JPH0717653B2 - Cem compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to formula (I)(In the formula, -COOR is a carboxylate ion, a carboxylic acid,
Metal salts of carboxylic acids or esterified carboxyls
The group is X Means an anion that constitutes an inorganic or organic acid
To taste. However, when COOR means carboxylate ion
, X is not necessarily required)
And a salt thereof.

<Structure of the Invention> More specifically, the cephem compound represented by the formula (I) is represented by the formula (Ia) 7β-amino-3- [4- (oxazole-
5-yl) -1-pyridinio] methyl-3-cephem-
4-carboxylate and salts thereof, and a compound of formula (Ib) COOR and X are the same as above) 7β-amino-3
-[4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylic acid salt and its salt can be shown separately.

The compound of the present invention is a cephalosporin antibiotic, especially compound 7β- [2- (2-aminothiazole-) having an excellent antibacterial action described in Japanese Patent Application No. 59-126773 (filed June 20, 1984). 4-yl) -2-methoxyiminoacetamido] -3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate useful as an intermediate. .

-COOR in the compound of the present invention has the above-mentioned meaning,
More specifically, it is as follows.

That is, -COOR is a carboxylate ion and -COO To
Means when --COOR represents a metal salt of a carboxylic acid.
Alkali metals and alkaline earth metals are
It is typically illustrated.

Also, when -COOR means an ester, it can be removed under mild organic chemical conditions such as t-butyl ester, p-methoxybenzyl ester, p-nitrobenzyl ester, diphenylmethyl ester, pivaloyloxymethyl ester. And various esters.

On the other hand, X Specific examples of are as follows.

That is, examples of anions constituting inorganic acids include halogen anions such as chlorine, bromine and iodine, sulfate ions, phosphate ions and the like, and examples of anions constituting organic acids include carboxy such as acetic acid and propionic acid. A typical example is rate ion. When the compound of the present invention forms a salt, for example, formates, acetates, trifluoroacetates, trifluoromethanesulfonates, methanesulfonates, oxalates, etc. Examples of the salt include salts with hydrochlorides, sulfates, perchlorates, nitrates, and other organically acceptable mineral acids. In addition, each of these salts is in the hydrated state, alcohols such as methanol, ethanol and isopropyl alcohol, ethers such as diethyl ether and isopropyl ether, esters such as ethyl acetate, and organic compounds such as dichloromethane, chloroform and benzene. It may exist in the form of a solvate with an organic solvent usually used in chemistry.

The hydrochloride salt and trifluoroacetate salt of the compound represented by the formula (Ia) in the compound of the present invention have been successfully obtained as crystals. For example, crystals of the monohydrochloride trihydrate of the compound of formula (Ia) are obtained by powder X-ray diffraction [d = lattice spacing, using copper X-ray with λ = 1.5418Å using a nickel filter]. I / I ₁ =
Relative intensity] shows the following characteristics.

In addition, it is easily expected that the crystals shown here change their hydrate state depending on the drying conditions, and that they can be converted into other salts after being neutralized with a base.

The compound of formula (I) of the present invention can be prepared according to the following reaction scheme.

R in the above formula₂Is a phenylmethyl group, 1-benzamide-1
-Functions that do not affect the reaction such as carboxybutyl group
R represents an optionally substituted alkyl group, R₃Is hydrogen or
A salt state such as thorium or potassium or a t-butyl group,
p-methoxybenzyl group, p-nitrobenzyl group, dif
Suitable for phenylmethyl group, pivaloyloxymethyl group, etc.
Indicates an alkyl group. Y is a halogen such as chlorine, bromine or iodine
And Z has the same meaning as an acetoxy group or Y. However
Y when COOR means carboxylate Be sure
Does not even need.

Hereinafter, each step will be described.

[Quaternization Step] When Z is an acetoxy group represented by the formula (III),
After dissolving or suspending the compound of formula (III) in water or a water-acetonitrile mixed solvent, excess sodium iodide and 5- (4-pyridyl) oxazole are added, and the mixture is stirred at room temperature to 10
Stir at 0 ° C, preferably while heating to 60-80 ° C.
At this time, the pH of the reaction mixture is preferably 4 to 8, and an acid or a base is sometimes added to adjust the pH. After the reaction, for example, the reaction mixture is added to a large amount of acetone, and the precipitate is collected by filtration.

