set to O, it becomes a suspended liquid. This was extracted with a mixture of n-butanol and ethyl acetate (volume ratio 2:3).
After washing the organic layer three times with water and drying, a 30% n-butanol solution of sodium 2-ethylhexanoate was added, and then ether was added to obtain an oily substance. When the obtained oily substance is dissolved in methanol and ether is added, a precipitate is deposited. When this is washed with water and dried, it becomes 71 [D-
α-(pyridine N-oxide-2-ylcarboxamide)-α-phenylacetamide]-3-[5-(3-
0.259 of disodium carboxypropionylamino)-1,3,4-thiadiazole-2-inolithiomethyl-Δ32-cephem-4-carboxylate is obtained. Example 8 7-[D-α-(2-oxoimidazolin-1-ylcarboxamide)-α-phenylacetamide] To a solution of sodium cephalosporanate 8001 in 50 ml of water (5
0.38 fI of -mercapto-1,3,4-thiadiazol-2-yl)succinamic acid is added, and then saturated sodium bicarbonate is added to adjust the pH to 7.2-7.5.

This solution was stirred at 55-60°C for 24 hours, cooled, and then adjusted to pH 2. When the temperature is O, a precipitate is deposited. This precipitate was collected, washed with water, dried, and dissolved in dimethylformamide 8a.
A 30% n-butanol solution 1a of sodium ethylhexanoate is added, and ethyl acetate is added to form a precipitate.
This precipitate was collected, washed with ether, and reprecipitated from methanol-ether to form 71[D-α-(2-oxoimidazolin-1-ylcarboxamide)-α-phenylacetamide]-3-[5-( (3-carboxypropionylamino)-1,3,4-thiadiazole-2-yl)
Disodium thiomethyl-Δ3-cephem-4-carboxylate 750Wi is obtained. Melting point ~246°C (decomposed) Infrared absorption spectrum Example 9 7-[D-α-(2-furoylureido)-α-phenylacetamide] sodium cephalosporanate 0.5
64f! was dissolved in 50a of water, and to this was added 0.2299 of (5-mercapto-1,3,4-thiadiazol-12-yl)-thioacetic acid and a saturated aqueous sodium bicarbonate solution with a pH of 6.8-7.4. Stir for 23 hours while heating to 55°C to 60°C.

The reaction solution was brought to room temperature and 2N monohydrochloric acid was added to adjust the pH to 2. Let it be O. Furthermore, a mixture of n-butanol:ethyl acetate (2:3) 5
After adding 0d and stirring well, the organic layer was washed three times with water (30R1) and dried over anhydrous magnesium sulfate. When the magnesium sulfate is removed and a 30% n-butanol solution of sodium 2-ethylhexanoate is added to the removed solution, a precipitate is deposited. Add a large amount of ether and wash thoroughly with ether. The filtered precipitate was reprecipitated from methanol-ether to give 71[D-α-(2-furoylureido)-α-phenylacetamide]-31(5-carboxymethylthio-1,3,4-thiadiazole). 0.45 g of slightly yellow powder of 1-2-inolithiomethyl-N-cephem-4-carboxylic acid disodium salt is obtained.Example 10 7-[D-α-(4-hydroxynicotinoylamide)]
-α-phenylacetamide]-sodium cephalosporanate 0.53fI and 5-mercapto-1,3,4
-Sodium thiadiazole-2-ylthioethylsulfonate 0.3f! 35a of water and 0 of sodium bicarbonate
．． Add 108g and stir at approximately 57°C for 22 hours.

