JPS5934715B2 - Method for producing 7-substituted acylamino-3-substituted-3-cephem-4-carboxylic acids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides novel 7-substituted acylamino-3-substituted-3
-Cephem-4-Carboxylic acids, which is expressed by the following formula.

(In the formula, R1 is a hydrogen atom or an alkyl-substituted thiadiazolylthio group, R2 is an alkyl group, and X is an amino group or a protected amino group.) This is carried out by reacting 3-cephem-4-carboxylic acids (1) or esters or salts thereof with carboxylic acids (2) or reactive derivatives thereof at the carboxy group.

The 7-amino-3-substituted 1-3-cephem-4-carboxylic acids used in this invention are represented by the above general formula (1), and more specifically, the thiadiazolylthio group substituted with a hydrogen atom or an alkyl group. means a compound having as R1.

These esters of 7-amino-3-mono-substituted-3-cephem-4-carboxylic acid (1) include 2-iodoethyl ester, 2,2,2-trichloroethyl ester, benzyl ester, 4-methoxybenzyl ester, t-
Butyl ester, t-pentyl ester, trityl ester, diphenyl methyl ester, bis(methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, ethynyl ester, 4-hydroxy-3,5-
Examples include di(t-butyl)benzyl ester and trimethylsilyl ester. In addition, the salts of 7-amino-3-monosubstituted-3-cephem-4-carboxylic acid (1) include, for example, alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium;
Examples include salts with tertiary organic bases such as trimethylamine, triethylamine, N-methylpiperazine, and pyridine. The other raw material, carboxylic acids, is represented by the general formula (), but more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
It means a compound having an alkyl group R2 such as butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, etc., and having an amino group or a protected amino group as X.

Examples of the protecting group for the amino group protected here include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-
Dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, tertiary ptoxycarbonyl, tertiary pentyloxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl , 2-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tripromoethoxycarbonyl, 1-cyclopropylethoxycarbonyl, 3-iodopropoxycarbonyl, 2-furfuryloxycarbonyl, 1- Easily eliminated acyl groups such as adamantyloxycarbonyl, 8-quinolyloxycarbonyl, trifluoroacetyl, trityl, 2-
Nitrophenylthio, 2,4-dinitrophenylthio,
2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethine, 3-hydroxy-4-pyridylmethine, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-2-propylidene, 3 -Ethoxycarbonyl-
2-butylidene, 1-acetyl-2-propylidene, 1
-Propionyl-2-propylidene, 1-benzoyl-
2-butitepylidene, 1,3-bis(ethoxycarbonyl)-2-propylidene, 1-(N-methylcarbamoyl)-2-propylidene, 1-(N,N-dimethylcarbamoyl)-2-propylidene, 1- {N-(2-methoxyphenyl)carbamoyl}-2-propylidene, 1-
{N-(4-methoxyphenyl)carbamoyl}-2-
Propylidene, 1-(N-phenylcarbamoyl)-2
-Propylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5oxocyclohexylidene, and other easily eliminated groups (among these, for example, 1-methoxycarbonyl-2 -propylidene is sometimes expressed as 1-methoxycarbonyl-1-propen-2-yl, and for example 2-ethoxycarbonylcitalohexylidene is sometimes expressed as 2-ethoxycarbonyl-1-cyclohexenyl). Also, hydrochloride of free amino group,
Acid salts such as hydrobromide and hydroiodide are also exemplified as protected amino groups. Examples of reactive derivatives at the carboxyl group of these carboxylates include acid halides, acid anhydrides, active amides, and active esters, but particularly frequently used ones include acid chlorides and acid azides. , dialkyl phosphoric acid mixed anhydride, phenyl phosphoric acid mixed anhydride, diphenyl phosphoric acid mixed anhydride, dibenzyl phosphoric acid mixed anhydride, halogenated phosphoric acid mixed anhydride, dialkyl phosphorous acid mixed anhydride, sulfite mixed anhydride, thiosulfuric acid mixed anhydride, Sulfuric acid mixed anhydrides, alkyl carbonic acid mixed anhydrides, aliphatic carboxylic acids (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid)
Acid anhydrides such as mixed anhydrides, aromatic carboxylic acid (e.g. benzoic acid) mixed anhydrides, symmetrical acid anhydrides, acid amides with imidazoles, 4-monosubstituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, cyanomethyl esters, Methoxymethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,
4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenyl azophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, Pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester, N,N
-dimethylhydroxylamine, 1-hydroxy-2-
Examples include esters such as esters with (1H)-pyridone, N-hydroxysuccinimide, or N-hydroxyphthalimide, and these are appropriately selected depending on the type of carboxylic acid () used.

This reaction is usually carried out in a solvent. Solvents include acetone, dioxane, acetonitrile, chloroform,
Examples include methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine, and other general organic solvents that do not participate in the reaction. Among these, hydrophilic solvents can also be used in combination with water. When using the carboxylic acid salt () in the form of a free acid or its salt in this reaction, for example, N,N'-
Dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,merized isopropylcarbodiimide, N-ethyl-N/- (3-dimethylaminopropyl)carbodiimide, N,N'-carbonyldi(2-methylimidazole), pentamethyleneketene-N-citalohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene , phosphorous acid trialkyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid isopropyl ester, phosphorous oxychloride,
Phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-J[hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide inner salt ,
It is advantageous to carry out in the presence of a condensing agent such as (chloromethylene)dimethylammonium chloride.

In addition, as salts of carboxylic acids (), alkali metal salts,
Examples include alkaline earth metal salts, ammonium salts, and salts with organic bases such as trimethylamine and synchlohexylamine. This reaction also involves alkali metal bicarbonate,
The reaction may be carried out in the presence of a base such as trialkylamine, N,N-dialkylbenzylamine, or pyridine, and a liquid base or the above-mentioned condensing agent can also be used as a solvent. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. The reaction product is isolated and collected by conventional methods. The reaction product obtained here may be subjected to ester hydrolysis and/or amino protecting group elimination reaction, if desired. The reaction conditions for ester hydrolysis vary depending on the type of ester group, and a method suitable for each ester is selected.

That is, for example, when the ester moiety of the above reaction product is 2-iodoethyl ester, 2,2,2-trichloroethyl ester, benzyl ester, etc., the reduction method is used; -butyl ester, t-pentyl ester, trityl ester, diphenyl methyl ester,
In the case of bis(methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, etc., a method using a strong acidic organic acid is used, and when the ester moiety is ethynyl ester, 4-hydroxy-3,5-di(t-butyl)benzyl ester, etc. For esters and the like, a method using an anhydrous basic catalyst is employed.

Typical examples of the reduction method include a method using a metal such as zinc and an acid such as acetic acid or acetic acid, and a method using catalytic reduction.

Catalysts for catalytic reduction include, for example, platinum catalysts such as platinum wire, platinum sponge, platinum black, platinum oxide, and colloidal platinum, palladium sponge, palladium black, palladium oxide, palladium barium sulfate, palladium barium carbonate, palladium carbon, and palladium silica gel. , palladium catalysts such as colloidal palladium, reduced nickel, nickel oxide, Raney nickel, Urushibara nickel, and the like. Further, examples of the organic acids used in the method using a strong acidic organic acid include dinic acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

Furthermore, examples of the basic catalyst used in the method using an anhydrous basic catalyst include sodium salt of thiophenol, lithium dimethyl copper [(CH3)2LiCu], and the like.

This reaction is usually carried out in a solvent, and any solvent can be used as long as it does not interfere with the reaction, and when the acid used in the reaction is liquid, it can also be used as a solvent.

Although the reaction temperature is not particularly limited, the reaction usually proceeds satisfactorily at room temperature to elevated temperature. The hydrolysis reaction of these esters can also be carried out as is without particularly isolating or purifying the above-mentioned reaction products. On the other hand, the elimination reaction of the amino protecting group is carried out by a commonly used method such as decomposition with an acid or catalytic reduction depending on the type of the protecting group.

Acid decomposition is one of the most commonly used methods and examples include benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, aralkoxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, substituted aralkylidene. , substituted alkylidene, substituted citaloalkylidene, etc. The acid used differs depending on the case, but the most commonly used are diprotic acid, trifluoroacetic acid, etc., which can be easily distilled off under reduced pressure. When a solvent is used in acid decomposition, a hydrophilic organic solvent, water, or a mixed solvent is often used. Catalytic reduction is applied to, for example, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2-pyridylmethoxycarbonyl, etc., and palladium catalysts are most often used, but other catalysts can also be used.
In addition, protective group elimination reactions are usually carried out by treating trifluoroacetyl with water, and treating halogen-substituted alkoxycarbonyl and 8-quinolyloxycarbonyl with heavy metals such as copper and zinc. In addition, when carboxylic acids () in which the acid salt of a free amino group exists as a protected amino group are used as raw materials, the removal of the amino protecting group from the reaction product can be performed by converting the reaction product into trimethylamine, triethylamine, By treatment with tertiary organic bases such as N-methylpiperazine, N,N-dimethylaniline, and pyridine, as well as bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, and ammonium carbonate. It is done. The removal of these amino protecting groups can also be carried out as is without particularly isolating or purifying the reaction product. Incidentally, either the hydrolysis reaction of the ester of the reaction product or the elimination reaction of the amino protecting group may be carried out first, or both may be carried out simultaneously. Further, only one or none of these methods may be performed, depending on preference. The thus obtained 7-substituted acylamino-3-1-substituted-3-cephem-4-carboxylic acids ([ID is converted into the desired salt such as sodium salt, potassium salt, triethylamine salt, synchlohexylamine salt, etc.) by a conventional method. In addition, since both the starting material compound (1) and the target compound (self) used in this invention are relatively unstable substances and easily decompose during treatment, the reaction should be carried out under mild conditions. , and is preferably isolated and collected.

The target products ([11)] obtained by the method of this invention are all new compounds and are useful as antibacterial substances that are stable to acids and penicillinase. Next, the method of the present invention will be explained using examples.

In the infrared absorption spectra of Examples, λInf means a curved point, and E means E.ゝ1? Example 1 Hydrochloride of 2,2,2-tritaloloethyl ester of 7-amino-3-methyl-3-cephem-4-carboxylic acid 3
820 ml of dry methylene chloride is suspended in 50 ml of dry methylene chloride.

To this, 810 η of triethylamine and 245 η of N,N-dimethylaniline were added dropwise while stirring under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Separately, N-tertiary-butoxycarbonyl-2-(3-mesylaminophenyl)-D-glycine 3440η, triethylamine 1010TI19
and 4 drops of N,N-dimethylbenzylamine were added to 50 ml of dry methylene chloride, and the mixture was stirred under dry ice-acetone cooling. To this, thaloloformic acid ethyl ester 108
A solution of 5TV dissolved in 2.5 ml of dry methylene chloride is added dropwise over 10 minutes while cooling to -25 to -30°C. After the dropwise addition is completed, this mixed solution is stirred at the same temperature for 15 minutes. The above-mentioned suspension prepared separately was added to this mixed solution at once after being cooled to -15°C in advance, and the mixture was stirred at -25 to -30°C for 4 hours. the reaction mixture with water,
3? After sequentially washing with hydrochloric acid and then water, the organic layer is separated. After washing this with a 3% aqueous sodium hydrogen carbonate solution and water and drying, methylene chloride is distilled off under reduced pressure. After dissolving the residue in 10a of ethyl acetate, 10ml of ether was added and the precipitated crystals were filtered out, resulting in Mp2O4~205
7-[D-N-tertiary-butoxycarbonyl-2-(3-mesylaminophenyl)glycinamide] at ℃ (decomposition)
2,2-3-methyl-3-cephem-4-carboxylic acid
, 2-trichloroethyl ester 4195η is obtained. 2,2 of 7-{D-N-tert-butoxycarbonyl-2-(3-mesylaminophenyl)glycinamide}-3-methyl-3-cefnim-4-carboxylic acid obtained as above ,2-trichloroethyl ester 3985W19
is dissolved in 17 ml of dimethylformamide. Add 5.0ml of acetic acid and 3985Tf of zinc powder to this solution! 9 were added one after another while stirring under ice-cooling, and the mixture was stirred at the same degree of flatness for 2 hours.
After removing insoluble materials from the reaction solution, the reaction solution was washed with 3 ml of dimethylformamide. Combine this washing with the previous deep water and add 5? Add to 100 WII hydrochloric acid under ice cooling. After adding 50 ml of water to this, it was extracted three times with 50 ml of ethyl acetate, and the extract was washed with water. This extract is 5? After back-extracting three times with 50 ml of an aqueous sodium bicarbonate solution, the aqueous layer is acidified with hydrochloric acid. This aqueous solution is back-extracted again with ethyl acetate, washed with water, dried, and then the solvent is distilled off under reduced pressure. The residue was dissolved in 10 ml of ethyl acetate and left at room temperature for 1 hour.
When ether is added and the precipitated crystals are removed, Mpl87
7-{D-N-tertiary-butoxycarbonyl-2-(3-mesylaminophenyl)glycinamide}-3-methyl-3-cephem-4-carboxylic acid 2687 wa obtained at ~189°C (decomposition) . Example 2 Hydrochloride of 2,2,2-trichloro-based methyl ester of 7-amino-3-methyl-3-cephem-4 carboxylic acid 26
．． 89 is suspended in 500 ml of dry methylene chloride.

25 ml of a dry methylene chloride solution containing 79% of triethylamine and 25ml of a dry methylene chloride solution containing 2.149% of 2,6-lutidine are sequentially added to this under ice cooling. To this solution, 26.09 g of N-tert-butoxycarbonyl-2-(3-mesylaminophenyl)-D-glycine was added, and then 159 g of synchrohexylcarbodiimide was gradually added, and this was mixed under ice-cooling for 1. Stir for 5 hours. Insoluble materials were removed from the reaction solution, and the furnace solution was diluted with 100 ml of ice-cooled 5% hydrochloric acid 4 times, once with water, and 10% aqueous sodium bicarbonate solution 10 times.
After sequentially washing three times with 0Tf11 and once with a saturated aqueous solution of sodium chloride, it is dried over magnesium sulfate. After treating this with activated carbon, the solvent is distilled off under reduced pressure. The residue is dissolved in 100 ml of ethyl acetate and left overnight at room temperature. When the precipitated crystals are collected, the Mpl is 89 to 191℃.
Colorless plate-like crystals of 71 {D-N-tertiary-butoxycarbonyl-2-(3-mesylaminophenyl)glycinamide}
2,2-3-methyl-3-cephem-4-carboxylic acid
, 31.39 of 2-trichloroethyl ester are obtained. The 2,2, 12.019 ml of 2-trichloroethyl ester are dissolved in 40 ml of dimethylformamide. To this, 15 ml of glacial acetic acid and 129 ml of zinc dust were sequentially added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After the reaction, insoluble matter is separated in a furnace and washed with ethyl acetate. 3% tear fluid and washing solution on ice
Pour into 300a of hydrochloric acid. Add this mixture to ethyl acetate
Extract 3 times with 50 ml. After washing the ethyl acetate extract with water,
Back-extract three times with 150 ml of 5% aqueous sodium bicarbonate solution. After washing this aqueous solution with ethyl acetate, the pH was adjusted to 2 with 10% hydrochloric acid, and the precipitate was poured into 150 ml of ethyl acetate again.
Extract 3 times. This extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. When the precipitated crystals were sequentially washed with ethyl acetate and ether, Mpl
7-{D-N-tertiary-butoxycarbonyl-2-(3-mesylaminophenyl)glycinamide}-3-methyl-3-cepheme-4-carboxylic acid 8.389 at 88l89°C (decomposition) obtain. Infrared absorption spectrum (Nujiol) Nuclear magnetic resonance absorption spectrum (DMSO-D6) 7-{DN-tert-butoxycarbonyl-2-(3-mesylaminophenyl) obtained as above
Glycinamide}-3-methyl-3-cephem-4-carboxylic acid (8.289 g) was added to 140 d of sulfuric acid under ice cooling, and the mixture was stirred at room temperature for 1.5 hours.

After the reaction, the acidic acid was distilled off under reduced pressure at 35°C, and 30 ml of 5% hydrochloric acid was added to the residue to dissolve it. Add this to 20ml of ethyl acetate
After washing with water and treating with activated carbon, a 10% aqueous sodium hydroxide solution was added under ice cooling to adjust the pH to 3. Collect a lot of precipitated crystals, wash with water, dry, and give Mpl99~
199.5 of C (decomposition) yields 6.189 of 7-{D-(3-methylsulfonylaminophenyl)glycinamide}-3-methyl-3-cefunim-4-carboxylic acid. (
Aoichi+131 acid (0.1N-HCI, C-1) ultraviolet absorption spectrum (PH6.4 phosphate buffer) λMax2
63.5mμ, E=172λInf228mμ, E=2
99 Nuclear Magnetic Resonance Absorption Spectrum (D2O+DCl) Infrared Absorption Spectrum (Nujiol) Example 3 1.329 chloroformic acid ethyl ester is dissolved in 20 ml of dry methylene chloride and cooled to -10°C.

To this, N-tertiary butoxycarbonyl-2-(3-ethylsulfonylaminophenyl)-D-glycine 449,
A solution consisting of 20ml of methylene chloride, 1.229ml of triethylamine and 2 drops of N,N-dimethylpenzylamine was added dropwise over 10 minutes, and then stirred at the same temperature for 1 hour.
On the other hand, 2,2,2-trichloroethyl ester of 7-amino-3methyl-3-cephem-4-carboxylic acid 3.8
2θ, triethylamine 0.99 and N,N-bis(
0.12f1 of trimethylsilyl)acetamide is dissolved in 40d of dry methylene chloride at -5C. This solution was added dropwise to the above solution at -15°C over 10 minutes, and the mixture was stirred at the same temperature for 2 hours. The methylene chloride solution is washed twice with 2% hydrochloric acid, washed with an aqueous sodium bicarbonate solution, further washed with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was distilled off from this solution under reduced pressure,
When the residue is crystallized by adding a small amount of ethanol, Mp
7-[D-N-tertiary-butoxycarbonyl-2-(3-ethylsulfonylaminophenyl)glycinamide]-3-methyl-3-ceph-4-carboxylic acid 2,2, Colorless crystals of 2-trichloroethyl ester 4
．． Get 29. Infrared absorption spectrum (Nujiol) Nuclear magnetic resonance absorption spectrum (CDCl3) 7-[D-N-tertiary-butoxycarbonylamino-2-(3-ethylsulfonylaminophenyl)glycinamide]- obtained as above 2,2,2-trichloroethyl ester of 3-methyl-3-cephem-4-carboxylic acid 4.29
15ml of dry dimethylformamide, and 45ml of acetic acid
Dissolve in m1.

Add 3.69 g of zinc powder to this solution under ice cooling and stir for 2 hours. Remove the zinc powder from the reaction solution, and add 2% hydrochloric acid to the distillate.
The mixture was poured into a mixture of me and 40 ml of ethyl acetate, and the ethyl acetate layer was separated. The aqueous layer is further extracted with 20 ml of ethyl acetate. Combine this extract with the previous extract and add 2% hydrochloric acid
Wash with 0 ml of water, and then add 20 ml of saturated aqueous sodium chloride solution.
111, and then dried with magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, and the residue was washed with diisopropyl ether, resulting in oily 7-[D-N-tert-butoxycarbonyl-2-(3-ethylsulfonylaminophenyl)glycinamide]. -3methyl-3-
Cefem-4-carboxylic acid 3,29 is obtained. Infrared absorption spectrum (liquid film method) ν? -1:3300,1765,1700 Nuclear magnetic resonance absorption spectrum (CD3OD) 7-[D-N-tertiary-butoxycarbonyl-2-(3-ethylsulfonylaminophenyl)glycinamide] obtained as above -3-
3.19 methyl-3-cephem-4-carboxylic acid was dissolved in 15 ml of sulfuric acid and stirred at room temperature for 2 hours.

The acidic acid is distilled off from the reaction solution at room temperature under reduced pressure. The residue is triturated with ether and drained. Add this to acetonitrile (
After stirring for 1 hour under ice-cooling, the precipitated crystals were filtered out, resulting in an Mpl of 79
7-[D-2(3-ethylsulfonylaminophenyl)glycinamide]-3-methyl- at ~182°C (decomposition)
1.7f white crystals of 3-cephem-4-carboxylic acid! get. Infrared absorption spectrum (nujiyor) ν? -1: 1770, 1695, 1600 nuclear magnetic resonance absorption spectrum (D2O+NaH(1)3) Example 4
7-[D-N-tert-butoxycarbonyl-2-(3-mesylaminophenyl)glycinamide]-3-methyl-3-cephem-4-carvone produced in the same manner as in the first step of Example 1 After adding 1,09 ml of 2,2,2-trichloroethyl ester of the acid to 20 ml of ice-cooled acid, the mixture was stirred at room temperature for 2 hours.

The acidic acid was distilled off from the reaction solution under reduced pressure, and water was added to the oily residue. A saturated aqueous solution of sodium hydrogen carbonate is added to this under ice cooling to adjust the pH to 8 to 9. When the precipitated crystals are separated from P, washed with water, and dried with phosphorus pentoxide, MplO7~1
0.789 of 2,2,2-trichloroethyl ester of 7-(D-2-(3-mesylaminophenyl)glycinamide)-3-methyl-3-cephem-4-carboxylic acid at 100C (decomposition) Infrared absorption spectrum (Nudiyol) ν?-1: 3350, 1785, 1740, 1685 Example 57-amino-3-methyl-3-cephem-4-
5.99% of the hydrochloride of carboxylic acid 2,2,2-trichloroethyl ester was suspended in 100ml of methylene chloride, and a methylene chloride solution containing 10TILI and 0.169% of 2,6-lutidine was added to the methylene chloride solution containing 1.559% of triethylamine. Add 10d of solution.

To this is added 5.89 g of N-tert-butoxycarbonyl-2-(4-mesylaminophenyl)-D-glycine and 3.39 g of synchrohexylcarbodiimide while cooling in ice water. After stirring this at the same temperature for 3 hours and filtering, the P solution is concentrated under reduced pressure. Add 200% ethyl acetate to the residue.
d was added, washed sequentially with 5% hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and water, dried, and concentrated.
7-[D-N-tertiary-butoxycarbonyl-2-(4-mesylaminophenyl) at pl29-136°C (decomposition)
2,2,2-trichloroethyl ester of glycinamide]-3-methyl-3-cephem-4-carboxylic acid 10
．． Get 839. Infrared absorption spectrum (Nujiol) να-1: 3290, 1770, 1680 Nuclear magnetic resonance absorption spectrum (CDCl3) 71 [D-N, tertiary butoxycarbonyl, 2-(4-mesylaminophenyl) glycinamide], 2,2,2-trichloroethyl ester of 3-methyl-3-cephem-4-carboxylic acid 109
After adding 12.5 d of acetic acid and 109 d of zinc dust to 337 n1 of a dimethylformamide solution in which the was dissolved under ice cooling,
Stir at the same temperature for 1 hour.

Filter the reaction solution and add 100 d of 5% hydrochloric acid, 50 ml of ice water.
1 and 100 TLI of ethyl acetate, and then extracted three times with 100 d of ethyl acetate. The extract is back-extracted twice with 1007 n1 of 5% aqueous sodium bicarbonate solution and washed with ethyl acetate. The aqueous layer was adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. Wash the ethyl acetate extract with water,
After drying, the solvent was distilled off under reduced pressure, resulting in Mpl8O~20
7-[D-N-tertiary-butoxycarbonyl-2-(4-mesylaminophenyl)glycinamide]-3-methyl-3-cephem-4-carboxylic acid at 0°C (decomposition) 7.8
Get 9. Infrared absorption spectrum (Nujiol) Nuclear magnetic resonance absorption spectrum (DMSO-D6) 71 [D-N1 tertiary butoxycarbonyl 2-(4-mesylaminophenyl) glycine amino circle 3-methyl-3-cephem-4
-Carboxylic acid 4.

69 was added to 70 ml of sulfuric acid while cooling with ice, and after stirring at the same temperature for 2 hours, the reaction solution was concentrated under reduced pressure.

Water is added to the residue, washed with ethyl acetate, and then an aqueous sodium hydrogen carbonate solution is added to adjust the pH to 6. This is 1/
Resin adsorbent (trade name: Amberlite XAD-2) concentrated to 2 volumes and washed with methanol in advance and then with water 4
After adsorption to 609, it is eluted with water and methanol. The eluate is concentrated, the precipitated crystals are filtered out, and washed with methanol.
-[D-2-(4-mesylaminophenyl)glycinamide]-3-methyl-3-cepheme-4-carboxylic acid 2
．． Get 19. Infrared absorption spectrum (Nujiol) νO-1: 3175, 1760, 1670 Nuclear magnetic resonance absorption spectrum (D2O) δPpm: 1.80 (S, 3H) 3.05 (S, 3H) Example 6 N-tertiary butoxy 2.0669 of carbonyl-2-(3-mesylaminophenyl)-D-glycine, 0.6069 of triethylamine and 15 ml of N,N-dimethylbenzylamine were added to 20 ml of tetrahydrofuran, and -
Cool to 10-12°C.

A tetrahydrofuran solution 10a containing 0.8209 g of chloroformic acid isobutyl ester was added dropwise thereto at the same temperature for 2 minutes, and then stirred at the same temperature for 30 minutes. Separately 7-amino-3-methyl-3-cephem-4-carboxylic acid 1.07
09 and triethylamine 0.5819 are added to 50% aqueous tetrahydrofuran 30a with ice cooling. This is added all at once to the solution prepared above at an internal temperature of -6°C. After stirring this for 1 hour under ice-cooling and further for 2 hours at room temperature, tetrahydrofuran was distilled off under reduced pressure. Add 15 d of a saturated aqueous solution of sodium hydrogen carbonate to the residual solution, and add 10 d of ethyl acetate.
Wash twice with m1. The ethyl acetate washing solution was extracted with 10 ml of a saturated aqueous solution of sodium bicarbonate, and after combining this extract with the previous aqueous solution, 30 ml of ethyl acetate was added! Laminate. Add 10% hydrochloric acid to adjust the pH to 2, shake thoroughly, and then remove insoluble matter. The ethyl acetate layer is separated, and the aqueous layer is extracted twice with 20 d of ethyl acetate. This extract is combined with the ethyl acetate solution, and then washed with 10 ml of water. The water washing solution is extracted twice with ethyl acetate 5a, and this extract is combined with the previous ethyl acetate solution. This is washed with 10 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, treated with activated carbon, and then the solvent is distilled off to obtain 3.47 g of a candy-like residue. 3.429 of this was added to anhydrous ether 30WLI and stirred overnight at room temperature, and the precipitated crystals were filtered out, washed with ether, and dried.
74°C (decomposition) [D-N-tertiary-butoxycarbonyl-2-(3-mesylaminophenyl)glycinamide-3-methyl-3-cephem-4-carboxylic acid 2.
326f! get. (Company) D=57 (C=1, methanol) Example 7 N-tertiary-butoxycarbonyl-2-(3-mesylaminophenyl)-D-glycine 3.449 and triethylamine 1.01f! is dissolved in 25 ml of dry methylene chloride.

This was added to 35 ml of a dry methylene chloride solution containing 1.369 chloroformic acid isobutyl ester at -10 to -15°C.
After the mixture was added dropwise for 15 minutes, the mixture was stirred at the same temperature for 15 minutes. Separately 7
-Amino-3-(5-methyl-1,3,4-thiadiazole-2-yl)thiomethyl-3-cephem-4-carboxylic acid (3.449 g) was suspended in 30 d of dry methylene chloride,
To this, N,O-bistrimethylsilylacetamide 3.
Add and dissolve 59 at room temperature. This was added dropwise to the solution containing the mixed acid anhydride prepared above at -15°C, stirred at the same temperature for 1.5 hours, and then further stirred at 10°C for 3 hours. The reaction solution was washed successively with 5% hydrochloric acid and water, dried, and then the solvent was distilled off. The oily residue was purified by silica gel column chromatography (eluent: chloroform) to yield oily 71{D-N1 tert-butoxycarbonyl-2-(3-mesylaminophenyl)glycinamide. }-3-(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid 3.89 is obtained. Infrared absorption spectrum (thin layer method) ν(?-1): 3300, 1780, 1725, 168
5,1670 71 {D-N-1 3rd obtained as above
butoxycarbonyl-2-(3-mesylaminophenyl)glycinamide}-3-(5-methyl-1,3,4
-Thiomethyl-3-cephem-4-carboxylic acid (2.239) was dissolved in 335 ml of dioxylic acid and stirred at 18-20°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. is added to powder, and when taken at home, 7-{D-2-(3-mesylaminophenyl)glycinamide}-3-(5-methyl-1,3,4-thiadizol-2-yl) is obtained. Thiomethyl-3-cephem-4-carboxylic acid 1.95f! get.

This was added to acetone 30a, stirred at 15 to 20°C for 1 hour, and then left to stand, after which the supernatant liquid was decanted and removed. After adding 30 ml of fresh acetone to the residue and stirring at 15-20°C for 3 hours, the precipitate is filtered and washed successively with acetone and ether to obtain the purified product in the form of a pale yellow powder. Infrared absorption spectrum (nujiol) ν(?-1):
1765, 1690, 1605 Nuclear Magnetic Resonance Absorption Spectrum Example 8 Sodium salt of N-(1-ethoxycarbonyl-1-propen-2-yl)-2-(3-mesylaminophenyl)-D-glycine 4.769 Suspend in 35 ml of methylene chloride.

To this suspension, 2 drops of N,N-dimethylbenzylamine and 6 ml of a methylene chloride solution containing 2.759 chloroformic acid ethyl ester were sequentially added dropwise at -14 to -16°C, and after stirring at the same temperature for 10 minutes, - Cool to 50°C. Separately, 7
4.3 ml of triethylamine was added to a suspension consisting of 2.259 -amino-3-methyl-3-cephem-4-carboxylic acid and 45 ml of methanol, and after stirring at room temperature for 30 minutes, methanol hydrochloric acid (0.795 mm01Δd
) Add 13.5ml. This was added dropwise to the solution prepared above over 10 minutes at -50±5°C, followed by stirring at the same temperature for 1 hour, at -30°C for 2 hours, and at -15°C for 30 minutes. The solvent is distilled off from the reaction solution under reduced pressure, ethyl acetate and an aqueous sodium hydrogen carbonate solution are added to the residue to dissolve it, and then the aqueous layer is separated. The organic solvent layer is extracted with an aqueous sodium bicarbonate solution, combined with the above aqueous layer, and then adjusted to pH 3.5 with 10% hydrochloric acid. This was washed twice with ethyl acetate, and the nonionic adsorption resin Amberlite-XAD-4 (
(Trademark, Rohm & Haas) into a 150 ml column. After washing this column with water, it is eluted with a 10% aqueous isopropyl alcohol solution. The eluate was concentrated under reduced pressure to 200 mJ and then lyophilized to yield 71 {2
2.96 g of powder of -(3-mesylaminophenyl)-D-glycinamide}-3-methyl-3-cephem-4-carboxylic acid is obtained. After dissolving this in 1N hydrochloric acid and adjusting the pH to 4 to 4.5 with a 1N aqueous sodium hydroxide solution, leave it in a cool place, filter out the precipitated crystals, and dry. (decomposition) to obtain a purified product of this product. Ultraviolet absorption spectrum (PH6.4 phosphate buffer) λNlax 263mμ, E=170.5 Infrared absorption spectrum (nujiol) ν? -1:3310,1747,1695,1600,
1140 nuclear magnetic resonance absorption spectrum (DCl+D2O)
Example 9 Bis(trimethylsilyl) was added to a solution consisting of 955.7Tf9 of the sodium salt of N-(1-methoxycarbonyl-1-propen-2-yl)-2-(3-mesylaminophenylin-D-glycine and 10 ml of ethyl acetate). ) Add 2 drops of acetamide and 393.3η of chloroformic acid isobutyl ester and stir for 1 hour.

To this was added a suspension consisting of 764η of hydrochloride of 7-amino-3-methyl-3-cepheme-4-carboxylic acid 2,2,2-trichloroethyl ester, 212m9 of triethylamine and 15ml of ethyl acetate at -16 to -11°C. After dropping, the mixture was stirred at the same temperature for 2 hours. Add 4 liters of 1N hydrochloric acid to the reaction solution.
m1 was added, and the organic solvent was distilled off under reduced pressure. After adding methylene chloride 5111 to the residual solution and stirring at room temperature for 1 hour, the precipitated crystals were filtered out and dried over phosphorus pentoxide.
~155, C (decomposition) 7-{2-(3-mesylaminophenyl)-D-glycinamide}-3-methyl-3-
1.05259 of the hydrochloride of cefem-4-carboxylic acid 2,2,2-trichloroethyl ester is obtained. Ultraviolet absorption spectrum (methanol) λMax: 270 mμ, E-96.5 Infrared absorption spectrum (nujiol) νMax (CTn-1): 3300, 3200, 177
7,1730,1698,1680,1150 nuclear magnetic resonance absorption spectrum (CD3OD) δ(,,m): 2,1
5 (3H, s), 3.02 (3H, s) 3.18, 3,
56 (2H, AB-Q, J=18Hz), 4.59, 5
．． 08 (2H, AB-Q, J=12z), 7-{2-(3-mesylaminophenyl)-D obtained as above
-glycinamide}-3-methyl-3-cephem-4-
Zinc dust 19 was added to a solution consisting of 517.8 watts of hydrochloride of carboxylic acid 2,2,2-trichloroethyl ester and 5 ml of 90% acetic acid, and the mixture was stirred for 3 hours under ice cooling.

The reaction solution is filtered and washed twice with 90% acetic acid 5TfLe. The washings and the filter solution are combined and concentrated under reduced pressure. Toluene is added to the residue and concentrated under reduced pressure again. 3 ml of water and 6 WL of ethyl acetate are added to the residue to dissolve it, and the pH is adjusted to 4 with a 20% aqueous sodium hydroxide solution. Shake this thoroughly and
The aqueous layer is separated, washed with ethyl acetate, and then treated with activated carbon. After concentrating this to about 2 ml and crystallizing it under ice-cooling, the precipitated crystals were filtered out and washed sequentially with water, acetone, and ether. 2-(3-mesylaminophenyl)-D-
212.4 w of glycinamide}-3-methyl-3-cephem-4-carboxylic acid are obtained. Example 10 7-{N-3 produced in the same manner as the first step of Example 1
2,2,2-trichloroethyl ester of 2-(3-mesylaminophenyl)-D-glycinamide}-13-methyl-3-cephem-4-carboxylic acid 2.6869 and dioxylic acid After stirring the solution consisting of 207!11 at room temperature for 2.5 hours, it is concentrated under reduced pressure, toluene is added to the residue and concentrated again.

This was dissolved in a solution consisting of 13 ml of glacial acetic acid and 1.5 ml of water, and 39 ml of zinc dust was added over 5 minutes under ice cooling, followed by stirring at the same temperature for 4 hours. After adding 10 ml of acetic acid to the reaction solution and stirring for 5 minutes, it was filtered and washed with 10 ml of acetic acid. The washing liquid was combined with the bottom liquid and concentrated under reduced pressure, and the residue was dissolved in 7 ml of water.
After dissolving in a mixture of 15T11 and ethyl acetate, 20
% aqueous sodium hydroxide solution is added dropwise while stirring on ice. After thoroughly shaking the mixture, the aqueous layer is separated, washed with ethyl acetate, treated with activated carbon, and left overnight in a refrigerator. The precipitated crystals were filtered out and washed sequentially with water, acetone and ether, resulting in an Mpl of 92-193.5℃ (decomposition).
1.41 g of 7-{2-(3-mesylaminophenyl)-D-glycinamide}-3-methyl-3-cephem-4-carboxylic acid is obtained. 4 Example 11 7-{{N-tert-butoxycarbonyl-2-(3-mesylaminophenyl)-D-glycinamide}-3-methyl- produced in the same manner as the first step of Example 1 A solution consisting of 1.3439 ml of 2,2,2-trichloroethyl ester of 3-cephem-4-carboxylic acid and 12 ml of dioxylic acid is stirred at room temperature for 2.5 hours, and then 4 ml of methyl isobutyl ketone are added.

To this, 4.329 g of zinc powder was added over 30 minutes while stirring under ice cooling, and the mixture was stirred at the same temperature for 6 hours.

After the reaction solution was filtered and washed with 0.5 ml of acidic acid, the washings were combined with the filter solution and concentrated under reduced pressure. After adding benzene to the residue and concentrating it again, 10 ml of water: F6 and 20 ml of methyl isobutyl ketone were added. After thoroughly shaking this, the aqueous layer is separated and further washed with 10 ml of methyl isobutyl ketone. This aqueous layer was adjusted to pH 4 with 10% hydrochloric acid under ice cooling, and then left overnight in a refrigerator. The precipitated crystals are mixed with water,
After washing with acetone and ether and drying,
736.7 η of 7-{2-(3-mesylaminophenyl)-D-glycinamide}-3-methyl-3-cephem-4-carboxylic acid with an Mpl of 92-193° C. (decomposition) is obtained.

Claims (1)

[Claims] 1 7-amino-3- represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 means a hydrogen atom or an alkyl-substituted thiadiazolylthio group)
Substituted-3-cephem-4-carboxylic acids or their esters or salts have general formulas▲mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_2 means an alkyl group, and X means an amino group or a protected amino group, respectively. 7 expressed by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R_1, R_2 and X have the same meanings as before) A process for producing 7-substituted acylamino-3-substituted-3-cephem-4-carboxylic acids, which comprises obtaining -substituted acylamino-3-substituted-3-cephem-4-carboxylic acids or esters thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 means a hydrogen atom or an alkyl-substituted thiadiazolylthio group) 7-amino-3-
Substituted-3-cephem-4-carboxylic acids or their esters or salts have general formulas▲mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_2 means an alkyl group, and X means an amino group or a protected amino group, respectively. The reaction product is then subjected to hydrolysis of the ester and/or elimination reaction of the amino protecting group to obtain the general formula ▲ formula, There are chemical formulas, tables, etc. ▼ (In the formula, R_
7-substituted acylamino-3-substituted-3-substituted acylamino-3-substituted-3-carboxylic acid or its ester (1 and R_2 have the same meanings as above) Method for producing cephem-4-carboxylic acids.