JPS5924159B2 - Method for producing 3-thiomethyl derivative of 7-acylaminocephalosporanic acid - Google Patents

Description

[Detailed description of the invention] The present invention is based on the formula (In the formula, X means an imino group or a sulfur atom.

7-acylaminocephalosporanic acid or a salt thereof represented by the formula [wherein R is the formula /1L. Y
4 insects 1 (in the left formula, Means a phenylamino group, lower alkylthio group, lower acylamino group ((lower acyl may be substituted with a carboxy group)), benzoylamino group ((phenyl ring may be substituted with a carboxy group)).

) or a heterocyclic group represented by the formula N (in the left formula,
R2 means a tetrazoal group represented by a hydrogen atom or a lower alkyl group. Same below. 3- of 7-acylaminocephalosporanic acid represented by the formula characterized by reacting a thiol derivative represented by
This invention relates to a method for producing thiomethyl derivatives.

All of the target substances 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 Proteus. .

The antibacterial activity (minimum effective inhibitory concentration) of the object of the present invention is as follows: thiadiazol-2-yl)thiomethyl-Δ3-cephaam-4
-Table 1 compared to carboxylic acid (generic name: cefazoline)
Shown below.

In the starting material (1) of the present invention, when X is an imino group, the ring represented by the formula ^ can take the enol form (do-kai) which is its tautomer.

The present invention includes the enol type, and the group 'no(
, specifically 4-oxo-1,4-dihydropyridin-2-yl group, (4-hydroxy-2-pyridyl group), 4-oxo-1,4-dihydropyridin-3-yl group, (4 -hydroxy-3-pyridyl group), 4-oxo-4H-thiopyran-2-yl group, 4-oxo-4H
-thiopyran-3-yl group. Starting material (1
Examples of the salts include alkali metal salts, ammonium salts, etc., as well as salts with organic bases such as synchrohexylamine, triethylamine, etc. Thiol type derivative ()
Specifically, the group R is 5-substituted -1, 3, 4
-oxadiazol-2-yl group, 5-monosubstituted-1.3.
4-thiadiazole-2-yl group, 5-monosubstituted-1,2-
4-triazol-3-yl group and unsubstituted or substituted 1H-tetrazol-5-yl group, and the substituents in the above-mentioned oxadiazole, thiadiazole and triazole include, for example, a methyl group, an ethyl group, a propyl group, Lower alkyl groups such as isopropyl, butyl, and isobutyl groups (these lower alkyl groups may be substituted with carboxy groups): unsubstituted or lower alkyl groups such as amino, methylamino, ethylamino, and dimethylamino groups Amino group substituted with lower alkyl group; Phenylamino group; Lower alkylthio group such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group; acetylamino group, propionylamino group, butyrylamino group, valerylamino group group, lower acylamino group such as isovalerylamino group (
lower alkyl group may be substituted with a carboxy group); benzoylamino (the phenyl ring may be substituted with a carboxy group), and substituents in tetrazole include methyl group, ethyl group, propyl group, Examples include lower alkyl groups such as isopropyl group. Examples of the alkali metal substituted product for the hydrogen of the mercapto group of the thiol type derivative () include compounds in which hydrogen is substituted with sodium, potassium, etc.

In order to carry out the present invention, the starting material (1) or a salt thereof may be reacted with a thiol derivative (2) or an alkali metal substituted for the hydrogen of its mercapto group.

This reaction is usually carried out in a non-reactive organic solvent such as acetone, ether, chloroform, nitrobenzene, dimethylsulfoxide, dimethylformamide, methanol, ethanol, etc., and water or a mixed solvent thereof. 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 (hydrogen), alkali metal carbonate (hydrogen),
It is preferable to carry out the reaction in the presence of a base such as a trialkylamine. 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 can be isolated and purified by conventional chemical operations. Further, the target compound () can be converted into an alkali metal salt, an ammonium salt, etc., or a salt with an organic base, such as triethylamine, synchlohexylamine, etc., according to a conventional method.

The starting material of the present invention is a new product, and is disclosed in, for example, Japanese Patent Application No. 12841/1984 and Japanese Patent Application No. 48/298 filed by the applicant of the present application.
It can be obtained by the method of No. 6840.

Example 1 7-[D-α-(4-hydroxynicotinoylamide)
-α-phenylacetamide] sodium cephalosporanate 0.807 and sodium salt of 2-mercapto-5-methylamino-1,3,4-thiadiazole 0.2
67 was dissolved in 50 ml of water, 1.3 d of 10% aqueous sodium bicarbonate solution was added, and the mixture was stirred for 9 hours while heating to 60°C.

After the reaction, remove the insoluble matter produced from the reaction solution, and add 2 to the solution.
Add N-hydrochloric acid to adjust the pH to 2. ▲Take the deposited precipitate,
After thoroughly washing with water, washing with ether twice with 10 ml each of a methanol-ether mixture (volume ratio 1:3), and drying under reduced pressure over phosphorus pentoxide to give 71[D-α-(4-hydroxynicotin) (noylamide) -α-phenylacetamide]
0.42y of pale yellow crystals of -3-(5-methylamino-1,3,4-thiadiazol-2-yl)thiomethyl-Δ3-cephem-4-carboxylic acid are obtained. Melting point 225~
229°C (decomposition) Nuclear magnetic resonance spectrum (DMSO) δ; 2.87 (3H), 3.56 (2H), 4.12 (
2H), 4.96 (1H), 5.68 (1H)-5.8
2 (1H), 6.50 (1H), 7.38 (5H)-7
．． 46 (1H), 7.80 (1H), 8.42 (1H)
．． ．． 9.42 (1H), 11.24 (1H), 12.1
2(1H) Example 2 7-[D-α-(4-hydroxynicotinoylamide)
-α-phenylacetamide] sodium cephalosporanate 0.807 and 2-mercapto-5-methyl-1
- Dissolve 0.20y of 3,4-oxadiazole in 50ml of water, add 1.0ml of 10% aqueous sodium bicarbonate solution, and stir for 16 hours while heating to 60°C.

After the reaction, insoluble matter is removed from the reaction solution (▲), and 2N monohydrochloric acid is added to the solution (▲) to adjust the pH to 2. Collect the deposited precipitate, wash it thoroughly with water, and add a methanol-ether mixture (1:3 volume ratio).
) Wash twice with 10 ml each and dry under reduced pressure over phosphorus pentoxide.
-[D-α-(4-hydroxynicotinoylamide)-α-phenylacetamide]-3-(5-methyl-1.
3,4-oxadiazol-2-yl)thiomethyl-Δ
Pale yellow crystals of 3-cephem-4-carboxylic acid 0.32y
get. Melting point 208-212℃ (decomposed) Nuclear magnetic resonance spectrum (DMSO) δ; 2.44 (3H), 3.56 (2H), 4.22 (
2H), 4.96 (1H), 5.70 (1H), 5.8
0 (1H), 6.42 (1H), 7.34 (5H), 7
．． 46 (1H), 7.72 (1H), 8.40 (1H)
, 9,40 (1H), 11.22 (1H), 12.10
(1H) Example 3 7-[D-α-(4-hydroxynicotinoylamide)
Dissolve 0.80f7 of sodium cephalosporanate (1α-phenylacetamide) and 0.21y of the sodium salt of 1-methyl-5-mercaptotetrazole in 50ml of water, add 1.5ml of 10% aqueous sodium bicarbonate solution, and heat to 60°C. Stir for 21 hours.

The reaction solution was treated in the same manner as in Example 1 to obtain 71 (D-α-
(4-hydroxynicotinoylamide)-α-phenylacetamide]-3-(1-methyltetrazole-5-
0.31y of pale yellow crystals of yl)thiomethyl-Δ3-cephem-4-carboxylic acid are obtained. Melting point 217~22'C
(Decomposition) Nuclear magnetic resonance spectrum (DMSO) δ; 3.62 (2H), 3.94 (3H), 4.28 (
2H), 5.02 (1H), 5.70 (1H), 5.8
2 (1H), 6.44 (1H), 7.38 (5H), 7
, 46 (1H), 7.80 (1H), 8.44 (1H)
, 9.44 (1H), 11.26 (1H), 12.20
(1H) Example 4 7-(D-α-(4-thiopyrone-3-carboxamide)-α-phenylacetamide) Sodium cephalosporanate 0.807 and 2-mercapto-5-methylamino-1.3.4 - Sodium salt of thiadiazole 0.
257 was dissolved in 50 ml of water, 1.0 ml of 10% aqueous sodium bicarbonate solution was added, and the mixture was stirred for 17 hours while heating to 60°C.

The reaction solution was treated in the same manner as in Example 2 to obtain 7-[D-α-(4-thiopyrone-3-carboxamide)-α-phenylacetamide]-3-(5-methylamino-1.3.
0,387 pale yellow crystals of 4-thiadiazol-2-yl)thiomethyl-Δ3-cephem-4-carboxylic acid are obtained. Melting point 194-197°C (decomposition) Nuclear magnetic resonance spectrum (DMSO) δ; 2.88 (3H), 3.58 (2H), 4,14 (
2H), 5.02 (1H), 5.72 (1H), 5.8
6 (1H), 7.40 (5H11H11H), 7,76
(1H), 8.40 (1H), 9,36 (1H), 10
．． 84(1H) Example 5 7-[D-α-(4-thiopyrone-3-carboxamide)-α-phenylacetamide] Sodium cephalosporanate 0.807 and 2-mercapto-5-methyl-1
- Dissolve 0.20y of 3,4-oxadiazole in 50ml of water, add 10ml of 10% aqueous sodium bicarbonate solution, and stir for 16 hours while heating to 60°C.

The reaction solution was treated in the same manner as in Example 1 to obtain 71 (D-α
-(4-thiopyrone-3-carboxamide)-α-phenylacetamide]-3-(5-methyl-1,3,4-
0.277 of pale yellow crystals of oxadiazol-2-yl)thiomethyl-Δ3cephem-4-carboxylic acid are obtained. Melting point 200-203℃ (decomposed) Nuclear magnetic resonance spectrum (DMSO) δ; 2.48 (3H), 3.56 (2H), 4.24 (
2H), 5.00 (1H), 5.72 (1H), 5.8
4 (1H), 7.38 (5H11H11H), 7.76
(1H), 8.38 (1H), 9.36 (1H), 10
．． 80(1H) Example 6 7-[D-α-(4-thiopyrone-3-carboxamide)-α-phenylacetamide] sodium cephalosporanate 1.07 and sodium salt of 1-methyl-5-mercaptotetrazole 0. 24y was dissolved in 307rL1 of water and stirred for 20 hours while heating to 60°C.

The following treatment was carried out in the same manner as in Example 1 to form 7-[D-α-(4-thiopyrone-31 carboxamide)-α-phenylacetamide]-3-(1-methyltetrazol-5-yl).
0.40 y of pale yellow powder of monothiomethyl-Δ3-cephem-4-carboxylic acid is obtained. Melting point 216-220°C (decomposed) Nuclear magnetic resonance spectrum (DMSO) δ; 3.58 (2H), 3.92 (3H), 4.24 (
2H), 5.02 (1H), 5,70 (1H), 5.8
6 (1H), 7.32 (5H, 1H), 8.30 (1H
), 8.68 (1H), 9,60 (1H), 10.80
(1H) Example 7 JyokD-α-(4-hydroxynicotinoylamide)
[alpha-phenylacetamide] sodium cephalosporanate 0.807 and sodium salt of 2-mercapto-5-acetylamino-1,3,4-thiadiazole 0.
297 was dissolved in 60 ml of water, 1.2 ml of 10% sodium bicarbonate aqueous solution was added, and 16
Stir the time.

Thereafter, the same treatment as in Example 1 was carried out to obtain 7-[D-α-(4-hydroxynicotinoylamide)-α-phenylacetamide]-3-(5-acetylamino-1,3,4-thiadiazole-2). 0.357 of pale yellow powder of Δ3-cephem-yl)thiomethyl-Δ3-cephem-4-carboxylic acid is obtained. melting point
222-225°C (decomposition) Nuclear magnetic resonance spectrum (DMSO) δ; 2.12 (3H), 3.54 (2H), 4.32 (
2H), 4.98 (1H), 5.72 (1H), 5.8
0 (1H), 6.44 (1H), 7.36 (5H), 7
．． 46(1H), 7.

70 (1H), 8.42 (1H), 9.40 (1H),
11.20 (1H), 12.12 (1H) Example 8 7-[D-α-(4-hydroxynicotinoylamide)
-α-phenylacetamide] sodium cephalosporanate 0.887 and sodium salt of 2-mercapto-5-propylthio-1,3,4-thiadiazole 0.3
67 was dissolved in 50 ml of water, 1.0 ml of 10% aqueous sodium bicarbonate solution was added, and the mixture was stirred for 16 hours while heating to 60°C.

Thereafter, the treatment was carried out in the same manner as in Example 1. yl)thiomethyl-Δ3-cephem-4
- Obtain 0.247 of a tan powder of carboxylic acid. Melting point 2
22-226°C (decomposition) Nuclear magnetic resonance spectrum (DMSO) δ; 1,14 (3H), 1.72 (2H), 3.20 (
2H), 3.60 (2H), 4.28 (2H), 5.0
4 (1H), 5.70 (1H), 5.82 (1H), 6
．． 50 (1H), 7.36 (5H), 7.

76 (1H), 8.42 (1H), 9.44 (1H),
11.24 (1H), 12.12 (1H) Example 9 7-[D-α-(4-hydroxynicotinoylamide)
-α-phenylacetamide] sodium cephalosporanate 0.807 and sodium salt of 2-mercapto-5-phenylamino-1,3,4-thiadiazole 0,
Dissolve 367 in 50 ml of water, add 1.2 ml of 10% sodium bicarbonate aqueous solution, and dissolve 167 while heating to 60°C.
Stir the time.

After the reaction, insoluble matter is removed from the reaction solution (▲), and 2N-hydrochloric acid is added to the solution (▲) to adjust the pH to 2. Collect the deposited precipitate, wash it thoroughly with water, and add methanol-ether mixture (volume ratio 1:
5) Wash twice with 15 ml each, then with ether, then dry under reduced pressure over phosphorus pentoxide to obtain 7-[D-α-(4-hydroxynicotinoylamide)-α-phenylacetamide]-3. 0.407 g of a yellow brown powder of 1-(5-phenylamino-1,3,4-thiadiazol-2-yl)thiomethyl-Δ3-cefemu-4-carboxylic acid is obtained. melting point
214-217℃ (resolved) nuclear magnetic resonance spectrum (DM
SO) δ; 2.86 (3H), 3.56 (2H), 4.26 (
2H), 4.98 (1H), 5.70 (1H), 5,8
2 (1H), 6.42 (1H), 7.36 (10H),
7.76 (1H), 8.40 (1H), 9.

40 (1H), 10.10 (1H), 11.20 (1H), 12,12
(1H) Example 10 7-[D-α-(4-hydroxynicotinoylamide)
Dissolve 2.4y of sodium cephalosporanate (1α-phenylacetamide) and 1,1y of 2-mercapto-5-(3-carboxypropionylamino)-1,3,4-thiadiazole in 150ml of water, and dissolve 10% sodium bicarbonate. Add 9ml of aqueous solution and heat to 55°C for 2 hours.
Stir for 2 hours.

After the reaction, insoluble matter is removed from the reaction solution (▲), and 2N monohydrochloric acid is added to the solution (▲) to adjust the pH to 2. Collect the deposited precipitate, wash it thoroughly with water, and add a methanol-ether mixture (volume ratio 1:
5) After washing twice with each 45TfL1 and then with ether, drying under reduced pressure over phosphorus pentoxide gave 71[D-α-
(4-Hydroxynicotinoylamide)-α-phenylacetamide]-3-[5-(3-carboxypropionylamino)-1,3,4-thiadiazol-2-yl]thiomethyl-Δ3-cephem-4-carvone 1.5y of pale yellow powder of acid is obtained. Melting point 218-221°C (decomposition) Nuclear magnetic resonance spectrum (D2O-NaOD) δ; 2.5
4(4H1-NHCOCH2CH2COONa) infrared absorption spectrum νKBrCTrL-1:1772(β-
lactam), Max Example 11 7-[D-α-(4-hydroxynicotinoylamide)
-α-phenylacetamide] sodium cephalosporanate 0.87 and 2-mercapto 5-0-carboxybenzoylamino-1,3,4-thiadiazole 0.
41y was dissolved in 50TfL1 of water, 3WL1 of a 10% sodium bicarbonate aqueous solution was added, and the mixture was heated to 55°C for 2 hours.
Stir for 1 hour.

Thereafter, the same treatment as in Example 9 was carried out to obtain 7-[D-α-(4-hydroxynicotinoylamide)-α-phenylacetamide]-3-(5-0-carboxybenzoylamino-1.3.4 -thiadiazol-2-yl)thiomethyl-Δ3-cephem-4-carboxylic acid pale yellow powder 0.
Get 547. Melting point 207-21FC Infrared absorption spectrum νKBrCTII-1:1770 (β-lactam) Ma
x Example 12 7-[D-α-(4-hydroxynicotinoylamide)
-α-phenylacetamide] Sodium cephalosporanate 0.87 and 3-mercapto-5-carboxymethyl-1,2,4-triazole 0.277 in 50 ml of water
1, add 3 ml of 10% aqueous sodium hydrogen carbonate solution, and stir for 22 hours while heating to 55°C.

Thereafter, the same treatment as in Example 9 was carried out to obtain 71 [D-α1 (4-
hydroxynicotinoylamide)-α-phenylacetamide]-3-(5-carboxymethyl-1,2,4-
0.287 of a pale yellow powder of triazol-3-yl)thiomethyl-Δ3-cephem-4-carboxylic acid is obtained. Melting point 210-213℃ Nuclear magnetic resonance spectrum (DMSO) δ; 3.82 (2H1-CHCOOH) '' 1-1, Infrared absorption spectrum νKBrC7rL-1: 1775 (β-lactam).M
ax Example 13 7-[D-α-(4-hydroxynicotymylamide)
-α-phenylacetamide] Sodium cephalosporanate 1,0y' was suspended in 65ml of water, and 290ml of 2-mercapto-5-methyl-1,3,4-thiadiazole
Then add 200Tn9 of sodium bicarbonate and heat and stir at 55-60°C for 24 hours.

Next, the reaction solution was brought to a pH of about 2 with N-hydrochloric acid under cooling, and the resulting white precipitate was collected, washed with water, further washed with ether, and dried.
-α-phenylacetamide]-3-(5-methyl-1
・3,4-thiadiazol-2-yl)thiomethyl-Δ
3-cefemu 4-carboxylic acid is obtained.

Infrared absorption spectrum Nuclear magnetic resonance spectrum (D6-DMSO) Example 14 7-[D-α(4-hydroxynicotinoylamide)-α-phenylacetamide]cephalosporanic acid 700
mku 5-mercapto-1H-tetrazole 140η,
Mix 145η of sodium hydrogen carbonate with 50ml of water,
Stir at 5°C for 22 hours.

After filtering the reaction solution, it was made into PHL with 1N hydrochloric acid under ice-cooling, and the precipitate was collected, washed with water, washed with ether, and dried.
400 m of 1[D-α-(4-hydroxynicotinoylamide)1α-phenylacetamide]-3-(1H-tetrazol-5-yl)1thiomethyl-Δ3-cepheme-4-carboxylic acid is obtained. Melting point ~250°C (gradually decomposes) NMR (D6-DMSO) δ (Ppm); 3.54 (2H), 4.24 (2H),
5.02 (1H), 5.72 (2H), 6.40 (1H
), 7.

34 (5H), 7.78 (1H), 8,40 (1H), 9.42 (1H)

Claims (1)

[Claims] 1 7-acylaminocephalosporanic acid or its salts represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X means an imino group or a sulfur atom. The same applies hereinafter) Formula R-SH [In the formula, R is the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the left formula, X_1 is an oxy group, a thio group, or an imino group,
^1 is a lower alkyl group that may be substituted with a carboxy group, an amino group that is unsubstituted or substituted with a lower alkyl group, a phenylamino group, a lower alkylthio group, a lower acylamino group ■Lower acyl is substituted with a carboxy group (2) which may be substituted with a benzoylamino group (2) or a phenyl ring (2) which may be substituted with a carboxy group. ) or a tetrazolyl group represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula on the left, R^2 means a hydrogen atom or a lower alkyl group). Same below. It is characterized by reacting a thiol derivative represented by the following formula or an alkali metal substituted product of the hydrogen of its mercapto group. 3- of 7-acylaminocephalosporanic acid represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼
Method for producing thiomethyl derivatives.