Next, insoluble matter was removed and the pH was adjusted with approximately 1.5N monohydrochloric acid under ice-cooling.
Collect the precipitate formed as approx. When this precipitate is washed with water, ether, and dried, 71[D-α-(4-hydroxyni-cotinoylamide)-α-phenylacetamide]2゛5={:゛"←sulfoethylthio-1,3 ，
4-Thiadiazo≦゜ru-゛]Il lychiomethyl-∆
0.451 of 3-cephem-4-carboxylic acid was obtained. Melting point 200-220°C (gradually decomposed) Infrared absorption spectrum (CIL-1) β-lactam 1774 Nuclear magnetic resonance spectrum (D, -DMSO) δ (Ppm) 1.89 (2H), 3.47 (2H), 3.59 (2H
), 4.34 (2H), 5.05 (1H), 5.79 (
1H), 5.87 (1H), 6.52 (1H), 7.4
1 (5H), 7.89 (1H), 8.49 (1H), 9
．． 47(1H) Example 117-[D-α-(4-oxo-4H-thiopyran-13-ylcarboxamide]-α
-Phenylacetamide] 700 grams of sodium cephalosporanate, 2.84 grams of (5-mercapto-1,3,4-thiadiazol-2-yl)thioacetic acid and 260 grams of sodium bicarbonate were added to 45 grams of water at 50-54°C. So 2
Stir for 0 hours.

The reaction solution was adjusted to pH approximately 2 with 1N hydrochloric acid under ice-cooling, and the resulting precipitate was collected. −
Phenylacetamido]-3-(5-carboxymethylthio-1,3,4-thiadiazol-2-yl)-thiomethyl-Δ3-cephem-4-carboxylic acid 5307!9
I got it. Melting point ~ 190°C (gradually decomposed) IR spectrum J/:]: ν-11778 (β-lactam) NMR
Spectrum (D6-DMSO) δ: 3.58 (2H)
, 4.14 (2H), 4.33 (2H), 5.02 (1
H), 5.77 (2H), 7.35 (6H), 8.39
(1H), 9.34 (1H), 9.48 (1H) Example 127-[D-α-(4-hydroxynicotinoylamide)-α-phenylacetamide]-cephalosporanic acid 0.5fI and 2- (1-carboxyethylthio)
-5-mercapto-1,3,4-thiadiazole 275
Add 310 g of sodium hydrogen carbonate and 37 g of water to W1 and heat at 50 to 55°C for 22 hours while stirring. Insoluble matter was removed, and the solution was cooled with ice and adjusted to pH approximately 2 with 1N hydrochloric acid to precipitate. The precipitate was collected, washed with water, washed with ether, and dried under reduced pressure to give 7-[D-α-(4-hydroxynicotinoylamide)-α-phenylacetoad]-3-{5-(1-
0.49 of carboxyethylthio)-1,3,4-thiadiazol-2-yl}thiomethyl-ΔS-cephem-4-carboxylic acid is obtained.

IR spectrum νk RXC! n1:1778 (β-
lacta gradient NMR spectrum (D6-DMSO) δ(P
pm): 1.54 (3H), 3.58 (2H), 4.2
0 (1H), 4.37 (1H), 4.45 (1H), 5
．． 02 (1H), approx. 5.76 (1H), 5.85 (1H
), 7.39 (5H), 7.82 (1H), 8.45 (
1H), 9.45 (1H) Example 137-[D-α-(4-hydroxynicotinoylamide)-α-phenylacetamide]-cephalosporanic acid 500 and 2-
(1-Carboxy 1-methylethylthio)-5-mercapto-1,3,4-thiadiazole 292 Immediately with sodium bicarbonate 320 Wi and water 37! 7-[D-α-(4-hydroxynicotinoylamide)-α-phenylacetamide] was prepared in the same manner as in Example 12 by adding Nt.
370 W of -3-{5-(1-carboxy-1-methylethylthio)-1,3,4-thiadiazol-2-yl}thiomethyl-Δ3-cephem-4-carboxylic acid is obtained.

IR spectrum ν翫v? D1:1777 (β-lactam) NMR spectrum (D6-DMSO) δ (Ppm
): 1.57 (6H), 3.59 (2H), 4.23 (
1H), 4.45 (1H), 5.01 (1H), about 5.
75 (1H), 5.84 (1H), 6.43 (1H),
7.37 (5H), 7.81 (1H), 8.43 (1H
), 9.42 (1H) Example 14 7-[D-α-(4-hydroxynicotinoylamide)
-α-phenylacetamide] sodium cephalosporanate 0.8f112-mercapto-1,3,4-thiadiazole-5-monoacetic acid 0.2849, sodium hydrogen carbonate 0.2719, water 507! LI! 55℃
Stir for 21 hours.