When Z is Y represented by the formula (III), the compound of the formula (III) is dissolved or suspended in an organic solvent such as dichloromethane, chloroform or acetone, and then an excess of 5- (4 -Pyridyl) oxazole was added and 0-10
Stir at 0 ° C, preferably at 5 ° C to room temperature. After the reaction, the precipitate is collected by filtration. If no precipitate is formed, the solvent is distilled off, the residue is solidified with ether or the like, and collected by filtration.

By the method described above, the compound represented by the formula (IV) is obtained.

In the quaternization step, when Z is chlorine in the compound represented by the formula (III), it is treated with excess sodium iodide in an organic solvent such as acetone at 0 ° C to room temperature,
A method is preferred in which the iodine compound is once used and then replaced with 5- (4-pyridyl) oxazole.

[Deacylation Step] The compound represented by the formula (IV) is treated with phosphorus pentachloride or the like in the presence of a base such as N, N-dimethylaniline, pyridine or triethylamine to give a solution of iminochloride. In this case, the reaction solvent is preferably anhydrous methylene chloride or chloroform, and the reaction temperature is preferably low, particularly -10 ° C or lower. Then, the resulting solution of imino chloride is mixed with a solution in which alcohol such as 1,3-butanediol is dissolved, and hydrolyzed via imino ether. In this case, the solvent for dissolving the alcohol such as 1,3-butanediol is preferably methylene chloride or chloroform. As the reaction proceeds, the deacylated hydrochloride salt precipitates, and the compound of formula (I) is obtained by filtering this.

In the compound represented by the formula (IV), -COOR is a
Means ruboxylate ion, Y When there is no
When the compound represented by formula (IV) is dissolved in an anhydrous solvent,
After suspension, trimethylchlorosilane or bistrisilane
When using a silylating agent such as methylsilylacetamide,
Include N, N-dimethylaniline, triethylamine, etc.
Silylation is performed by adding a base to obtain a silyl ester. Profit
Subject the resulting silyl ester to the deacylation reaction described above.
Good.

The compound represented by the formula (I) of the present invention includes the compound represented by the formula (Ia) and the compound represented by the formula (Ib), and the compound represented by the formula (Ia) is represented by the formula (Ia). It can also be produced by deesterifying the compound of b). For example, the hydrochloride salt of formula (Ib) is sometimes added with a cation scavenger such as anisole and treated with an acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, hydrochloric acid or palladium. -The salt represented by the formula (Ia) can be obtained by hydrogenolysis in the presence of a catalyst such as carbon or Raney nickel.

When an acid is used in this deesterification step, even if the ester of the compound represented by formula (Ib) as the starting material is the hydrochloride, the compound represented by formula (Ia) is It is often replaced with salt.

<Effects of the Invention> As described above, the compound of the present invention is not only extremely useful as an intermediate for excellent pharmaceutical substances, but also has the following characteristics.

That is, generally, the cephem compound is difficult to crystallize, but among the compounds of the present invention, the hydrochloride salt and trifluoroacetate salt of the compound of the formula (Ia) are water or a soluble solvent such as water-isopropyl alcohol and an insoluble solvent. It could be crystallized from a mixture with. The fact that this type of compound can be isolated as crystals is extremely valuable industrially, such as increasing the purity of the final drug.

The present invention will be described below with reference to Examples and Reference Examples.

Example 1 7β-Amino-3- [4- (oxazol-5-yl)
Hydrochloride of -1-pyridinio] methyl-3-cephem-4-carboxylate 7β- (D-5-benzamido-5-carboxypentanamide) -3-acetoxymethyl-3-cephem-4
-Carboxylic acid 59 g, 5- (4-pyridyl) oxazole 4
2.7 g, sodium iodide 226 g and water 75 ml under nitrogen stream 60
Heat to ° C and stir for 3 hours. After the reaction, the reaction mixture was added to 1.
Add to 5 acetone with stirring, collect the precipitate by filtration,
After washing with acetone and ether, vacuum drying, 7β-
63.7 g of a crude product of (D-5-benzamido-5-carboxypentanamide) -3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate (Compound A). As a powder.

30 g of crude compound A and 37.6 ml of N, N-dimethylaniline
While stirring at room temperature in 600 ml of anhydrous methylene chloride, 37.6 ml of trimethylchlorosilane was added, and the mixture was stirred at the same temperature for 1 hour.
After that, the reaction mixture is cooled to −35 ° C., 31 g of phosphorus pentachloride is added, and the mixture is stirred at the same temperature for 1 hour. Then, 46 ml of 1,3-butanediol was dissolved in 380 ml of anhydrous methylene chloride, and the reaction mixture was added to the solution cooled to -20 ° C with stirring to about 1: 1.
The temperature is raised to 0 ° C. over time. After the reaction was completed, the precipitate was collected by filtration, washed with methylene chloride and ether, and dried in vacuum to give 7β-amino-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-. 25.1 g of crude dihydrochloride salt of 4-carboxylate (compound B) are obtained as a powder.

The crude product obtained here can be used for the reaction and the like of Reference Example 1 without purification.

The crude dichlorine salt (1.8 g) was subjected to reverse phase high performance liquid chromatography (carrier develocyl), and water-1N hydrochloric acid (50
(0: 1) was developed, and the precipitated crystals obtained by concentrating the fraction containing the target substance were collected by filtration with a small amount of water-ethanol (1: 3) mixed solution, and a small amount of water-ethanol (1: 3). The monohydrochloride of compound B is obtained by washing with the mixed solution of 1) and vacuum drying.

FT-NMR (δ value ppm in D ₂ O): 3.39, 3.76 (2H, ABq, J = 18Hz, H at 2nd position of cephem ring) 5.26 (1H, d, J = 6Hz, H at 6th position of cephem ring) 5.37 (1H, d, J = 6Hz, H at the 7th position of the cephem ring) 5.40,5.59 (2H, ABq, J = 14Hz, H of CH ₂ group at the 3rd position of the cephem ring) 8.24 (1H, s, 4th position of the oxazole ring) H) 8.37 (2H, 2, J = 7Hz, H at the 3rd position of the pyridine ring) 8.58 (1H, s, H at the 2nd position of the oxazole ring) 8.99 (2H, d, J = 7Hz, H at the 2nd position of the pyridine ring) Moisture value measured by Karl Fischer method: 12.8% Elemental analysis C ₁₆ H ₁₄ N ₄ O ₄・ HCl ・ 3H ₂ O theoretical value C 42.81, H 4.71, N 12.48, S 7.14, Cl 7.90 analytical value C 42.78, H 4.50, N 12.44, S 7.42, Cl 8.20 Example 2 7β-Phenylacetamido-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylic acid p-methoxybenzyl Ester iodide 7β-phenylacetamide-3-chloromethyl-3 −
72 g of cephem-4-carboxylic acid p-methoxybenzyl ester and 112 g of sodium iodide were dissolved in 650 ml of acetone, and the mixture was stirred for 3 hours under ice cooling. After that, acetone was distilled off, the residue was dissolved in a large amount of chloroform, washed with 10 sodium thiosulfate aqueous solution and water, dried over anhydrous sodium sulfate,
The chloroform is distilled off.

The obtained residue was dissolved in 50 ml of methylene chloride, and 5- (4-
44 g of pyridyl) oxazole was added, and the mixture was stirred at room temperature for 1 hour, and then stirred overnight in a constant temperature bath at 5 ° C. After the reaction, the precipitated crystals were collected by filtration, washed with chilled methylene chloride and ether, and dried under vacuum to give 7β-phenylacetamido-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-.
Cefem-4-carboxylic acid p-methoxybenzyl ester iodide (Compound C) 86 g is obtained.

FT-NMR (δ value ppm in DMSO-d ₆ ): 3.45 to 3.70 (4H, m, methylene at 2-position of cephem ring and methylene of phenylacetamide at 7-position) 3.74 (3H, s, methoxy group) 5.19 (1H, 1H, d, J = 6Hz, H at 6-position of cephem ring 5.28 (2H, ABq, J = 6Hz, methylene of P-methoxybenzyl ester) 5.58 (2H, bq, methylene at 3-position of cephem ring) 5.87 (1H, dd, J = 6 and 8Hz, H at the 7th position of the cephem ring) 6.94,7.38 (each 2H, each d, J = 8Hz, phenyl H of P-methoxybenzyl ester) 7.31 (5H, bs, 7th position of phenylacetamide phenyl) H) 8.46 (2H, d, J = 7.5Hz, H at the 3-position of the pyridine ring) 8.58 (1H, s, H at the 4-position of the oxazole ring) 8.97 (1H, s, H at the 2-position of the oxazole ring) 9.02 (2H, d, J = 7.5Hz, H at the 2-position of the pyridine ring) 9.20 (1H, d, J = 8Hz, H of the 7-position amide) Elemental analysis C ₃₂ H ₂₉ N ₄ O ₆ S Theoretical value C 53.04, H 4.03, N 7.73 Analytical value C 52.78, H 3.98, N 7.73 Example 3 7β-amino-3- [4 (Oxazol-5-yl)
-1-Pyridinio] methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride hydrochloride Phosphorus pentachloride 41.6 g Dissolved in 600 ml of anhydrous methylene chloride, 16 ml of pyridine was added, and after stirring at room temperature for 2 hours, -10 After cooling to ℃, add 29 g of compound C and stir at the same temperature for 5 hours. Then 1,3-
40 ml of butanediol are dissolved in 400 ml of anhydrous methylene chloride, the reaction mixture is added to the solution cooled to -40 ° C with stirring and stirred at -10 to -15 ° C overnight. After the reaction, the precipitate was collected by filtration, washed with methylene chloride and ether, and dried under vacuum to obtain 7β-amino-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylic acid. 24.5 g of acid p-methoxybenzyl ester chloride hydrochloride (Compound D) are obtained.

