JPH0321555B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a novel cefem compound, and more particularly to a method for producing 7-substituted-3-cephem-4-carboxylic acid and its salts, which are useful as antibacterial agents. The method for producing the cefem compound provided by this invention is represented by the following reaction formula. [wherein R ¹ is amino or protected amino,
R ² is carboxy or its ester, R ³ is hydrogen,
means lower alkyl, lower alkenyl, lower alkynyl or cyclo(lower) alkyl, respectively] The terms and definitions stated in this specification are as follows. 2-amino or 2-protected aminothiazole-
The 4-yl group has a tautomeric relationship with the 2-imino or 2-protected iminothiazolin-4-yl group. The tautomerism of the thiazolyl group and thiazolinyl group can be shown by the following balanced equation. (wherein R ¹ is amino or protected amino,
R ¹ 'imino or protected imino) Therefore, the two groups represented by the above formula are essentially the same, and isomers containing such groups are considered to be the same compound. Therefore, both tautomeric forms of compounds having such groups in the molecule are included within the scope of this invention. In this specification, for convenience, the expression "2-amino (or protected amino) thiazol-4-yl" and the formula (In the formula, R ¹ has the same meaning as before.) Let us comprehensively express it as follows. The "protecting group" in "protected amino" represented by R ¹ is a general N-protecting group, such as substituted or unsubstituted aryl (lower) alkyl (e.g. benzyl, benzhydryl, trityl,
4-methoxybenzyl, 3,4-dimethoxybenzyl, etc.), halo(lower)alkyl (e.g. trichloromethyl, trichloroethyl, trifluoromethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene,
Examples include substituted cycloalkylidene and acyl. "Acyl" in the protecting group includes substituted or unsubstituted lower alkanoyl (e.g. formyl,
acetyl, chloroacetyl, trifluoroacetyl, etc.), substituted or unsubstituted aryl (lower) alkanoyl (e.g. phenyl acetyl, phenylpropionyl, etc.), substituted or unsubstituted lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, trichloroethoxycarbonyl, 2
-pyridylmethoxycarbonyl, etc.), substituted or unsubstituted aryl (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.), lower cycloalkoxycarbonyl (e.g. cyclopentyloxycarbonyl,
(cyclohexyloxycarbonyl, etc.), 8-quinolyloxycarbonyl, succinyl, phthaloyl, etc. Furthermore, this protecting group also includes reaction products of boron compounds, silicon compounds, aluminum compounds or phosphorus compounds with amino groups, such compounds as trimethylsilyl chloride, trimethoxysilyl chloride, boron trichloride,
Examples include butoxyboron dichloride, aluminum trichloride, diethoxyaluminum chloride, phosphorus dibromide, phenyl phosphorus dibromide, and the like. Preferred examples of carboxy esters represented by ^R2 include alkyl esters (e.g. methyl ester, ethyl ester, propyl ester,
Isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, heptyl ester, octyl ester,
1-cyclopropylethyl ester, etc.), alkenyl esters (e.g. vinyl ester, allyl ester, etc.), alkynyl esters (e.g. ethynyl ester, propynyl ester, etc.), alkoxyalkyl esters (e.g. methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester) , 1-methoxyethyl ester,
1-ethoxyethyl ester, etc.), alkylthioalkyl esters (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.), haloalkyl esters (e.g., 2-iodoethyl ester, 2,2,2- trichloroethyl ester, etc.), alkanoyloxyalkyl esters (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester,
pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, palmitoyloxymethyl ester, etc.), alkanesulfonylalkyl ester (e.g. mesylmethyl ester, 2-mesylethyl ester, etc.) , substituted or unsubstituted aralkyl esters (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4
-hydroxy-3,5-ditertiary butyl benzyl ester, etc.), substituted or unsubstituted aryl esters (e.g. phenyl ester, tolyl ester,
tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, etc.), esters with silyl compounds (e.g. trialkylsilyl compounds, dialkylalkoxysilyl compounds or trialkoxysilyl compounds), e.g. Silyl esters (e.g. trimethylsilyl ester, triethylsilyl ester, etc.), dialkyl alkoxysilyl esters (e.g. dimethylmethoxysilyl ester, dimethylethoxysilyl ester, diethylmethoxysilyl ester, etc.), trialkoxysilyl esters (e.g. trimethoxysilyl ester, triethoxysilyl ester, etc.) esters, etc.). Examples of "lower alkyl" in R ³ include:
Examples include methyl, ethyl, propyl, butyl and the like. Examples of the "lower alkenyl" for R ³ include vinyl, allyl, propenyl, butenyl, and the like. Examples of the "lower alkynyl" for R ³ include ethynyl, propynyl, butynyl, and the like. Examples of the "cyclo(lower) alkyl" for R ³ include cyclobutyl, cyclopentyl, cyclohexyl, and the like. The manufacturing method of this invention will be explained below. The target compound () and its salt can be obtained by reacting the compound () or its salt with the compound () or its salt. The starting compound () is a new compound and is produced by the method described below.

