JPS625918B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel 7α-methoxycephalosporin and a method for producing the same, and aims to have a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, as well as β-methoxycephalosporin.
It is an object of the present invention to provide 7α-methoxycephalosporins that are stable against lactamase and effective against diseases of humans and animals, and a method for producing the same. Conventional 7α-methoxycephalosporins are
Although it is known to exhibit antibacterial activity against Gram-positive bacteria, it does not exhibit particularly effective antibacterial activity against Pseudomonas aeruginosa, which can lead to clinically serious infections, and it also does not exhibit antibacterial activity against β-lactamase. It has drawbacks such as instability. Therefore, the present inventors conducted intensive research on new 7α-methoxycephalosporins that do not have the above-mentioned drawbacks, and as a result, a new 7α-methoxycephalosporin represented by the general formula () was found to meet the expectations. The present invention was completed based on the discovery that the object was fully satisfied. The 7α-methoxycephalosporin of the present invention has the following general formula () (In the formula, R ¹ is a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R ² is a heterocyclic ring consisting of a nitrogen-containing five-membered ring that may have an alkyl, carbamoyl alkyl, hydroxyalkyl, or alkenyl group) Formula thio group; R ³ and R ⁴ are hydrogen atoms; A is an alkyl group; B is a furyl group or 1.
Indicates a 4-cyclohexadienyl group. ) is a new compound represented by a heterocyclic thio group-substituted methyl group consisting of a nitrogen-containing five-membered ring which may have an alkyl, carbamoylalkyl, hydroxyalkyl or alkenyl group at the 3rd position of the cefem ring, and a methyl group substituted with a thio group at the 7th position. α-methoxy group is substituted and further 7
The β-amino group at position is the following group (In the formula, R ³ , R ⁴ , A and B have the above-mentioned meanings.) The present invention will be explained in more detail below. In the general formula of this specification, "carboxyl protection forming group" and "salt forming cation" refer to those commonly used in the field of penicillins and cephalosporins. Specifically, examples of the "carboxyl protection forming group" include the following. (a) Ester-forming groups that have the property of being eliminated by catalytic reduction, chemical reduction, or treatment under mild conditions, such as substituted arylsulfonylalkyl groups such as p-toluenesulfonylethyl; benzyl, 4-nitrobenzyl, diphenylmethyl ,
Trityl, 3,5-di(tert.-butyl)-4-
Substituted or unsubstituted aralkyl groups such as hydroxybenzyl; benzoyloxymethyl groups;
Substituted or unsubstituted alkyl groups such as tert.-butyl and trichloroethyl; phenacyl groups; alkyloxyalkyl groups such as methoxymethyl; and the like. (b) Ester-forming groups that have the property of being easily eliminated by enzymes in vivo, such as acyloxyalkyl groups such as pivaloyloxymethyl;
Alkyloxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl groups; phthalidyl groups; indanyl groups, etc. (c) An organic silyl group, an organic phosphorus group, or an organic tin group that has the property of being easily eliminated by treatment with water or alcohol, such as (CH ₃ ) ₃ Si−,

【formula】

【formula】

[Manufacturing method (1)]

General formula () (In the formula, R ¹ , R ² , R ³ , R ⁴ , A and B have the above-mentioned meanings.) A cephalosporin represented by the general formula () M ^1+- OCH ₃ () is added in the presence of methanol. (In the formula, M ¹ represents an alkali metal.) A method of reacting methanol with an alkali metal salt represented by the following formula, and then reacting with a halogenating agent. Manufacturing method (1) is, for example, known in the art (Japanese Patent Application Laid-open No. 1983-
70788 and JP-A No. 51-113890), a cephalosporin represented by the general formula ( It is dissolved or suspended in one or more mixed solvents such as dimethylformamide, dimethylacetamide, acetonitrile, methanol, etc., and an alkali metal salt of methanol () is added together with methanol to react. In this case, use an excess amount of methanol and use an alkali metal salt of methanol ().
The amount used is preferably 2 to 6 equivalents relative to the cephalosporin of general formula (). Moreover, an excess amount means 1 equivalent or more with respect to the cephalosporin of formula (). Then, a halogenating agent is added and reacted. All of the above reactions are generally carried out at reaction temperatures of -120 to -10
The reaction time is 5 to 30 minutes. Thereafter, the reaction is stopped by making the reaction system acidic. The halogenating agents that can be used in this method are those commonly known as positive halogen sources. That is, it refers to any halogen compound capable of supplying a positive halogen atom, such as Cl ⁺ , Br ⁺ , or I ⁺ . Specifically, halogens such as chlorine and bromine, N-haloimides such as N-chlorosuccinimide and N-bromosuccinimide;
- Haloamides; N-halosulfonamides such as N-chlorobenzenesulfonamide and N-chloro-p-toluenesulfonamide; 1-halobenzotriazoles; 1-halotriazines; tert.
-Organic hypohalogenites such as -butylhypochlorite and tert.-butyliodite; and halohydantoins such as N.N-dibromohydantoin. The halogenating agent is preferably tert.-butylhypochlorite. The halogenating agent has the general formula ()
An amount sufficient to provide an equivalent amount of positive halogen for the cephalosporin represented by is used. Suitable acids for stopping the reaction may be those which, when added to the cold reaction mixture, do not cause solidification of the reaction mixture or freezing of heavy viscous mixtures, such as 98% formic acid, glacial acetic acid, etc. , trichloroacetic acid, methanesulfonic acid, etc. can be used. After stopping the reaction, excess halogenating agent is removed by treatment with a reducing agent such as trialkyl ester of phosphorous acid or sodium thiosulfate. Furthermore, in the compound of the present invention of general formula (),
When R ₁ is a hydrogen atom, R ¹ becomes a salt-forming cation or carboxyl protection-forming group, and when R ¹ is a salt-forming cation, R ₁ becomes a hydrogen atom or a carboxyl protection-forming group, or R ¹ becomes a hydrogen atom or a carboxyl protection-forming group. When it is a carboxyl protection-forming group, R ¹ can be converted into a hydrogen atom or a salt-forming cation, respectively, by a conventional method. In addition, in the present invention, if R ² is a group active in the reaction, it should be protected with any protective group normally used to protect carboxyl groups, amino groups, hydroxyl groups, etc. during this reaction. After the reaction, the protecting group may be removed by a conventional method to convert it to R ² . The 7α-methoxycephalosporins () thus obtained are isolated and collected from the reaction mixture according to a conventional method. Furthermore, the compound represented by the general formula () of the present invention can also be produced by the method shown below. [Manufacturing method (2)] General formula () A method of reacting a 7α-methoxycephalosporin represented by the following with a compound represented by the general formula () R ² M ² (). [Manufacturing method (3)] General formula () For the compound represented by the general formula () A method obtained by reacting a reactive derivative at the carboxyl group of a compound represented by [Manufacturing method (4)] General formula () The compound represented by the general formula () A method of reacting a compound represented by or a reactive derivative thereof at the carboxyl group. In the above formulas () to (), R ⁷ represents a hydrogen atom, an organic silyl group, or an organic phosphorus group, and M ²
represents a hydrogen atom, an alkali metal or an alkaline earth metal, and R ¹ , R ² , R ³ , R ⁴ , A and B have the meanings described above. Furthermore, R ⁶ represents a substituent that can be easily replaced by a nucleophilic reagent, such as halogen atoms such as chlorine and bromine; lower alkanoyloxy groups such as formyl, acetoxy, propionyloxy, butyryloxy, and pivaloyloxy; benzoyloxy, naphthoyloxy, etc. Arylcarbonyloxy groups such as thiobenzoyloxy and thionaphthoyloxy; Arylcarbonylthio groups such as benzoylthio and naphthoylthio; Arylthiocarbonylthio groups such as thiobenzoylthio and thionaphthoylthio; carbamoyloxy Group; thiocarbamoyloxy group; pyridine-N-oxide-2
-yl group; pyridazine-N-oxide-6-yl group is mentioned. Each of these groups represented by R ⁶ may be further substituted with various substituents such as a halogen atom, nitro group, alkyl group, alkoxy group, alkylthio group, and acyl group. As the reactive derivative in the carboxyl group of the compound represented by the above general formula (), reactive derivatives of carboxylic acids that are generally used in the synthesis reaction of acid amide compounds are applied, such as acid halides, acid cyanides, organic Alternatively, mixed acid anhydrides with inorganic acids, active esters, active amides, etc. can be mentioned. In addition, as reactive derivatives at the carboxyl group of the compound represented by the above general formula (),
Reactive derivatives commonly used in acid amide synthesis reactions such as acid halides, acid anhydrides, mixed acid anhydrides with organic or inorganic acids, activated amides, and active esters can be used. Specifically, acid chloride of the compound of formula (); acid cyanide; acid azide; aliphatic carboxylic acid, aromatic carboxylic acid, alkyl carbonic acid, aralkyl carbonic acid, dialkyl phosphoric acid, diphenyl phosphoric acid, methanesulfonic acid, p- Mixed acid anhydride with toluenesulfonic acid, etc.; imidazole,
Acid amides with 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole, saccharin, etc.; active esters such as cyanomethyl ester, substituted phenyl ester, substituted phenyl thioester, and the like. In addition, the compounds of the above general formulas () and () can be prepared by known methods, such as those published in the Journal of the Society of Organic Synthetic Chemistry.
It can be synthesized according to the method described in Vol. 35, No. 47, pp. 563-574. Furthermore, the method for producing the compound represented by the general formula () of the present invention is not limited to the production methods (1) to (4) described herein, and other conventionally known methods can be applied to produce the compound. be able to. The compound represented by the general formula () obtained in this way not only has a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, but also has extremely excellent antibacterial activity against Pseudomonas. It is also stable against β-lactamases, making it a valuable novel compound as a therapeutic agent for human and animal diseases. Next, the antibacterial activity of representative compounds of the present invention compounds () will be shown.

【table】

【table】

[Table] The compounds represented by the general formula () of the present invention are:
It is administered to humans and animals in the form of the free acid, as well as in the form of non-toxic salts or physiologically acceptable esters. The compound is prepared in the form of a conventional penicillin or cephalosporin drug, such as a tablet, capsule, syrup, or injection, and is administered orally or parenterally. Next, examples of compounds represented by the general formula () of the present invention will be shown. Example 1 (1) 2.55 g of DL-α-amino-2-furylacetic acid was suspended in 35 ml of methylene chloride, 4.81 ml of trimethylchlorosilane was added under ice cooling, and then 5.04 ml of triethylamine was added to the suspension at 5 to 10°C for 10 minutes. It takes a few minutes to drip. After reacting at 15 to 20°C for 1 hour, 7.01 g of a mixture of 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride and triethylamine hydrochloride [(4-ethyl-2,
The content of 3-dioxo-1-piperazine carbonyl chloride; 58.02% (weight/weight)] from 5 to
It takes 15 minutes to add at 10°C and react for 1 hour at 10-15°C. Next, 20 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and then at 5-7°C for 30 minutes. Take the precipitated crystals, wash them sequentially with 5 ml of methylene chloride and 5 ml of water, and dry them to obtain a melting point of 179~
DL-α-(4-ethyl-
4.75 g (yield: 85.6%) of 2-furylacetic acid (2,3-dioxo-1-piperazinecarboxamide) is obtained. IR (KBr) cm ^-1 ; ν _C=O 1735, 1709, 1650 NMR (DMSO-d ₆ ) ppm value; 1.09 (3H, t, -
_CH3 ), 3.18-3.71 (4H, m,

[Formula]), 3.78 ~4.09 (2H, m,

[Formula]), 5.53 (1H, d,

[Formula]), 6.44 (2H, m,

【formula】), 7.61 (1H, s,

[Formula]), 9.69 (1H, d,

[Formula]) (2) DL-α-(4-ethyl-2,3-dioxo-
0.94 g of 1-piperazinecarboxamide)-2-furylacetic acid was suspended in 15 ml of dry methylene chloride,
Add 0.35 ml of N-methylmorpholine under ice cooling to make a homogeneous solution. This solution was then cooled to -20°C, and a solution of 0.32 ml of ethyl chlorocarbonate and 2 ml of dry methylene chloride was added dropwise over 5 minutes, followed by cooling to -15°C.
Stir for 60 minutes. Cooled again to -20°C and diphenylmethyl 7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl] ^-Δ3 -cephem-4-carboxylate.
A solution of 1.50 g in 15 ml of dry methylene chloride is added dropwise over 10 minutes and stirred for a further 90 minutes at -10°C. After the reaction mixture was heated to room temperature, it was poured into 10 ml of water, and the organic layer was separated. Add 10 ml of fresh water, adjust the pH to 6.5 with an aqueous sodium bicarbonate solution, separate the organic layer, add 10 ml of water, and 10 ml of saturated saline.
Wash sequentially with ml. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure and the residue is treated with diethyl ether to obtain 2.0 g of a white powder.
This is used for thin layer chromatography (developing solution;
Two components (R
values; 0.28 and 0.24). This was subjected to column chromatography using 40 g of silica gel (developing solution: benzene: ethyl acetate =
2:1) to separate the upper and lower components by thin layer chromatography, yielding 1.1 g of the upper and lower components. Γ upper component (estimated structure; diphenylmethyl = 7
-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(2
-furyl)acetamide]-3-[5-(1-
Methyl-1,2,3,4-tetrazolyl)thiomethyl] ^-Δ3 -cephem-4-carboxylate Melting point 128-138℃ (decomposition) IR (KBr) cm ^-1 ; ν _C=O 1800, 1705, 1680 NMR (CDCl ₃ ) ppm value; 1.11 (3H, t, -
_CH3 ), 3.30~4.30 (10H, m,

[Formula]), 3.76 (3H, s, -CH ₃ ), 4.91 (1H, d,

[Formula]), 5.72-5.93 (2H, m,

[Formula]), 6.25 (2H, m,

[Formula]), 6.82 (1H, s,

[Formula]), 7.20-7.53 (12H, m, ph x 2,

【formula】

[Formula]), 9.80 (1H, d,

[Formula]) Γ lower component (estimated structure; diphenylmethyl = 7
-[L-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(2
-furyl)acetamide]-3-[5-(1-
Methyl-1,2,3,4-tetrazolyl)thiomethyl] ^Δ3 -cephem-4-carboxylate Melting point 128-136℃ (decomposition) IR (KBr) cm ^-1 ; ν _C=O 1800, 1705, 1680 NMR ( CDCl ₃ ) ppm value; 1.08 (3H, t, -
_CH3 ), 3.20~4.30 (10H, m,

[Formula]), 3.86 (3H, s, -CH ₃ ), 5.00 (1H, d,

[Formula]) 5.61 to 5.98 (2H, m,

[Formula]), 6.31 (2H, m,

[Formula]), 6.83 (1H, s,

[Formula]), 7.29 (11H, m, ph×2,

[Formula]), 7.94 (1H, d,

【formula】), 9.88 (1H, d,

[Formula]) (3) Add 0.86 g of the upper component obtained in Example 1-(2) to 14 ml of dry chloroform and 3.5 ml of dry tetrahydrofuran.
ml of mixed solvent and cooled to -75°C in a dry ice-methanol bath. Lithium methoxide methanol solution (1.948 mmole/ml) 1.97
ml and stirred at the same temperature for 3 minutes, then
tert.-Add 0.20ml of butyl bipochlorite-70
Stir for 15 minutes at ~-65°C. Add 0.20 ml of acetic acid, return to room temperature, evaporate the solvent under reduced pressure, and dissolve the residue in a mixture of 10 ml of ethyl acetate and 10 ml of water. Separate the organic layer, add 10ml of water,
Adjust the pH to 2.5 with 2N hydrochloric acid and separate the organic layer. Wash twice with 10 ml of saturated brine, dry over magnesium sulfate, and then evaporate the solvent under reduced pressure. The residue is purified by column chromatography using 15 g of silica gel (developing solution: benzene:ethyl acetate = 2:1) to obtain 0.30 g of a white powder. Dissolve the white powder obtained above in 3.0 ml of anisole, add 3.0 ml of trifluoroacetic acid under ice cooling, and stir at the same temperature for 30 minutes. The solvent was distilled off under reduced pressure, and 5 ml of ethyl acetate and 5 ml of water were added to the residue.
Then, while stirring, add saturated sodium bicarbonate solution to bring the pH to 6.5 and dissolve. Separate the aqueous layer,
Add 10 ml of methyl acetate, adjust the pH to 2.0 with 2N hydrochloric acid, and separate the organic layer. More methyl acetate than the aqueous layer
Extract with 10ml, combine with the organic layer and add saturated saline.
Wash twice with 10 ml each. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and ether was added to the residue. Upon treatment, 7β-[D-α-4-ethyl-2.3 -dioxo-1-piperazinecarboxamide)-α-(2-furyl)acetamide]-
7α-Methoxy-3-[5-(1-methyl-1.
2,3,4-tetrazolyl)thiomethyl]-Δ
³ -Cefem-4-carboxylic acid 0.17g (yield
70.8%). IR (KBr) cm ^-1 ; ν _C=O 1770, 1700, 1670 NMR (DMSO-d ₆ ) ppm value; 1.07 (3H, t, -
_CH3 ), 3.28~4.01 (8H, m,

[Formula]), 3.38 (3H, s, -CH ₃ ), 3.88 (3H, s, -CH ₃ ), 4.10
~4.45 (2H, m,

[Formula]), 5.03 (1H, s,

[Formula]), 5.73 (1H, d,

[Formula]) 6.39 (2H, m,

[Formula]), 7.54 (1H, bs,

[Formula]), 9.51-9.70 (2H, m,

[Formula]) The following compound was obtained in the same manner. Γ7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α
-(2-furyl)acetamide]-7α-methoxy-3-[5-(1-carbamoylmethyl-
1,2,3,4-tetrazolyl)thiomethyl]-Δ ³ -cephem-4-carboxylic acid Γ7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-
^Γ7β -[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α
-(2-furyl)acetamide]-7α-methoxy-3-[5-(1-vinyl-1,2,3,
4-tetrazolyl)thiomethyl]-Δ ³ -cephem-4-carboxylic acid Example 2 (1) 2.5 g of D(-)-α-amino-1,4-cyclohexadienyl acetic acid was suspended in 20 ml of water and cooled on ice. Drop 2.3 ml of triethylamine and dissolve. 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride (purity
58.02%) 6.3% PH with 2.5ml of triethylamine
Add for 30 minutes while adjusting to 6.5-8.0. After stirring for 30 minutes at 10-15°C, the reaction solution is washed with 20 ml of ethyl acetate, 30 ml of ethyl acetate is added, and the pH is adjusted to 2.2 with 6N hydrochloric acid. Separate the organic layer,
Furthermore, the aqueous layer is extracted with 15 ml of ethyl acetate, and the organic layer is combined and washed twice with 20 ml of water and then with 20 ml of saturated saline. After drying over magnesium sulfate and removing the solvent under reduced pressure, a white powder of D(-)-α(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)- having a melting point of 104-108°C was obtained.
4.2 g (yield: 80.0%) of 1,4-cyclohexadienyl acetic acid is obtained. IR (KBr) cm ^-1 ; ν _C=O 1705, 1670 NMR (DMSO-d ₆ ) ppm; 1.10 (3H, t, -
CH ₃ ), 2.61 (4H, m,

[Formula]), 3.18~ 3.69 (4H, m,

[Formula]), 3.70-4.13 (3H, m,

【formula】

[Formula]), 4.56 (1H, d,

[Formula]), 5.60 (2H, m,

[Formula]), 5.70 (1H, s,

[Formula]), 9.49 (1H, d,

[Formula]) (2) D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-1,4
-Dissolve 2.3 g of cyclohexadienyl acetic acid in 20 ml of dry methylene chloride, add 0.79 ml of N-methylmorpholine at -20°C, then add 0.75 ml of ethyl chlorocarbonate dropwise at -20 to -15°C over 5 minutes. . After stirring at the same temperature for 60 minutes, diphenylmethyl=7-amino-3-[5-(1-methyl-
1,2,3,4-tetrazolyl)thiomethyl]
^-Δ3 -Cefem-4-carboxylate 3.0
A solution of 15 g of dry methylene chloride in 30 ml at -20°C.
The mixture was added dropwise over a period of minutes, and the mixture was further stirred at -10°C for 120 minutes. Pour the reaction solution into 50 ml of water and separate the organic layer. Add another 30 ml of water, adjust the pH to 7.0 with saturated aqueous sodium bicarbonate solution, remove the organic layer, wash with 30 ml of water and 30 ml of saturated saline, and dry over magnesium sulfate. The solvent was distilled off under reduced pressure, and 30 ml of benzene was added to the residue to remove the precipitate. Diphenylmethyl = 7β-[D(-)-α-(4-ethyl-2.3) having a melting point of 151-155°C
-dioxo-1-piperazinecarboxamide)
-α-(1,4-cyclohexadienyl)acetamide]-3-[5-(1-mer-1,2,
3,4-tetrazolyl)thiomethyl]-Δ ³ -
3.9 g of cefem-4-carboxylate (yield
80.7%). IR (KBr) cm ^-1 ; ν _C=O 1770, 1700, 1665 NMR (CDCl ₃ ) ppm value; 1.15 (3H, t, -
CH ₃ ), 2.62 (4H, m,

[Formula]), 3.23~ 3.70 (6H, m,

[Formula]) 3.71 (3H, s, - CH ₃ ), 3.70-4.35 (4H, m,

【formula】), 4.92~5.28 (2H, m,

[Formula]), 5.57 (2H, m,

[Formula]), 5.75-5.97 (2H, m,

[Formula]), 6.78 (1H, s,

[Formula]), 7.75 (11H, m,

[Formula]), 9.57 (1H, d,

[Formula]) (3) Diphenylmethyl=7β-[D(-)-α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(1,4-cyclohexadienyl)acetamide]-3-[5-(1
-Methyl-1,2,3,4-tetrazolyl)thiomethyl] ^-Δ3 -cephem-4-carboxylate (0.80 g) was dissolved in a mixture of 15 ml of dry chloroform and 4 ml of dry latrahydrofuran, and mixed with molecular sieve 3A1. 0g added, dry ice-
Cool to −70°C in a methanol bath. Methanol solution of lithium methoxide (1.948 mmol/ml)
Add 1.8ml and stir at the same temperature for 3 minutes, then
tert. -Add 0.18 butyl hypochloride all at once. After stirring at -70 to -65℃ for 15 minutes, 0.2ml of acetic acid
Add and heat to room temperature. After separating the molecular sieve, the solvent is distilled off under reduced pressure. Add 20 ml of ethyl acetate and 10 ml of water to dissolve the residue, adjust the pH to 6.5 with a saturated aqueous sodium bicarbonate solution, and separate the organic layer. Add another 10 ml of water, adjust the pH to 2.5 with 6N hydrochloric acid, and wash the organic layer sequentially with 10 ml of water and 10 ml of saturated saline. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was dissolved in 15 g of silica gel.
Separation and purification by column chromatography (developing solution: benzene: ethyl acetate = 2:1), the solvent of the eluent was distilled off under reduced pressure, and the residue was treated with ether to form a white powder of diphenylmethyl 7β. -[D(-)-α-(4-ethyl-2.
3-dioxo-1-piperazinecarboxamide)-α-(1,4-cyclohexadienyl)acetamide]-7α-methoxy-3-[5-(1
-Methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ ³ -cephem-4-carboxylate 0.5 g (yield 60.3%) is obtained. IR (KBr) cm ^-1 ; ν _C=O 1775, 1710, 1675 NMR (CDCl ₃ ) ppm value; 1.17 (3H, t, -
CH ₃ ), 2.75 (4H, m,

[Formula]), 3.29~ 3.68 (6H, m,

[Formula]), 3.47 (3H, s, -CH ₃ ), 3.77 (3H, s, -CH ₃ ), 3.80-4.89
(4H, m,

[Formula]) 4.99 (1H, s,

[Formula]), 5.61 (2H, m,

[Formula]), 5.95 (1H, s,

【formula】) 6.87 (1H, s,

[Formula]), 7.28-7.45 (11H, m,

[Formula]) 9.55 (1H, d,

[Formula]) (4) Diphenylmethyl=7β[D(-)-α-(4
-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(1,4-cyclohexadienyl)acetamide]-7α-methoxy-
3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl] ^-Δ3 -cephem-4
- Dissolve 0.4 g of carboxylate in 5 ml of anisole, add 5 ml of trifluoroacetic acid under ice cooling,
Stir at the same temperature for 30 minutes. The solvent was distilled off under reduced pressure, 10 ml of methyl acetate and 10 ml of water were added to the residue, and then a saturated aqueous sodium bicarbonate solution was added with stirring to adjust the pH.
Adjust to 6.5. Separate the aqueous layer, add 5 ml of fresh methyl acetate, adjust the pH to 2.2 with 6N HCl, and leave it in the refrigerator overnight. Take the precipitated crystals and add 2 5ml each of water.
7β-[D
(-)-α-(4-ethyl-2,3-dioxo-
1-piperazinecarboxamide)-α-(1.4
-cyclohexadienyl)acetamide]-7
α-Methoxy-3-[5-(1-methyl-1.
2,3,4-tetrazolyl)thiomethyl]-Δ
³ -Cefem-4-carboxylic acid 0.2g (yield
62.7%). IR (KBr) cm ^-1 ; ν _C=O 1770, 1710, 1685 NMR (DMSO-d ₆ ) ppm value; 1.10 (3H, t, -
CH ₃ ), 2.18 (4H, m,

[Formula]), 3.34~ 3.73 (6H, m,

[Formula]), 3.41 (3H, s, -CH ₃ ), 3.79-4.37 (4H, m,

[Formula]), 3.93 (3H, s, -CH ₃ ), 4.97 (1H, d,

[Formula]), 5.06 (1H, s,

[Formula]), 5.61 (2H, m,

[Formula]), 5.87 (1H, s,

[Formula]), 9.38 (1H, d,

[Formula]), 9.53 (1H, s,

【formula】)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R ² is a heterocyclic ring consisting of a nitrogen-containing five-membered ring that may have an alkyl, carbamoyl alkyl, hydroxyalkyl, or alkenyl group) Formula thio group; R ³ and R ⁴ are hydrogen atoms; A is an alkyl group; B is a furyl group or 1.
Indicates a 4-cyclohexadienyl group. ) 7α-methoxycephalosporin. 2 General formula (In the formula, R ¹ is a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R ⁵ is 1, 2, 3, or 4 which may have an alkyl, carbamoyl alkyl, hydroxyalkyl, or alkenyl group)
-tetrazolylthio or 1,3,4-thiadiazolylthio group; A ¹ is a C _1-4 alkyl group; B
represents a furyl group or a 1,4-cyclohexadienyl group. ) 7α- according to claim 1
Methoxycephalosporins. 3 Claims in which R ⁵ is a 5-(1,2,3,4-tetrazolyl)thio or 2-(1,3,4-thiadiazolyl)thio group having an alkyl, carbamoylalkyl, hydroxyalkyl or alkenyl group 7α-methoxycephalosporins according to item 2. 4 R ⁵ is a 5-(1-methyl-1,2,3,4-tetrazolyl)thio group, 5-(1-carbamoylmethyl-1,2,3,4-tetrazolyl)thio group,
5-[1-(2-hydroxyethyl)-1・2・
The 7α-methoxycephalosporin according to claim 3, which is a 3,4-tetrazolyl]thio group or a 5-(1-vinyl-1,2,3,4-tetrazolyl)thio group. 5 General formula [In the formula, R ¹ is a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R ² is a heterocycle consisting of a nitrogen-containing five-membered ring that may have an alkyl, carbamoyl alkyl, hydroxyalkyl, or alkenyl group Formula thio group; R ³ and R ⁴ are hydrogen atoms; A is an alkyl group; B is a furyl group or 1.
Indicates a 4-cyclohexadienyl group. ] A cephalosporin represented by is reacted with an alkali metal salt of methanol represented by the general formula M ^1+- OCH ₃ (in the formula, M ¹ represents an alkali metal) in the presence of methanol, and then a halogenating agent and General formula, characterized by reacting A method for producing 7α-methoxycephalosporins represented by the formula (wherein R ¹ , R ² , R ³ , R ⁴ , A and B have the above-mentioned meanings).