FT-NMR (δ value ppm in DMSO-d _{6 with} D ₂ O added): 3.74 (3H, s, methoxy group) 5.21 to 5.37 (4H, m, H and p- at the 6th and 7th positions of the cephem ring)
Methylene of methoxybenzyl ester) 5.62 (2H, ABq, J = 16Hz, methylene at the 3rd position of the cephem ring) 6.93,7.39 (2H each, d, J = 8Hz, phenyl H of P-methoxybenzyl ester) 8.40 (2H , d, J = 7.5 Hz, H at the 3-position of the pyridine ring) 8.54 (1H, s, H at the 4-position of the oxazole ring) 8.91 (1H, s, H at the 2-position of the oxazole ring) 8.98 (2H, d, J = 7.5 Hz, H at the 2-position of the pyridine ring) Example 4 7β-amino-3- [4- (oxazol-5-yl)
-1-Pyridinio] methyl-3-cephem-4-carboxylate trifluoroacetic acid salt To 10 g of the compound D obtained in Example 3 was added 20 ml of anisole, and 100 ml of trifluoroacetic acid was added while stirring with ice cooling.
Stir for 0 minutes. After the reaction, anisole and trifluoroacetic acid were distilled off, and ether was added to the residue for solidification and filtration to obtain a crude product. 25 ml of water is added to the obtained crude product, and the insoluble matter is filtered off.
300 ml of isopropyl alcohol was added dropwise to the filtrate while stirring with ice cooling, and the precipitated crystals were collected by filtration, washed with isopropyl alcohol, ether, and methylene chloride in this order, and dried under vacuum to obtain 7β-amino-3- [4- (oxazol-5-yl). -1-Pyridinio] methyl-3-cephem-4-carboxylate
6.5 g of crystals of trifluoroacetate are obtained.

FT-NMR (δ value ppm in D ₂ O): 3.38,3.74 (2H, ABq, J = 18Hz, H at 2nd position of cephem ring) 5.24 (1H, d, J = 6Hz, H at 6th position of cephem ring) 5.36 (1H, d, J = 6Hz, H at 7th position of cephem ring) 5.29,5.58 (2H, d, J = 14Hz, methylene at 3rd position of cephem ring) 8.23 (1H, s, H at 4th position of oxazole ring) 8.36 (2H, d, J = 7Hz, H at 3rd position of pyridine ring) 8.57 (1H, s, H at 2nd position of oxazole ring) 8.99 (2H, d, J = 7Hz, H at 2nd position of pyridine ring) By Karl Fischer method Moisture content: 3.5% Elemental analysis C ₁₆ H ₁₄ N ₄ O ₄ · S · CF ₃ COOH · H ₂ O Theoretical value C 44.08, H 3.49, N 11.42 Analytical value C 44.32, H 3.69, N 11.43 Obtained 7β-amino-3- [4- (oxazole-5)
-Yl) -1-pyridinio] methyl-3-cephem-4
Crystals of -carboxylate-trifluoroacetate-hydrate are powder X-ray diffraction using copper X-ray of λ = 1,5418Å with nickel filter [d = lattice spacing, I / I ₁ = relative Strength] indicates the following characteristics.

Reference Example 1 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate sulphate (syn isomer) 312 mg phosphorus pentachloride in 15 ml anhydrous methylene chloride. After dissolution, -3
Cooled to 0 ° C. and stirred with stirring 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid 444 m
Add g and stir for another 40 minutes at the same temperature. In the solution of the acid chloride thus obtained, the hydrochloride of compound B 47
A solution of 4 mg and bistrimethylsilylacetamide (1.5 ml) in anhydrous acetonitrile (10 ml) at room temperature was prepared at -30 ° C.
Add dropwise while keeping the temperature below and stir at the same temperature for 30 minutes. rear,
The reaction mixture is diluted with chloroform, the organic layer is washed with 8% brine and dried over anhydrous sodium sulfate. Ether was added to the residue obtained by distilling off the solvent to solidify and collect by filtration to obtain 7β.
-[2- (2-Tritylaminethiazol-4-yl)
900 mg of crude 2--2-methoxyacetamido] -3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate hydrochloride are obtained.