[Table] ↓

[Table] (In the formula, R ¹ and R ² have the same meanings as before.) Examples of compounds () include hydroxylamine, lower alkoxyamine (e.g. methoxyamine, ethoxyamine, propoxyamine, butoxyamine, etc.), lower alkenyl Oxyamines (e.g. vinyloxyamine, allyloxyamine,
propenyloxyamine, butenyloxyamine, etc.), lower alkynyloxyamines (e.g., ethynyloxyamine, propynyloxyamine, butynyloxyamine, etc.) or cyclo(lower) alkoxyamines (e.g., cyclobutoxyamine,
cyclopentyloxyamine, cyclohexyloxyamine, etc.). Salts of the compound () include hydrochloride, hydrobromide, sulfate and the like. The reaction is usually carried out in a solvent such as water, alcohol, etc., which does not adversely affect the reaction, and the reaction temperature is appropriately selected from the range of cooling to heating. When using a salt of the compound (), for example, an alkali metal hydroxide (e.g. sodium hydroxide,
potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkaline earth metal phosphates (e.g., magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphates (e.g.,
Inorganic bases such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), alkali metal acetates (e.g.
sodium acetate, potassium acetate, etc.), trialkylamines (e.g., trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine,
N-methylmorpholine, 1,5-diazabicyclo[4,3,0]-5-nonene, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-7 - carried out in the presence of a base, such as an organic base such as undecene. Next, examples of the present invention will be described. Production of raw material compound (2) Production example (1) Hydrochloride of 4-nitrobenzyl ester of 7-amino-3-cephem-4-carboxylic acid (9
g), trimethylsilylacetamide (24.81
g) and bis(trimethylsilyl)acetamide (9ml) were added to dry ethyl acetate (100ml) and stirred at 45°C for 1 hour. On the other hand, combine phosphoryl chloride (8.4 ml) with dimethylformamide (4.0 ml) and dry ethyl acetate (16.0 ml).
was added dropwise to the stirred mixture under ice-cooling, and stirring was continued for a while. To this solution, add ethyl acetate (240 ml) and 2-
(2-Formamido-4-thiazolyl)glyoxylic acid (5.35 g) was slowly added at -3°C, and the resulting mixture was stirred at the same temperature for 15 minutes. This solution was added dropwise to the cephalosporin compound-containing solution obtained above at -15°C, and further stirred at the same temperature for 30 minutes. Further water (50 ml) was added, and the precipitate was filtered, washed with water, and dried over phosphorus pentoxide under reduced pressure.
