JPS596308B2 - Tetrazole thiol derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to tetrazole thiol derivatives useful as intermediates for the production of a novel series of cephalosporin compounds that have antibacterial properties when administered parenterally.

Compounds of the invention have the formula: ゛゜be.''

,, (CHRI)n-S02R2 [wherein each R1 is hydrogen; n is 1 to 5; R2 means hydroxy, amino or lower alkylamino].

As used herein, the term "lower alkyl" has 1 to 1 carbon atoms.
It means a group of 4.

Advantageously R2 is hydroxy or amino.

Particularly preferred compounds are 1-sulfomethyltetrazolethiol, 1-(2-sulfoethyl)tetrazolethiol, 1-(2-sulfamoylethyl)tetrazolethiol, 1-(3-sulfopropyl)tetrazolethiol, 1-(3-sulfopropyl)tetrazolethiol, -sulfamoylpropyl)tetrazolethiol, 1-(5-sulfopentyl)tetrazolethiol, and 1-(5-sulfamoylpentyl)tetrazolethiol.

Formula [1] where R2 is hydroxy or lower alkylamino
Tetrazolethiol is an N-alkyldithiocarbamate ester such as methyl 2-sulfoethyldithiocarbamate or methyl 3-(Nt-butylsulfamoylpropyl)dithiocarbamate or its corresponding sodium or potassium salt. It is produced by reacting with an azide such as azide.

The N-alkyldithiocarbamate ester is an aminosulfonic acid such as 2-aminoethanesulfonic acid or an amino(N-alkyl)sulfonamide such as 3-aminopropane-Nt-butylsulfonamide or a corresponding salt thereof. It is prepared by treatment with carbon disulfide and an alkyl halide such as methyl iodide in the presence of a base such as sodium hydroxide or potassium hydroxide.
The amino(N-alkyl)sulfonamide is prepared by reacting an N-alkylphthalimidoalkylsulfonamide, obtained by treating a phthalimidoalkylsulfonic acid halide, preferably a chloride, with an alkylamine, with hydrazine.

The phthalimidoalkylsulfonic acid halides are known and have been described by Winterbottom et al.
m et al., J. Amer. Chem. SOc. , Volume 69, 1
393 (1947)] and Griffin et al.
ffin and Hey. J. Chem. SOc. , 33
34 (1952)].

When R2 is amino, the compound of formula [1] has the corresponding N
-Alkylsulfamoylalkyltetrazole-5-
A thiol, preferably N-t-butylsulfamoylalkyltetrazole-5-thiol, is prepared by treating it with, for example, anisole and trifluoroacetic acid to remove the N-alkyl group, which N-alkyl group is protected by an amine. It also serves as the basis.

The compound of formula [1] can exist, for example, as a salt with an alkali metal such as sodium or potassium, or as a salt with an acid or base.

Moreover, some of the compounds of formula [1] have asymmetric carbon atoms and optical isomers exist. All of these are within the scope of the present invention. The compound of formula [1] has the formula: [wherein each R1 is hydrogen; n is 1 to 5; R2 is hydroxy, amino or lower alkylamino; R3 is an acyl selected from the group consisting of the formula: and Group;
2,0H,. C00H or SO3H or formyloxy when X is phenyl; Y is thienyl, tetrazolyl, cyano, sydone or aminomethylphenyl;
Z is methyl, trifluoromethyl, trifluoroethyl, cyanomethyl or pyridyl; m means 0 to 2] An intermediate for producing a novel cephalosporin compound having antibacterial properties or a non-toxic pharmaceutically acceptable salt thereof It is useful for the body.

The compound of formula [] is obtained by acylating 7-aminocephalosporanic acid with an appropriately protected acylating agent, then substituting the 3-acetoxy group with the desired tetrazole thiol represented by formula [1], and then Produced by removing the protecting group.

The carboxylic acid group of the acylating agent can be activated by any conventional method such as mixed acid anhydride, acid chloride, acid imidazolide or active ester. Butyl, trichloroethyl, benzyl, benzyloxymethyl, p-
Reagents such as synclohexylcarbodiimide can be used protected with easily removable protecting groups such as nitrophenyl, p-methoxyphenyl, p-methoxybenzyl or p-nitrobenzyl ester.

When A is NH2, the α-amino group of the acylating agent is preferably a t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, methyl acetoacetate adduct or a compound commonly used in peptide synthesis prior to acylation. Protected with known easily removable protecting groups such as similar groups. Alternatively, 7-formamidocephalosporanic acid, obtained by reacting 7-aminocephalosporanic acid with formic acid and acetic anhydride, is reacted with a tetrazolethiol of formula [1] and then treated with an acid such as hydrochloric acid. The formyl group is removed by treatment to form a compound of the formula: [wherein each R1 is hydrogen; n is 1 to 5; R2 is hydroxy, amino or lower alkylamino; R4 is hydrogen or a protected ester group]. The 7-amino-3-monosubstituted tetrazolylthiomethylcephalosporin core is amylated with a suitable acylating agent, and then the protecting group, if any, is removed to give a compound of formula []. obtain.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 71 d of carbon disulfide is added to a solution of 112 t (2.0 mol) of potassium hydroxide and 111 t (1.0 mol) of aminomethane sulfonic acid in 250 d of water (25° C.).

The reaction mixture is stirred for 12 hours and 250 d of ethanol are added. Attach a reflux condenser to the reaction vessel and add 62% methyl iodide.
Add d (1.0 mol). Cool the exothermic reaction to room temperature and collect the solid product. This solid substance is extracted with hot methanol, and the extract is concentrated to obtain methyl sulfomethylene dithiocarbamate as a potassium salt. Methyl potassium sulfomethyldithiocarbamate salt 45.3t (0
．． 19 mol) and sodium azide 16.9f (0.
A mixture of 26 mol) of water and 425d is heated at 80° C. for 4.75 hours.

The reaction mixture is passed through an Amberlite IR-120H ion exchange resin column and eluted with water until the pH of the eluate becomes 3.5. The eluate is extracted with ether and the aqueous solution is evaporated to dryness to yield 1-sulfomethyltetrazole-5-thiol. Melting point of disodium salt 0.5 hydrate: 293~
294°C (decomposition). Infrared absorption vector: 3.5, 6.
22, 6.91, 7.35, 7.86, 8, 27, 8.
5. Dissolve 9.6 μm-sulfomethyltetrazole-5-thiol in acetone and add 30% isopropanol solution of sodium 2-ethylhexanoate.

1-sulfomethyltetrazole-5-thiol sodium salt is precipitated and collected as ▲.

7-D-mandelamide cephalosporanic acid methanolate 27.4f7 (0.062 mol), 1-sulfomethyltetrazole-5-thiol sodium salt 10.2r
(0.047 mol) and sodium bicarbonate 9.2r (
A mixture of 0.109 mol) in 300 ml of water is heated at 70° C. for 1 hour.

The reaction mixture was cooled (ice bath) and diluted with 3N hydrochloric acid to PHL. 8 acidic. The mixture was extracted with ethyl acetate, filtered and chromatographed on an Amberlite XAD-8 column eluting with water containing increasing concentrations of methanol to obtain 7-D-mandelamide. -3-(1-sulfomethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid is obtained. Dissolve this compound in methanol and add a 5% methanol solution of sodium methoxide to pH 7. Add until O. Ethanol was added to precipitate the formed salt, which was collected, dissolved in water, and lyophilized to give 71D-mandelamide-3-(1-sulfomethyltetrazol-5-ylthiomethyl)-3-cepheme-4. - Obtain the carboxylic acid disodium salt. Elemental analysis, C
Example 2 2-phthalimidoethanesulfonyl chloride 2.73f as l8Hl6N6O8S3.2Na.1.75H,0
(0.01 mol) in 20 ml of chloroform was added dropwise to a solution of t-butylamine 2,19r (0.03 mol) in chloroform 20d (5°C).

Warm the reaction mixture to room temperature and stir for 3 hours. The precipitate was removed by ▲, the ▲ solution was evaporated to dryness, and the residue was purified by chromatography on silica gel using chloroform-methanol (19:1) as an eluent to obtain 2-N-t-butyl Phthalimide ethanesulfonamide is obtained. ) 2-N-t-butylphthalimidoethanesulfonamide 2.10? (6.78 mmol) is suspended in ethanol 20a and 0.344f of hydrazine hydrate is added.

The reaction mixture is refluxed for 3 hours and then evaporated to dryness. The residue was suspended in 45 ml of water, and the pH was adjusted to 3.0 with dilute hydrochloric acid. O acidic. This acidic solution was filtered through P, and the solution ▲ was evaporated to dryness to obtain 2-aminoethane-Nt-butylsulfonamide hydrochloride. 1.25 f (5.78 mmol) of 2-aminoethane-Nt-butylsulfonamide hydrochloride was mixed with 1.171 (11,56 mmol) of triethylamine in 2 ml of ethanol.
Add to 0ml solution.

0.44 t (5.78 mmol) of carbon disulfide was added, the mixture was stirred at 25°C for 1.5 hours, and then a solution of 0.82y (5.78 mmol) of methyl iodide in 5 ml of ethanol was added. The mixture was stirred for 1.5 hours. The mixture was evaporated to dryness, the residue was dissolved in water, and the pH was adjusted to 2 with dilute hydrochloric acid.
O acidic. The aqueous mixture was extracted with ethyl acetate and the extract was dried over magnesium sulfate and evaporated to dryness.
-(N-t-butylsulfamoyl)ethyldithiocarbamate methyl is obtained. Methyl 2-(Nt-butylsulfamoyl)ethyldithiocarbamate was treated with sodium azide for 35 minutes in the same manner as in Example 1 above to obtain 1-(2-Nt-butylsulfamoylethyl)tetrazole. -5-thiol is obtained.

Melting point 153-155°C. 1-(2-N-t-butylsulfamoylethyl)tetrazole-5-thiol 1.0
f was suspended in 10 ml of anisole, and trifluoroacetic acid 2
Add 0ml.

The solution is heated at 56° C. for 3.5 hours and then cooled. The precipitate is collected and washed with petroleum ether to obtain l-(2-sulfamoylethyl)tetrazole-5-thiol. Melting point 158-162°C. Infrared absorption spectrum: 3.
45-3.6, 6.63, 7.45, 8.5, 8.74
, 10.92μ sodium bicarbonate 0.210r (2.5
A solution of 0.272 f (1 mmol) of 7'-aminocephalosporanic acid in 5 WL of water and 2.5 ml of acetone (15 DEG C.) is added to a solution of 0.272 f (1 mmol) of 7'-aminocephalosporanic acid in 5 WL of water and 2.5 ml of acetone.

This solution was heated at 45°C and 1-(2-sulfamoylethyl)tetrazole-5-thiol 0.314? ′
1C: Sll-t- - ~ A-g ・ν
- - 4-&--The reaction mixture is refluxed for 2 hours, maintaining the pH between 7.4 and 7.6 by addition of aqueous sodium bicarbonate. The mixture was cooled and adjusted to pH 4 with dilute hydrochloric acid.
O acidic. The precipitate was collected and 7-amino-3-[1
-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid is obtained. 7-amino-3-[1-(2-sphamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4 in a solution of 1.26 r (15 mmol) of sodium bicarbonate in 75 ml of acetone and 50 ml of water (5°C) - Add 2.1y (5 mmol) of carboxylic acid. This solution is -10
℃ and 1.55y (5.5 mmol) of D-0-dichloroacetylmandeloyl chloride in 25m of acetone.
1 solution. The reaction mixture was heated at this temperature for 30 minutes while maintaining the pH at 7.2 by the addition of aqueous sodium bicarbonate.
Stir for 1.5 minutes, then at 25° C. for 1.5 hours. The mixture was extracted with ether and the aqueous layer was adjusted to pH 9 with 5% sodium carbonate.
．． 3 and stir at 25°C for 1.5 hours. The aqueous mixture is extracted with ether, adjusted to pH 4.5 and extracted again with ether. The aqueous phase was diluted with dilute hydrochloric acid to PHL. 5 and extracted with ethyl acetate. The extract is evaporated to dryness and the residue is suspended in ethyl acetate and filtered. ▲ Dilute the liquid with ether and petroleum ether to obtain 71D-mandelamide-3
-[1(2-sulfamoylethyl)tetrazole-5
-ylthiomethyl]-3-cephem-4-carboxylic acid is obtained. Infrared absorption spectrum: 5.68, 5.97, 6.
22μ Example 32-aminoethanesulfonic acid 5.0f
(0.4 mol) to potassium hydroxide 45f (0.8 mol)
Add to a solution of 100ml of water (25°C).

24.4 Tff (0.4 mol) of carbon disulfide is added and the reaction mixture is refluxed for 2.5 hours. Ethanol was added to the warm solution, the mixture was cooled to room temperature, and methyl iodide 57r
(0.4 mol) and the resulting mixture was stirred for 1.5 hours. The mixture was evaporated under vacuum and the residue was reduced to 3%
2-sulfoethyldithiocarbamate methyl potassium salt is obtained by recrystallization from ethanol containing water. 2-
Methyl potassium sulfoethyldithiocarbamate salt (
0.5 hydrate) 21.5 t (0.087 mol) and sodium azide 7.16 f (0.11 mol) of water 200
Reflux the mixture in m1 for 2 hours.

The solution is cooled to 25° C. and extracted with ethyl acetate. The aqueous phase is treated with Amberlite IR-120H resin, washed with ether and evaporated to give an oil. Dissolve this oil in acetone, filter the solution, and evaporate the solution to dryness.
-(2-sulfoethyl)tetrazole-5-thiol is obtained. This thiol was dissolved in isopropanol and the PH
Cyclohexylamine is added until the number is 8-9, and acetonitrile is added to obtain 1-(2-sulfoethyl)tetrazole-5-thiol as its cyclohexylamine salt. Melting point of dihydrate: 167-168.5℃ (decomposition)
.

Infrared absorption spectrum: 3.25-3.55, 6.07,
6.7, 7.35, 8.01, 8.44, 9.65μm
-(2-sulfoethyl)tetrazole-5-thiol・
The synchlohexylamine salt is dissolved in water and treated with Amberlite IR-120H resin to yield 1-(2-sulfoethyl)tetrazole-5-thiol.

1-(2-Sulfoethyl)tetrazole-5-thiol 2.1 V (0.01 mol) in 100 WLI solution of water 6. Sodium D-mandelamide cephalosporanate.
4f (0.015 mol) and 1.6 sodium bicarbonate
Add 8V (0.02 mol).

The mixture was stirred at 70°C for 2.5 hours, then cooled and
PHL. with N-hydrochloric acid. 8 acidic. The acidic solution was extracted with ethyl acetate and ether and PHO. 71 D-mandelamide 3-[1
-(2-sulfoethyl)tetrazole-5-methylthiomethyl]-3-cephem-4-carboxylic acid is obtained. Similar to the method of Example 1 above, this compound is treated with sodium methoxide to obtain the disodium salt.

Elemental analysis, Cl, Hl8N6O8s3・2Na・2H2
0, Example 4 In the method of Example 3 above, an equivalent amount of 3-aminopropanesulfonic acid is used in place of 2-aminoethanesulfonic acid to obtain methyl potassium 3-sulfopropyldithiocarbamate salt.

Similarly to Example 3, 3-sulfopropyldithiocarbamic acid methyl potassium salt was reacted with sodium azide to form 1-(3-sulfopropyl)tetrazole-5-
Get thiols.

Synchhexylamine salt 0.5 hydrate melting point 148~
151°C ~ Infrared absorption spectrum: 3.5-3.6, 6.15, 6.
85-6.9, 7,3, 8.35, 9.52μ Examples
5 In the method of Example 2 above, 3-phthalimidopropanesulfonyl chloride was used in place of 2-phthalimidoethanesulfonyl chloride to obtain 3-N-t-butylphthalimidopropanesulfonamide, and similarly, 3-phthalimidopropanesulfonamide was obtained.
-(3-N-t-butylsulfamoylpropyl)tetrazole-5-thiol.

In the same manner as in Example 2, 1-(3-N-t-butylsulfamoylpropyl)tetrazole-5-thiol was treated with trifluoroacetic acid to obtain 1-(3-sulfamoylpropyl)tetrazole-5- Get thiols. Melting point 15
9-160℃ o infrared absorption spectrum: 3.4-3.8,
6.0-6.1, 6.75, 7.2, 9.76μ Example 6 In the method of Example 3 above, using an equivalent amount of 5-aminopentanesulfonic acid instead of 2-aminoethanesulfonic acid. Methyl 5-sulfopentyldithiocarbamate
Obtain potassium salt.

In the same manner as in Example 3, methyl potassium 5-sulfopentyldithiocarbamate was reacted with sodium azide to form 1-(5-sulfopentyl)tetrazole-5-.
Get thiols.

Disodium salt melting point 287-289°C. Infrared absorption spectrum: 3.48-3.52, 6.85-6.92, 7
．． 3, 8.35-8.48, 9.5 μ7-D-mandelamide cephalosporanic acid sodium salt 4.551 (0
．． 010 mol) and 1-( obtained in the same manner as above)
3.257 (0.011 mol) of tetrazole-5-thiol disodium salt of 5-sulfopentide in 80 ml of water
1 mixture (pH 7.2, adjusted with sodium bicarbonate) to 6
Heat at 5°C for 4.5 hours.

The reaction mixture was cooled and diluted with 3N hydrochloric acid to PHL. 6 and extracted with ethyl acetate. The pH of the aqueous phase is brought to 7.0 with sodium bicarbonate and the solution is chromatographed on an XAD-4 resin column, eluting with water and then methanol. The product was dissolved in methanol, ethanol was added to this solution, and 71D-mandelamide-3-[1
-(5-sulfopentyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid is precipitated as its disodium salt. Elemental analysis, C22H24N
6O8S3・2Na・1.5H20・0.75C2H6
0, 1-(4-sulfobutyl)tetrazole-5-thiol is obtained in the same manner as described above in Example 7.

Claims (1)

[Claims] 1 Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is hydrogen; n is 1 to 5; R^2 means hydroxy, amino, or lower alkylamino] The compound shown in 2 1-(2-N-t-butylsulfamoylethyl)
Claim 1 which is tetrazole-5-thiol
Compounds described in Section. 3. The compound according to claim 1, which is 1-sulfomethyltetrazole-5-thiol. 4. The compound according to claim 1, which is 1-(2-sulfoethyl)tetrazole-5-thiol. 5. The compound according to claim 1, which is 1-(5-sulfopentyl)tetrazole-5-thiol. 6 1-(2-sulfamoylethyl)tetrazole-
The compound according to claim 1, which is a 5-thiol. 7. The compound according to claim 1, which is 1-(5-sulfamoylpentyl)tetrazole-5-thiol.