The crude product thus obtained was dissolved in 15 ml of formic acid, and at room temperature.
Stir for 1.5 hours. After that, the formic acid is distilled off, and ether is added to the residue to solidify it, followed by filtration. The obtained crude product is subjected to reverse phase high performance liquid chromatography [Carrier Develocyl] and developed with a mixed solution of water-acetonitrile (9: 1). The fraction containing the target product was concentrated, 2N sulfuric acid was added, and the precipitated crystals were collected by filtration to give 7β- [2- (2-tritylaminethiazol-4-yl) -2-methoxyacetamide] -3-.
[4- (oxazol-5-yl) -1-pyridinio]
147 mg of methyl-3-cephem-4-carboxylate hydrochloride (syn isomer) are obtained.

FT-NMR (δ value ppm in D ₂ O): 3.50,3.72 (2H, ABq, J = 18Hz, H at the 2nd position of the cephem ring) 4.05 (3H, s, methoxy group) 5.32 (1H, d, J = 5Hz, H at 6th position of cephem ring 5.36,5.60 (2H, ABq, J = 14Hz, H of CH ₂ group at 3rd position of cephem ring) 5.89 (1H, d, J = 5Hz, H at 7th position of cephem ring) 7.13 (1H, sd, H at the 5-position of the thiazole) 8.20 (1H, s, H at the 4-position of the oxazole ring) 8.33 (2H, d, J = 7Hz, H at the 3-position of the pyridine ring) 8.55 (1H, s, oxazole ring 2 H) 8.97 (2H, d, J = 7Hz, H at the 2nd position of the pyridine ring) Elemental analysis C ₂₂ H ₁₉ N ₇ O ₆ S ₂ · H ₂ SO ₄ · 2H ₂ O Theoretical value C 39.11, H 3.37, N 14,51, S 14.24 Analytical value C 38.87, H 3.31, N 14,27, S 14.45 Reference Example 2 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamido] -3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate hydrochloride (syn isomer) Phosphorus pentachloride (936 mg) in anhydrous methylene chloride (20 ml) After dissolution, -3
Cool to 0 ° C. and stir 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid 1.33 with stirring.
Add mg and stir for another 40 minutes at the same temperature. A solution of the acid chloride thus obtained was added dropwise to a solution prepared by dissolving 2.75 g of compound D and 5 ml of bistrimethylserial acetamide in 20 ml of anhydrous acetonitrile under cooling at -30 ° C.
Stir at 5-20 ° C for 50 minutes. After that, the reaction mixture is diluted with chloroform, the organic layer is washed with 8% saline and dried over anhydrous sodium sulfate. Ether was added to the residue obtained by distilling off the solvent to solidify and then collected by filtration to obtain 7β- [2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [4- (Oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride crude product
Get 2.55g.

The crude product thus obtained is dissolved in 50 ml of formic acid and stirred at room temperature for 3 hours. After that, the formic acid is distilled off, and ether is added to the residue to solidify it, followed by filtration. The obtained crude product is subjected to phase high performance liquid chromatography [Carrier Develosil] and developed with a mixed solution of water-acetonitrile (9: 1). After concentrating the fraction containing the desired product, 2N sulfuric acid was added, and the precipitated crystals were collected by filtration to give 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [4. −
500 mg of (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate sulphate (syn isomer) are obtained.

Elemental analysis C ₂₂ H ₁₉ N ₇ O ₆ S ₂・ H ₂ SO ₄・ 2H ₂ O theoretical value C 39.11, H 3.37, N 14,51, S 14.24 Analytical value C 38.91, H 3.48, N 14, The 53, S 14.00 NMR and IR spectral data were in agreement with those obtained in Reference Example 1.

 ─────────────────────────────────────────────────── ─── Continuation of front page (56) References JP-A-60-237090 (JP, A) JP-A-60-222490 (JP, A)

Claims (2)

[Claims] 1. Crystals of the hydrochloride of 7β-amino-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate. 2. Crystals of trifluoroacetic acid salt of 7β-amino-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate.