JPH0332554B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is a method for producing a β-lactam antibiotic derivative by acylating an amino group of a β-lactam antibiotic. Various β-lactam antibiotics obtained by acylating the amino group of 6-aminopenicillanic acid or 7-amibanosephalosporanic acid derivatives exhibit excellent antibacterial activity and are widely used as antibacterial agents. Many methods for acylating the amino group of 6-aminopenicillanic acid or 7-aminosephalosporanic acid derivatives are already known. Namely, acid chloride method using phosphorus pentachloride or thionyl chloride,
Vilsmeyer method with DMF-POCl ₃ , mixed acid anhydride method with isobutyloxycarbonyl chloride, N-hydroxybenzotriazole-
Examples include active esterification using DCC or triphenylphosphine-diethyl azodicarboxylate. These acylation methods have severe restrictions on the reaction temperature and the solvent used, and side reactions are likely to occur during the reaction. For example, the double bond at the 3-position of cephalosporin is rearranged to the 2-position, or when the acylating agent has an oxime group. If the acylating agent has a tert-butoxycarbonyl group, which is sensitive to acid, as a protecting group, the protecting group may be removed. These side reactions often make isolation of the target product complicated in conventional acylation methods. In addition, when an active esterification method such as N-hydroxybenzotriazole-DCC or triphenylphosphine-diethyl azocarboxylate is used, products derived from the reaction reagents are produced in addition to the side reactions mentioned above, resulting in the formation of the target compound. separation becomes difficult. The present inventors have studied various methods for acylating the amino groups of β-lactam antibiotics, and have made earnest efforts to overcome the above-mentioned drawbacks. The present invention has been completed by discovering that this is an extremely excellent acylation method that does not cause any side reactions and does not produce products that are difficult to separate using reaction reagents. In the general formula (), R ¹ is a hydrogen atom or an alkoxy group such as a methoxy or ethoxy group. R ² is a hydrogen atom, a metal atom (for example, lithium, sodium, or potassium)
or an ester residue [for example, a carboxyl group-protecting group (the carboxyl group-protecting group is not particularly limited, and the carboxyl group-protecting group of β-lactam antibiotics can be used. For example, tert-butyl, benzhydryl, , 2,2-trichloroethyl, allyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, methoxymethyl, benzyloxymethyl or phenacyl), -CHR ⁵ OCO ₂ R ⁶ group (wherein R ⁵ is hydrogen atom,
or a lower alkyl group such as a methyl, ethyl group, and R ⁶ is a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, tert-pentyl,
Hexyl or 3-hexyl, carbon number 1-6
cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. ), -CH ₂ OCOR ⁷ (wherein R ⁷ is a lower alkyl group, such as methyl, ethyl, propyl, isopropyl, isobutyl,
sec-butyl, isobutyl, or tert-butyl groups, or cycloalkyl groups substituted with lower alkyl groups, such as 1-methyl-1-cyclopentyl, 1-methyl-1-cyclohexyl, or 1-ethyl-1-cyclopentyl It is. )
It is. ]. A is

[Formula] or

[Formula] [In the formula, B is a hydrogen atom, a halogen atom, such as a fluorine, chlorine, or bromine atom, a lower alkoxy group, such as a methoxy, ethoxy, or propoxy group, a vinyl group, or -CH ₂ D (wherein D is a hydrogen atom , halogen atoms such as fluorine, chlorine, bromine or iodine atoms, lower alkoxy groups such as methoxy or ethoxy groups, acetoxy groups, carbamoyloxy groups, lower alkylthio groups such as methylthio or ethylthio groups, aromatic heterocyclic thio groups , for example 1-methyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio, 1-(2-dimethylaminoethane-1-yl)-1H-tetrazol-5-ylthio, 1 ，
3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, or 2,5-dihydro-6-hydroxy-
2-Methyl-5-oxo-as-triazine-3-
ylthio group, or pyridinio group, such as 1-pyridinio or 4-carbamoyl-1-pyridinio group). ]. The present invention is a method for producing a compound () by reacting a compound having the general formula () with a compound having the general formula () using phosphorus oxychloride in the presence of a base to lead to a compound having the general formula (). In the general formula (), R ³ is a chloromethyl group,
Dichloromethyl group, phenoxymethyl group which may have a substituent (the substituent is a halogen atom, such as chlorine or bromine atom, methoxy group, nitro group, or acetoxy group, and the substituent is ortho, meta, or ), an aromatic heterocyclic substituted methyl group, such as 2-tenyl, furfuryl, or a protected amino group (the protecting group for the amino group is not particularly limited and may be a normal protecting group for the amino group). For example, trityl, formyl, chloroacetyl, trifluoroacetyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, or allyloxycarbonyl. ) 2-aminothiazole-4-
ylmethyl group,

[Formula] Group [In the formula, R ⁸ is a phenyl group, a hydroxyl group at the ortho, meta, or para position, or a protected hydroxyl group (there are no particular limitations on the protecting group, and the protection of hydroxyl groups that is widely used is (for example, trimethylsilyl, tert-butyldimethylsilyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, allyloxycarbonyl, or 2,2,2-trichloroethoxycarbonyl), aromatic heterocyclic group,
For example, 2-furyl or 2-thienyl group,

[Formula] {where R ¹⁰ is a hydrogen atom or a hydroxyl group-protecting group (there are no particular limitations on the hydroxyl group-protecting group, such as trimethylsilyl, tert-butyldimethylsilyl, benzyloxycarbonyl,
Examples include p-nitrobenzyloxycarbonyl, allyloxycarbonyl, methoxymethyl, and tetrahydropyranyl. ). R ¹¹ is a lower alkyl group, such as a methyl, ethyl, propyl, isopropyl group. }. R ⁹ is a hydrogen atom, a protecting group for an amino group (there are no particular limitations on the protecting group for an amino group, such as formyl, acetyl, chloroacetyl, trifluoroacetyl, trityl, tert-butoxycarbonyl, 2,
2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, or allyloxycarbonyl), an acyl group R ¹² CO {wherein R ¹² is 4-ethyl-
2,3-dioxopiperazin-1-yl, 6,7-dihydroxychromone-3 with hydroxyl group protected
-yl, 4-hydroxy-6-methylpyridine-
3-yl, 4-hydroxy-1,5-naphthyridin-3-yl, or N-(3,4-dihydroxybenzoyl)-N-methylamino group (use a general hydroxyl protecting group) For example, acetyl, trifluoroacetyl, chloroacetyl, benzoyl, p
-Nitrobenzoyl, tetrahydropyranyl, methoxymethyl, benzyloxymethyl, trimethylsilyl, tert-butyldimethylsilyl, trityl, tert-butyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, p
-nitrobenzyloxycarbonyl or allyloxycarbonyl group. )}. ],

[Formula] [In the formula, R ⁸ has the same meaning as described above, and R ¹³ is a carboxy group, a protected carboxy group (the protecting group for the carboxy group is not particularly limited, but examples include tert-butyl, trityl, benzhydryl). , trimethylsilyl, tert-butyldimethylsilyl, 2,2,2-trichloroethyl, p
-nitrobenzyl, p-methoxybenzyl, or allyl), or a sulfonic acid group. },

[Formula] Group [In the formula, R ¹⁴ is a hydrogen atom or a protecting group for an amino group (There are no particular limitations on the protecting group for an amino group, such as trityl, formyl, chloroacetyl, trifluoroacetyl,
tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, or allyloxycarbonyl. ).
R ¹⁵ represents a straight chain or branched alkyl group which may have a substituent having 1 to 3 carbon atoms, such as methyl, ethyl, propyl, isopropyl group {substituents include methyl, ethyl, fluorine, These are chlorine, bromine atom, hydroxyl group, acetoxy group, dimethylamino group, or carboxy group. For example -
CH ₂ CH ₂ R ¹⁶ (in the formula, R ¹⁶ is a fluorine, chlorine, bromine atom,
A hydroxyl group, an acetoxy group, a dimethylamino group, or a carboxy group. ) or

[Formula] Group (in the formula, R ¹⁷ is a hydrogen atom, methyl, or ethyl group, R ¹⁸ is a hydrogen atom, methyl, or ethyl group, R ¹⁹ is a hydrogen atom or a protecting group for a carboxy group (as a protecting group for a carboxy group, There are no particular limitations, such as tert-butyl, trityl, benzhydryl, trimethylsilyl, tert-butyl,
Butyldimethylsilyl, 2,2,2-trichloroethyl, p-nitrobenzyl, p-methoxybenzyl or allyl. )}. X is NH group,
It is an oxygen or sulfur atom. Note that the oxime in the formula has syn coordination. ], or

[Formula] [In the formula, Z is a hydrogen atom, a halogen atom, such as a chlorine, bromine, or iodine atom, a mesyloxy, tosyloxy, or benzenesulfonyloxy group, and R ¹⁵ has the same meaning as described above. Note that the oxime in the formula has syn coordination. ]. R ⁴ is a hydrogen atom, a metal atom such as sodium, lithium, or potassium, or an ammonium ion {such as dimethylamine, diethylamine, diisopropylamine, dioctylamine, dicyclohexylamine, cyclohexylisopropylamine, triethylamine, tributylamine, DABCO, N,
N-dimethylaniline, N,N-diethylaniline, pyridine, lutidine, collidine, 4-dimethylaminopyridine, quinoline, isoquinoline, etc. and R ³ CO ₂ H (wherein R ³ is R ³ in the general formula ())
It is an ammonium ion generated from }. A compound having the general formula () and a compound having the general formula () are combined in an organic solvent (the solvents to be used are not particularly limited; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, and dioxane; 1 to 3 equivalents of secondary or tertiary Secondary amines (there are no particular limitations as long as they do not interfere with this reaction. For example, secondary amines such as dimethylamine, diethylamine, diisopropylamine, dioctylamine, dicyclohexylamine, dicyclohexylamine, or cyclohexylisopropylamine, triethylamine, tributylamine, DABCO, N,N-dimethylaniline, N,N-diethylaniline, pyridine, lutidine, collidine, 4-dimethylaminopyridine,
Phosphorous oxychloride is added at -30° to room temperature in the presence of a tertiary amine such as quinoline or isoquinoline, and the mixture is allowed to react for 10 minutes to several hours. When the reaction solution is treated according to a conventional method, the general formula () (in the formula R ¹ ,
R ² , R ³ or A have the same meaning as above)
A compound having the following properties is obtained, and the desired product is purified by chromatography, recrystallization, or reprecipitation as necessary. The present invention will be illustrated by giving examples below. Example 1 1-(isopropyloxycarbonyloxy)
Ethyl 7-[2-(2-formylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylate (isomer derived from the ester moiety A) 2-(2formylaminothiazol-4-yl)
-(Z)-2-methoxyiminoacetic acid 252 mg and 1
-(isopropyloxycarbonyloxy)ethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate 547 mg of paratoluenesulfonate (isomer A) was suspended in 6 ml of ethyl acetate, N,N-diethyl Add 47 mg of aniline, −
Cool to 10°C. Add phosphorus oxychloride to this solution.
A solution of 169 mg of ethyl acetate (1 ml) was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was washed with dilute hydrochloric acid, a 5% aqueous sodium bicarbonate solution, and then brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is washed with diisopropyl ether to obtain 537 mg of the above compound. NMR (δppm, heavy acetone): 1.28 (6H, d, J = 6Hz), 1.54 (3H, d, J =
5.5Hz), 3.28 (3H, s), 3.58 (2H, s), 3.96
(3H, s), 4.23 (2H, s), 4.82 (1H, Sep, J=
6Hz), 5.15 (1H, d, J=5Hz), 5.91 (1H, dd,
J=5Hz, J=9Hz), 6.78 (1H, q, J=5.5
Hz), 7.33 (1H, s), 8.38 (1H, d, J9Hz), 8.59
(1H, s) Example 2 1-(isopropyloxycarbonyloxy)
Ethyl 7-[2-(2-formylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylate (isomer derived from the ester moiety B) 252 mg of 2a 2-(2-formylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid and
411 mg of 1-(isopropyloxycarbonyloxy)ethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate hydrochloride (isomer B) was suspended in 6 ml of methylene chloride, 253 mg of pyridine was added, and the mixture was heated to -15°C. Cooling. In this solution,
A solution of 169 mg of phosphorus oxychloride in methylene chloride (1 ml) was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. Add ethyl acetate, dilute hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution,
After washing with brine, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is washed with diisopropyl ether and taken up to give 515 mg of the above compound. NMR (δppm, heavy acetone): 1.28 (3H, d, J = 6Hz), 1.53 (3H, d, J =
5.5Hz), 3.26 (3H, s), 3.57 (2H, s), 3.94
(3H, s), 4.22 (2H, s), 4.83 (1H, Sep, J=
6Hz), 5.14 (1H, d, J=5Hz), 5.88 (1H, dd,
J=5Hz), J=9Hz), 6.86 (1H, q, J=5
Hz), 7.34 (1H, s), 8.38 (1H, d, J=9Hz),
8.53 (1H, s) 2b 351 mg of the above compound is obtained by changing the solvent of Example 2a to tetrahydrofuran and reacting in the same amount under the same conditions. 2c Instead of pyridine in Example 2a, 199 mg of dicyclohexylamine and 328 mg of N,N-diethylaniline were used in the same amounts and reacted under the same conditions to obtain 494 mg of the above compound. Example 3 1-(isopropyloxycarbonyloxy)
Ethyl 7-(4-methanesulfonyloxy-
(Z)-2-methoxyimino-3-oxobutyrylamino)-3-methoxymethyl-3-cepheme-
4-Carboxylate (isomer B derived from the ester moiety) 4-methanesulfonyloxy-(Z)-2-methoxyimino-3-oxobutyric acid dicyclohexylamine salt 4.42 g, 1-(isopropyloxycarbonyloxy)ethyl 7- Amino-3-methoxymethyl-3-cephem-4-carboxylate
5.47 g of para-toluene sulfonate (isomer B),
Example 1 using 2.98 g of N,N-diethylaniline, 1.61 g of phosphorus oxychloride, and 70 ml of ethyl acetate.
By reacting and treating in the same manner as above, and recrystallizing from ethanol, 5.46 g of the above compound is obtained.
mp120-121℃ NMR (δppm, deuterochloroform): 1.30 (6H, d, J = 6Hz), 1.55 (3H, d, J =
5.5Hz), 3.18 (3H, s), 3.30 (3H, s), 3.53
(2H, s), 4.14 (3H,, s), 4.85 (1H, Sep, J
= 6Hz), 4.95 (1H, d, J = 5Hz), 5.22 (2H,
s), 5.76 (1H, dd, J=5Hz), J=9Hz),
6.87 (1H, q, J = 5.5Hz), 7.12 (1H, d, J =
9Hz) Example 4 Tertiary-butyl 7-[2-(2-formylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylate 2-(2-formyl 378 mg of aminothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid, 451 mg of tertiary-butyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate,
Example 1 Using 492 mg of N,N-diethylaniline, 253 mg of phosphorus oxychloride, and 7 ml of ethyl acetate.
React and treat in the same manner as above to obtain 664 mg of the above compound. mp140-156℃ (decomposition) NMR (δppm, heavy dimethyl sulfoxide): 1.48 (9H, s), 3.20 (3H, s), 3.50 (2H, s),
3.87 (3H, s), 4.10 (2H, s), 5.12 (1H, d, J
=5Hz), 5.76 (1H, dd, J=5Hz, J=8.5Hz),
7,34 (1H, s), 8.47 (1H, s), 9.62 (1H, d,
J=8.5Hz), 12.52 (1H, s) Example 5 Diphenylmethyl 7-[2-(2-chloroacetamidothiazol-4-yl)-(Z)-2-methoxyiminoacetamide]-3-(1,3,4-
Thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate 2-(2-chloroacetamidothiazole-4
-yl)-(Z)-2-methoxyaminoacetic acid 153 mg,
diphenylmethyl 7-amino-3-(1,3,
4-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylate 248 mg, N,
N-diethylaniline 187 mg, phosphorus oxychloride 85
The reaction and treatment were carried out in the same manner as in Example 1 using 5 ml of ethyl acetate and 5 ml of ethyl acetate to obtain 290 mg of the above compound. NMR (δppm deuterium chloroform): 3.69 (2H, s), 3.98 (3H, s), 4.07 (2H, s),
4.38 (2H, ABq, J=14Hz), 5.03 (1H, d, J=
5Hz), 5.92 (1H, dd, J=5Hz, J=9Hz),
6.88 (1H, s), 7.09 (1H, s), 7.17 (1H, s),
7.0~7.5 (10H, m), 7.84 (1H, d, J=9Hz),
8.85 (1H, s) Example 6 Diphenylmethyl 7-[2-(2-formylaminothiazol-4-yl)-(Z)-2-tert-butoxycarbonylmethoxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylate 2-(2- Formylaminothiazol-4-yl)-(Z)-2-tert-butoxycarbonylmethoxyiminoacetic acid 254 mg, diphenylmethyl 7-amino-3-vinyl-3-cephem-4-
300 mg of carboxylate hydrochloride, 334 mg of N,N-diethylaniline, 118 mg of phosphorus oxychloride and 5 ml of methylene chloride are reacted and treated in the same manner as in Example 2a to obtain 451 mg of the above compound. NMR (δppm, deuterochloroform) 1.42 (9H, s), 3.52 (2H, s), 4.62 (2H, s),
5.05 (1H, d, J=5Hz), 4.9~5.6 (3H, m),
5.85 (1H, dd, J=5Hz, J=9Hz), 6.90 (1H,
s), 7.0-7.5 (10H, m), 7.39 (1H, s), 8.52
(1H, s), 8.74 (1H, d, J=9Hz) Example 7 2,2,2-trichloroethyl 7-[2-(2
-tritylaminothiazol-4-yl)-(Z)
-2-(2-fluoroethoxy)iminoacetamide]-3-methyl-3-cephem-4-carboxylate 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-fluoroethoxy ) iminoacetic acid 499 mg, 2,2,2-trichloroethyl 7
Using 350 mg of -amino-3-methyl-3-cephem-4-carboxylate hydrochloride, 463 mg of N,N-diethylaniline, 161 mg of phosphorous oxychloride and 7 ml of methylene chloride, react in the same manner as in Example 2a,
Work up to obtain 650 mg of the above compound. NMR (δppm, deuterochloroform): 2.18 (3H, s), 3,33 (2H, ABq, J=18
Hz), 4.23 (2H, s), 4.5-5.1 (2H, m), 4.80
(2H, ABq, J=12Hz), 4.99 (1H, d, J=5
Hz), 5.78 (1H, dd, J=5Hz), J=8Hz),
6.63 (1H, s), 6.97 (1H, d, J=8Hz), 7.22
(16H, s) Example 8 Diphenylmethyl 7[2-(2-aminothiazol-4-yl)-(Z)-2.methoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylate 2-(2-aminothiazol-4- il) - (Z)
-2-methoxyiminoacetic acid 254 mg, diphenylmethyl 7-amino-3-acetoxymethyl-3-
Cefem-4-carboxylate 503 mg, dicyclohexylamine 228 mg, N,N-diethylaniline 344 mg, phosphorus oxychloride 192 mg and ethyl acetate
Using 15 ml, it was reacted in the same manner as in Example 2c, and subjected to column chromatography using silica gel.
588 mg of the above compound is obtained. Developing solvent: n-hexane-ethyl acetate (1:2) → ethyl acetate NMR (δppm, deuterated chloroform) 1.92 (3H, s), 3.32 (2H, s), 3.87 (3H, s),
4.75 (2H, ABq, J=13Hz), 4.88 (1H, d, J=
5Hz), 5.65 (2H, s), 5.86 (1H, dd, J=5Hz,
J=9Hz), 8.50 (1H, s), 6.77 (1H, s), 7.17
(10H, s), 8.00 (1H, d, J=9Hz) Example 9 Diphenylmethyl 7-[2-(2-chlorcetamidothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylate 2-(2-chloracetamidothiazole -4
-yl)(Z)-2-methoxyiminoacetic acid 139 mg,
diphenylmethyl 7amino-3-methyl-3-
Using 190 mg of cefem-4-carboxylate, 90.6 mg of dicyclohexylamine, 74.5 mg of N,N-diethylaniline, 76.7 mg of phosphorus oxychloride, and 3 ml of methylene chloride, the reaction was carried out in the same manner as in Example 2c.
Work up to obtain 295 mg of the above compound. NMR (δppm, deuterochloroform) 2.08 (3H, s), 3.28 (2H, ABq, J = 18Hz),
3.98 (2H, s), 4.00 (3H, s), 5.06 (1H, d, J
=5Hz), 5.94 (1H, dd, J=5Hz, J=9Hz),
6.87 (1H, s), 6.94 (1H, s), 7.1~7.5 (10H,
m), 8.28 (1H, d, J=9Hz) Example 10 Diphenylmethyl 7[2-(2-formylaminothiazol-4-yl)-(Z)-methoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylate 2-(2-formylaminothiazol-4-yl )-(Z)-2-methoxyiminoacetic acid 533 mg, diphenylmethyl 7-amino-3-chloromethyl-
3-Cefem-4-carboxylate hydrochloride 1.0
Using 422 mg of dicyclohexylamine, 661 mg of N,N-diethylaniline, 337 mg of phosphorus oxychloride, and 12 ml of methylene chloride, the reaction and treatment were carried out in the same manner as in Example 2c to obtain 1.084 g of the above compound. NMR (δppm, heavy dimethyl sulfoxide): 3.67 (2H, s), 3.90 (3H, s), 4.44 (2H, s),
5.25 (1H, d, J=5Hz), 5.94 (1H, dd, J=5
Hz, J=9Hz), 6.94 (1H, s), 7.1~7.6 (10H,
m), 7.40 (1H, s), 8.49 (1H, s), 9.70 (1H,
d, J=9Hz) Example 11 Diphenylmethyl 7-(D-α-tertiary-butoxycarbonylaminophenyl acetamide)-3-methoxymethyl-3-cephem-4-
Carboxylate D-α-tertiary-butoxycarbonylaminophenyl acetic acid 276 mg, diphenylmethyl 7-amino-3-methoxymethyl-3-cephem-4-
Using 410 mg of carboxylate, 373 mg of N,N-diethylaniline, 169 mg of phosphorus oxychloride, and 7 ml of methylene chloride, react in the same manner as in Example 2a,
Work up to obtain 461 mg of the above compound. NMR (δppm, deuterochloroform): 1.40 (9H, s), 3,13 (CH, s), 3.34 (2H,
s), 4.14 (2H, s), 4.81 (1H, d, J=4.5Hz),
5.17 (1H, d, J6Hz), 5.72 (1H, dd, J=4.5Hz,
J = 9Hz), 6.84 (1H, d, J = 9Hz), 6.85 (1H,
s), 7.0 to 7.5 (16H, m) Example 12 Diphenylmethyl 7-(4-methoxyphenoxy)acetamido-3-methoxymethyl-3-
Cefem-4-carboxylate 4-methoxyphenoxyacetic acid 200mg, diphenylmethyl 7-amino-3-methoxymethyl-3
-Cefem-4-carboxylate 410 mg, N,
N-diethylaniline 373 mg, phosphorus oxychloride 169
The reaction and treatment were carried out in the same manner as in Example 1 using 7 ml of ethyl acetate and 7 ml of ethyl acetate to obtain 550 mg of the above compound. NMR (δppm, deuterium chloroform) 3,14 (3H, s), 3,44 (2H, s), 3.68 (3H,
s), 4.17 (2H, s), 4.43 (2H, s), 4.90 (1H,
d, J=5Hz), 5.80 (1, dd, J=5Hz, J=9
Hz), 6.75 (4H, s), 6.87 (1H, s), 7.0~7.5
(10H, m), Example 13 Diphenylmethyl 7β-(4-nitrophenoxy)acetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate 118 mg of 4-nitrophenoxyacetic acid and N,N-diethyl 179 mg of aniline is dissolved in 3 ml of methylene chloride and cooled to -10°C. After 92 mg of phosphorus oxychloride was added dropwise and stirred for 5 minutes, 262 mg of diphenylmethyl 7β-amino-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate was chlorinated. Add a methylene (2 ml) solution dropwise and stir for 1 hour. Ethyl acetate is added, and the mixture is washed with dilute hydrochloric acid, a 5% aqueous sodium bicarbonate solution, and then brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography using silica gel to obtain 44 mg of the above compound. Developing solvent:
Ethyl acetate-cyclohexane (1:1) NMR (δppm, deuterochloroform) 3.52 (3H, s), 3.56 (2H, s), 3.78 (3H, s),
4.48 (2H, ABq, J=13Hz), 4.63 (2H, s),
5.03 (1H, s), 6.84 (1H, s), 6.95 (2H, d, J
=9Hz), 7.1-7.6 (11H, m), 8.13 (2H, d, J
=9Hz) Example 14 Phenacyl 6-(4-nitrophenoxy)acetamidopenicillanate 4-nitrophenoxyacetic acid 207 mg, Phenacyl 6-aminopenicilanate hydrochloride 371 mg, N,
N-diethylaniline 463 mg, phosphorus oxychloride 161
The reaction and treatment were carried out in the same manner as in Example 2a using 7 ml of methylene chloride and 430 mg of the above compound. NMR (δppm, deuterochloroform) 1.69 (6H, s), 4.54 (1H, s), 4.61 (2, s),
5.38 (3H, ABq, J=16Hz), 5.4~5.8 (2H, m),
6.8-8.2 (6H, m), 6.93 (2H, d, J=9Hz),
8.11 (2H, d, J=9Hz) Example 15 7-(4-nitrophenoxy)acetamide-
3-acetoxymethyl-3-cephem-4-carboxylic acid 434 mg of 4-nitrophenoxyacetic acid was suspended in 4 ml of ethyl acetate, and 298 mg of N,N-diethylaniline was added.
and cooled to -10℃. Phosphorus oxychloride 337mg
was added dropwise, and after stirring for 5 minutes, 545 mg of 7-aminocephalosporanic acid and 840 mg of sodium hydrogen carbonate were added.
% aqueous acetone (14 ml) solution under ice cooling.
Stir for an hour. After concentrating the acetone under reduced pressure, a 5% aqueous sodium hydrogen carbonate solution was added, and the mixture was washed with ethyl acetate. Add ethyl acetate to the aqueous layer, add concentrated hydrochloric acid dropwise while stirring to bring the pH to 2, and separate the organic layer. 3
% hydrochloric acid and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 630 mg of the above compound. NMR (δppm, heavy dimethyl sulfoxide) 2.05 (3H, s), 3.56 (2H, s), 4.79 (2H, s),
4.87 (2H, ABq, J=13Hz), 5.09 (1H, d, J=
5Hz), 5.70 (1H, dd, J=5Hz, J=8Hz),
7.09 (2H, d, J=9Hz), 8.16 (2H, d, J=9
Hz), 9.18 (1H, d, J=8Hz) Example 16 7-(4-methoxyphenoxy)acetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid 545 mg of 7-aminocephalosporanic acid was suspended in 7 ml of anhydrous methylene chloride and cooled on ice. 1.03 mg of N,O-bistrimethylsilylacetamide was added dropwise, and the mixture was stirred at room temperature for 50 minutes. Meanwhile, 401 mg of 4-methoxyphenoxyacetic acid was dissolved in 5 ml of anhydrous methylene chloride, and 298 mg of N,N-diethylaniline was added to the mixture.
Cool to ℃, add 337 mg of phosphorus oxychloride dropwise, and stir for 5 minutes. This solution is added to the previous solution at -10°C and stirred for 30 minutes. After concentration under reduced pressure, ethyl acetate was added, and the mixture was washed twice with 5% hydrochloric acid and once with brine, dried over anhydrous magnesium sulfate, and compressed under reduced pressure to obtain 730 mg of the above compound. NMR (δppm, heavy dimethyl sulfoxide) 2.03 (3H, s), 3.53 (2H, s), 3.78 (3H, s),
4.52 (2H, s), 4.85 (2H, ABq, J=13Hz),
5.08 (1H, d, J=5Hz), 5.70 (1H, dd, J=5
Hz, J=8Hz), 6.7-7.0 (4H, m), 8.88 (1H,
d, J=8Hz) Example 17 Diphenylmethyl 7-[D-[2-(2,3-
dioxo-4-ethylpiperazin-1-yl)carbonylamino]phenylacetamide]-3-
(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate Diphenylmethyl 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4 - carboxylate 247 mg,
D-[2,3-dioxo-4-tylpiperazi-1
-yl)carbonylamino]phenylacetic acid 160mg
Then, 164 mg of N,N-diethylaniline was dissolved in 10 ml of methylene chloride and cooled to -10°C. After dropping 77 mg of phosphorus oxychloride, stir at the same temperature for 20 minutes, add ethyl acetate, wash with dilute hydrochloric acid, 5% aqueous sodium bicarbonate solution, and then brine, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. , 372 mg of the above compound was obtained. NMR (δppm, deuterochloroform) 1.07 (3H, t, J=7Hz), 3.1-4.2 (8H, m),
3.75 (3H, s), 4.22 (2H, s), 4.94 (1H, d, J
=5Hz), 5.5-5.9 (2, m), 6.83 (1H, s), 7.1
~7.7 (15H, m), 7.01 (1H, d, J=Hz), 9.97
(1H, d, J=7Hz)

Claims (1)

[Claims] 1. General formula [In the formula, A is [Formula] or [Formula] {B is a hydrogen atom, a halogen atom, an alkoxy group, a vinyl group, or -CH ₂ D (D is a hydrogen atom, a halogen atom,
alkoxy group, acetoxy group, carbamoyloxy group, alkylthio group, aromatic heterocyclic thio group, or pyridinio group)}, R ¹ is a hydrogen atom or an alkoxy group, R ² is a hydrogen atom, a metal atom, or an ester Residues are shown. ] to a compound having the general formula R ³ COOR ⁴ ( ) [wherein R ³ CO represents an acyl group and R ⁴ represents a hydrogen atom, a metal atom or an ammonium ion. ] A general formula characterized by reacting a carboxylic acid or a salt of a carboxylic acid having A method for producing a compound having the formula [wherein A, R ¹ , R ² and R ³ have the same meanings as described above].