(2-formamido-4-thiazolyl)glyoxyroylamino]-3-cephem-4-carboxylic acid 4-nitrobenzyl ester (7.124 g) was obtained. The ethyl acetate layer was separated, washed with saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. When this was concentrated under reduced pressure, the same target substance (1.03 g) as above was recovered. Total yield 8.154g IRνNujiol max: 1775, 1725, 1650cm ^-1 NMRδ (DMSO-d ₆ , ppm): 3.65 (2H, m),
5.17 (1H, d, J = 5.2Hz), 5.42 (2H, s),
5.90 (1H, dd, J = 5.2Hz, 7.8Hz), 6.66 (1H,
t, J = 5.0Hz), 7.67 (2H, d, J = 9Hz),
8.22 (2H, d, J = 9Hz), 8.39 (1H, s),
8.55 (1H, s), 9.87 (1H, d, J = 7.8Hz) (2) 7-[2-(2-formamido-4-thiazolyl)glyoxyroylamino]-3-cephem-4-carboxylic acid 4 - A mixture of nitrobenzyl ester (3.0 g), methanol (60 ml) and tetrahydrofuran (80 ml) is added to a mixture of 10% palladium on carbon (1.5 g), acetic acid (10 ml) and methanol (10 ml) in an atmosphere of nitrogen gas. In addition, catalytic reduction was carried out at normal pressure and room temperature for 4 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The precipitate was collected by filtration, washed with diisopropyl ether (50 ml), and dried to obtain a powder (1.34 g). A mixture of water (100 ml) and ethyl acetate (100 ml) was added to this powder, and the pH was adjusted to 6.0 with sodium bicarbonate, and the aqueous layer was separated and washed with ethyl acetate and diethyl ether. The remaining ether was distilled off by blowing in nitrogen gas, and the aqueous solution was pH adjusted with 10% hydrochloric acid.
Adjusted to 2.0. The obtained crystals were collected by filtration and dried with phosphorus pentoxide to give 7-[2-(2-formamido-4-thiazolyl)glyoxyroylamino]
-3-cephem-4-carboxylic acid (0.47 g) was obtained. On the other hand, the filtrate was concentrated under reduced pressure, and a mixture of diethyl ether and petroleum ether was added to the residue for crystallization. This was collected by filtration, washed with diethyl ether and petroleum ether, and dried under reduced pressure to obtain the same target substance (1.1 g) as above.
Total yield: 1.57g IRνnujiol max: 1780, 1670cm ^-1 NMRδ (DMSO-d ₆ , ppm): 3.63 (2H, m, J
= 4Hz), 5.17 (1H, d, J = 5.2Hz), 5.87
(1H, dd, J = 5.2Hz, 8.2Hz), 6.53 (1H,
t, J=4Hz), 8.42 (1H, s), 8.59 (1H,
s), 9.83 (1H, d, J = 8.2Hz) (3) 7-[2-(2-formamido-4-thiazolyl)glyoxyroylamino]-3-cephem-4-carboxylic acid (2.44 g) Methanol (40
ml) To the solution was added a mixture of concentrated hydrochloric acid (2.44 g) and methanol (10 ml) under ice-cooling, and the mixture was stirred at 20-22°C for 5 hours and then filtered. The filtrate was concentrated under reduced pressure;
Water (100 ml) was added to the residue, and while stirring, sodium hydrogen carbonate was added to adjust the pH to 6.5, followed by filtration.
Wash the filtrate with ethyl acetate and add 10% hydrochloric acid.
The pH was set to 3.5. The generated precipitate was collected by filtration, washed with water, and dried over phosphorus pentoxide under reduced pressure to obtain 7-[2-
(2-Amino-4-thiazolyl)glyoxyroylamino]-3-cephem-4-carboxylic acid (0.492 g) was obtained. The filtrate and washing liquid are collected using porous nonionic adsorption resin “Diaion HP-20”.
(trademark, manufactured by Mitsubishi Chemical Industries, Ltd.) column chromatograph, and eluted with 15% isopropanol. The isopropanol was distilled off under reduced pressure, and the residual liquid was freeze-dried to obtain the same target substance (1.561 g) as above. Total yield 2.053g IRνNujiol max: 1780, 1668cm ^-1 NMRδ (D ₂ O, ppm): 3.57 (2H, m), 5.17
(1H, d, J = 4.8Hz), 5.78 (1H, d, J =
4.8Hz), 6.33 (1H, m), 8.26 (1H, s) Example 1 7-[2-(2-amino-4-thiazolyl)glyoxyroylamino]-3-cephem-4-carboxylic hydrochloride (1.78 g) in water (100 ml),
While stirring under ice cooling, sodium hydrogen carbonate was added to adjust the pH to 6.0. Sodium acetate (0.38 g) and methoxylamine hydrochloride (1.37 g) were added to this solution, the pH was adjusted to 7.0 with sodium hydrogen carbonate, and the mixture was stirred at 48°C for 1 hour. Add this solution to ethyl acetate (200ml)
and diethyl ether (100 ml), and the diethyl ether was distilled off by blowing nitrogen gas into the mixture. The pH was adjusted to 3.5 by adding 10% hydrochloric acid to the aqueous solution while stirring on ice. The precipitate was collected by filtration, washed with water, and dried over phosphorus pentoxide under reduced pressure to obtain 7-[2-
(2-amino-4-thiazolyl)-2-methoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 120 mg) was obtained. mother liquor,
Porous nonionic adsorption resin “Diaion HP-”
20" (trademark, manufactured by Mitsubishi Chemical Industries, Ltd.) column chromatograph, and eluted with 40% aqueous acetone. The extract was concentrated under reduced pressure, lyophilized, and further dried with phosphorus pentoxide to obtain the same target substance (950
mg) was obtained. Total yield 1070mg. IRνnujiol max: 3460, 3290, 3150, 1780,
1655, 1623 cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.60 (2H, broad
s), 3.84 (3H, s), 5.12 (1H, d, J=5
Hz), 5.84 (1H, d, d, J = 5Hz, 8Hz),
6.52 (1H, t), 6.76 (1H, s), 7.26 (2H,
Example 2 According to the method of Example 1, the following compound was obtained. (1) 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3
-Cefem-4-carboxylic acid (syn isomer) IRνnudiol max: 3350-3200, 1770, 1670,
1630cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.60 (2H, broad
s), 5.10 (1H, d, J=5Hz), 5.83 (1H,
dd, J = 5Hz, 8Hz), 6.47 (1H, t, J =
4Hz), 6.67 (1H, s), 9.47 (1H, d, J=
8Hz) (2) 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide]-3-
Cefem-4-carboxylic acid (syn isomer) IRνnudiol max: 3500, 3300, 3200, 1785,
1625, 1600 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.20 (3H, t, J
=7Hz), 3.57 (2H, m), 4.08 (2H, q, J
=7Hz), 5.08 (1H, d, J = 5Hz), 5.83
(1H, dd, J = 5Hz, 8Hz), 6.47 (1H,
m), 6.73 (1H, s), 7.20 (2H, m), 9.58
(1H, d, J=8Hz) (3) 7-[2-(2-aminothiazol-4-yl)-2-propoxyiminoacetamide]-3
-Cefem-4-carboxylic acid (syn isomer) IRνnudiol max: 3250, 1770, 1650, 1660,
1620cm ^-1 NMRδ (DMSO-d ₆ , ppm): 0.93 (3H, t, J
= 7Hz), 1.67 (2H, sextet, J = 7Hz),
3.60 (2H, m), 4.03 (2H, t, J=7Hz),
5.13 (1H, d, J = 5Hz), 5.83 (1H, dd, J
=5Hz, 8Hz), 6.48 (2H, t, J = 4Hz),
6.70 (1H, s), 7.18 (2H, m), 9.53 (1H,
d, J=8Hz) (4) 7-[2-(2-aminothiazol-4-yl)-2-butoxyiminoacetamide]-3-
Cefem-4-carboxylic acid (syn isomer) IRν Nudiol max: 3320, 1775, 1660 cm ^-1 NMR δ (DMSO-d ₆ , ppm): 0.88 (3H, t, J
=7Hz), 1.1-1.9 (4H, m), 3.58 (2H,
broad s), 4.05 (2H, t, J=7Hz), 5.08
(1H, d, J=5Hz), 5.80 (1H, dd, J=
5Hz, 8Hz), 6.44 (1H, broad s), 7.18
(2H, s), 9.51 (1H, d, J = 8Hz) (5) 7-[2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetamide]
-3-Cefem-4-carboxylic acid (syn isomer) IRν Nudiol max: 3300, 1775, 1650, 1540 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 0.6-2.0 (9H,
m), 3.56 (2H, d, J=2Hz), 4.03 (2H,
t, J = 6Hz), 5.08 (1H, d, J = 5Hz),
5.81 (1H, dd, J=5Hz, 8Hz), 6.46 (1H,
t, J=4Hz), 6.69 (1H, s), 7.20 (2H,
s), 9.15 (1H, d, J = 8Hz) (6) 7-[2-(2-aminothiazol-4-yl)-2-hexyloxyiminoacetamide]
-3-Cefem-4-carboxylic acid (syn isomer) IRν Nudiol max: 3250, 1760, 1640, 1600 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.88 (3H, m),
1.1−1.9 (8H, m), 3.60 (2H, m), 4.06
(2H, t, J = 6Hz), 5.10 (1H, t, J =
5Hz), 5.82 (1H, dd, J=5Hz, 8Hz),
6.46 (1H, m), 6.70 (1H, s), 7.26 (2H,
m), 9.56 (1H, d, J = 8Hz) (7) 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamide]-
3-Cefem-4-carboxylic acid (syn isomer) IRν Nudiol max: 3300, 1780, 1660, 1630 cm ^-1 NMR δ (DMSO-d ₆ , ppm): 3.67 (2H, d, J
= 4Hz), 4.67 (2H, m), 5.17 (1H, d, J
=5Hz), 5.25 (1H, m), 5.50 (1H, m),
5.90 (1H, dd, J=5Hz, 8Hz), 6.03 (1H,
m), 6.55 (1H, m), 6.80 (1H, s), 7.50
(2H, m), 9.68 (1H, d, J = 8Hz) (8) 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamide]-3-cephem-4-carvone Acid (syn isomer) IRν Nudiol max: 3500, 3300, 1780, 17 0, 1660, 1630 cm ^-1 NMR δ (DMSO-d ₆ , ppm): 3.48 (1H, m),
3.67 (2H, m), 4.80 (2H, d, J=2Hz),
5.17 (1H, d, J = 5Hz), 5.88 (1H, dd, J
=5Hz, 8Hz), 6.55 (1H, m), 6.85 (1H,
s), 7.33 (2H, m), 9.73 (1H, d, J=8
Hz) (9) 7-[2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer) IRνnudiol max: 3350, 1775, 1665, 1620,
1540cm ^-1 NMRδ (DMSO−d ₆ , ppm): 0.8−2.2 (10H,
m), 3.60 (2H, broad s), 4.04 (1H, m),
5.09 (1H, d, J = 5Hz), 5.83 (1H, dd, J
=5Hz, 9.Hz), 6.45 (1H, t, J = 4Hz),
6.67 (1H, s), 7.19 (2H, s), 9.48 (1H,
d, J=9Hz)

Claims (1)

[Claims] 1. General formula (wherein R ¹ is amino or protected amino,
R ² means carboxy or its ester) or a salt thereof has the general formula R ³ −ONH ₂ () (where R ³ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cyclo (lower ) means alkyl) or its salt is reacted to form the general formula (wherein R ¹ , R ² and R ³ each have the same meaning as above) A method for producing a cefem compound or a salt thereof, which is characterized by obtaining a cefem compound or a salt thereof.