The reaction solution was adjusted to pH 2 with 1N hydrochloric acid under ice cooling, and the precipitate formed was collected, washed with water, and dried to obtain 7-[D-α-(4-hydroxynicotinoylamide)-α-phenylacetamide]-3. 0.459 of -(5-carboxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-Δ3-cephem-4-carboxylic acid is obtained. 1R Spectre
ν Hyodo ζ 1:1774 (β-lactam) NMR spectrum (D6-DMSO) δ (Ppm) 3.58 (2H
), 3.17 (2H), 4.19 (1H), 4.53 (
1H), 5.00 (1H), 5.71 (1H), 5.8
2 (1H), 6.42 (1H), 7.35 (5H), 7
．． 79 (1H), 8.42 (1H), 9.41 (1H)
, 11.19 (1H), 12.04 (1H) Example 1
5 7-[D-α-(4-hydroxy-3-methylpyridin-5-ylcarboxamide)-α-phenylacetamide]cephalosboranic acid sodium salt 400mf112
-carboxymethylthio-5-mercapto-1,3,4
-thiadiazole 193 buttocks and sodium bicarbonate 17
2 watts to 30 liters of water! Add to ILI and stir at 50-53°C for 22 hours.

Thereafter, in the same manner as in Example 12, 4-thiadiazol-2-yl)thiomethyl-Δ3-cephem-4-carboxylic acid 300
I got 1!11. IR spectrum ν? μγ? -1:1
778 (β-lactam) NMR spectrum (D6-
DMSO) δ (Ppm): 1.94 (3H), 3.55
(2H), 4.11 (2H), approximately 4.25 (2H), 5
．． 00 (1H), 5.74 (2H), 7.34 (5H)
, 7.73 (1H), 8.

34(1H), 9.38(1H) Example 16 7-[D-α-(4-hydroxy-2-methylpyrimidin-5-ylcarboxamide)-α-phenylacetamide]cephalosporanic acid 300, 2- Mercapto
1,3,4-thiadiazole-5-thioacetic acid 112w,
Sodium hydrogen carbonate 183 is dissolved in water 18a,
The following procedure was carried out in the same manner as in Example 12. ,4-thiadiazol-2-yl)thiomethyl-Δ3-cephem-4-carboxylic acid 24
Get 0wa.

Infrared absorption spectrum ν air C! ILl: 1780 (β-lactam) nuclear magnetic resonance spectrum (D6-DMSO) δ (Ppm) 2.36
(3H), 3.56 (2H), 4.12 (2H), 42
0 (1H), 4.50 (1H), 5.20 (1H), 5
．． 72 (1H), 5.84 (1H), 7.83 (5H)
, 8.60 (1H) Example 17 7-[D-α-(4-hydroxy-6-methylnicotinoylamide)-α-phenylacetamide]cephalosporanic acid 250, 2-mercapto-5-carboxymethylthio- 1,3,4-thiadiazole 1201!11
Add 102 ml of sodium bicarbonate to 20 ml of water and heat to 50-53° C. for 24 hours while stirring.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is an oxygen atom, a sulfur atom, or a
m means 0 or 1; a 5- to 6-membered heterocyclic group (or its N-oxide) containing ~2 nitrogen atoms; 7-acylaminocephalosporanic acid derivatives or their salts represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X represents an oxygen atom, a sulfur atom, an imino group, or a single bond, A represents a lower alkylene group, Y represents a carboxyl group or a sulfo group, and n represents 0 or 1. A thiadiazolyl derivative represented by (the same applies hereinafter) or its mercapto group with an alkali metal substituted for hydrogen are reacted. A method for producing a new cephalosporin derivative represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼.