JPH0240677B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to novel cefem compounds. More specifically, this invention:
Novel 7-substituted-3-cephem-4-carboxylic acid having antibacterial activity, pharmaceutically acceptable salts thereof,
and their production methods, intermediates for their production,
The present invention relates to methods for producing these intermediates, pharmaceutical compositions based on them, and methods for using them for the prevention or treatment of infectious diseases in humans and animals. It is therefore an object of this invention to develop novel 7-substituted-
3-Cefem-4-carboxylic acid, its pharmaceutically acceptable salts, their production methods, pharmaceutical compositions containing one or more of them as active ingredients, against infectious diseases of humans and animals caused by pathogenic microorganisms The present invention provides methods for their use for prophylaxis or treatment, intermediates for the production of pharmaceutically active 7-substituted-3-cephem-4-carboxylic acids and salts, and methods for producing the intermediates. The 7-substituted-3-cefem-4-carboxylic acid that is the object of this invention is novel and is represented by the following general formula (). [In the formula, R ¹ is an amino group or a protected amino group, R ² is hydrogen, halogen, lower alkoxy,
Aryl group optionally having a substituent selected from nitro, halo lower alkyl and protected carboxy, aryl optionally substituted with amino lower alkyl or protected amino lower alkyl, halogen, cyano, carboxy , protected carboxy, lower alkylthio, aryloxy, di-lower alkylcarbamoyl, lower alkanesulfonyl, lower alkoxy, lower alkoxy,
a lower alkyl group, a lower alkenyl group having a substituent selected from amino and protected amino;
a 5-membered heterocyclic group having a heteroatom selected from S and O, substituted with a lower alkynyl group, a cycloalkyl group optionally substituted with carboxy or protected carboxy, a cyclo-lower alkenyl group, or an oxo group; , R ³ is hydrogen or a lower alkyl group, R ⁴ is hydrogen, an acyloxy lower alkyl group, a substituted or unsubstituted thiadiazolylthio lower alkyl group, a substituted or unsubstituted tetrazolylthio lower alkyl group, a substituted or unsubstituted tetrazolopyrida dinylthio lower alkyl group, substituted or unsubstituted dihydrotriazolopyridazinylthio lower alkyl group, substituted or unsubstituted dihydrotriazinylthio lower alkyl group, lower alkyl group, or halogen, R ⁵ is a carboxy group,
or protected carboxy group] According to the present invention, the target 7-substituted-3-
Cefem-4-carboxylic acid () is produced by the following method. Method 1 Method 2 Method 3 Method 4 Method 5 Method 6 Method 7 Method 8 Method 9 Method 10 [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as before, R ^5a is a protected carboxy group, R ^4e is a substituted or unsubstituted thiadiazolyl group, a substituted or unsubstituted tetrazolyl group, Substituted or unsubstituted tetrazolopyridazinyl group, substituted or unsubstituted dihydrotriazolopyridazinyl group, or substituted or unsubstituted dihydrotriazinyl group, A is a lower alkylene group, R ^4c is a protected amino lower thiadiazolylthio-lower alkyl substituted with alkyl, tetrazolylthio-lower alkyl substituted with protected amino-lower alkyl, tetrazolopyridazinylthio-lower alkyl substituted with protected amino-lower alkyl, protected dihydrotriazolopyridazinylthio-lower alkyl group substituted with amino lower alkyl, or dihydrotriazinylthio-lower alkyl group substituted with protected amino lower alkyl, R ^4d is thiadiazine substituted with amino lower alkyl zolylthio lower alkyl group, tetrazolylthio lower alkyl group substituted with amino lower alkyl, tetrazolopyridazinylthio lower alkyl group substituted with amino lower alkyl, dihydrotriazolopyridazinylthio lower substituted with amino lower alkyl an alkyl group or a dihydrotriazinylthio-lower alkyl group substituted with amino-lower alkyl, R ^2a is a hydroxy protecting group, R ^4a is the formula -S-R ^4e (in the formula,
R ^4e is a group that can be substituted with a group represented by (the same meaning as above), R ^2b is a protected amino lower alkyl group,
R ^2c is an amino lower alkyl group, R ^2d is a protected carboxy lower alkyl group, a protected carboxy-substituted al-lower alkyl group, or a protected carboxy-substituted cycloalkyl group,
R ^2e is a carboxy lower alkyl group, a carboxy-substituted alkyl lower alkyl group, or a carboxy-substituted cycloalkyl group, and R ⁸ is of the formula -
The ester moiety of the esterified carboxy group represented by COOR ⁸ , R ^2f is a protected amino lower alkyl group or an al lower alkyl group substituted with a protected amino lower alkyl group, R ^2g is an amino lower alkyl group, or an a(lower)alkyl group substituted with amino-lower alkyl.] Among the raw material compounds of this invention, compound () is novel and is produced by the following production method. [In the formula, R ² , R ^2a , R ^2f , R ^2g , and R ¹ have the same meanings as before, and R ^2h represents a substituent selected from halogen, lower alkoxy, nitro, halo-lower alkyl, and protected carboxy. an aryl group that may have an aryl group, or a cycloalkyl group that may be substituted with carboxy or protected carboxy, Z is a carboxy group or a protected carboxy group, and R ¹⁰ is a protected amino (C ₃ - _C6 ) alkyl group, ^R11 is an amino ( _C3 - _C6 ) alkyl group, ^R6
is a carboxyl group protecting group, M is an alkali metal, X
represents a hydroxy group or a reactive derivative thereof, R ⁹ represents an amino group having a protecting group, R ^1a represents a protected amino group, and R ⁷ represents a lower alkyl group.] The object compound of this invention () and the raw material compound ( ), the following formula The substructure shown by is the following formula

[expression] and

It shall include both of the two geometric isomers represented by the formula. In this specification, among all the compounds having the above partial structure, the compound having the geometric structure represented by formula (A) is referred to as a "syn isomer", and the compound having the geometric structure represented by formula (A')
Those shown are called "anti-isomers". In the target compound having the above formula () and the starting compound having the formula (), the target compound and the starting compound include tautomers with respect to the thiadiazolyl group. That is, in the formulas representing the target compound and the starting compound, the formula

[Formula] (wherein R ¹ means an amino group or a protected amino group) is a group represented by the formula

If it is a group represented by [Formula] (in which R ¹ has the same meaning as before), the group

[Expression] is also an expression

It can be represented by a tautomer represented by the following formula: (wherein R ¹ ' means an imino group or a protected imino group). These groups (B) and (B′) are represented by the following formula There is a so-called tautomeric equilibrium relationship shown by . In this specification, including the claims and examples, target compounds and starting compounds having the above groups are referred to simply as one form of expression, i.e., the formula

[In the formula, R ^2f means lower alkyl group, Y means acid residue]

This is carried out by reacting the compounds shown below. Suitable acid residues include hydrohalic acids such as hydrochloric acid and hydrobromic acid, inorganic acids such as sulfuric acid, lower alkanesulfonic acids such as methanesulfonic acid and ethanesulfonic acid, benzenesulfonic acid, p
-Contains residues of organic acids such as arenesulfonic acids such as toluenesulfonic acid. This reaction is preferably carried out in the presence of a base as described above,
This is usually carried out in a solvent such as dimethylformamide. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling, at room temperature, or under heating. Production method (9) Compound () is produced by reacting compound () with compound (). When X is an acid residue, this reaction is preferably carried out in the presence of a base as exemplified in Method 1, and when X is a hydroxy group, triphenylphosphine and diethylazoformate are reacted. Preferably, this is carried out in the presence of a condensing agent, such as a reaction product of. This reaction is usually carried out in a solvent such as acetonitrile, dimethylformamide, tetrahydrofuran, or any other solvent that does not adversely affect the reaction. The reaction temperature is not particularly limited, but
The reaction is usually carried out under cooling or heating to about the boiling point of the solvent. Manufacturing method (10) Compound () or its salts are
) is produced by subjecting it to an amino-protecting group elimination reaction. The elimination reaction of the amino protecting group of compound () is
This is done in the same way as described for method 4 above. Suitable solvents include water, ethanol, chloroform, diethyl ether, and the like. Although the reaction temperature is not particularly limited, the reaction is usually carried out with or under heating. In this reaction, the protected amino group of R ² may be changed to a free amino group, and this case is also included in this method. Manufacturing method (11) Compound () or its salts are
) or its salts to an amino-protecting group introduction reaction. This reaction is carried out in substantially the same manner as described for Method 1 above. When the protecting group introduced is a lower alkoxycarbonyl group, this reaction gives the compound () the formula (In the formula, R ^l2 is a lower alkoxycarbonyl group, R ^l3
(respectively means an aryl group) is advantageously carried out by reacting a compound represented by the following. Manufacturing method (12) Compound (XII) or its salts
XI) or a salt thereof is produced by subjecting it to a reaction for introducing a substituent on a hydroxy group. When the substituent to be introduced is an aryl group which may have a suitable substituent, this reaction is performed on the compound (
XI) or its salts (In the formula, R ²ⁱ is an aryl group which may have an appropriate substituent, X ² is a halogen, and Y is an acid residue.) This can be carried out by reacting the compounds shown below. Suitable acid residues include halogens, toluenesulfonyloxy groups, sulfuric acid residues, and the like. This reaction is usually carried out in a solvent such as an alcohol such as methanol or ethanol, water, a mixture thereof, or any other solvent that does not adversely affect the reaction, preferably in the presence of a base.
Although the reaction temperature is not particularly limited, it is usually carried out under cooling, room temperature or heating. When the substituent to be introduced is a cycloalkyl group optionally substituted with an appropriate carboxy or protected carboxy, the reaction is carried out on compound (XI) or a salt thereof with the formula R ^2j -Y (XI) (wherein R ^2j means a cycloalkyl group optionally substituted with carboxy or protected carboxy, and Y has the same meaning as above). This reaction is carried out in substantially the same manner as described for production method (8) above. Production method (13) Compound () or a salt thereof is produced by subjecting compound () or a salt thereof to a ring-closing reaction. This reaction is usually carried out in a solvent such as an alcohol such as methanol or ethanol. Also,
This reaction is carried out in the presence of a dehydrating agent such as an acid anhydride such as magnesium sulfate or acetic anhydride. Although the reaction temperature is not particularly limited, the reaction is usually carried out with heating, under heating, or at room temperature. Production method (14) Compound () or a salt thereof is produced by reacting compound () with HN ₃ or a salt thereof. Suitable salts of HN ₃ include alkali metal salts. This reaction usually involves water, dioxane,
The reaction is carried out in a mixture of these and other solvents that do not adversely affect the reaction. Although the reaction temperature is not particularly limited, it is usually carried out under heating. Production method (15) Compound () or a salt thereof is produced by subjecting compound () or a salt thereof to an amino-protecting group elimination reaction. This reaction is carried out in substantially the same manner as described for Method 4 above. Production method (16) Compound () or a salt thereof is produced by subjecting compound () or a salt thereof to an amino protecting group introduction reaction. This reaction is carried out in substantially the same manner as described for production method (11) above. The starting compound (XII) in the above method 9 is new, and this compound can be used in the above methods 1, 2, 5,
It can be manufactured according to the same manufacturing method as No. 6, 7, 8 or 10. In the method of the present invention, the above-mentioned tautomer may change into another tautomer during the reaction and/or post-treatment, and this case is also encompassed by the present invention. Furthermore, when the 4-position of the target compound () is obtained in the form of a free acid and/or when the target compound () has a free amino group, these can be converted into salts by conventional methods. The object compound of this invention () and its pharmaceutically acceptable salts are all novel compounds with excellent antibacterial activity, inhibiting the growth of a wide range of pathogenic microorganisms including Gram-positive bacteria and Gram-negative bacteria, and exhibiting antibacterial properties. Useful as a substance. Next, in order to demonstrate the usefulness of the target compound (2), the results of an in vitro antibacterial test on representative compounds are shown. [Test compound] (1) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-cephem-
4-Carboxylic acid (syn isomer) (2) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(1,3,
4-Thiadiazol-2-yl)thiomethyl-
3-Cefem-4-carboxylic acid (syn isomer) (3) 7-[2-cyclopenten-1-yl)oximino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide] -3
-Cefem-4-carboxylic acid (syn isomer) (4) 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetamide]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (5) 7-[2-(2-cyclohexen-1-yl)oxyimino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetamide]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cepheme-4-carboxylic acid (syn isomer) (6) 7-[2-(4-chlorophenokiimino)
-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (7) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(1-allyl-1H
-tetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer) (8) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-(2-
7-[2-(1-carboxyethoxyimino)-2-(5-amino- 1,2,4-thiadiazol-3-yl)acetamide]-3-
[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-
4-Carboxylic acid (syn isomer) (10) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(tetrazolo[1,5-b]pyridin-6-yl)thiomethyl-3-cephem-4-carboxylic acid Isomers) [Test Method] In vitro antibacterial activity was measured by the agar plate multiple dilution method described below. Tributicase Soy Broth (Bacterial count 10 ⁸ /
One platinum loop of the test strain cultured overnight in ml) was inoculated onto heart infusion agar (HI agar) containing each concentration of the test compound, and after incubation at 37°C for 20 hours, the lowest inhibitory concentration (MIC) μ
Measured in g/ml. [Test results] As shown in the table below.

[Table] The target compound of this invention () is administered for therapeutic purposes.
When providing this product, the above compound is used as the main ingredient.
containing a pharmaceutically acceptable carrier, e.g.
Organic or non-organic, suitable for oral, parenteral or topical use.
prepared by adding solid or liquid excipients.
It can be used in the form of a drug. Such preparations
As for solid products such as capsules, tablets, granules, and ointments,
body, and liquids such as liquids, suspensions, and emulsions.
be caught. Additionally, if necessary, supplements may be added to the formulation.
agents, stabilizers, wetting agents or emulsifiers, buffering agents, etc.
Other commonly used additives may also be included.
Ru. The dosage of the compound depends on the age, condition, and disease of the patient.
This varies depending on the type, type of compound (), etc.
About 50 compounds of the invention () per use on average
When administered in amounts of mg, 100mg, 250mg or 500mg,
It is effective against diseases caused by pathogenic microorganisms.
It was confirmed. Generally, the daily dosage is 5 mg or more.
Administer approximately 3000mg or more to the patient
can do. Next, this invention will be explained by manufacturing examples and examples.
This will be explained in more detail. Production example 1 (1) N-hydroxyphthalimide (8.15g),
Liethylamine (5.05g), N,N-dimethyl
Formamide (60ml) and 1-bromo-2-cy
A mixture of chlorhexene (8.05g) was added to 3.5 g at room temperature.
Stir for hours. Pour the reaction mixture into water (300ml)
Then remove the precipitate and add water and n-hexane in that order.
After washing and drying, N-(2-cyclohexyl
Sen-1-yloxy)phthalimide (9.8
g), mp87°C was obtained. IR (nujiyor): 1770, 1720, 1610cm ^-1 NMR(d ₆ −DMSO, δ): 1.50−2.17 (6H,
m), 4.60-4.77 (1H, m), 5.73-6.27 (2H,
m), 7.90 (4H, S) (2) N-hydroxyphthalimide (52.16g) but
Lomocycloheptane (62.41g), dimethylsulfate
Phoxide (385 ml) and potassium carbonate (44.16
The mixture of g) was stirred at 70°C for 74 hours. reaction mixture
The mixture was cooled on ice and added to ice water (1.5). analysis
Remove the material, wash it twice with ice water, and then dry it.
and N-(cycloheptyloxy)phthalimide
(63 g), mp 110-112°C was obtained. NMR(d ₆ −DMSO, δ): 1.57 (8H, m),
1.90 (4H, m), 4.20 (1H, m), 7.93 (4H,
S) (3) N-hydroxyphthalimide (58.2g), 1
-Chloro-2-cyclopentene (36.9g),
ethylamine (53.9g) in acetonitrile
(370ml) and the mixture in Production Example 1-(1) and 1-(2).
When processed according to a similar method, N-(2-series
Clopenten-1-yloxy)phthalimide
(56.5g) was obtained. IR (Nujiyor): 1780, 1730, 1610cm ^-1 NMR(d ₆ −DMSO, δ): 7.92 (7H, S),
6.28 (1H, m), 6.00 (1H, m), 5.42 (1H,
m), 2.9-1.98 (4H, m) Production example 2 N-(cycloheptyloxy)phthalimide
(2.59g), hydrazine hydrate (0.48g)
The mixture was refluxed in a bottle (12ml) for 5 minutes. reaction mixture
When the mixture is cooled and filtered, cycloheptyloxy
A liquid containing cyamine was obtained. Production example 3 (1) N-(2-cyclopenten-1-yloxy
c) Phthalimide (22.9g) and hydrazine hydration
(4.75 g) in ethanol (115 ml)
was stirred for 5 minutes. The reaction mixture was filtered (2
-cyclopenten-1-yl)oxyamine
The liquid containing 2-(5-formamide-
1,2,4-thiadiazol-3-yl)gly
Added to an aqueous solution of sodium oxylate (22.4 g)
I got it. The mixture was adjusted to pH 2 with 10% hydrochloric acid and stirred for 2 hours.
After stirring, it was concentrated. PH1 the concentrate with 10% hydrochloric acid
When the precipitate is removed and dried, 2-(2-shield)
clopenten-1-yl)oxyimino-2-
(5-formamide-1,2,4-thiadiazole
(3-yl) acetic acid (syn isomer {20.0g),
mp150℃ (decomposition) was obtained. IR (Nujiyor): 3400, 3100, 1720, 1690,
1540cm ^-1 NMR(d ₆ −DMSO, δ): 1.80−2.50 (4H,
m), 5.30-5.50 (1H, m), 5.83-6.30 (2H,
m), 8.90 (1H, S) (2) N-(2-cyclohexen-1-yloxy
c) Phthalimide (7.29g), hydrazine hydrate
(1.5 g) in ethanol (40 ml)
Stir for a minute. Cool and filter the reaction mixture.
and (2-cyclohexen-1-yl)oxy
An amine-containing liquid (liquid A) was obtained. the other 2
-(5-formamide-1,2,4-thiadia
S- of zol-3-yl)thioglyoxylic acid
Methyl ester (6.93g) and 1N sodium hydroxide
Stir the mixture of aqueous solution (90 ml) at room temperature for 30 min.
Stirred. 2-(5-formamide-1,2,4
-Thiadiazol-3-yl)glyoxylic acid
The reaction mixture containing sodium was adjusted to pH 7 with 10% hydrochloric acid.
After adding liquid A to this, the pH was adjusted with 10% hydrochloric acid.
was set as 3. This mixture was stirred at room temperature for 3 hours.
Ta. Concentrate the reaction mixture and add ethyl acetate.
Ta. Add 10% hydrochloric acid to this to adjust the pH to 1, and remove the precipitate.
Then, 2-(2-cyclohexene-1
-yl)oxyimino-2-(5-formamide
Do-1,2,4-thiazol-3-yl)acetic acid
(Syn isomer: 2.5 g) was obtained. On the other hand, acetic acid
The chilled layer was separated from the liquid and evaporated to dryness. residue
When treated with diethyl ether and powdered, the same
The desired substance (1.5g) was obtained. Total yield: 4.0
g, mp 190-192°C (decomposed). IR (Nujiyor): 3550, 3400, 3200, 2500,
1690, 1590, 1540cm ^-1 NMR(d ₆ −DMSO, δ): 1.5−2.3 (6H, m),
4.73-5.0 (1H, m), 5.76-6.23 (2H, m),
8.97 (1H, s), 13.60 (1H, broad s) (3) Sodium hydroxide (11.2g) in water (140ml)
2-(5-formamide-1,2,4
-thiadiazol-3-yl)thioglyoxy
S-methyl ester of fluoric acid (27g) was added at 10℃.
I got it. This mixture was stirred at 20°C for 30 minutes. 2-
(5-formamide-1,2,4-thiadiazole
Contains sodium (3-yl)glyoxylate
Cool the reaction mixture and adjust the pH to 7 with 10% hydrochloric acid.
After that, add cyclopentyloxyamine to this
(15.3g) in ethanol (150ml).
Ta. This mixture was adjusted to pH 3 with 10% hydrochloric acid, and at 1.5 hours
Stir for a while. Sodium bicarbonate reaction mixture
Adjust the pH to 7 with an aqueous solution and distill off the ethanol.
Ta. The residue was washed with ethyl acetate. acetic acid in the aqueous layer
Ethyl was added and the pH was adjusted to 1 with 10% hydrochloric acid. analysis
When extracted, 2-cyclopentyloxy
Lumino-2-(5-formamide-1,2,
4-thiadiazol-3-yl)acetic acid
3.99 g) was obtained. Ethyl acetate solution
and dried the extract with magnesium sulfate.
It was then concentrated. Remove the precipitate and remove it.
Washing with chill ether yields the same target substance.
(8.1 g) was obtained. Total yield: 12.09g, mp180
~185℃ (decomposition). IR (Nujiyor): 3130, 3040, 2680, 2610,
2520, 1720, 1690, 1660, 1600, 1550cm ^-1 NMR(d ₆ −DMSO, δ): 1.33−2.10 (8H,
m), 4.67-5.0 (1H, m), 8.88 (1H, s),
13.50 (1H, s) (4) Following the same method as Production Examples 3(1) to 3(3),
A compound was prepared. 2-cycloheptyloxyimino-2-(5
-Formamide-1,2,4-thiadiazole
-3-yl)acetic acid (syn isomer). NMR(d ₆ −DMSO, δ): 1.50 (8H, m),
1.80 (4H, m), 4.37 (1H, m), 8.81 (1H,
s), 9.88 (1H, s) Production example 4 2-(2-cyclopenten-1-yl)oxy
imino-2-(5-formamide-1,2,4-
Thiadiazol-3-yl)acetic acid (syn isomer:
20.0g) and 1N aqueous sodium hydroxide solution (200ml)
The mixture was stirred at 50-55°C for 1 hour. reaction mixture
After cooling the material and adjusting the pH to 7 with 10% hydrochloric acid, add ethyl acetate.
and then adjust the pH to 1 with 10% hydrochloric acid, then add acetic acid.
Extracted with chill. The extract was dissolved in sodium chloride saturated water.
After washing with solution and drying with magnesium sulfate,
The medium was distilled off. Dilute the residue with diisopropyl ether.
When processed and powdered, 2-(2-cyclopentene)
(1-yl)oxyimino-2-(5-amino
-1,2,4-thiadiazol-3-yl)acetic acid
(Syn isomer) (1.40g), mp150℃ (decomposition) was obtained.
It was done. IR (Nujiyor): 3300, 3150, 1710, 1620,
1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.80−2.50 (4H,
1), 5.30-5.50 (1H, m), 5.83-6.30 (2H,
m), 8.20 (2H, s) Production Example 5 Following the same method as Production Example 4, the following compound was prepared.
Manufactured. (1) 2-(2-cyclohexen-1-yl)oxy
Shiimino-2-(5-amino-1,2,4-thi)
adiazol-3-yl)acetic acid (syn isomer),
mp173℃. IR (Nujiyor): 3400, 3300, 3200, 1720,
1620, 1600, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.50−2.17 (6H,
m), 4.53-4.83 (1H, m), 5.57-6.13 (2H,
m), 8.18 (2H, s) (2) 2-cyclopentyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl) acetic acid (syn isomer), mp160-165℃ (min
solution). IR (Nujiyor): 3470, 3290, 3200, 2400,
1715, 1615, 1600, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.17−2.10 (8H,
m), 4.60−4.97 (1H, m), 8.22 (2H, s) (3) 2-cycloheptyloxyimino-2-(5
-Formamide-1,2,4-thiadiazole
-3-yl)acetic acid (syn isomer), mp116-119
°C (decomposition). IR (Nujiyor): 3250, 3200, 1650, 1600,
1520, 1400, 1260, 1150, 1000, 820, 720cm
^-1 Production example 6 (1) 4-(3-aminopropyl)morpholine
(122.6 g) in dioxane (520 ml),
% sodium hydroxide (35.1g) in water (420ml)
Add to the solution at 0°C and further at 0-5°C for 0.5 hours.
Carbon disulfide (64.71 g) was then added dropwise. child
The mixture was stirred at the same temperature for 1 hour, and further 0 to 5
Methyl iodide (120.65g) over 0.5 hours at °C
was added and stirred at the same temperature for 2 hours. precipitate
When taken, washed twice with water and dried, it becomes a pale yellow powder.
4-[3-{N-methylthio(thiocarbo)
Nyl)amino}propyl]morpholine (174.55
g) was obtained. NMR(d ₆ −DMSO, δ): 1.73 (2H, m), 2.3
(6H, m), 2.48 (3H, s), 3.2−3.9 (6H,
m), 9.91 (1H, broad s) (2) 4-[3-{N-methylthio(thiocarboni
Aminopropylmorpholine (152g)
Sodium acetate was added to a dioxane (430 ml) solution of
Add a solution of dido (42.25g) in water (290ml) and add for 2 hours.
Stir for a while. The solvent was distilled off from the reaction mixture and the pH
After adjusting to 8, wash with diethyl ether.
Ta. After adjusting the aqueous layer to pH5, cool it and remove the precipitate.
Take it out, wash it twice with ice water, dry it, and it will turn white.
Colored crystalline 1-(3-morpholinopropyl)
1H-tetrazole-5-thiol (116g),
mp210-212°C (decomposition) was obtained. IR (Nujiyor): 3550, 3500, 2350, 1610,
1410, 1360, 1280, 1190, 1130, 1090,
1050, 990, 880, 825, 785cm ^-1 NMR(d ₆ −DMSO, δ): 2.14 (2H, m),
2.99 (2H, t, J=7Hz), 3.09 (4H, m),
3.79 (4H, m), 4.24 (2H, t, J = 7Hz) Production Example 7 (1) The following compound was prepared in the same manner as Production Example 6 (1).
manufactured something. 1-[3-{N-methylthio(thiocarboni)
Aminopropylpiperidine, white powder
At the end, mp74-76℃. IR (Nujiyor): 3450, 3150, 1670, 1560,
1410, 1340, 1315, 1255, 1030, 1000, 950,
880, 860, 800, 750cm ^-1 (2) The following compound was prepared using the same method as in Production Example 6(2).
manufactured something. 1-(3-pipezinopropyl)-1H-tet
Razol-5-thiol, mp142-144℃ (min.
solution). IR (Nujiyor): 3500, 3350, 2450, 1635,
1360, 1280, 1200, 1185, 1120, 1100,
1085, 1070, 1000, 965, 950, 810cm ^-1 NMR(d ₆ −DMSO, δ): 1.3−1.9 (6H, m),
2.20 (2H, m), 3.07 (2H, t, J=7Hz),
3.17 (4H, m), 4.24 (2H, t, J = 7Hz) Production example 8 (1) Tetrabutylammonium bromide (3.22g)
chloroformic acid in a mixture of methylene chloride (300ml)
Ethyl (10.85g) was added at -20℃, and then -10
Sodium cyanide for 15 min at ~-13°C
After adding a solution of (49 g) in water (200 ml), -13℃
The mixture was stirred for 1 minute. Separate the organic layer from the reaction mixture.
After separating and drying with magnesium sulfate, let it cool to room temperature.
I warmed it up. methylene chloride layer by tilting method
It was separated and the insoluble matter was washed with methylene chloride. salt
Combine the dichloromethane layers (370 ml) and distill under normal pressure.
Then, a solution containing ethyl cyanoformate (335ml)
Obtained at bp 42-117°C. (2) Hydrogen chloride (32.5g) ethanol (34.5g)
The solution was cooled to -10°C, and the shea obtained in Production Example 8(1)
A solution containing ethyl phenolic acid (335 ml) was heated to -10℃ in advance.
and added to the cooled mixture. The resulting solution is -5
After stirring at ~5 °C for 6 h and cooling to -10 °C,
Methylene chloride (400ml) was added. this mixture
, triethylamine (85.8g), methylene chloride
(80 ml) and water (200 ml) at -5
It was added dropwise at ~0°C. Separate the methylene chloride layer;
After washing with water (200ml x 2), use magnesium sulfate.
When the solvent was distilled off, 78.8% of the 2
-Products containing ethyl imino-2-ethoxyacetate
(112 g) was obtained. This product is purified by distillation method.
Then, a pure product can be obtained at bp80-88℃/40mmHg.
Ta. (3) Ethyl 2-imino-2-ethoxyacetate (purity
78.8%: 60g) and ammonium chloride (17.4g)
of methanol (180 ml) was stirred at room temperature.
Stir and cool to -15 to -10°C. 1-methoxy
Mixture containing carbonylformamidine hydrochloride
Bromine (51.2g) was added dropwise over a period of 10 minutes, and then
Triethylamine (71.1g) was added over 30 minutes.
Potassium thiocyanate (31.0g) over 30 minutes
A methanol (150 ml) solution of each was added. anti
The reaction mixture was incubated at -10 to -5°C for 15 minutes and then at 0 to 5°C.
The mixture was stirred for 1.5 hours. Collect the precipitate and methane
After washing with water, cold water (200ml) was added.
Stir the mixture, remove the precipitate and wash with cold water.
After drying, 5-amino-1,2,4-thia
Methyl diazole-3-carboxylate (32.5g)
was gotten. (4) Ethyl cyanoformate (25.0g) in methylene chloride
(55 ml) solution of 43.5% hydrogen chloride (16.8 g).
Add the tanolic solution with stirring at 3°C,
After stirring at ~5°C for 5 hours, it was stirred at -5~-3°C.
I left it overnight. Methyl chloride is added to the resulting mixture at a temperature below 6°C.
Add water (120ml) and further stir at below 6℃.
Thylamine (20.2g) in methylene chloride (20ml)
The solution was added over a period of 30 minutes. This mixture for 40 minutes
Stir and add water (40 ml) below 6°C. Living
Stir the mixture for 3 minutes and separate the methylene chloride layer.
After separating and drying with magnesium sulfate, remove the solvent.
Distilled away. Diisopropyl ether (40ml)
In addition to the residue, after removing insoluble matter, diisopropylene
Washed with pyl ether (10ml). mother liquor and washing solution
When the solvent was distilled off, pale yellow oily 2-
Ethyl imino-2-ethoxyacetate (26.2g)
Obtained. Add ammonium chloride to this oil (26.2g).
Add nium (6.42g) and methanol (90ml).
The mixture was stirred at room temperature for 2 hours and diisopropyl
ether (450ml) was added. Chill the mixture on ice
and stirred for 30 minutes. When you remove the precipitate, it turns white.
Powdered 1-methoxycarbonylformamide
Hydrochloride (13.8g), mp150-155℃ (decomposition)
Obtained. IR (Nujiyor): 3350-3050, 1780, 1710,
1695, 1290, 1270, 1070, 980, 800cm ^-1 NMR(d ₆ −DMSO, δ): 3.97 (3H, s), 9.8
(4H, broad s) (5) 1-methoxycarbonylformamidine hydrochloride
-5 to a solution of salt (7.6 g) in methanol (55 ml)
Bromine (8.8g) was added dropwise over 5 minutes at ~0°C.
did. Add triethylamine (11.1g) to this,
Add potassium thiocyanate over 10 minutes.
(5.3g) in methanol (30ml) for 20 minutes.
I added it as needed. The reaction mixture was heated at 0-5℃ for 1.5 hours.
Stir for a while, remove the precipitate, and add methanol (11
ml), then dry and add water (15.5 ml).
Ta. Stir this mixture for 30 minutes and remove the precipitate.
After washing with water 3 times (5 ml each) and drying, it turns white.
Powdered 5-amino-1,2,4-thiadiazole
Methyl ru-3-carboxylate (6.3g) was obtained.
It was. (6) Ethyl 2-imino-2-ethoxyacetate (36.2
g), ammonium bromide (21.2g), methanol
(180 ml) was stirred at room temperature for 4 hours and stirred.
diisopropyl ether (400ml) while continuing
added. Let the mixture stand for 30 minutes to remove the precipitate.
did. Diisopropyl ether (200ml) to the liquid
was added and left for 10 minutes. When you remove the precipitate, it turns white.
Colored powder of 1-methoxycarbonylformamide
Hydrobromide (16.1 g) was obtained. on the other hand
Concentrate the liquid to about 150ml and add diisopropyl ether.
Teru (200 ml) was added and left for 30 minutes. precipitate
When taken, the same substance in the form of a white powder (11.6
g) was obtained. Total yield: 27.7g. IR (Nujiyor): 3350-3150, 1780, 1710,
1690, 1290, 1270, 1060, 980, 850, 800,
730cm ^-1 NMR(d ₆ −DMSO, δ): 3.91 (3H, s),
11.0 (4H, broad s) (7) Ethyl 2-imino-2-ethoxyacetate (18.1
g), ammonium chloride (5.8g) in ethanol
(90 ml) and stirred at room temperature for 6 hours.
Ta. Remove insoluble matter and wash mother liquor with ethanol
did. The solution and washing solution were combined and the solvent was distilled off. Residue
Acetone (50ml) was added to the distillate oil. precipitate
Take it and wash it twice with acetone (10ml each).
1-Ethoxycarbonylformua in white powder form
Midine hydrochloride (1.2g) was obtained. mixed with liquid
The liquids were combined and evaporated to dryness. Remove the residue with acetone
After processing and powdering, filtration, acetone and chloride
Wash with methylene and diisopropyl ether in that order.
Then, the same substance (7.3g) in the form of white powder was obtained.
It was. Total yield: 8.5g. IR (Nujiyor): 3400-3100, 1770, 1730-
1680, 1650, 1300−1260, 1120, 1010, 860,
760cm ^-1 Production example 9 5-amino-1,2,4-thiadiazole-3
-Production of methyl carboxylate 1-Ethoxycarbonylformamidine bromide water
Solution of oxalate (16.6g) in anhydrous methanol (84ml)
and sodium (1.93 g) in anhydrous methanol (42
ml) solution was added at 0°C. Add bromine to this mixture.
(12.8g) and anhydrous meth of sodium (1.93g)
Nord (42 ml) solutions were added alternately at 0°C to generate
Add potassium thiocyanate (8.1 g) to the suspension.
Add water-methanol (100ml) solution and keep at 0℃ for 1 hour.
The mixture was stirred for an additional 6 hours at room temperature. This mixture
Pass the material through cellulose powder and evaporate the liquid to dryness.
I set it. The residue was dissolved in a mixture of ethyl acetate and water,
Separate the ethyl acetate layer and dilute with anhydrous magnesium sulfate.
Dry. Evaporate the solvent and dissolve the residue in diethyl ether.
The title compound (9.0
g), mp 202-205°C was obtained. IR (Nujiyor): 3400, 3250, 3100, 1710,
1610, 1540cm ^-1 NMR(d ₆ -DMSO,) δ: 3.85 (3H, s), 8.25 (2H, s) Production example 10 5-formamide-1,2,4-thiadiazole
Production of methyl ru-3-carboxylate In a mixture of sulfuric acid (33g) and acetic anhydride (22g),
5-amino-1,2,4-thiadiazole-3-
Add methyl carboxylate (6.2g) and leave at room temperature for 2 days.
Stir for a while. The reaction mixture was concentrated under reduced pressure and the residue
treated with a mixture of diethyl ether and n-hexane.
The title compound (7.2 g) is crystallized by
mp210-215°C was obtained. IR (nujiyor): 3100, 1720, 1680cm ^-1 NMR(d ₆ -DMSO) δ: 3.90 (3H, s), 8.85 (1H, s) Production example 11 5-formamide-3-(2-methylthio-2
-Methylsulfinyl acetyl)-1,2,4
-Production of thiadiazole 5-formamide-1,2,4-thiadiazole
Methyl Ru-3-carboxylate (9.2g)
Tylthiomethyl sulfoxide (6.1g) in N,N
- Mixture added to dimethylformamide (100ml)
While keeping things cool in an ice bath, add 50% sodium hydride.
Thorium (7.1g) was added. the resulting mixture
The mixture was stirred at room temperature for 1 hour and then at 40°C for 1 hour.
Methylene chloride was added to the reaction mixture cooled to room temperature.
(300ml), remove the formed precipitate and chloride it.
Washed with methylene. On the other hand, hydrochloric acid (14.7ml), ice water
(200ml) and methylene chloride (200ml).
The mixture was stirred and the above precipitate was added thereto. No
The solution was removed, the methylene chloride layer was separated and washed with anhydrous sulfur.
Dry with magnesium acid. Obtained by distilling off the solvent
The resulting residue is treated with diethyl ether to crystallize it.
Then, the title compound (4.5g), mp130~132℃
Obtained. IR (nujiyor): 3100, 1680, 1670cm ^-1 NMR(d ₆ -DMSO) δ: 2.22 2.28 (3H, 2s) 2.68 2.85 (2H, 2s) 5.70 5.80 (1H, 2s) 8.86 (1H, s) Production example 12 (5-formamide-1,2,4-thiadiazo
methyl (3-yl)thioglyoxylate
Production of ester 5-formamide-3-(2-methylthio-2
-Methylsulfinyl acetyl)-1,2,4-
Thiadiazole (0.85g) and sodium periodate
(0.2g) in glacial acetic acid (10ml) was heated at 70°C.
The mixture was stirred for 45 minutes. distilling off the solvent from the reaction mixture;
The residue was dissolved in a mixture of ethyl acetate and water. this
Add sodium bicarbonate aqueous solution to the mixture to adjust the pH to 7.
and treated with an aqueous solution of sodium thiosulfate.
Separate the organic layer and dry with anhydrous magnesium sulfate.
After that, the solvent was distilled off. The residue was dissolved in diethyl ether.
When treated with a mixture of petroleum ethers and crystallized,
The title compound (280mg), mp186-187℃ was obtained.
Ta. IR (nujiyor): 3100, 1680, 1660cm ^-1 NMR(d ₆ -DMSO) δ: 2.55 (3H, s), 8.95 (1H, s) Production example 13 5-formamide-3-(2-methylthio-2
-Methylsulfinyl acetyl)-1,2,4-
Thiadiazole (10g) and sodium periodate
(2.0g) in glacial acetic acid (50ml) was mixed with 70%
Stirred at ℃ for 50 minutes. The solvent was distilled off and the residue was
Washed with xane. 1N sodium hydroxide to the residue
Aqueous solution (160 ml) was added and stirred at room temperature for 1 hour.
O-allylhydroxyamine hydrochloride in the reaction mixture
(4.31g) and adjusted the pH to 3-4 with 10% hydrochloric acid.
Ta. After removing insoluble materials, the solution was washed with ethyl acetate.
After cleaning, adjust the pH to 1 with 10% hydrochloric acid, and then add ethyl acetate.
Extracted with. Mix the extract with anhydrous magnesium sulfate.
The mixture was combined and the solvent was evaporated to dryness. diethyl ether and
Treat the residue with a mixture of diisopropyl ether
When powdered, 2-allyloxyimino-2-
(5-formamide-1,2,4-thiadiazole
(ru-3-yl) acetic acid (syn isomer, 5.6 g),
mp169-172°C (decomposition) was obtained. IR (Nujiyor): 3130, 2500, 1720, 1690,
1590, 1550cm ^-1 NMR(d ₆ −DMSO) δ: 4.79 (2H, d, J=6Hz), 5.1−5.6
(2H, m), 5.8-6.4 (1H, m), 8.88
(1H, s) Production Example 14 The following compound was prepared in the same manner as Production Example 13.
Obtained. (1) 2-benzyloxyimino-2-(5-hor
Muamide-1,2,4-thiadiazole-3-
yl) acetic acid (syn isomer), mp90-95°C (min
solution). IR (Nujiyor): 1720, 1680, 1590, 1550,
1530cm ^-1 NMR(d ₆ −DMSO) δ: 5.28 (2H, s), 7.37 (5H, s), 8.83
(1H,s) (2) 2-(2-propynyloxyimino)-2-
(5-formamide-1,2,4-thiadiazole
R-3-yl)acetic acid (syn isomer), mp150
~155℃ (decomposition). IR (Nujiyor): 3570, 3360, 3260, 3120,
1720, 1670, 1550, 1530cm ^-1 NMR(d ₆ -DMSO) δ: 3.55 (1H, t, J = 2Hz), 4.88 (2H,
d, J = 2Hz), 8.85 (1H, s) (3) 2-(2-phenoxyethoxyimino)-2
-(5-formamide-1,2,4-thiadia
zol-3-yl)acetic acid (syn isomer),
mp147-150℃ (decomposition). IR (Nujiyor): 3200, 1740, 1720, 1640,
1590, 1530cm ^-1 NMR(d ₆ −DMSO) δ: 4.0−4.7 (4H, m), 6.7−7.5 (5H, m),
8.83(1H,s) (4) 2-hydroxyimino-2-(5-forma
Mido-1,2,4-thiadiazole-3-i
) Acetic acid (syn isomer), mp240-241℃ (min.
solution). IR (Nujiyor): 3550, 3460, 1665, 1635,
1560cm ^-1 Production example 15 (5-formamide-1,2,4-thiadiazo
(3-yl) S-methyl thioglyoxylate
Ester (6.64g) dissolved in 1N sodium hydroxide
Dissolve in solution (80ml), then adjust to pH8.5 with 10% hydrochloric acid.
After adjusting the temperature, the mixture was stirred at room temperature for 30 minutes. On the other hand, N-(2,
2,2-trifluoroethoxy)phthalimide
(8.78g) and hydrazine hydrate (1.7g)
(40 ml) was stirred for 5 minutes, then
Cooled in an ice bath. Remove the precipitate and evaporate the liquid.
Washed with nol. Combine the solution and washing solution, O-
(2,2,2-trifluoroethyl)hydroxy
This mixture containing amine is added to the above aqueous solution.
added to. Adjust the pH of the mixture to 3-4 with 10% hydrochloric acid.
and stirred at room temperature for 1.5 hours. Add this solution to carbonated water.
Neutralize with an aqueous sodium solution and reduce to half in vacuo.
After concentrating until dry, the mixture was washed with ethyl acetate. aqueous solution
The solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate.
Ta. Dry the extract with anhydrous magnesium sulfate and remove the solution.
After the solvent is evaporated to dryness, the residue is diisopropyl.
When treated with ether and crystallized, 2-(2,
2,2-trifluoroethoxyimino)-2-
(5-formamide-1,2,4-thiadiazole
(ru-3-yl) acetic acid (syn isomer, 2.46 g),
mp180-185°C (decomposition) was obtained. NMR(d ₆ −DMSO) δ: 4.80and5.07 (2H, ABq, J=9Hz),
8.85 (1H, s) Production Example 16 The following compound was prepared in the same manner as Production Example 15.
Obtained. (1) 2-methylthiomethoxyimino-2-(5-
Formamide-1,2,4-thiadiazole-
3-yl)acetic acid (syn isomer), mp146-148℃
(Disassembly). IR (Nujiyor): 3300, 2600, 2550, 1730,
1705, 1680, 1600, 1530cm ^-1 NMR(d ₆ −DMSO) δ: 2.23 (3H, s), 5.40 (2H, s), 8.87
(1H,s) (2) 2-(2-methylthioethoxyimino)-2
-(5-formamide-1,2,4-thiadia
zol-3-yl)acetic acid (syn isomer). IR (Nujiyor): 3230, 1720, 1690, 1590,
1520cm ^-1 NMR(d ₆ −DMSO) δ: 2.17 (3H, s), 2.82 (2H, t, J = 7
Hz), 4.42 (2H, t, J=7Hz), 8.87
(1H,s) (3) 2-phenoxyimino-2-(5-formua
Mido-1,2,4-thiadiazole-3-i
) Acetic acid (syn isomer), mp145-147°C (min.
solution). IR (Nujiyor): 3130, 1720, 1690, 1585,
1550cm ^-1 NMR(d ₆ -DMSO) δ: 7.0-7.6 (5H, m), 8.88 (1H, s) (4) 2-[2-(2-hexyloxyethoxy)
Ethoxyimino]-2-(5-formamide-
1,2,4-thiadiazol-3-yl)acetic acid
(Syn isomer). IR (CHCl ₃ ): 3420, 3180, 1740, 1700,
1600, 1530, 1460cm ^-1 NMR(d ₆ −DMSO) δ: 0.87 (3H, t, J=5Hz), 0.87−1.73
(8H, m), 3.20−3.90 (8H, m), 4.23
−4.53 (2H, m), 8.84 (1H, s), 13.55
(1H, broad s) (5) 2-trityloxyimino-2-(5-form
Muamide-1,2,4-thiadiazole-3-
yl) acetic acid (anti-isomer), mp188-190℃
(Disassembly). IR (nujiyor): 3150, 1620, 1600, 1540cm
^-1 NMR(d ₆ -DMSO) δ: 7.00 (15H, s), 8.92 (1H, s) Production example 17 (5-formamide-1,2,4-thiadiazo
(3-yl) S-methyl thioglyoxylate
Ester (6g) and sodium hydroxide (4.2g)
of water (50 ml) at 50-55℃ for 1 hour.
Stirred. After the reaction is complete, cool to room temperature and add 10% hydrochloric acid.
Adjusted to PH7. On the other hand, N-(ethoxycarbony
rumethoxy) phthalimide (12.9g) and hydrazi
Add carbon hydrate (2.08g) to ethanol (60ml).
The mixture was heated to reflux for 5 minutes and cooled in an ice bath.
Ta. Remove the precipitate and wash the liquid with ethanol
did. Combine the solution and washing solution, and add O-(ethoxylic
This liquid contains (bonylmethyl) hydroxylamine
was added to the above aqueous solution. Add this mixture to 10% hydrochloric acid
The pH was adjusted to 3 to 4, and the mixture was stirred at room temperature for 1.5 hours. this
Neutralize the solution with aqueous sodium bicarbonate solution and reduce pressure
Concentrate under reduced pressure until the volume is reduced to half and wash with ethyl acetate.
Ta. This aqueous solution was made acidic with 10% hydrochloric acid, and
Extracted with chill. Dry the extract with magnesium sulfate.
After drying and distilling off the solvent, the residue is diisopropyl
When treated with ether and crystallized, 2-ethoxy
Carbonylmethoxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetic acid
(Syn isomer, 1.8g), mp135-140℃ (decomposition)
Obtained. IR (Nujiyor): 3500, 3330, 3210, 2670,
2550, 1740, 1610, 1540cm ^-1 NMR(d ₆ −DMSO) δ: 1.24 (3H, t, J=7Hz), 4.14 (2H,
q, J=7Hz), 4.80 (2H, s), 8.15
(2H, broad s) Production Example 18 The following compound was prepared in the same manner as Production Example 17.
Obtained. (1) 2-cyanomethoxyimino-2-(5-ami
(n-1,2,4-thiadiazol-3-yl)
Acetic acid (syn isomer), mp 130-135°C (decomposed). IR (Nujiyor): 3350, 3150, 1730, 1630,
1540cm ^-1 NMR(d ₆ -DMSO) δ: 5.17 (2H, s), 8.28 (2H, broad s) (2) 2-(1-ethoxycarbonyl-1-methyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetic acid
(isomer), mp165-168℃ (decomposition) IR (nudylol): 3450, 3350, 1750, 1730,
1630, 1530cm ^-1 NMR(d ₆ −DMSO) δ: 1.18 (3H, t, J=7Hz), 1.50 (6H,
s), 4.15 (2H, q, J = 7Hz), 8.23
(2H, broad s) (3) 2-(N,N-diethylcarbamoylmethoxy
(shiimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetic acid (synisomer
body), mp150-155℃ (decomposition). IR (Nujiyor): 3400, 3150, 1745, 1635,
1610, 1595, 1535cm ^-1 NMR(d ₆ −DMSO) δ: 1.03 (3H, t, J=7Hz), 1.10 (3H,
t, J = 7Hz), 3.28 (4H, q, J = 7
Hz), 4.90 (2H, s), 8.23 (2H, broad
s) (4) 2-Mesylmethoxyimino-2-(5-ami
(n-1,2,4-thiadiazol-3-yl)
Acetic acid (syn isomer). IR (Nujiyor): 3450, 3400, 3270, 2600,
2460, 1735, 1640, 1620, 1530cm ^-1 NMR(d ₆ −DMSO) δ: 3.00 (3H, s), 5.38 (2H, s), 8.22
(2H, broad s) Production Example 19 The following compound was prepared in the same manner as Production Example 4.
Obtained. (1) 2-allyloxyimino-2-(5-amino
-1,2,4-thiadiazol-3-yl) vinegar
Acid (syn isomer), mp93-95°C (decomposition). IR (Nujiyor): 3430, 3100, 1710, 1615,
1525cm ^-1 NMR(d ₆ −DMSO) δ: 4.72 (2H, d, J=6Hz), 5.1−5.5
(2H, m), 5.7-6.3 (1H, m), 8.17
(1H, broad s) (2) 2-benzyloxyimino-2-(5-amino)
(n-1,2,4-thiadiazol-3-yl)
Acetic acid (syn isomer), mp158-160°C (decomposed). IR (Nujiyor): 3430, 3380, 3260, 1730,
1640, 1610, 1535cm ^-1 NMR(d ₆ −DMSO) δ: 5.22 (2H, s), 7.33 (5H, s), 8.17
(2H, broad s) (3) 2-(2-propynyloxyimino)-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetic acid (syn isomer), mp155-157℃
(Disassembly). IR (Nujiyor): 3500, 3310, 3160, 2600,
2480, 1745, 1610, 1535cm ^-1 NMR(d ₆ −DMSO) δ: 3.53 (1H, t, J = 2Hz), 4.87 (2H,
d, J = 2Hz), 8.23 (2H, broad s) (4) 2-(2-phenoxyethoxyimino)-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetic acid (syn isomer), mp150-153
°C (decomposition). IR (Nujiyor): 3470, 3300, 3150, 2550,
1750, 1620, 1600, 1540, 1500cm ^-1 NMR(d ₆ −DMSO) δ: 4.0−4.7 (4H, m), 6.7−7.5 (5H, m),
8.20(2H, broad s) (5) 2-(2,2,2-trifluoroethoxy
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetic acid (syn isomer),
mp140-143℃ (decomposition). IR (Nujiyor): 3450, 3350, 3260, 1745,
1670, 1645, 1615, 1515cm ^-1 NMR(d ₆ −DMSO) δ: 4.72and4.95 (2H, ABq, J=9Hz),
8.25(2H, broad s) (6) 2-methylthiomethoxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetic acid (syn isomer), mp140-143℃ (min.
solution). IR (Nujiyor): 3500, 3300, 3150, 2670,
2580, 1740, 1615, 1605, 1530cm ^-1 NMR(d ₆ −DMSO) δ: 2.22 (3H, s), 5.33 (2H, s), 8.20
(2H, brroad s) (7) 2-(2-methylthioethoxyimino)-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetic acid (syn isomer), mp140-143
°C (decomposition). IR (Nujiyor): 3430, 3340, 3230, 2650,
2450, 1720, 1610, 1520cm ^-1 NMR(d ₆ −DMSO) δ: 2.08 (3H, s), 2.72 (2H, t, J = 7
Hz), 4.28 (2H, t, J=7Hz), 8.17
(2H, broad s) (8) 2-phenoximino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetic acid
(syn isomer), mp145-147℃ (decomposed). IR (Nujiyor): 3350, 3170, 2500, 1730,
1710, 1645, 1630, 1595, 1535cm ^-1 NMR(d ₆ −DMSO) δ: 7.0−7.5 (5H, m), 8.30 (2H, broad
s) (9) 2-[2-(2-hexyloxyethoxy)
ethoxyimino]-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetic acid
isomers). IR (CHCl ₃ ): 3350, 3230, 2600, 2500,
1730, 1620, 1520, 1460cm ^-1 NMR(d ₆ −DMSO) δ: 0.87 (3H, t, J=5Hz), 0.87−1.73
(8H, m), 3.20-3.90 (8H, m), 4.13
-4.47 (2H, m), 8.17 (2H, broad s) (10) 2-triethyloxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
) Acetic acid (syn isomer), mp173-174°C (min.
solution). IR (Nujiyor): 3450, 1735, 1620, 1540cm
^-1 NMR(d ₆ -DMSO) δ: 7.35 (15H, s), 8.22 (2H, s) (11) 2-triethyloxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
) Acetic acid (syn isomer), mp170-171℃. IR (Nujiyor): 3300, 3150, 1680, 1635,
1520cm ^-1 NMR(d ₆ -DMSO) δ: 7.33 (18H, s), 8.13 (2H, s) Production example 20 2-Hydroxyimino-2-(5-formamide
Do-1,2,4-thiadiazol-3-yl) vinegar
acid (syn isomer, 3.3g) and dichloroacetic acid chloride
(9.0 g) in methylene chloride (50 ml).
The mixture was stirred at room temperature for 6.5 hours. Remove the precipitate,
Dissolved in ethyl acetate. After removing the insoluble matter, the mother
The liquid was evaporated to dryness. Diisopropyl ether residue
2-dichloroacetoxy
Minnow-2-(5-formamide-1,2,4-thi)
adiazol-3-yl)acetic acid (syn isomer,
2.3g), mp123°C was obtained. IR (nujiyor): 3150, 1790, 1690, 1550cm
^-1 Production example 21 2-hydroxyimino-2-(5-formamide
Do-1,2,4-thiadiazol-3-yl) vinegar
Acid (syn isomer, 9.5g) and dimethylformamide
Trityl chloride was added to the mixture of (80 ml) under stirring at room temperature.
(22.8g) and stirred for 3 minutes, then
Ruamine (4.1 g) was added slowly. The resulting mixture
The mixture was stirred for 10 minutes and ethyl acetate (250 ml) was added.
added. This mixture was washed three times with water and diluted with sodium chloride.
After washing with a saturated aqueous solution of magnesium, magnesium sulfate
The mixture was dried with a vacuum and concentrated. Sodium hydrogen carbonate in the residue
aqueous solution (50ml) and diisopropyl ether
(100ml) was added. Remove the precipitate and remove the water in the mother liquor.
The layer parts were separated. Collect the precipitate and add it to the above water layer.
and ethyl acetate was added. 10% hydrochloric acid
In addition, the pH was adjusted to 2, and the mixture was extracted with ethyl acetate. extract liquid
was dried over magnesium sulfate and concentrated under reduced pressure.
Ta. When the residue is washed with hexane, 2-trityl
Oximino-2-(5-formamide-1,
2,4-thiadiazol-3-yl)acetic acid
isomer, 17.1 g), mp 175-176°C (decomposition). IR (Nujiyor): 3180, 3070, 1700, 1600,
1540cm ^-1 NMR(d ₆ −DMSO) δ: 7.35 (15H, s), 8.83 (1H, s), 13.52
(1H, broad s) Production example 22 (1) N-(3-aminopropyl)acetamide
(146g) in dioxane (710ml), 97%
Solution of sodium hydroxide (52g) in water (620ml)
In addition, it takes 35 minutes at -1 to 3℃ to remove carbon disulfide.
(96 g) was added dropwise. This mixture was heated to 0-2℃.
Stirred for 1 hour. N-(3-acetamidopro
pills) mixtures containing sodium dithiocarbamate
The compound was converted to methyl iodide at 0-5°C for 35 minutes.
(179 g) and stirred at the same temperature for 3 hours.
Dioxane was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
(1 time with 300 ml, 4 times with 200 ml). Lottery
Dry the extract over magnesium sulfate and concentrate under reduced pressure.
Then, oily N-(3-acetamidopropylene)
) Methyl dithiocarbamate (193.18g)
Obtained. (2) N-(3-acetamidopropyl) dithioka
Methyl rubamate (193g) in dioxane (610g)
ml) solution and sodium azide (79.42g) in water
(500ml) The mixture of solutions was stirred at reflux for 4 hours.
Dioxane was distilled off, and the remaining aqueous layer was diluted with diethyl ethyl ethyl ether.
After washing with ether (150ml x 2), add 17.5% salt.
The pH was adjusted to 1 with acid and cooled in an ice bath. precipitate
When taken and washed with ice water, a white powder of 1-
(3-acetamidopropyl)-1H-tetrazo
Rule-5-thiol (91.75g), mp152-154
°C was obtained. NMR(d ₆ −DMSO) δ: 1.87 (3H, s), 1.97 (2H, m), 3.17
(2H, m), 4.28 (2H, t, J=7Hz),
7.9 (1H, broad s), 15.0 (1H, broad
s) (3) 1-(3-acetamidopropyl)-1H-
Tetrazole-5-thiol (85g) and 6N salt
The mixture of acid (1) was stirred at reflux for 75 minutes. anti
The reaction mixture was concentrated under reduced pressure, and the precipitate was collected.
When washed with hexane and diethyl ether, 1
-(3-aminopropyl)-1H-tetrazo
Ru-5-thiol hydrochloride (67.15g) was obtained.
Ta. NMR(D ₂ O) δ: 2.45 (2H, m), 3.23 (2H, t, J = 7
Hz) 4.50 (2, t, J=7Hz) (4) 2-tertiary butoxycarbonyloxyimino
-2-Phenylacetonitrile (12.3g)
Oxane (30ml) solution was added to 1-(3-aminopropylene).
lopyru)-1H-tetrazole-5-thiol
Hydrochloride (9.78g) and triethylamine (11.1
g) Mixture of dioxane (25 ml) and water (25 ml)
Add to the solution under ice-cooling and stirring, and stir at room temperature for 1 hour and 45 minutes.
did. Dioxane is distilled off and diethyl ethyl is added to the residue.
and a small amount of water. Separate the aqueous layer after shaking
The organic layer was extracted twice with 10% potassium carbonate aqueous solution.
I put it out. Add the separated aqueous layer to the extract and add diethyl
After washing with ether three times, adjust the pH to 1 with hydrochloric acid.
The mixture was then extracted with diethyl ether. extraction
Wash the liquid with water, dry it, and evaporate it to dryness under reduced pressure.
Ta. Diisopropyl residual oil (10.92g)
When treated with ether and crystallized, 1-[3-
(N-tertiary butoxycarbonylamino)pro
Pill〕-1H-tetrazole-5-thiol
(9.6 g), mp 75-77°C was obtained. IR (Nujiyor): 3380, 3260, 1650, 1530,
1170, 1050cm ^-1 NMR (CDCl) ₃ ) δ: 1.50 (9H, s), 2.14 (2H, m), 3.25
(2H, m), 4.39 (2H, t, J=7Hz),
4.9−6.7 (1H, broad) Example 1 Phosphorus chloride (450 mg) in methylene chloride (10 ml) cooled
In the solution, 2-(4-chlorophenoximino)-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetic acid (syn isomer: 650 mg) at -15
The mixture was added at ℃ and stirred for 30 minutes at the same temperature. On the other hand 7-ami
No-3-(1,3,4-thiadiazole-2-i)
) Thiomethyl-3-cephem-4-carboxylic acid
(785 mg) and trimethylsilylacetamide (2.1
Add a mixture of g) to methylene chloride (10 ml).
The mixture was warmed to a clear liquid and cooled to -20°C. This solution
was added to the above active solution at -20°C and incubated at -15°C for 40 minutes.
Stirred. Pour the reaction mixture into cold sodium bicarbonate water.
The mixture was poured into a solution (20 ml) and stirred at room temperature for 30 minutes. chloride
Distill the methylene and add ethyl acetate to the remaining aqueous solution.
I got it. Adjust this mixture to pH 3-4 with 10% hydrochloric acid.
Then extracted with ethyl acetate. Pour the extract into a sulfuric acid mug
After drying with nesium and treatment with activated carbon, the solvent was distilled off.
I left. Treat the residue with diethyl ether to dissolve
and add a mixture of acetone and diethyl ether.
It precipitated again. The precipitate is dissolved in sodium bicarbonate aqueous solution.
A precipitate is obtained by dissolving it in water and adjusting the pH to 1-2 with 10% hydrochloric acid.
It was done. When this is taken and washed with water, 7-[2-(4
-chlorophenoximino)-2-(5-amino
-1,2,4-thiadiazol-3-yl)acetate
toamide]-3-(1,3,4-thiadiazole
-2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer: 0.35g), mp150-155℃
(decomposition) was obtained. IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 3.67 (2H, broad
s), 4.27 and 4.50 (2H, ABq, J=14
Hz), 5.17 (1H, d, J = 4Hz), 5.80 (1H,
dd, J=4 and 8Hz), 7.00−7.50 (4H,
m), 8.22 (2H, s), 9.50 (1H, s), 9.80
(1H, d, J = 8Hz) Example 2 Phosphorus chloride (1.04g) in methylene chloride (25ml) cooled
In the solution, 2-(4-fluorophenoxyimino)
-2-(5-amino-1,2,4-thiadiazole
-3-yl)acetic acid (syn isomer: 1.4g)
It was added at 15°C and stirred at the same temperature for 30 minutes. On the other hand 7-A
Minnow-3-(1,3,4-thiadiazole-2-
yl)thiomethyl-3-cephem-4-carvone
Acid (1.65g) and trimethylsilylacetamide
(5g) and methylene chloride (25ml) are heated.
A clear solution was obtained and cooled to -15°C. This melt
Add the liquid to the above active mixture and stir at 0-5℃ for 1 hour.
Stirred. Concentrate the reaction mixture and add ethyl acetate to the residue.
and added water. After removing insoluble matter, add hydrogen carbonate
The ethyl acetate layer was poured into a thorium aqueous solution. water layer
After separating and adding ethyl acetate, adjust the pH to 4 with 10% hydrochloric acid.
did. Extracted with ethyl acetate and magnesium sulfate
After drying, concentrate to about 10ml and remove the precipitate.
Wash with ethyl acetate and diethyl ether and dry.
When dried, 7-[2-(4-fluorophenoxy)
imino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid
1.2g), mp140-145℃ (decomposition) was obtained.
Ta. IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 3.57 and 3.80
(2H, ABq, J=18Hz), 4.27 and 4.57
(2H, ABq, J = 13Hz), 5.20 (1H, d, J
= 4Hz), 5.87 (1H, dd, J = 4 and 8
Hz), 7.17-7.3 (4H, m), 8.20 (2H, s),
9.50 (1H, s), 9.83 (1H, d, J = 8Hz) Example 3 Phosphorus pentachloride (2.08g) in methylene chloride (50ml) cooled
Add 2-phenoximino-2- to the solution at -15°C.
(5-amino-1,2,4-thiadiazole-3
-yl) acetic acid (syn isomer: 2.64 g) and
Stir at temperature for 30 minutes. On the other hand, 7-amino-3-ceph
4-nitrobenzyl ester of em-4-carboxylic acid
ter (3.35g) and trimethylsilylacetamide
(10g) and methylene chloride (50ml) are heated.
A clear solution was obtained, and the mixture was cooled to -15°C again. This melt
Add the above active mixture to the liquid and keep at 0-5℃ for 0.5 hours.
Stirred. Sodium bicarbonate reaction mixture
(5.9 g) in cold water (100 ml),
After drying the layer with magnesium sulfate, it was evaporated to dryness.
It was dry. Treat the residue with diethyl ether to form a powder.
When this is dried, 7-[2-pheno
Kixiimino-2-(5-amino-1,2,4-thi)
Asiazol-3-yl)acetamide]-3-
4-nitrobenzyl cefem-4-carboxylic acid
Ester (syn isomer: 5.1g), mp140-145℃
(decomposition) was obtained. IR (Nujiyor): 3300, 1775, 1720, 1680,
1625, 1600, 1590, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 3.60 (2H, broad
s), 5.23 (1H, d, J = 4Hz), 5.42 (2H,
s), 6.00 (1H, dd, J=4 and 8Hz),
6.67 (1H, t, J = 4Hz), 7.0-7.50 (5H,
m), 7.73 (2H, d, J=8Hz), 8.27 (2H,
d, J=8Hz), 8.30 (2H, s), 9.97 (1H,
d, J = 8 Hz) Example 4 Following the same method as Examples 1 to 3, 5 and 7 to 12.
The following compound was obtained. (1) 7-[2-phenoxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-carboxyme)
Chil-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp175-180℃ (decomposition). IR (Nujiyor): 3400, 3200, 1770, 1700,
1660, 1620, 1580, 1510cm ^-1 NMR(d ₆ −DMSO, δ): 3.70 (2H, broad
s), 4.23 and 4.50 (2H, ABq, J=14
Hz), 5.17 (1H, d, J = 4Hz), 5.30 (2H,
s), 5.89 (1H, dd, J=4 and 8Hz),
7.0−7.5 (5H, m), 8.22 (1H, s), 9.83
(1H, d, J=8Hz) (2) 7-[2-phenoxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-allyl-1H
-tetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp145-150℃ (decomposition). IR (Nujiyor): 3450, 3350, 3180, 1780,
1710, 1680, 1610, 1590, 1510cm ^-1 NMR(d ₆ −DMSO, δ): 3.70 (2H, broad
s), 4.28 and 4.45 (2H, ABq, J=13
Hz), 4.83-5.10 (2H, m), 5.18 (1H, d,
J=4Hz), 5.20-5.43 (2H, m), 5.93 (1H,
dd, J=4 and 8Hz), 5.67−6.30 (1H,
m), 7.0-7.57 (5H, m), 8.30 (2H, s),
9.92 (1H, d, J = 8Hz) (3) 7-[2-phenoxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-methyl-1H
-tetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp155-158℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1720, 1680, 1620, 1590, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 3.77 (2H, broad
s), 3.95 (3H, s), 4.33 (2H, broad s),
5.27 (1H, d, J = 4Hz), 5.93 (1H, dd, J
=4 and 8Hz), 7.0-7.67 (5H, m), 8.37
(2H, s), 10.0 (1H, d, J=8Hz) (4) 7-[2-phenoxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
) acetamide] cephalosporanic acid (sin)
isomers), mp150-155℃ (decomposition). IR (Nujiyor): 3450, 3350, 3180, 1775,
1710, 1680, 1610, 1580, 1515cm ^-1 NMR(d ₆ −DMSO, δ): 2.03 (3H, s),
3.62 (2H, broad s), 4.77 and 5.03 (2H,
ABq, J = 14Hz), 5.28 (1H, d, J = 4
Hz), 5.97 (1H, dd, J=4 and 8Hz),
7.0−7.67 (5H, m), 8.37 (2H, s), 9.97
(1H, d, J=8Hz) (5) 7-[2-(2-methoxy-5-nitrophe
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
]-3-(1,3,4-thiadiazole-2
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp160-169°C (decomposition). IR (Nujiyor): 3380, 3220, 3100, 1780,
1690, 1620, 1600, 1520, 1340, 1280,
1085, 1065, 820, 750cm ^-1 NMR(d ₆ −DMSO, δ): 3.71 (2H, m),
3.98 (3H, s), 4.25 and 4.66 (2H, ABq,
J=14Hz), 5.23 (1H, d, J=5Hz), 5.94
(1H, dd, J=5 and 9Hz), 7.33 (1H,
d, J=8Hz), 8.10 (1H, d, J=8Hz),
8.19 (1H, s), 8.34 (2H, broad s), 9.58
(1H, s), 9.87 (1H, d, J = 9Hz) (6) 7-[2-(4-fluorophenoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(Tetrazolo[1,5-b]pyridazine-6-
yl)thiomethyl-3-cephem-4-carbo
acid (syn isomer), mp125-130°C (decomposition). IR (Nujiyor): 3300, 3190, 1770, 1670,
1615, 1520, 1495cm ^-1 NMR(d ₆ −DMSO, δ): 3.80 (2H, broad
s), 4.30 and 4.65 (2H, ABq, J=13
Hz), 5.27 (1H, d, J = 5Hz), 5.95 (1H,
dd, J=5 and 8Hz), 7.25 (2H, s),
7.35 (2H, s), 7.80 (1H, d, J=10Hz),
8.37 (2H, broad s), 8.62 (1H, d, J=10
Hz), 9.92 (1H, d, J = 8Hz) (7) 7-[2-(4-fluorophenoxyimide
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
4-nitrobenzyl fem-4-carboxylic acid
Ester (syn isomer), mp135-140℃ (min
solution). IR (Nujiyor): 3300, 3200, 1770, 1720,
1680, 1625, 1605, 1500, 1495cm ^-1 NMR(d ₆ −DMSO, δ): 3.45 − 3.75 (2H,
m), 5.15 (1H, d, J=5Hz), 5.35 (2H,
s), 5.92 (1H, dd, J=5 and 8Hz),
6.58 (1H, t, J=4Hz), 7.08 (2H, s),
7.18 (2H, s), 7.60 (2H, d, J=8Hz),
8.13 (2H, d, J = 8Hz), 8.17 (2H, broad
s), 9.75 (1H, d, J = 8Hz) (8) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(5-
Hydroxymethyl-1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp135-140℃
(Disassembly). IR (Nujiyor): 3450, 3280, 3180, 1760,
1720, 1660, 1620, 1580, 1520, 1480cm ^-1 NMR(d ₆ −DMSO, δ): 3.72 (2H, broad
s), 4.27 and 4.55 (2H, ABq, J=13
Hz), 4.80 (2H, s), 5.22 (1H, d, J=5
Hz), 5.88 (1H, dd, J=5 and 8Hz),
7.25 (2H, d, J = 9Hz), 7.42 (2H, d, J
=9Hz), 8.23 (2H, broad s), 9.85 (1H,
d, J=8Hz) (9) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(1-
Carboxymethyl-1H-tetrazole-5-
yl)thiomethyl-3-cephem-4-carbo
acid (syn isomer), mp135-140°C (decomposition). IR (Nujiyor): 3400, 3250, 3170, 1765,
1700, 1680, 1650, 1615, 1580, 1510, 1480
cm ^-1 NMR(d ₆ −DMSO, δ): 3.70 (2H, broad
s), 4.27 and 4.48 (2H, ABq, J=13
Hz), 5.22 (1H, d, J = 5Hz), 5.30 (2H,
s), 5.93 (1H, dd, J=5 and 8Hz),
7.35 (2H, d, J = 9Hz), 7.48 (2H, d, J
= 9Hz), 8.37 (2H, broad s), 9.97 (1H,
d, J=8Hz) (10) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamido]-2-methyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp150-155℃ (decomposition). IR (Nujiyor): 3400, 3270, 3180, 1770,
1620, 1580, 1520, 1480cm ^-1 NMR(d ₆ −DMSO, δ): 1.45 (3H, d, J
=7Hz), 3.60-4.10 (1H, m), 5.20 (1H,
d, J=5Hz), 5.80 (1H, dd, J=5 and
and 8Hz), 6.62 (1H, d, J = 6Hz), 7.35
(2H, d, J=9Hz), 7.48 (2H, d, J=
9Hz), 8.03-8.73 (2H, m), 9.97 (1H, d,
J=8Hz) (11) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-cephe
4-nitrobenzyl ester of mu-4-carboxylic acid
Tel (syn isomer), mp155-160℃ (decomposition). IR (Nujiyor): 3300, 3180, 1770, 1720,
1680, 1625, 1600, 1580, 1520, 1480cm ^-1 NMR(d ₆ −DMSO, δ): 3.62 (2H, broad
s), 5.18 (1H, d, J=5Hz), 5.38 (2H,
s), 5.95 (1H, dd, J=5 and 8Hz),
6.63 (1H, t, J = 4Hz), 7.25 (2H, d, J
= 9Hz), 7.38 (2H, d, J = 9Hz), 7.65
(2H, d, J=8Hz), 8.20 (2H, d, J=
8Hz), 8.23 (2H, broad, s), 9.85 (1H,
d, J=8Hz) (12) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
(2-hydroxyethyl)-1H-tetrazole
-5-yl]thiomethyl-2-cephem-4-
Carboxylic acid (syn isomer), mp120-125℃ (min
solution). IR (Nujiyor): 3400, 3300, 3180, 1765,
1670, 1615, 1580, 1520, 1480cm ^-1 NMR(d ₆ −DMSO, δ): 3.50−3.93 (4H,
m), 4.12-4.48 (4H, m), 5.18 (1H, d,
J=5Hz), 5.88(1H, dd, J=5 and 8
Hz), 7.28 (2H, d, J=9Hz), 7.45 (2H,
d, J=9Hz), 8.30 (2H, broad s), 9.94
(1H, d, J=8Hz) (13) 7-[2-(3,4-dichlorophenoxy
imino)-2-(5-amino-1,2,4-thi
Asiazol-3-yl)acetamide] Cef
Allosporanic acid (syn isomer), minutes below 200℃
Solution. IR (Nujiyor): 3600, 3400, 1770, 1720,
1680, 1530, 1250, 1120, 970cm ^-1 NMR(d ₆ −DMSO, δ): 2.03 (3H, s),
3.60 (2H, m), 4.65 and 5.05 (2H, ABq,
J=15Hz), 5.27 (1H, d, J=5Hz), 5.97
(1H, dd, J=5 and 8Hz), 7.13−7.77
(3H, m), 8.35 (2H, m), 9.90 (1H, d,
J=8Hz) (14) 7-[2-(3,4-dichlorophenoxy
imino)-2-(5-amino-1,2,4-thi
Asiazol-3-yl)acetamide]-3
-(1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), decomposes below 160℃. IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1250, 1205, 1060cm ^-1 NMR(d ₆ −DMSO, δ): 3.77 (2H, m),
4.28 and 4.68 (2H, ABq, J=14Hz), 5.37
(1H, d, J=5Hz), 5.97 (1H, dd, J=
5 and 8Hz), 7.16-7.80 (3H, m), 8.36
(2H, s), 9.60 (1H, s), 9.93 (1H, d,
J=8Hz) (15) 7-[2-(3-trifluoromethylphene
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
4-di]-3-cephem-4-carboxylic acid
Trobenzil (syn isomer), mp136-140℃
(Disassembly). IR (Nujiyor): 3370, 3200, 1780, 1730,
190, 1680, 1630, 1610, 1520, 1450, 1325,
1280, 1160, 1125, 975, 850, 740cm ^-1 NMR(d ₆ −DMSO, δ): 3.7 (2H, m), 5.22
(1H, d, J=5Hz), 5.37 (2H, s), 5.99
(1H, dd, J=5 and 8Hz), 6.63 (1H,
m), 7.50 (4H, broad s), 7.66 (2H, d,
J=9Hz), 8.20 (2H, d, J=9Hz), 9.89
(1H, d, J=8Hz) (16) 7-[2-(3-trifluoromethylphene
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
]-3-(1,3,4-thiadiazole-2
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), decomposes below 164℃. IR (Nujiyor): 3300, 3180, 1765, 1670,
1610, 1520, 1320, 1165, 1120, 1060, 930,
790,700cm ^-1 NMR(d ₆ −DMSO, δ): 3.73 (2H, m),
4.23 and 5.63 (2H, ABq, J=14Hz), 5.27
(1H, d, J = 5Hz), 5.93 (1H, dd, J =
5 and 8Hz), 7.55 (4H, broad s), 8.34
(2H, broad s), 9.60 (1H, s), 9.99 (1H,
d, J = 8Hz) (17) 7-[2-(3-ethoxycarbonylphene
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
]-3-(1,3,4-thiadiazole-2
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), decomposes below 162℃. IR (Nujiyor): 3350-3150, 1770, 1720-
1660, 1620, 1520, 1290, 1270, 1100,
1060, 900, 760cm ^-1 NMR(d ₆ −DMSO, δ): 1.32 (3H, t, J
=7Hz), 3.71 (2H, m), 4.25 and 4.60
(2H, ABq, J = 14Hz), 4.32 (2H, q, J
=7Hz), 5.23 (1H, d, J = 5Hz), 5.73
(1H, dd, J=5 and 8Hz), 7.40−7.95
(4H, m), 8.67 (2H, broad s), 9.59 (1H,
s), 9.98 (1H, d, J = 8Hz) (18) 7-[2-(4-fluorophenoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(2-hydroxyethyl)-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp145-150
°C (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1670,
1610, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 3.50−3.83 (4H,
m), 4.0-4.53 (4H, m), 5.13 (1H, d, J
= 4Hz), 5.83 (1H, dd, J = 4 and 8
Hz), 7.12 (2H, s), 7.23 (2H, s), 8.18
(2H, s), 9.77 (1H, d, J = 8Hz) (19) 7-[2-(4-fluorophenoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-carboxymethyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp150-155℃ (min
solution). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520, 1500cm ^-1 NMR(d ₆ −DMSO, δ): 3.57 (2H, broad
s), 4.27 and 4.53 (2H, ABq, J=14
Hz), 5.23 (1H, d, J = 8Hz), 5.37 (2H,
s), 5.93 (1H, dd, J=4 and 8Hz),
7.25 (2H, s), 7.37 (2H, s), 8.32 (2H,
s), 9.92 (1H, d, J = 8Hz) (20) 7-[2-(4-fluorophenoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[2-carboxymethyl-3-oxo-2,3
-dihydro-1,2,4-triazolo[4,3
-b]pyridazin-6-yl]thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer),
mp165-170℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1710,
1620, 1540, 1520, 1500cm ^-1 NMR(d ₆ −DMSO, δ): 3.67 and 3.90
(2H, ABq, J=18Hz), 4.13 and 4.37
(2H, ABq, J=13Hz), 4.73 (2H, s),
5.23 (1H, d, J = 4Hz), 5.90 (1H, dd, J
= 4 and 8 Hz), 7.08 (1H, d, J = 10
Hz), 7.17 (2H, s), 7.28 (2H, s), 7.72
(1H, d, J=10Hz), 8.23 (2H, s), 9.83
(1H, d, J = 8Hz) (21) 7-[2-(4-fluorophenoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(2-carboxyethyl)-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp140-145
°C (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1700,
1620, 1520, 1500cm ^-1 NMR(d ₆ −DMSO, δ): 2.90 (2H, t, J
= 6Hz), 3.70 (2H, broad s), 4.40 (2H,
t, J=6Hz), 4.27 and 4.47 (2H, ABq,
J=13Hz), 5.17 (1H, d, J=4Hz), 5.87
(1H, dd, J=4 and 8Hz), 7.15 (2H,
s), 7.25 (2H, s), 8.22 (2H, s), 9.83
(1H, d, J = 8Hz) (22) 7-[2-(4-fluorophenoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-allyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp145-150℃ (decomposed). IR (Nujiyor): 3450, 3350, 3150, 1780,
1705, 1670, 1610, 1510cm ^-1 NMR(d ₆ −DMSO, δ): 3.66 and 3.84
(2H, ABq, J=18Hz), 4.30 and 4.50
(2H, ABq, J = 14Hz), 5.00 (2H, d, J
= 5Hz), 5.24 (1H, d, J = 4Hz), 5.20−
5.40 (2H, m), 5.96 (1H, dd, J=4 and
8Hz), 5.80-6.20 (1H, m), 7.28 (2H,
s), 7.34 (2H, s), 8.32 (2H, s), 9.96
(1H, d, J = 8Hz) (23) 7-[2-(4-fluorophenoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide] Cephalo
Sporanic acid (syn isomer), mp156-161℃ (min
solution). IR (Nujiyor): 3450, 3300, 3200, 1770,
1730, 1680, 1610, 1510, 1500cm ^-1 NMR(d ₆ −DMSO, δ): 2.04 (3H, s),
3.52 and 3.68 (2H, ABq, J=18Hz), 4.74
and 5.02 (2H, ABq, J=14Hz), 5.26
(1H, d, J = 4Hz), 5.94 (1H, dd, J =
4 and 8Hz), 7.26 (2H, s), 7.34 (2H,
s), 8.30 (2H, s), 9.94 (1H, d, J=8
Hz) (24) 7-[2-phenoximino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(tetrazolo[1,
5-b]Pyridazin-6-yl)thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp175-180℃ (decomposition). IR (Nujiyor): 3300, 3200, 1775, 1680,
1615, 1585, 1520cm ^-1 (25) 7-[2-phenoximino)-2-(5
-Amino-1,2,4-thiadiazole-3-
yl) acetamide]-3-[1-{2-(N
-Tertiary butoxycarbonylamino)ethyl}
-1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp150-155℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1590, 1520cm ^-1 (26) 7-[2-(3-trifluoromethylphene
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-cephem-4-carboxylic acid
decomposes below 193℃. IR (Nujiyor): 3450, 3320, 3200, 1770,
1710, 1665, 1630, 1560, 1515, 1325,
1170, 1110, 940cm ^-1 (27) 7-[2-phenoxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-cephem-4-cal
Bonic acid (syn isomer), mp168-170°C (decomposition). IR (Nujiyor): 3400, 3200, 1780, 1660,
1620, 1600, 1590, 1540cm ^-1 (28) 7-[2-(4-chlorophenoxyimide)
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
fem-4-carboxylic acid (syn isomer),
mp145-150℃ (decomposition). IR (Nujiyor): 3400, 3260, 3180, 1775,
1675, 1625, 1600, 1520, 1480cm ^-1 (29) 7-[2-(4-fluorophenoxyimide)
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
fem-4-carboxylic acid (syn isomer),
mp130-135℃ (decomposition). IR (Nujiyor): 3400, 3270, 3180, 1765,
1675, 1605, 1500cm ^-1 (30) 7-[2-phenoximino)-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-[1-(2-amido)
Noethyl)-1H-tetrazol-5yl]
Omethyl-3-cephem-4-carboxylic acid
isomer), mp180-185℃ (decomposition). IR (Nujiyor): 3300, 3250, 1760, 1670,
1620, 1590, 1520cm ^-1 Example 5 Phosphorous chloride (2.08 g) was cooled in methylene chloride (45 ml).
Add 2-(tert-butoxycarbonylmethoxy) to the solution.
(shiimino)-2-(5-amino-1,2,4-thi)
adiazol-3-yl)acetic acid (syn isomer:
2.51g) was added at -17℃ and stirred at the same temperature for 50 minutes.
Ta. On the other hand, 7-amino-3-(tetrazolo[1,5
-b]Pyridazin-6-yl)thiomethyl-3-
Cefem-4-carboxylic acid (3.34g) and trimethy
Lucilylacetamide (12g) in methylene chloride
(45 ml) and warm the mixture to make a clear liquid, -
Cooled to 20°C. Add this solution to the above active mixture
and stirred at -10 to -15°C for 1 hour. reaction mixture
Evaporate the substance and add ethyl acetate and sodium bicarbonate to the residue.
um aqueous solution was added. Separate the aqueous layer and add 10% hydrochloric acid
After adjusting the pH to 3-4, the mixture was extracted with ethyl acetate. extraction
The solution was dried over magnesium sulfate and evaporated under reduced pressure.
Ta. Treatment of the residue with diethyl ether gives 7-
[2-(tertiary butoxycarbonylmethoxyimide)
-2-(5-amino-1,2,4-thiasia)
zol-3-yl)acetamide]-3-(tet
lazolo[1,5-b]-pyridazin-6-yl)
Thiomethyl-3-cephem-4-carboxylic acid
isomer: 2.4g), mp125-130℃ (decomposition) was obtained.
It was done. IR (Nujiyor): 3400, 3300, 3180, 1770,
1720, 1680, 1620, 1525cm ^-1 NMR(d ₆ −DMSO, δ): 1.47 (9H, s),
3.73 (2H, broad s), 4.28 and 4.60 (2H,
ABq, J=13Hz), 4.65 (2H, s), 5.18 (1H,
d, J=5Hz), 5.87(1H, dd, J=5 and
and 8Hz), 7.78 (1H, d, J = 10Hz), 8.17
(2H, broad s), 8.62 (1H, d, J=10
Hz), 9.55 (1H, d, J=8Hz) Example 6 Method similar to Examples 1 to 3, 5, and 7 to 12
The following compound was obtained according to the following. (1) 7-[2-{3-(N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-methyl-3-ceph
M-4-carboxylic acid (syn isomer), mp114
~119℃ (decomposition). NMR(d ₆ −DMSO, δ): 1.40 (9H, s),
1.74 (3H, s), 1.80 (2H, m), 3.00 (4H,
m), 4.14 (2H, m), 5.10 (1H, d, J=5
Hz), 5.72 (1H, dd, J=5 and 8Hz),
6.70 (1H, broad s), 8.10 (2H, broad
s), 9.44 (1H, d, J = 8Hz) (2) 7-[2-[3-(N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-chloro-3-ceph
4-nitrobenzyl ester of em-4-carboxylic acid
Stell (syn isomer), mp91-100°C (decomposition). NMR(d ₆ −DMSO＋D ₂ O, δ): 1.38 (9H,
s), 1.80 (2H, m), 3.06 (2H, m), 3.7−
4.3 (4H, m), 5.33 (1H, d, J=5Hz),
5.49 (2H, s), 5.95 (1H, d, J=5Hz),
7.74 (2H, d, J = 9Hz), 8.92 (2H, d, J
=9Hz) (3) 7-[2-{3-(N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl) acetamide]-3-[1-{2-(N
-Tertiary butoxycarbonylamino)ethyl}
-1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp107-112℃ (decomposition). NMR(d ₆ −DMSO＋D ₂ O, δ): 1.32 (9H,
s), 1.34 (9H, s), 1.80 (2H, m), 3.10
(2H, m), 3.30 (2H, m), 3.70 (2H, m),
4.0−4.5 (6H, m), 5.13 (1H, d, J=5
Hz), 5.83 (1H, d, J = 5Hz) (4) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-cephem-4-cal
4-nitrobenzyl ester of bonic acid
(decomposition), mp125-130℃ (decomposition). IR (Nujiyor): 3300, 1770, 1720, 1680,
1630, 1610, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 3.60 (2H, broad
s), 4.57-4.83 (2H, m), 5.17 (1H, d,
J=4Hz), 5.0-5.35 (2H, m), 5.40 (2H,
s), 5.93 (1H, dd, J=4 and 8Hz),
5.87−6.17 (1H, m), 6.63 (1H, t, J=3
Hz), 7.70 (2H, d, J = 9Hz), 8.10 (2H,
s), 8.23 (2H, d, J=9Hz), 9.57 (1H,
d, J=8Hz) (5) 7-[2-(2,2,2-trifluoroethane
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
Cephalosporanic acid (syn isomer), mp185~
195℃ (decomposition). IR (Nujiyor): 3470, 3330, 3210, 3060,
1770, 1735, 1700, 1670, 1620, 1555, 1520
cm ^-1 NMR(d ₆ −DMSO, δ): 2.00 (3H, s),
3.53 (2H, broad s), 4.65 and 4.87 (2H,
ABq, J=9Hz), 4.70 and 4.93 (2H,
ABq, J = 13Hz), 5.12 (1H, d, J = 5
Hz), 5.78 (1H, dd, J=5 and 8Hz),
8.12 (2H, broad s), 9.62 (1H, d, J=8
Hz) (6) 7-[2-(2,2,2-trifluoroethyl
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-(1-allyl-1H-tetrazole-5
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp125-130°C (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 3.68 (2H, broad
s), 4.30 and 4.40 (2H, ABq, J=13
Hz), 4.68 and 4.92 (2H, ABq, J=9
Hz), 4.87-5.10 (2H, m), 5.15 (1H, d,
J = 5Hz), 5.17-5.47 (2H, m), 5.83 (1H,
dd, J = 5 and 8Hz), 5.67−6.27 (1H,
m), 8.25 (2H, broad s), 9.77 (1H, d,
J=8Hz) (7) 7-[2-(2,2,2-trifluoroethane
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-(1-methyl-1H-tetrazole-5
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp145-150°C (decomposed). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1525cm ^-1 NMR(d ₆ −DMSO, δ): 3.70 (2H, broad
s), 3.95 (3H, s), 4.32 (2H, broad s),
4.68 and 4.92 (2H, ABq, J=9Hz), 5.15
(1H, d, J=5Hz), 5.85 (1H, dd, J=
5 and 8Hz), 8.25 (2H, broad s), 9.75
(1H, d, J=8Hz) (8) 7-[2-{2-(N-tertiary butoxylic
bonylamino)ethoxyimino}-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-2-methyl-3-cephene
Mu-4-carboxylic acid (syn isomer), mp215~
220℃ (decomposition). IR (Nujiyor): 3230, 3150, 1775, 1680,
1620, 1525cm ^-1 NMR(d ₆ −DMSO＋D ₂ O, δ): 1.37 (9H,
s), 1.43 (3H, d, J=7Hz), 3.0−3.5
(2H, m), 4.0−4.4 (2H, m), 5.10 (1H,
d, J = 4.5Hz), 5.8-6.1 (1H, m), 6.53
(1H, d, J = 6.9Hz) (9) 7-[2-{2-(N-tertiary butoxylic
bonylamino)ethoxyimino}-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-[1-{2-(N-
tertiary-butoxycarbonylamino)ethyl}-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp181-186℃ (decomposition). IR (Nujiyor): 3320, 1780, 1680, 1620,
1520, 1165cm ^-1 NMR(d ₆ −DMSO＋D ₂ O, δ): 1.32 (18H,
s), 3.07-3.52 (4H, m), 3.7 (2H, broad
s), 4.0−4.5 (6H, m), 5.15 (1H, d, J
= 4.5Hz), 5.85 (1H, d, J = 4.5Hz), 8.23
(2H, broad s) (10) 7-[2-trityloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(5-methyl-
1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp147-161℃ (decomposition). IR (Nujiyor): 3420, 1780, 1680, 1615,
1525cm ^-1 NMR(d ₆ −DMSO＋D ₂ O, δ): 2.72 (3H,
s), 3.73 (2H, broad s), 4.30 and 4.67
(2H, ABq, J = 14Hz), 5.35 (1H, d, J
= 5.0Hz), 6.15 (1H, d, J = 5.0Hz), 7.50
(15H, s) (11) 7-[2-{2-(N-tertiary butoxylic
bonylamino)ethoxyimino}-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-carboxyme)
Chil-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp105℃ (decomposition). IR (Nujiyor): 3305, 3160, 1770, 1670,
1520, 1245cm ^-1 NMR(d ₆ −DMSO＋D ₂ O, δ): 1.37 (9H,
s), 3.0−3.5 (2H, m), 3.72 (2H, broad
s), 3.94-4.3 (2H, m), 4.1-4.6 (2H,
m), 5.13 (1H, d, J = 4.5Hz), 5.33 (2H,
s), 5.7−6.0 (1H, m) (12) 7-[2-(tertiary butoxycarbonylmeth
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-(1,3,4-thiadiazole-2-i)
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp140-145°C (decomposed). IR (Nujiyor): 3300, 3175, 1770, 1720,
1680, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.50 (9H, s),
3.73 (2H, broad s), 4.33 and 4.58 (2H,
ABq, J=13Hz), 4.65 (2H, s), 5.17 (1H,
d, J=4Hz), 5.85(1H, dd, J=4 and
and 8Hz), 8.18 (2H, s), 9.50 (1H, d, J
= 8 Hz), 9.53 (1H, s) (13) 7-[2-(tertiary butoxycarbonyl
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Cephalosporanic acid (syn isomer),
mp125-130℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1680, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.50 (9H, s),
2.10 (3H, s), 3.62 (2H, broad s), 4.68
(2H, s), 4.77 and 5.03 (2H, ABq, J=
13Hz), 5.20 (1H, d, J = 4Hz), 5.88 (1H,
dd, J=4 and 8Hz), 8.18 (2H, s),
9.55 (1H, d, J = 8Hz) (14) 7-[2-(tertiary butoxycarbonyl
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-(1-allyl-1H-tetrazole
-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp130-135℃ (min
solution). IR (Nujiyor): 3400, 3280, 3180, 1770,
1720, 1680, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.42 (9H, s),
3.67 (2H, broad s), 4.27 and 4.43 (2H,
ABq, J=13Hz), 4.62 (2H, s), 4.87−
5.07 (2H, m), 5.10 (1H, d, J=5Hz),
5.13−5.43 (2H, m), 5.82 (1H, dd, J=5
and 8Hz), 5.60−6.20 (1H, m), 8.10
(2H, broad s), 9.47 (1H, d, J = 8Hz) (15) 7-[2-(tertiary poxycarbonyl
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
[do]-3-[1-{2-(N-tertiary butoxy
carbonylamino)ethyl}-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp110-115℃
(Disassembly). IR (Nujiyor): 3300, 3200, 1775, 1680,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.32 (9H, s),
1.42 (9H, s), 3.33 (2H, broad s), 3.53
−3.80 (2H, m), 413 −4.47 (4H, m), 4.58
(2H, s), 5.08 (1H, d, J=5Hz), 5.78
(1H, dd, J=5 and 8Hz), 8.07 (2H,
broad s), 9.45 (1H, d, J = 8Hz) (16) 7-[2-(tertiary butoxycarbonyl
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-(1-phenyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp135-140℃
(Disassembly). IR (Nujiyor): 3400, 3300, 3200, 1775,
1720, 1685, 1620, 1525, 1500cm ^-1 NMR(d ₆ −DMSO, δ): 1.43 (9H, s),
3.70 (2H, broad s), 4.32 and 4.57 (2H,
ABq, J=13Hz), 4.65 (2H, s), 5.12 (1H,
d, J=5Hz), 5.85(1H, dd, J=5 and
and 8Hz), 7.67 (5H, s), 8.17 (2H, broad
s), 9.50 (1H, d, J = 8Hz) (17) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-2-methyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp133-146℃ (decomposition). IR (Nujiyor): 3280, 3170, 1775, 1685,
1670, 1625, 1520cm ^-1 NMR(d ₆ −DMSO＋D ₂ O, δ): 1.40 (9H,
s), 1.46 (3H, d, J=7Hz), 1.56−2.06
(2H, m), 3.03 (2H, t, J=7Hz), 3.1−
4.1 (1H, m), 4.23 (2H, t, J=7Hz),
5.13 (1H, d, J = 5Hz), 5.97 (1H, d, J
= 5Hz), 6.65 (1H, d, J = 6.5Hz) (18) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1-allyl-
1H-tetrazol-5-yl)thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp150-155℃ (decomposition). IR (Nujiyor): 3300, 3200, 1775, 1670,
1620, 1520cm ^-1 (19) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(tetrazolo
[1,5-b]pyridazin-6-yl)thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp180-185℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1525cm ^-1 (20) 7-[2-(2,2,2-trifluoroe
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
[do]-3-[1-{2-(N-tertiary butoxy
carbonylamino)ethyl}-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-Carboxylic acid (syn isomer), powder. (21) 7-[2-(2,2,2-trifluoroe
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
]-3-(5-aminomethyl-1,3,4-
Thiadiazol-2-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp150-155℃ (decomposition). IR (Nujiyor): 3300, 3180, 1760, 1670,
1610, 1520cm ^-1 (22) 7-[2-(2,2,2-trifluoroe
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-[tetrazolo[1,5-b]pyrida
Zin-6-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp165-170℃
(Disassembly). IR (Nujiyor): 3420, 3300, 3190, 1770,
1705, 1670, 1620, 1525cm ^-1 (23) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-chloro-3-
Cefem-4-carboxylic acid (syn isomer),
mp111-115℃ (decomposition). IR (Nujiyor): 3300-3100, 1780, 1690-
1660, 1520, 1270cm ^-1 (24) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
il) Acetamide]-3-Cefem-4-ka
Rubonic acid (syn isomer), mp160-165℃ (min
solution). (25) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(2-aminoethyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp184-196℃
(Disassembly). IR (Nujiyor): 3400-3100, 1760, 1660,
1610, 1520, 1170, 1060, 1010cm ^-1 (26) 7-[2-(2-aminoethoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(1-
Carboxymethyl-1H-tetrazole-5-
yl)thiomethyl-3-cephem-4-carbo
acid (syn isomer), mp190-198°C (decomposition). IR (Nujiyor): 3250, 3160, 1760, 1650,
1615, 1522, 1020cm ^-1 (27) 7-[2-carboxymethoxyimino)-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), mp170-175℃ (decomposition). IR (Nujiyor): 3250, 3150, 1770, 1710,
1680, 1610, 1520cm ^-1 (28) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-aryl)
Ru-1H-tetrazol-5-yl)thiomethi
Leu-3-cephem-4-carboxylic acid (synisomer
body), mp145-150℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1765,
1720, 1680, 1620, 1520cm ^-1 (29) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamido]cephalosborane
Acid (syn isomer), mp160-165°C (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1680, 1520cm ^-1 (30) 7-[2-(2-aminoethoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamido]-2-methyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp190-195℃ (decomposition). IR (Nujiyor): 3300, 3150, 1760, 1660,
1575, 1520, 1400cm ^-1 (31) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-2-meth
Chill-3-cefem-4-carboxylic acid
sex body), mp182-187℃ (decomposition). IR (Nujiyor): 3260, 3150, 1758, 1660,
1616, 1575, 1520, 1400cm ^-1 (32) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[tetrazo
b[1,5-b]pyritazin-6-yl)thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp170-175℃ (decomposition). IR (Nujiyor): 3400, 3300, 3180, 1765,
1720, 1680, 1615, 1520cm ^-1 (33) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-meth
Chill-3-cefem-4-carboxylic acid
(decomposition), mp175-195℃ (decomposition). IR (Nujiyor): 3300-3100, 1770-1740,
1660, 1620, 1570, 1520, 1280, 1170,
1060, 1020cm ^-1 (34) 7-[2-(3-aminopropoxyimide
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-k
Rolo-3-cephem-4-carboxylic acid
(decomposition), mp190-205℃ (decomposition). IR (Nujiyor): 3400-3150, 1760, 1660,
1630−1590, 1520, 1340, 1170, 1030cm ^-1 (35) 7-[2-(2-aminoethoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
(2-aminoethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp182-187°C (decomposition). IR (Nujiyor): 3350, 3150, 1760, 1660,
1625, 1565, 1520cm ^-1 (36) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(2
-aminoethyl)-1H-tetrazole-5-
yl]thiomethyl-3-cephem-4-carbo
acid (syn isomer), mp185-190°C (decomposed). IR (Nujiyor): 3250, 1755, 1660, 1590,
1520cm ^-1 (37) 7-[2-(2,2,2-trifluoroe
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-[1-(2-aminoethyl)-1H
-tetrazol-5-yl]thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp185-190℃ (decomposition). IR (Nujiyor): 3300, 3170, 1760, 1670,
1615, 1500cm ^-1 (38) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-fe)
Nyl-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp155-160℃ (decomposition). IR (Nujiyor): 3400, 3300, 3180, 1765,
1720, 1680, 1615, 1520, 1495cm ^-1 (39) 7-[2-hydroxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(5-methyl-1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), mp153-162℃ (decomposition). IR (Nujiyor): 3260, 3160, 1763, 1665,
1608, 1520cm ^-1 (40) 7-[2-hydroxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(5-methyl-1,
3,4-thiadiazol-2-yl)thiomethy
pivaloy of lu-3-cephem-4-carboxylic acid
oxymethyl ester (syn isomer),
mp132-135℃ (decomposition). IR (Nujiyor): 3270, 3160, 1775, 1745,
1675, 1610, 1520, 1115cm ^-1 Example 7 Phosphorus pentachloride (2.5 g) in methylene chloride (60 ml) cooled
In the solution, 2-(2-cyclopenten-1-yl)
Oximino-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetic acid (syn isomer:
2.54g) was added at -15℃ and stirred at the same temperature for 45 minutes.
Ta. On the other hand, 7-amino-3-(-1,3,4-thia
diazol-2-yl)thiomethyl-3-cefe
Mu-4-carboxylic acid (4.0g) and trimethylsilicate
Ruacetamide (12g) in methylene chloride (60ml)
Heat the mixture to make a clear liquid and bring it to -15℃.
Cooled. Add this solution to the above active mixture,
Stirred at 0 to -5°C for 0.5 hour. Charcoal the reaction mixture
Cold water solution (150ml) of sodium oxyhydrogen (7.1g)
and stirred at room temperature for 15 minutes. Separate the aqueous layer and add vinegar
Added to ethyl acid. Add 10% hydrochloric acid to this mixture
The pH was set to 3 and passed. Remove the ethyl acetate layer from the liquid.
After separation and washing with saturated aqueous sodium chloride solution
Dry. The residue was treated with diethyl ether,
When the precipitate was dried, a crude product (1.8 g) was obtained.
It was done. Dissolve this product in aqueous sodium bicarbonate solution.
The pH was adjusted to 3 with 10% hydrochloric acid. remove the precipitate
After washing with water and drying, 7-[2-(2-cyclo
penten-1-yl)oxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4-thiazidi
Azol-2-yl)thiomethyl-3-cephem
-4-carboxylic acid (syn isomer: 1.4g), mp155
~160°C was obtained. IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 2.0−2.50 (1H,
m), 3.70 (2H, broad s), 4.30 and 4.57
(2H, ABq, J = 13Hz), 5.13 (1H, d, J
=4Hz), 5.27-5.43 (1H, m), 5.80 (1H,
dd, J=4 and 8Hz), 5.83−6.20 (2H,
m), 8.08 (2H, s), 9.45 (1H, d, J=8
Hz), 9.50 (1H, s) Example 8 Phosphorus chloride (2.5g) is cooled in methylene chloride (60ml)
Add 2-(2-cyclopenten-1-yl)ol to the solution.
Kixiimino-2-(5-amino-1,2,4-thi)
adiazol-3-yl)acetic acid (syn isomer:
2.54g) was added at -15℃ and stirred at the same temperature for 30 minutes.
Ta. On the other hand, 7-amino-3-cephem-4-carbo
acid (2.2g) and trimethylsilylacetamide
(11g) in methylene chloride (60ml)
was heated to form a clear liquid and cooled to -15°C. this
Add the above active mixture to the solution and stir at -5℃ for 20 minutes.
Stirred. The reaction mixture was diluted with sodium bicarbonate (7
Add to a cold aqueous solution (150 ml) of g) for 1 hour at room temperature.
Stirred. The aqueous layer was separated and added to ethyl acetate.
Bring the mixture to pH 3 with 10% hydrochloric acid and dilute with ethyl acetate.
Extracted. The extract was diluted with a saturated aqueous solution of sodium chloride.
Washed and dried with magnesium sulfate, then evaporated to dryness.
It was dry. Collect the precipitate and add ethyl acetate and diethyl
After sequential drying with ether, the crude product (1.5 g)
Obtained. Dissolve this product in aqueous sodium bicarbonate solution.
The pH was adjusted to 2 with dilute hydrochloric acid. Remove the precipitate and add water
Dry after washing. Pour the product (1.2g) into aqueous acetone.
It was treated with activated carbon and evaporated to dryness. Shen
After removing the deposits, washing with water and drying, 7-[2-
(2-cyclopenten-1-yl)oxyimino
-2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-cephem-
4-carboxylic acid (syn isomer 0.93g), mp180~
185°C (decomposition) was obtained. IR (Nujiyor): 3500, 3430, 3300, 3200,
1770, 1690, 1660, 1640, 1620, 1580, 1510
cm ^-1 NMR(d ₆ −DMSO, δ): 1.87−2.50 (4H,
m), 3.60 (2H, broad s), 5.07 (1H, d,
J=8Hz), 5.27-5.50 (1H, m), 580 (1H,
dd, J = 4 and 8 Hz), 5.87−6.23 (2H,
m), 6.47 (1H, broad s), 8.10 (2H, s),
9.47 (1H, d, J = 8Hz) Example 9 Phosphorus pentachloride (1.25g) in methylene chloride (30ml) cooled
Add 2-(2-cyclohexen-1-yl)ol to the solution.
Kixiimino-2-(5-amino-1,2,4-thi)
adiazol-3-yl)acetic acid (syn isomer:
1.34g) was added at -15℃ and stirred at the same temperature for 30 minutes.
Ta. On the other hand, 7-amino-3-(1,3,4-thiazidi
Azol-2-yl)thiomethyl-3-cephem
-4-carboxylic acid (1.98g) and trimethylsilyl
Acetamide (6g) in methylene chloride (30ml)
The added mixture was heated to a clear liquid, then -15°C.
Cooled to . Add this solution to the above active mixture.
The mixture was stirred at 0 to 5°C for 0.5 hour. The reaction mixture is
A cold solution of sodium bicarbonate (4.03 g) in water (100
ml) and stirred for 30 minutes until room temperature. Separate the aqueous layer
Add to ethyl acetate and adjust to PH4 with 10% hydrochloric acid.
After that, the mixture was extracted with ethyl acetate. The extract is soaked in magnesium sulfate.
It was dried with sodium and evaporated to dryness. Dilute the residue with diethyl ethyl ether
When the powder obtained by treatment with ether is dried,
Crude product (400 mg) was obtained. Use this product with hydrogen carbonate.
It was dissolved in a thorium aqueous solution and the pH was adjusted to 2 with hydrochloric acid. analysis
When the material is removed, washed with water and dried, it becomes 7-[2-(2
-Cyclohexen-1-yl)oxyimino-2
-(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1,3,4-
Thiadiazol-2-yl)thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer: 250mg),
mp150-155°C (decomposition) was obtained. IR (Nujiyor): 3300, 3180, 1770, 1660,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.50−2.17 (6H,
m), 3.70 (2H, broad s), 4.33 and 4.58
(2H, ABq, J=14Hz), 4.67−4.83 (1H,
m), 5.17 (1H, d, J = 4Hz), 5.83 (1H,
dd, J=4 and 8Hz), 5.60−6.12 (2H,
m), 8.15 (2H, s), 9.53 (1H, d, J=8
Hz), 9.93 (1H, s) Example 10 Phosphorus pentachloride (1.50g) in methylene chloride (30ml) cooled
In the solution, 2-(2-cyclohexen-1-yl)
Oximino-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetic acid (syn isomer:
1.61g) was added at -15°C. This mixture is −13～
After stirring at -10℃ for 30 minutes and distilling off the solvent, the residue
Tetrahydrofuran (20ml) was added. On the other hand 7-
Amino-3-(tetrazolo[1,5-b]pyrida
Zin-6-yl)thiomethyl-3-cephem-4
-Carboxylic acid (2.86g), sodium bicarbonate
(2.52g), water (80ml) and acetone (45ml).
The mixture was cooled to 5-10°C. This solution contains the above activity.
Add the mixture, stir at 5-10℃ for 20 minutes, then leave it
The mixture was warmed to room temperature and then evaporated to dryness. Vinegar on the residue
Add ethyl acetate, adjust the pH to 2 with 10% hydrochloric acid, and then add ethyl acetate.
Extracted with chill. Treat the extract with activated carbon (0.5g).
After drying with magnesium sulfate, the solvent was distilled off.
did. The residue was treated with diethyl ether and solidified.
A crude product (2.37 g) was obtained.
Dissolve this product in an aqueous sodium hydrogen carbonate solution and add hydrochloric acid.
The pH was set to 2. When the precipitate is removed, 7-[2-
(2-cyclohexen-1-yl)oxyimino
-2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(tetrazo
B[1,5-b]pyridazin-6-yl)thiome
Chil-3-cephem-4-carboxylic acid (synisomer
body: 2.28g), mp170-175℃ (decomposition) was obtained.
Ta. IR (Nujiyor): 3400, 3300, 3180, 1670,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.40−2.20 (6H,
m), 3.73 (2H, broad s), 4.27 and 4.65
(2H, ABq, J=13Hz), 4.65−4.88 (1H,
m), 5.18 (1H, d, J=5Hz), 5.80 (1H,
dd, J=5 and 8Hz), 5.78−6.02 (2H,
m), 7.80 (1H, d, J = 10Hz), 8.17 (2H,
broad s), 8.60 (1H, d, J=10Hz), 9.55
(1H, d, J = 8Hz) Example 11 Phosphorus pentachloride (1.5g) in methylene chloride (30ml) cooled
In the solution, 2-cyclopentyloxyimino-2-
(5-amino-1,2,4-thiadiazole-3
-yl)acetic acid (syn isomer: 1.37g) at -15℃
The mixture was added and stirred at -13 to -10°C for 30 minutes. On the other hand 7-ami
No-3-(1,3,4-thiadiazole-2-i)
) Thiomethyl-3-cephem-4-carboxylic acid
(2.18 g) and trimethylsilylacetamide (6
Add g) to methylene chloride (30ml) and heat until clear.
After obtaining the solution, it was cooled to -20°C. Add this solution above
to the active mixture of 0.5
Stir for hours. Sodium bicarbonate reaction mixture
Add to a cold saturated aqueous solution (60 ml) of and stir at room temperature for 30 minutes.
did. Separate the aqueous layer and add to ethyl acetate and 10% salt.
After adjusting the pH to 2-3 with acid, extract with ethyl acetate.
Ta. Dry the extract with magnesium sulfate and remove the solvent.
It was evaporated to dryness. Wash the residue with diethyl ether.
A crude product (2.62 g) was obtained. Add this product to carbonated water.
Dissolve in sodium aqueous solution and adjust to PH2 with hydrochloric acid.
did. When the precipitate is removed, 7-[2-cyclope
methyloxyimino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetamide
]-3-(1,3,4-thiadiazole-2-
yl)thiomethyl-3-cephem-4-carvone
Acid (syn isomer: 2.22g), mp140-145℃ (min.
solution) was obtained. IR (Nujiyor): 3400, 3300, 3200, 1770,
1670, 1620, 1525cm ^-1 NMR(d ₆ −DMSO, δ): 1.33−2.10 (8H,
m), 3.72 (2H, broad s), 4.33 and 4.58
(2H, ABq, J=13Hz), 4.60−4.90 (1H,
m), 5.17 (1H, d, J=5Hz), 5.82 (1H,
dd, J=5 and 8Hz), 8.15 (2H, s),
9.52 (1H, d, J = 8Hz), 9.58 (1H, s) Example 12 Phosphorus pentachloride (1.25g) in methylene chloride (25ml) cooled
In the solution, 2-cyclopentyloxyimino-2-
(5-amino-1,2,4-thiadiazole-3
-yl)acetic acid (syn isomer: 1.28g) at -15℃
and stirred at -13 to -10°C for 30 minutes. On the other hand 7-a
mino-3-cefem-4-carboxylic acid (1.1g),
Trimethylsilylacetamide (5.5g) and salt
A mixture of methylene chloride (25 ml) was heated to form a clear liquid.
and cooled to -15°C. Add this solution to the above active mixture
and stirred at -10°C for 0.5 hour. reaction mixture
into a saturated aqueous solution (55 ml) of sodium bicarbonate.
After stirring at room temperature for 30 minutes, methylene chloride was distilled off.
did. Wash the residue with ethyl acetate, and add ethyl acetate to the aqueous layer.
Added chill. Adjust this mixture to pH 3 with 10% hydrochloric acid.
After that, the mixture was extracted with ethyl acetate. Pour the extract into a sulfuric acid mug
Dry with nesium, treated with activated carbon and then evaporated to dryness
When the residue was washed with diethyl ether, the crude product was obtained.
(1.03g) was obtained. This product is made using sodium bicarbonate.
The mixture was dissolved in an aqueous solution of mucilage, and the pH was adjusted to 3 with 10% hydrochloric acid. precipitation
When you take something, 7-[2-cyclopentyloxy
Shiimino-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-ce
Fem-4-carboxylic acid (syn isomer: 860mg),
mp170-175°C was obtained. IR (Nujiyor): 3520, 3420, 3320, 3220,
3160, 1770, 1685, 1655, 1635, 1625,
1570, 1505cm ^-1 NMR(d ₆ −DMSO, δ): 1.33−2.07 (8H,
m), 3.43-3.77 (2H, m), 4.60-4.93 (1H,
m), 5.15 (1H, d, J=5Hz), 5.90 (1H,
dd, J = 5 and 8Hz), 6.43−6.67 (1H,
m), 8.23 (2H, broad s), 9.63 (1H, d,
J=8Hz) Example 13 Following the same method as Examples 1-3, 5 and 7-12.
The following compound was obtained. (1) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]cephalosporanic acid (syn isomer),
mp154-159℃ (decomposition). IR (Nujiyor): 3300, 1770, 1720, 1670,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 2.0 (3H, s), 2.0
−2.40 (4H, m), 3.52 (2H, broad s),
4.70 and 4.97 (2H, ABq, J=14Hz), 5.12
(1H, d, J=4Hz), 5.27−5.40 (1H, m),
5.82 (1H, dd, J=4 and 8Hz), 5.83−
6.17 (2H, m), 8.13 (2H, s), 9.50 (1H,
d, J=8Hz) (2) 7-[2-(2-cyclopentene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-(1-methyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp155-160℃
(Disassembly). IR (Nujiyor): 3300, 1770, 1670, 1620,
1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.90−2.30 (4H,
m), 3.62 (2H, broad s), 3.88 (3H, s),
4.25 (2H, broad s), 5.07 (1H, d, J=4
Hz), 5.20-5.40 (1H, m), 5.80 (1H, dd,
J=4 and 8Hz), 5.83−6.17 (2H, m),
8.08 (2H, s), 9.47 (1H, d, J = 8Hz) (3) 7-[2-(2-cyclopentene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1-carboxymethyl-1H-
Tetrazol-5-yl)thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp155-160℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.83−2.50 (4H,
m), 3.67 (2H, broad s), 4.27 and 4.48
(2H, ABq, J = 14Hz), 5.17 (1H, d, J
= 4Hz), 5.30 (2H, s), 5.27−5.50 (1H,
m), 5.82 (2H, dd, J=4 and 8Hz),
5.83−6.20 (2H, m), 8.17 (2H, s), 9.50
(1H, d, J=8Hz) (4) 7-[2-(2-cyclopentene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-[1-(2-carboxyethyl)
-1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp150-155℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.90−2.50 (4H,
m), 2.97 (2H, t, J=6Hz), 3.73 (2H,
broad s), 4.30 and 4.50 (2H, ABq, J
= 14Hz), 4.52 (2H, t, J = 6Hz), 5.20
(1H, d, J=4Hz), 5.30−5.57 (1H, m),
5.90 (1H, dd, J=4 and 8Hz), 5.93−
6.33 (2H, m), 8.33 (2H, s), 9.77 (1H,
d, J=8Hz) (5) 7-[2-(2-cyclopentene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(1-allyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp160-165℃
(Disassembly). IR (Nujiyor): 3300, 1770, 1670, 1620,
1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.93−2.33 (4H,
m), 3.60 (2H, broad s), 4.22 and 4.37
(2H, ABq, J=13Hz), 4.83−5.0 (2H,
m), 5.0-5.40 (4H, m), 5.60-6.17 (4H,
m), 8.07 (2H, s), 9.47 (1H, d, J=8
Hz) (6) 7-[2-(2-cyclopentene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(tetrazolo[1,5-b]pyri
dazin-6-yl)thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp170-175
°C (decomposition). IR (Nujiyor): 3400, 3300, 3190, 1770,
1670, 1615, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.90−2.43 (4H,
m), 3.68 (2H, broad s), 4.22 and 4.58
(2H, ABq, J = 13Hz), 5.10 (1H, d, J
= 5Hz), 5.20-5.47 (1H, m), 5.78 (1H,
dd, J=5 and 8Hz), 5.80−6.20 (2H,
m), 7.75 (1H, d, J = 10Hz), 8.13 (2H,
broad s), 8.55 (1H, d, J=10Hz), 9.52
(1H, d, J=8Hz) (7) 7-[2-(2-cyclopentene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{2-(N-Third Class Butoki
cycarbonylamino)ethyl}-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp95-100
°C (decomposition). IR (Nujiyor): 3300, 3190, 1770, 1680,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.40 (9H, s),
2.07-2.50 (4H, m), 3.30-3.57 (2H, m),
3.67-3.87 (2H, m), 4.27-4.57 (4H, m),
5.17 (1H, d, J = 5Hz), 5.23−5.57 (1H,
m), 5.70−6.30 (3H, m), 8.17 (2H, broad
s), 9.53 (1H, d, J = 8Hz) (8) 7-[2-(2-cyclohexene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-cephem-4-carboxylic acid (sin
isomers), mp175-180℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1670,
1630, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.50−2.13 (6H,
m), 3.63 (2H, broad s), 4.60−4.83 (1H,
m), 5.12 (1H, d, J = 4Hz), 5.77−6.0
(3H, m), 6.50 (1H, t, J=3Hz), 8.15
(2H, s), 9.55 (1H, d, J=8Hz) (9) 7-[2-(2-cyclohexene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]cephalosporanic acid (syn isomer),
mp160-165℃ (decomposition). IR (Nujiyor): 3300, 3200, 1775,
1720.1670, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.50−2.10 (6H,
m), 2.07 (3H, s), 3.60 (2H, broad s),
4.67−4.83 (1H, m), 4.77 and 5.03 (2H,
ABq, J = 14Hz), 5.17 (1H, d, J = 4
Hz), 5.77-6.10 (3H, m), 8.17 (2H, s),
9.60 (1H, d, J = 8Hz) (10) 7-[2-(2-cyclohexene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-(1-methyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp170-173℃
(Disassembly). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.50−2.17 (6H,
m), 3.16 (2H, broad s), 3.93 (3H, s),
4.30 (2H, broad s), 4.55-4.80 (1H, m),
5.10 (1H, d, J = 4Hz), 5.80 (1H, dd, J
= 4 and 8Hz), 5.80−5.93 (2H, m),
8.08 (2H, s), 9.50 (1H, d, J=8Hz) (11) 7-[2-(2-cyclohexene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1-carboxymethyl-1H-
Tetrazol-5-yl)thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp170-175℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1650, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.50−2.27 (6H,
m), 3.75 (2H, broad s), 4.30 and 4.55
(2H, ABq, J=14Hz), 4.67−4.83 (1H,
m), 5.17 (1H, d, J = 4Hz), 5.37 (2H,
s), 6.17-5.77 (3H, m), 8.18 (2H, s),
9.57 (1H, d, J = 8Hz) (12) 7-[2-(2-cyclohexene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-[1-(2-carboxyethyl)
-1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp165-170℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.50−2.17 (6H,
m), 3.77 (2H, broad s), 4.37 and 4.50
(2H, ABq, J = 14Hz), 4.53 (2H, t, J
= 6Hz), 4.67-4.93 (1H, m), 5.23 (1H,
d, J=4Hz), 5.93(1H, dd, J=4 and
and 8Hz), 5.97-6.17 (2H, m), 8.70 (2H,
s), 9.80 (1H, d, J = 8Hz) (13) 7-[2-(2-cyclohexene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(1-allyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp160-165℃
(Disassembly). IR (Nujiyor): 3300, 3200, 1780, 1680,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.50−2.16 (6H,
m), 3.66 (2H, broad s), 4.25 and 4.43
(2H, ABq, J=14Hz), 4.55−4.80 (1H,
m), 4.93-5.0 (2H, m), 5.10 (1H, d, J
=4Hz), 5.20-5.37 (2H, m), 5.67-6.20
(4H, m), 8.08 (2H, s), 9.50 (1H, d,
J=8Hz) (14) 7-[2-(2-cyclohexene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{3-(N-Third Class Butoki
cyclocarbonylamino)propyl}-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp100~
105℃ (decomposition). IR (Nujiyor): 3300, 3170, 1770, 1670,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.37 (9H, s),
1.50−2.20 (8H, m), 2.92 (2H, t, J=6
Hz), 3.68 (2H, broad s), 4.07−4.47 (4H,
m), 4.53-4.83 (1H, m), 5.10 (1H, d,
J=5Hz), 5.80(1H, dd, J=5 and 8
Hz), 5.70-5.93 (2H, m), 8.10 (2H, broad
s), 9.47 (1H, d, J = 8Hz) (15) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(3-yl)acetamide] Cephalospora
acid (syn isomer), mp140-145°C (decomposition). IR (Nujiyor): 3480, 3370, 3250, 1785,
1730, 1680, 1630, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 1.33−2.17 (8H,
m), 2.03 (3H, s), 3.57 (2H, broad s),
4.60−4.90 (1H, m), 4.73 and 4.97 (2H,
ABq, J = 13Hz), 5.15 (1H, d, J = 5
Hz), 5.80 (1H, dd, J=5 and 8Hz),
8.10 (2H, broad s), 9.47 (1H, d, J=8
Hz) (13) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-methyl)
Chil-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp145-150℃ (decomposition). IR (Nujiyor): 3400, 3290, 3180, 1770,
1670, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.33−2.07 (8H,
m), 3.70 (2H, broad s), 3.93 (3H, s),
4.32 (2H, broad s), 4.10−4.90 (1H, m),
5.12 (1H, d, J = 5Hz), 5.78 (1H, dd, J
=5 and 8Hz), 8.10 (2H, broad s),
9.47 (1H, d, J = 8Hz) (17) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-ka)
ruboxymethyl-1H-tetrazole-5-i
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp155-160℃ (decomposition). IR (Nujiyor): 3400, 3290, 3180, 1765,
1720, 1670, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.27−2.07 (8H,
m), 3.70 (2H, broad s), 4.28 and 4.53
(2H, ABq, J=13Hz), 4.70−4.93 (1H,
m), 5.17 (1H, d, J=5Hz), 5.33 (2H,
s), 5.85 (1H, dd, J=5 and 8Hz),
8.23 (2H, broad s), 9.60 (1H, d, J=8
Hz) (18) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-a
Lyle-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp135-140℃ (decomposition). IR (Nujiyor): 3400, 3300, 3190, 1770,
1670, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.30−2.10 (8H,
m), 3.73 (2H, broad s), 4.32 and 4.50
(2H, ABq, J=13Hz), 4.60−4.90 (1H,
m), 4.83-5.17 (2H, m), 5.17 (1H, d,
J = 5Hz), 5.17-5.50 (2H, m), 5.87 (1H,
dd, J = 5 and 8Hz), 5.67−6.33 (1H,
m), 8.20 (2H, broad s), 9.60 (1H, d,
J=8Hz) (19) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(tetra
Zoro[1,5-b]pyridazin-6-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomer), mp160-165℃ (decomposition). IR (Nujiyor): 3570, 3440, 3320, 3180,
1775, 1710, 1660, 1620, 1580, 1540, 1520
cm ^-1 NMR(d ₆ −DMSO, δ): 1.40−2.03 (8H,
m), 3.78 (2H, broad s), 4.27 and 4.65
(2H, ABq, J=13Hz), 4.67−4.93 (1H,
m), 5.20 (1H, d, J=5Hz), 5.87 (1H,
dd, J = 5 and 8 Hz), 7.78 (1H, d, J
= 10Hz), 8.15 (2H, broad s), 8.58 (1H,
d, J = 10Hz), 9.53 (1H, d, J = 8Hz) (20) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(2-methoxycarbonylethyl)-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp125~
130℃ (decomposition). IR (Nujiyor): 3480, 3370, 3250, 1780,
1740, 1685, 1625, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 1.30−2.07 (8H,
m), 2.80−3.20 (2H, m), 3.58 (3H, s),
3.67 (2H, broad s), 4.20−4.70 (4H, m),
4.60−4.90 (1H, m), 5.12 (1H, d, J=5
Hz), 5.78 (1H, dd, J=5 and 8Hz),
8.07 (2H, broad s), 9.43 (1H, d, J=8
Hz) (21) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(3-yl)acetamide]-3-(4-methyl)
Chill-5-oxo-6-hydroxy-4,5-
Dihydro-1,2,4-triazine-3-y
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), pale yellow powder, mp195-199℃
(Disassembly). IR (Nujiyor): 3300, 3200, 1770, 1710−
1670, 1590, 1520, 1240, 1170, 1090,
1000, 720cm ^-1 (22) 7-[2-cycloheptyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), white powder, mp150-154℃ (decomposed). IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1520, 1400, 1240, 1160, 1060, 1000
cm ^-1 NMR(d ₆ −DMSO, δ): 1.50 (8H, m),
1.82 (4H, m), 3.54 and 3.76 (2H, ABq,
J=20Hz), 4.32 (1H, m), 4.24 and 4.60
(2H, ABq, J = 14Hz), 5.10 (1H, d, J
= 5Hz), 5.74 (1H, dd, J = 5 and 8
Hz), 8.02 (2H, m), 9.48 (1H, s), 9.38
(1H, d, J=8Hz) (23) 7-[2-cycloheptyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-cephem
-4-carboxylic acid (syn isomer), white powder,
mp170-175℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1670, 1620, 1520, 1280, 1240, 1160,
1000, 980, 730cm ^-1 NMR(d ₆ −DMSO, δ): 1.50 (8H, m),
1.85 (4H, m), 3.60 (2H, m), 4.0−4.50
(1H, m), 5.13 (1H, d, J=5Hz), 5.87
(1H, dd, J=5 and 8Hz), 6.50 (1H,
m), 8.13 (2H, m), 9.37 (1H, d, J=8
Hz) (24) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
{3-(N-tertiary butoxycarbonylamino)
propyl}-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), light brown powder. IR (Nujiyor): 3300, 1770, 1670, 1520,
1240, 1160, 1000cm ^-1 (25) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
2,4-thiadiazol-5-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), mp175-178℃ (decomposition). IR (Nujiyor): 3300, 3200, 1775, 1680,
1620, 1525cm ^-1 (26) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(3-morpholinopropyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp183-188℃
(Disassembly). IR (Nujiyor): 3300, 3150, 1770, 1670,
1610, 1530cm ^-1 (27) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mid]-3-[1-(2-aminoethyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp175-180℃ (decomposition). IR (Nujiyor): 3400, 3300, 3170, 1760,
1665, 1610, 1520cm ^-1 (28) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(3-aminopropyl)-1H-tetrazole-
5-yl]thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), white powder, mp195~
199℃ (decomposition). IR (Nujiyor): 3300, 3150, 1760, 1660,
1620, 1520, 1280, 1180, 1000cm ^-1 (29) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-(3-aminopropyl)-
H-tetrazol-5-yl]thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer),
mp185-190℃ (decomposition) IR (nujiol): 3280, 3150, 1760, 1665,
1620, 1520cm ^-1 (30) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(3-piperidinopropyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
- Carboxylic acid (syn isomer), mp230℃ (min.
solution). IR (Nujiyor): 3300, 3200, 1770, 1670,
1600, 1520cm ^-1 Example 14 7-[2-phenoxyimino-2-(5-amino)
No-1,2,4-thiadiazol-3-yl)a
Cetamido] Cephalosporanic acid (syn isomer:
3.5g), tetrazolo[1,5-b]pyridazine-
6-thiol (1.35g) and sodium bicarbonate
(1.1g) was added to phosphate buffer (130ml) at pH 6.8.
The mixture was stirred at 70°C for 2 hours. Place the reaction mixture on ice.
After cooling in solution and mixing in ethyl acetate, add 10% salt
The pH was adjusted to 3 with acid. Remove insoluble matter and dilute the solution with acetic acid ethyl chloride.
Extracted with chill. Dry the extract with magnesium sulfate.
After drying, the solvent was distilled off. Dilute the residue with diethyl ether
7-[2-phenoxyimino
-2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(tetrazo
B[1,5-b]pyridazin-6-yl)thiome
Chil-3-cephem-4-carboxylic acid (synisomer
body: 0.7 g), mp 175-180°C (decomposed). IR (Nujiyor): 3300, 3200, 1775, 1680,
1615, 1585, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 3.77 (2H, broad
s), 4.23 and 4.63 (2H, ABq, J=13
Hz), 5.23 (1H, d, J = 4Hz), 5.93 (1H,
dd, J=4 and 8Hz), 7.00-7.50 (5H,
m), 7.77 (1H, d, J = 10Hz), 8.30 (2H,
s), 8.60 (1H, d, J=10Hz), 9.85 (1H,
d, J=8Hz) Example 15 7-[2-phenoximino-2-(5-ami
No-1,2,4-thiadiazol-3-yl)a
Cetamido] Cephalosporanic acid (syn isomer:
4.0g), 1-[2-(N-tertiary butoxycarbo
nylamino)ethyl]-1H-tetrazole-5
-thiol (2.45g) and sodium bicarbonate
The mixture was added to phosphate buffer (150ml) with a pH of 6.8 to 70%
Stirred at ℃ for 1.5 hours. Cool the reaction mixture in an ice bath.
After cooling and mixing with ethyl acetate, adjust the pH to 3 with 10% hydrochloric acid.
And so. Insoluble matter was removed, and the liquid was extracted with ethyl acetate.
I put it out. The extract was dried with magnesium sulfate.
After that, the solvent was distilled off. The residue was dissolved in diethyl ether.
When treated, 7-[2-phenoxyimino-2-
(5-amino-1,2,4-thiadiazole-3
-yl)acetamide]-3-[1-{2-(N
-Tertiary butoxycarbonylamino)ethyl}-
1H-tetrazol-5-yl]thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer: 1.4
g), mp 150-155°C (decomposition) was obtained. IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1590, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.27 (9H, s), 3.3
-3.5 (2H, m), 3.70 (2H, broad s), 4,
3-4.6 (4H, m), 5.18 (1H, d, J = 4
Hz), 5.90 (1H, dd, J=4 and 8Hz),
7.0−7.5 (5H, m), 8.28 (2H, s), 9.88
(1H, d, J=8Hz) Example 16 7-[2-allyloxyimino-2-(5-a
mino-1,2,4-thiadiazol-3-yl)
Acetamide] Cephalosporanic acid (syn isomer
body: 3.3g), 1-allyl-1H-tetrazole-
5-thiol (1.4g) and sodium bicarbonate
(1.3g) was added to phosphate buffer (210ml) of pH 6.8.
The mixture was stirred at 70°C for 2 hours. Place the reaction mixture on ice.
After cooling in solution and mixing in ethyl acetate, add 10% salt
The pH was adjusted to 2 with acid. Remove insoluble materials and dilute the solution with acetic acid ethyl chloride.
Extracted with chill. Dry the extract with magnesium sulfate.
After drying, the solvent was distilled off. Dilute the residue with diethyl ether
When treated with chill, 7-[2-allyloxyimide
No-2-(5-amino-1,2,4-thiadiazole)
-3-yl)acetamide]-3-(1-a
Lyle-1H-tetrazol-5-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body: 2.1 g), mp 150-155°C (decomposed). IR (Nujiyor): 3300, 3200, 1775, 1670,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 3.68 (2H, droad
s), 4.28 and 4.45 (2H, ABq, J=13
Hz), 4.60-4.83 (2H, m), 4.93-5.07 (2H,
m), 5.12 (1H, d, J = 4Hz), 5.17−5.57
(4H, m), 5.83 (1H, dd, J=4 and 8
Hz), 5.77-6.37 (2H, m), 8.22 (2H, s),
9.67 (1H, d, J = 8Hz) Example 17 The following compounds were prepared according to the same method as Examples 14 to 16.
I got something. (1) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(tetrazolo[1,
5-b]Pyridazin-6-yl)thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp180~185℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1670,
1620, 1525cm ^-1 NMR(d ₆ -DMSO, δ) 3.73 (2H, broad s), 4.27and4.63 (2H,
ABq, J=14Hz), 4.60−4.83 (2H, m) 5.18
(1H, d, J = 4Hz), 5.23-5.53 (2H,
m), 5.83 (1H, dd, J=4and8Hz), 5.87―
6.33 (1H, m), 7.82 (1H, d, J=10Hz),
8.20 (2H, s), 8.68 (1H, d, J=10Hz),
9.68 (1H, d, J = 8Hz) (2) 7-[2-(2,2,2-trifluoroethane
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-[1-{2-(N-tertiary butoxylic
Bonylamino)ethyl}-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), powder (3) 7-[2-(2,2,2-trifluoroethyl)
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-(5-aminomethyl-1,3,4-thia
diazol-2-yl)thiomethyl-3-cef
M-4-carboxylic acid (syn isomer), mp150
~155℃ (decomposition) IR (nujiol): 3300, 3180, 1760, 1670,
1610, 1520cm ^-1 NMR(d ₆ -DMSO, δ) 3.60 (2H, brosd s), 4.05and4.28 (2H,
ABq, J=13Hz), 4.57 (2H, s),
4.73and4.95 (2H, ABq, J=9Hz), 5.07
(1H, d, J = 5Hz), 5.73 (1H, dd, J =
5and8Hz), 8.17 (2H, broad s), 9.63 (1H,
d, J=8Hz) (4) 7-[2-(2,2,2-trifluoroethane
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-(tetrazolo[1,5-b]pyridazine
-6-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp165-170℃ (min.
Solution) IR (Nujiyor): 3420, 3300, 3190, 1770,
1705, 1670, 1620, 1525cm ^-1 NMR(d ₆ −DMSO, δ) 3.60and3.80 (2H, ABq, J=18Hz),
4.23and4.58 (2H, ABq, J=13Hz),
4.67and4.87 (2H, ABq, J=9Hz), 5.13
(1H, d, J=5Hz), 5.82 (1H, dd, J=
5and8Hz), 7.72 (1H, d, J=10Hz), 8.17
(2H, broad s), 8.55 (1H, d, J=10
Hz), 9.68 (1H, d, J = 8Hz) (5) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{3
-(N-tertiary butoxycarbonylamino)
lopyl}-1H-tetrazol-5-yl]
Omethyl-3-cephem-4-carboxylic acid
(isomer), light brown powder IR (Nujiol): 3300, 1770, 1670, 1520,
1240, 1160, 1000cm ^-1 NMR(d ₆ −DMSO, δ) 1.33 (9H, s), 1.40−2.07 (10H, m), 2.95
(2H, m), 3.63 (2H, m), 4.0−4.43 (4H,
m), 4.70 (1H, m), 5.07 (1H, d, J=5
Hz), 5.73 (1H, dd, J=5and8Hz), 6.80
(1H, m), 8.07 (2H, m), 9.89 (1H, d,
J=8Hz) (6) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1,2,
4-thiadiazol-5-yl)thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp175-178℃ (decomposition) IR (nujiol): 3300, 3200, 1775, 1680,
1620, 1525cm ^-1 NMR(d ₆ −DMSO, δ) 1.50−2.00 (8H, m), 3.67 (2H, broad s),
4, 34and4.60 (2H, ABq, J=14Hz), 4.67
-4.83 (1H, m), 5.17 (1H, d, J=4Hz),
5.82 (1H, dd, J=4and8Hz), 8.12 (2H,
s), 8.73 (1H, s), 9.50 (1H, d, J=8
Hz) (7) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(3
-morpholinopropyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp183-188℃ (min.
Solution) IR (Nujiyor): 3300, 3150, 1770, 1670,
1610, 1530cm ^-1 NMR(d ₆ −DMSO, δ) 1.50−1.90 (8H, m), 2.00−2.27 (2H, m),
2.50-2.83 (6H, m), 3.50-3.83 (6H, m),
4.23-4.53 (4H, m), 4.70-4.86 (1H, m),
5.13 (1H, d, J = 4Hz), 5.80 (1H, dd, J
=4and8Hz), 8.13 (2H, s), 9.50 (1H, d,
J=8Hz) (8) 7-[2-cyclopenten-1-yl)oxy
Shiimino-2-(5-amino-1,2,4-thi)
Asiazol-3-yl)acetamide]-3
-(1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(Syn isomer), mp155-160℃ (decomposition) IR (Nudyol): 3300, 3200, 1770, 1670,
1620, 1520cm ^-1 (9) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-(1-methyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp155-160℃
(Decomposition) IR (nujiol): 3300, 1770, 1670, 1620,
1520cm ^-1 (10) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1-carboxymethyl-1H-
Tetrazol-5-yl)thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer),
mp155-160℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 (11) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-[1-(2-carboxyethyl)
-1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp150-155℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 (12) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(1-allyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp160-165℃
(Decomposition) IR (nujiol): 3300, 1770, 1670, 1620,
1520cm ^-1 (13) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-tetrazolo[1,5-b]pyrida
Zin-6-yl)thiomethyl-3-cephem-
4-Carboxylic acid (syn isomer), mp170-178℃
(Decomposition) IR (nujiol): 3400, 3300, 3190, 1770,
1670, 1615, 1520cm ^-1 (14) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{2-(N-Third Class Butoki
cycarbonylamino)ethyl}1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-Carboxylic acid (syn isomer), mp95-100℃
(Decomposition) IR (nujiol): 3300, 3190, 1770, 1680,
1620, 1520cm ^-1 (15) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mid]-3-[1-(2-aminoethyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp175-180℃ (decomposition) IR (nujiol): 3400, 3300, 3170, 1760,
1665, 1610, 1520cm ^-1 (16) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl]acetoa
Mido-3-(1,3,4-thiadiazole-2
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer) mp150-155℃ (decomposition) IR (Nudiyol): 3300, 3180, 1770, 1660,
1620, 1520cm ^-1 (17) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(tetrazolo[1,5-b]pyri
dazin-6-yl)thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp170-175
°C (decomposition) IR (nujiol): 3400, 3300, 3180, 1670,
1620, 1520cm ^-1 (18) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-(1-methyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp170-173℃
(Decomposition) IR (nujiol): 3350, 3250, 1780, 1680,
1620, 1520cm ^-1 (19) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1-carboxymethyl-1H-
Tetrazol-5-yl)thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer),
mp170~175℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1720,
1650, 1620, 1520cm ^-1 (20) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-{1-(2-carboxyethyl)
-1H-tetrazol-5-yl}thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp165-170℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 (21) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(1-allyl-1H-tetrazo
(3-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp160-165℃
(Decomposition) IR (nujiol): 3300, 3200, 1780, 1680,
1520cm ^-1 (22) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{3-(N-Third Class Butoki
cyclocarbonylamino)propyl}-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp100~
105℃ (decomposition) IR (nujiol): 3300, 3170, 1770, 1670,
1620, 1520cm ^-1 (23) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-(3-aminopropyl)-
1H-tetrazole]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp185~
190 (decomposition) IR (nujiol): 3280, 3150, 1760, 1665,
1620, 1520cm ^-1 (24) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), mp140-145℃ (decomposition) IR (nujiol): 3400, 3300, 3200, 1770,
1670, 1620, 1520cm ^-1 (25) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-methyl)
Chil-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
mp145-150℃ (decomposition) IR (nujiol): 3400, 3290, 3180, 1770,
1670, 1620, 1520cm ^-1 (26) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-ka)
ruboxymethyl-1H-tetrazole-5-i
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp155-160℃ (decomposition) IR (Nujiol): 3400, 3290, 3180, 1765,
1720, 1670, 1620, 1520cm ^-1 (27) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-a
Lyle-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
mp135-140℃ (decomposition) IR (nujiol): 3400, 3300, 3190, 1770,
1670, 1620, 1520cm ^-1 (28) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(tetra
Zolo[1.5-b]pyridazin-6-yl)thio
Methyl-3-cephem-4-carboxylic acid
isomer), mp160-165℃ (decomposition) IR (Nudyol): 3570, 3440, 3320, 3180,
1775, 1710, 1660, 1620, 1580, 1540, 1520
cm ^-1 (29) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(3-aminopropyl)-1H-tetrazole-
5-yl]thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), white powder, mp195~
199℃ (decomposition) IR (nujiol): 3300, 3150, 1760, 1660,
1620, 1520, 1280, 1180, 1000cm ^-1 (30) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(2-methoxycarbonylethyl)-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp125~
130℃ (decomposition) IR (nujiol): 3480, 3370, 3250, 1780,
1740, 1685, 1625, 1530cm ^-1 (31) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(3-yl)acetamide]-3-(4-methyl)
Chill-5-oxo-6-hydroxy-4,5-
Dihydro-1,2,4-triazine-3-y
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), yellow powder, mp195-199℃
(Decomposition) IR (nujiol): 3300, 3200, 1770, 1710−
1670, 1590, 1520, 1240, 1170, 1090,
1000, 720cm ^-1 NMR(d ₆ −DMSO, δ) 1.3−2.1 (8H, m), 3.32 (3H, s), 3.66
(2H, m), 4, 11 (2H, m), 4.76 (1H,
m), 5.16 (1H, d, J=5Hz), 5.83 (1H,
dd, J=5and8Hz), 8.13(2H, broad s),
9.50 (1H, d, J = 8Hz), 12.50 (1H, broad
s) (32) 7-[2-cycloheptyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), white powder, mp150-154℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1670,
1620, 1520, 1400, 1240, 1160, 1060, 1000
cm ^-1 (33) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(3-piperidinopropyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
- Carboxylic acid (syn isomer), mp230℃ (decomposition) IR (Nudyol): 3300, 3200, 1770, 1670,
1600, 1520cm ^-1 NMR(d ₆ −DMSO, δ) 1.3−2.0 (6H, m), 2.10−2.3 (2H, m),
2.73−3.10 (6H, m), 3.57 (2H, broad s),
4.10−4.50 (4H.m), 4.60−4.80 (1H, m),
5.00 (1H, d, J = 4Hz), 5.67 (1H, dd, J
=4and8Hz), 9,06 (2H, s), 9.37 (1H,
d, J=8Hz) Example 18 7-[2-(3-trifluoromethylphenoxy
(shiimino)-2-(5-amino-1,2,4-thi)
Asiazol-3-yl)acetamide]-3-
Cefem-4-carboxylic acid 4-nitrobenzyl
(Syn isomer): 4.4g) in tetrahydrofuran
(80ml), water (50ml) and acetic acid (4.4ml).
The added solution was heated with 10% palladium on charcoal at room temperature and pressure.
Reduction was carried out using 2.2 g of hydrogen for 3 hours. catalyst
was distilled off and washed with tetrahydrofuran. liquid
and the washing liquid were combined, and the solvent was distilled off. Add ethyl acetate to the residue
and aqueous sodium bicarbonate solution to adjust the pH to 8.
After separating the aqueous layer and adjusting the pH to 1 to 2, it was diluted with ethyl acetate.
Extracted. The extract is mixed with water and aqueous sodium chloride solution.
sequentially washed, treated with activated carbon, and then treated with magnesium sulfate.
The solvent was distilled off. Diethyl the residue
Washing with ethyl gave a yellow powder (1.0g).
It was. Add water (10ml) to this crude product and stir for 30 minutes.
did. When the washed product is washed with water and dried under reduced pressure,
Yellow powdered 7-[2-(3-trifluoromethyl)
rufenoxyimino)-2(5-amino-1,2,
4-thiadiazol-3-yl)acetamide]
-3-Cefem-4-carboxylic acid (syn isomer:
1.0g) was obtained. This product decomposes at 193℃. IR (Nujiyor): 3450, 3320, 3200, 1770,
1710, 1665, 1630, 1560, 1515, 1325,
1170, 1110, 940cm ^-1 NMR(d ₆ −DMSO, δ) 3.63 (2H, m), 5.21 (1H, d, J=5Hz),
5.94 (1H, dd, J=5and8Hz), 6.48 (1H,
m), 7.53 (4H, broad s), 8.27 (2H,
s), 9.87 (1H, d, J=8Hz) Example 19 7-[2-phenoxyimino-2-(5-ami
No-1,2,4-thiadiazol-3-yl)a
Cetamide]-3-Cefem-4-carboxylic acid
4-nitrobenzyl (syn isomer: 4.5g),
Mixture of tetrahydrofuran (45ml) and water (20ml)
10% palladium-carbon (2.5 g)
The above solution was reduced to normal temperature and pressure. After leaving the catalyst
After distilling off the solvent and adding ethyl acetate to the residue, charcoal
The pH was adjusted to 8 with an aqueous sodium oxyhydrogen solution. Separate the aqueous layer
Separate the mixture, add ethyl acetate to it, and adjust the pH to 3 with hydrochloric acid.
Ta. The resulting mixture was extracted with ethyl acetate;
After washing the liquid with water, dry it with magnesium sulfate and distill off the solvent.
Then, 7-[2-phenoxyimino-2-(5
-amino 1,2,4-thiadiazole-3-i
) Acetamide]-3-Cefem-4-carbo
acid (syn isomer: 1.4 g), mp168-170℃ (min.
solution) was obtained. IR (Nujiyor): 3400, 3200, 1780, 1660,
1620, 1600, 1590, 1540cm ^-1 NMR(d ₆ −DMSO, δ) 3.58 (2H, broad s), 5.15 (1H, d, J=4
Hz), 5.90 (1H, dd, J=4and8Hz), 6.47
(1H, t, J=3Hz), 3.97-7.60 (5H, m),
8.27 (2H, s), 9.92 (1H, d, J = 8Hz) Example 20 Following the same method as Examples 18 and 19, the following compound
I got something. (1) 7-[2-{3-(N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-chloro-3-ceph
Em-4-carboxylic acid (syn isomer). IR (Nujiyor): 3300-3100, 1780, 1690-
1660, 1520, 1270cm ^-1 (2) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-cephe
Mu-4-carboxylic acid (syn isomer), mp145~
150℃ (decomposition) IR (nujiol): 3400, 3260, 3180, 1775,
1675, 1625, 1600, 1520, 1480cm ^-1 NMR(d ₆ −DMSO, δ) 3.63 (2H, broad s), 5.20 (1H, d, J=5
Hz), 5, 93 (1H, dd, J=5and8Hz), 6.52
(1H, t, J = 4Hz), 7.33 (2H, d, J =
9Hz), 7.47 (2H, d, J = 9Hz), 8.32 (2H,
broad s), 9.90 (1H, d, J = 8Hz) (3) 7-[2-(4-fluorophenoxyimide
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
Fem-4-carboxylic acid (syn isomer),
mp130-135℃ (decomposition) IR (nujiol): 3400, 3270, 3180, 1765,
1675, 1605, 1500cm ^-1 NMR(d ₆ −DMSO, δ) 3.63 (2H, broad s), 5.22 (1H, d, J=5
Hz), 5.97 (1H, dd, J=5and8Hz), 6.53
(1H, t, J=4Hz), 7.25 (2H, s), 7.37
(2H, s), 8.30 (2H, broad s), 9.90 (1H,
d, J=8Hz) (4) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-cephem-4-cal
Bonic acid (syn isomer), mp160-165℃ (decomposition) NMR (d ₆ −DMSO, δ) 3.52 (2H, d, J = 4Hz), 4.60−4.77 (2H,
m), 5.07 (1H, d, J = 4Hz), 5.0−5.50
(2H, m), 5.83 (1H, dd, J=4and8Hz),
5.70−6.23 (1H, m), 6.45 (1H, t, J=4
Hz), 8.13 (2H, s), 9.57 (1H, d, J=8
Hz) (5) 7-[2-(2-cyclopentene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp155-160℃ (min.
Solution) IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1520cm ^-1 (6) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-cephem-4-carboxylic acid (sin
isomer), mp180-185℃ (decomposition) IR (Nudiyol): 3500, 3430, 3300, 3200,
1770, 1690, 1660, 1640, 1620, 1580,
1510cm ^-1 (7) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]cephalosporanic acid (syn isomer),
mp154-159℃ (decomposition) IR (nujiol): 3300, 1770, 1720, 1670,
1620, 1520cm ^-1 (8) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-(1-methyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp155-160℃
(Decomposition) IR (Nujiyor): 3300.1770, 1670, 1620,
1520cm ^-1 (9) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1-carboxymethyl-1H-
Tetrazol-5-yl)thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer),
mp155-160℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 (10) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-[1-(2-carboxyethyl)
-1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp150-155℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 (11) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(1-allyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp160-165℃
(Decomposition) IR (nujiol): 3300, 1770, 1670, 1620,
1520cm ^-1 (12) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-tetrazolo[1,5-b)pyrida
Zin-6-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp170-175℃
(Decomposition) IR (nujiol): 3400, 3300, 3190, 1770,
1670, 1615, 1520cm ^-1 (13) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{2-(N-Third Class Butoki
cycarbonylamino)ethyl}-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp95-100
°C (decomposition) IR (nujiol): 3300, 3190, 1770, 1680,
1620, 1520cm ^-1 (14) 7-[2-cyclopenten-1-yl)o
Kixiimino-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-[1-(2-aminoethyl)-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp175~
180℃ (decomposition) IR (nujiol): 3400, 3300, 3170, 1760,
1665, 1610, 1520cm ^-1 (15) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp150-155℃ (min.
Solution) IR (Nujiyor): 3300, 3180, 1770, 1660,
1620, 1520cm ^-1 (16) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-cephem-4-carboxylic acid (sin
isomer), mp175-180℃ (decomposition) IR (Nudiyol): 3300, 3200, 1770, 1670,
1630, 1520cm ^-1 (17) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(tetrazolo[1,5-b]]pi
ridazin-6-yl)thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp170~
175℃ (decomposition) IR (nujiol): 3400, 3300, 3180, 1670,
1620, 1520cm ^-1 (18) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]cephalosporanic acid (syn isomer),
mp160~165℃ (decomposition) IR (nujiol): 3300, 3200, 1775, 1720,
1670, 1620, 1520cm ^-1 (19) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-(1-methyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp170-173℃
(Decomposition) IR (nujiol): 3350, 3250, 1780, 1680,
1620, 1520cm ^-1 (20) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1-carboxymethyl-1H-
Tetrazol-5-yl)thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer),
mp170~175℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1720,
1650, 1620, 1520cm ^-1 (21) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-[1-(2-carboxyethyl)
-1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp165-170℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 (22) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(1-allyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp160-165℃
(Decomposition) IR (nujiol): 3300, 3200, 1780, 1680,
1620, 1520cm ^-1 (23) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl]acetoa
Mido-3-[1-{3-(N-tertiary butoxy)
carbonylamino)propyl}-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp100-105
°C (decomposition) IR (nujiol): 3300, 3170, 1770, 1670,
1620, 1520cm ^-1 (24) 7-[2-(2-cyclohexene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-(3-aminopropyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp185-190℃ (decomposition) IR (nujiol): 3280, 3150, 1760, 1665,
1620, 1520cm ^-1 (25) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), mp140-145℃ (decomposition) IR (nujiol): 3400, 3300, 3200, 1770,
1670, 1620, 1525cm ^-1 (26) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-cephem
-4-carboxylic acid (syn isomer), mp170-175
°C (decomposition) IR (nujiol): 3520, 3420, 3320, 3220,
3160, 1770, 1685, 1655, 1635, 1625,
1570, 1505cm ^-1 (27) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(3-yl)acetamide] Cephalospora
phosphoric acid (syn isomer), mp140-145℃ (decomposition) IR (Nudiyol): 3480, 3370, 3250, 1785,
1730, 1680, 1630, 1530cm ^-1 (28) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-methyl)
Chil-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
mp145-150℃ (decomposition) IR (nujiol): 3400, 3290, 3180, 1770,
1670, 1620, 1520cm ^-1 (29) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-ka)
ruboxymethyl-1H-tetrazole-5-i
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp155-160℃ (decomposition) IR (Nujiol): 3400, 3290, 3180, 1765,
1720, 1620, 1520cm ^-1 (30) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-a
Lyle-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
mp135-140℃ (decomposition) IR (nujiol): 3400, 3300, 3190, 1770,
1670, 1620, 1520cm ^-1 (31) 7-[2-cyclopentylimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(tetrazolo
[1,5-b]pyridazin-6-yl)thiome
Chill-3-cefem-4-carboxylic acid
mp160-165℃ (decomposition) IR (Nudyol): 3570, 3440, 3320, 3181,
1775, 1660, 1620, 1580, 1540, 1520cm ^-1 (32) 7-[2-cyclopentylimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-{3-
(N-tertiary butoxycarbonylamino)pro
pill}-1H-tetrazol-5-yl]thio
Methyl-3-cephem-4-carboxylic acid
isomer), light brown powder. IR (Nujiyor): 3300, 1770, 1670, 1520,
1240, 1160, 1000cm ^-1 (33) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(3-aminopropyl)-1H-tetrazole-
5-yl]thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), white powder, mp195~
199℃ (decomposition) IR (nujiol): 3300, 3150, 1760, 1660,
1620, 1520, 1280, 1180, 1000cm ^-1 (34) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(2-methoxycarbonylethyl)-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp125~
130℃ (decomposition) IR (nujiol): 3480, 3370, 3250, 1780,
1740, 1685, 1625, 1530cm ^-1 (35) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(3-yl)acetamide]-3-(4-methyl)
Chill-5-oxo-6-hydroxy-4,5-
Dihydro-1,2,4-triazine-3-y
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), yellow powder, mp195-199℃
(Decomposition) IR (nujiol): 3300, 3200, 1770, 1700−
1670, 1520, 1240, 1170, 1090, 1000, 720
cm ^-1 (36) 7-[2-cyclopentyloxyimino-
2((5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1,2,
4-thiadiazol-5-yl)thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp175-178℃ (decomposition) IR (nujiol): 3300, 3200, 1775, 1680,
1620, 1525cm ^-1 (36) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(3-morpholinopropyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp183-188℃
(Decomposition) IR (nujiol): 3300, 3150, 1770, 1670,
1610, 1530cm ^-1 (38) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), white powder, mp150-154℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1670,
1620, 1520, 1400, 1240, 1160, 1060, 1000
cm ^-1 (39) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-cephem
-4-carboxylic acid (syn isomer), white powder,
mp170~175℃ (decomposition) IR (nujiol): 3400, 3300, 3200, 1770,
1670, 1620, 1520, 1280, 1240, 1160,
1000, 980, 730cm ^-1 (40) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(3-Piperidinopropyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
- Carboxylic acid (syn isomer), mp230℃ (decomposition) IR (Nudyol): 3300, 3200, 1770, 1670,
1600, 1520cm ^-1 Example 21 7-[2-phenoxy-2-(5-amino-
1,2,4-thiadiazol-3-yl)aceto
Amide]-3-[1-{2-(N-tertiary butoki
cycarbonylamino)ethyl}1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer: 1.4g) formic acid (14
ml) The solution was stirred at room temperature for 3 hours and the solvent was distilled off.
Ta. The residue was mixed with ethyl acetate and sodium bicarbonate.
It was dissolved in a liquid and the pH was adjusted to 2 with 10% hydrochloric acid. Separate the aqueous layer
Wash with ethyl acetate and concentrate to remove ethyl acetate.
Distilled out. Column chromatography dye the aqueous layer
Yaion HP-30 resin (trademark: Mitsubishi Chemical Industries, Ltd.)
After washing with water, wash with 50% aqueous methanol.
It eluted. Methanol is distilled off from the eluate under reduced pressure.
When the remaining aqueous layer is freeze-dried, 7- [2-
Enoxyimino-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]-
3-[1-(-aminoethyl)-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer: 0.3g), mp180~
185°C (decomposition) was obtained. IR (Nujiyor): 3300, 3250, 1760, 1670,
1620, 1590, 1520cm ^-1 NMR(d ₆ −DMSO, δ) 3.40 (2H, broad s), 3.60 (2H, broad
s), 4.23 (2H, broad s), 4.60 (2H,
broad s), 5.13 (1H, d, J=4Hz), 5.83
(1H, dd, J=4and8Hz), 7.0−7.5 (5H,
m), 8.33 (2H, s), 9.90 (1H, d, J=8
Hz) Example 22 7-[2-{3-(N-tertiary butoxycarbo
nylamino)propoxyimino}-2-(5-a
mino-1,2,4-thiadiazol-3-yl)
acetamide]-3-[1-{2-(N-tertiary
butoxycarbonylamino)ethyl}-1H-te
Torazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer: 4.0g)
The acid (40ml) solution was stirred at room temperature for 2.5 hours. reaction
Evaporate the mixture and dry under reduced pressure to obtain an oil.
It was. Add water (40ml) and 1N hydrochloric acid (50ml) to this.
When it was heated, it became a clear solution. Add this solution to the diamond
Ion HP-20 resin (trademark: Mitsubishi Chemical Industries, Ltd.
Co., Ltd.) column chromatograph, and water and
Sequential elution with 5% aqueous methanol yielded 7-[2
-(3-aminopropoxyimino)-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-[1-(2-aminoe)
Thiome)-1H-tetrazol-5-yl]thiome
Chil-3-cephem-4-carboxylic acid (synisomer
body: 0.95g), mp184-195℃ (decomposition) was obtained.
Ta. IR (Nujiyor): 3400-3100, 1760, 1660,
1610, 1520, 1170, 1060, 1010cm ^-1 NMR(d ₆ −DMSO＋D ₂ O, δ) 1.9 (2H, m), 2.8 (2H, m), 3.3 (2H, m),
3.5 (2H, m), 4,1 (4H, m), 4.5 (2H,
m), 4.90 (1H, d, J=5Hz), 5.56 (1H,
d, J=5Hz) Example 23 7-[2-{2-(N-tertiary butoxycarbo
nylamino)ethoxyimino}-2-(5-amino)
No-1,2,4-thiadiazol-3-yl)a
Cetamido]-3-(1-carboxymethyl-
1H-tetrazol-5-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer: 1.9
A solution of g) in formic acid (28 ml) was stirred at room temperature for 2 hours.
Ta. When the reaction mixture is treated according to a conventional method, 7-
[2-(2-aminoethoxyimino)-2-(5
-amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-carboxymethylene)
ru-1H-tetrazol-5-yl)thiomethyl
-3-Cefem-4-carboxylic acid (syn isomer:
0.55 g) mp 190-198°C (decomposition) was obtained. IR (Nujiyor): 3250, 3160, 1760, 1650,
1615, 1522, 1020cm ^-1 NMR (DCl, δ) 3.11 (2H, broad s), 3.28−3.65 (2H, m),
4.35 (2H, broad s), 4.48−4.78 (2H, m),
5, 25 (1H, d, J = 4.5Hz), 5.42 (2H,
s), 5.88 (1H, d, J = 4.5Hz) Example 24 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-3
-[1-{2-(N-tertiary butoxycarbonyl
aminoethyl}-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
isomer: 3.5 g) formic acid (35 ml) at room temperature.
The mixture was stirred for 2 hours. Evaporate the reaction mixture and leave a residue
was washed with diethyl ethyl and acetone in that order.
Washing residue (2.65g) was dissolved in sodium bicarbonate aqueous solution.
(60 ml), stirred and filtered to remove insoluble matter.
Ethyl acetate was added to the liquid, and the pH was adjusted to 3 with 3% hydrochloric acid.
The aqueous layer was then separated. On the other hand, add water to the supernatant obtained above.
Ethyl acetate was added. Add 10% hydrochloric acid to this mixture.
The pH was adjusted to 3 and the aqueous layer was separated. Combine the water layers and 10%
After adjusting the pH to 2 with hydrochloric acid, washing with ethyl acetate, then
Ethyl acetate was distilled off. Column chromatography of the residue
Graph (Nonionic adsorption resin Diaion HP-
20: Deployed to Mitsubishi Chemical Industries, Ltd.), water, 30
% aqueous methanol, 50% aqueous methanol and 100%
Eluted with % methanol. Collect fractions containing the target substance
When the solvent is distilled off and freeze-dried, 7-[2-
(2-cyclopenten-1-yl)oxyimino
-2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(2
-aminoethyl)-1H-tetrazole-5-i
) Thiomethyl-3-cephem-4-carboxylic acid
(Syn isomer: 580 mg), mp175-180℃ (decomposition)
Obtained. IR (Nujiyor): 3400, 3300, 3170, 1760,
1665, 1610, 1520cm ^-1 NMR(d ₆ −DMSO, δ) 1.87−2.52 (4H, m), 3.27−3.73 (4H, m),
4.13−4.13 (2H, m), 4.57−4.80 (2H, m),
5.03 (1H, d, J = 5Hz), 5.27−5.53 (1H,
m), 5.70 (1H, d, J=5Hz), 5.85−6.27
(2H, m) Example 25 The following compounds were prepared according to the same method as Examples 21 to 24.
I got something. (1) 7-[2-(2-aminoethoxyimino)-
2-(amino-1,2,4-thiadiazole-
3-yl)acetamido]-2-methyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp190~195℃ (decomposition) IR (nujiol): 3300, 3150, 1760, 1660,
1575, 1400cm ^-1 NMR(D ₂ O + DCl, δ) 1.55 (3H, d, J = 7Hz), 3.5 (2H, t, J
= 4.6Hz), 3.7-4.2 (1H, m), 4.67 (2H, t,
J=4.6Hz), 5.27 (1H, d, J=4.5Hz), 6.03
(1H, d, J = 4.5Hz), 6.90 (1H, d, J =
6Hz) (2) 7-[2-(3-aminopropoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamido]-2-methyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp182-187℃ (decomposition) IR (nujiol): 3260, 3150, 1758, 1660,
1616, 1575, 1520, 1400cm ^-1 NMR (DCl+D ₂ O, δ) 1.55 (3H, d, J = 6.5Hz), 1.93−2.50 (2H,
m), 3.25 (5H, t, J = 7Hz), 3.70−4.15
(1H, m), 4.5 (2H, t, J=6Hz), 5.23
(1H, d, J = 4.5Hz), 6.05 (1H, d, J =
4.5Hz), 6.88 (1H, d, J = 6Hz) (3) 7-[2-(3-aminopropoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamido]-3-methyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp175-195℃ (decomposition) IR (nujiol): 3300-3100, 1700-1740,
1660, 1620, 1570, 1520, 1280, 1170,
1060, 1020cm ^-1 NMR(d ₆ −DMSO＋D ₂ O, δ) 1.87 (3H, s), 1.9 (2H, m), 2.9 (2H, m),
3.2 (2H, m), 4.2 (2H, m), 4.93 (1H, d,
J=8Hz), 5.60 (1H, d, J=5Hz) (4) 7-[2-(3-aminopropoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]]-3-chloro
rho-3-cephem-4-carboxylic acid (synisomer
body), mp190-205℃ (decomposition) IR (nujiol): 3400-3150, 1760, 1660,
1630−1590, 1520, 1340, 1170, 1030cm ^-1 NMR(d ₆ −DMSO, δ) 2.00 (2H, m), 2.90 (2H, m), 3.33and3.83
(2H, ABq, J=16Hz), 4.20 (2H, m),
5.09 (1H, d, J=5Hz), 5.60 (1H, m),
8.15 (2H, m), 9.50 (1H, m) (5) 7-[2-(2-aminoethoxyimino)-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(2-aminoethyl)1H-tetrazole-5-
yl]thiomethyl-3-cephem-4-carbo
acid (syn isomer), mp182-187℃ (decomposition) IR (Nudiyol): 3350, 3150, 1760, 1660,
1625, 1565, 1520cm ^-1 NMR(d ₆ −DMSO, δ) 3.2−3.9 (6H, m), 4.05, 4, 32 (2H,
ABq, J=14Hz), 4.4-5.0 (4H, m), 5.22
(11H, d, J=4.5Hz) (6) 7-[2-(2,2,2-trifluoroethyl
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-[1-2-aminoethyl)-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp185~
190℃ (decomposition) IR (nujiol): 3300, 3170, 1760, 1670,
1615, 1500cm ^-1 NMR(d ₆ −DMSO, δ) 3.17−3.83 (4H, m) 4.28 (2H, broad s),
4.47−4.93 (4H, m), 5, 10 (1H, d, J=
5Hz), 5.73 (1H, dd, J=5anp8Hz), 8.20
(2H, broad s), 9.65 (1H, d, J=8Hz) (7) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(3
-aminopropyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), white powder, mp195-199
°C (decomposition) IR (nujiol): 3300, 3150, 1760, 1660,
1620, 1520, 1280, 1000cm ^-1 NMR(d ₆ −DMSO, δ) 1.70 (8H, m), 2.20 (2H, m), 2.87 (2H,
m), 3.57 (2H, m), 4.03-4.60 (4H, m),
4.70 (1H, m), 5.00 (1H, d, J=5Hz),
5.63 (1H, dd, J=5and8Hz), 8.10 (2H,
m), 9.40 (1H, d, J = 8Hz) (8) 7-[2-(2-cyclohexene-1-i
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-(3-aminopropyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4 carboxylic acid (syn isomer),
mp185-190℃ (decomposition) IR (nujiol): 3280, 3150, 1760, 1665,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ) 1.47−2.30 (8H, m), 2.73−3.13 (2H, m),
3.63 (2H, droad s), 4.17−4.60 (4H, m),
4.60−4.90 (1H, m), 5.03 (1H, d, J=5
Hz), 5.73 (1H, dd, J=5and8Hz), 5.75−
5.99 (2H, m), 8.13 (2H, road s), 9.43
(1H, d, J=8Hz) Example 26 7-[2-tertiary butoxycarbonylmethoxy
imino-2-(5-amino-1,2,4-thiazi
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid
(1.6g), trifluoroacetic acid (10ml) and
A mixture of Nisole (2 ml) was stirred at room temperature for 30 minutes.
Ta. Concentrate the reaction mixture and dilute the residue with diethyl ethyl ether.
The mixture was treated with a vacuum cleaner to powder and dried. product
(1.6g) was dissolved in an aqueous sodium bicarbonate solution,
After washing with ethyl acetate, it was added to ethyl acetate.
The mixture was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate.
did. Wash the extract with saturated aqueous sodium chloride solution
After drying with magnesium sulfate, the solvent was distilled off.
Ta. Treat the residue with diethyl ethyl to powder
When dried, 7-[2-carboxyfura]
Tsushiyimino-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-3
-(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
Isomer: 0.52g), mp170-175℃ (decomposition) was obtained.
It was. IR (Nujiyor): 3250, 3150, 1770, 1710,
1680, 1610, 1520cm ^-1 NMR(d ₆ −DMSO, δ) 3.67 (2H, broad s), 4.25 (2H, ABq, J
= 13Hz), 4.63 (2H, s), 5.12 (1H, d, J
=4Hz), 5.80 (1H, dd, J=4and8Hz),
8.15 (2H, s), 9.55 (1H, d, J=8Hz),
9.58 (1H, s). Example 27 Following the same method as Example 26, the following compounds were prepared.
Obtained. (1) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(1-allyl)
-1H-tetrazol-5-yl)thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp145-150℃ (decomposition) IR (nujiol): 3400, 3300, 3200, 1765,
1720, 1680, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ) 3.70 (2H, droad s), 4.30and4.47 (2H,
ABq, J=13Hz), 4.68 (2H, s), 4.83−
5.15 (2H, m), 5.15 (1H, d, J=5Hz),
5.17−5.50 (2H, m), 5.85 (1H, dd, J=
5and8Hz), 5.60-6.20 (1H, m), 8.13 (2H,
broad s), 9.53 (1H, d, J=8Hz) (2) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]cephalosporanic acid
(Syn isomer), mp160-165℃ (decomposition) IR (Nujiol): 3300, 3200, 1770, 1720,
1680, 1520cm ^-1 NMR(d ₆ −DMSO, δ) 2.10 (3H, s), 3.60 (2H, broad s), 4.70
(2H, s), 4.77and5.03 (2H, ABq, J=14
Hz), 5.20 (1H, d, J = 4Hz), 5.88 (1H,
dd, J=4and8Hz), 8.18 (2H, s), 9.57
(1H, d, J=8Hz) (3) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(tetrazolo
[1.5-b]pyridazin-6-yl)thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp170-175℃ (decomposition) IR (nujiol): 3400, 3300, 3180, 1765,
1720, 1680, 1615, 1520cm ^-1 NMR(d ₆ −DMSO, δ) 3.75 (2H, droad s), 4.28and4.60 (2H,
ABq, J=13Hz), 4.67 (2H, s), 5.17 (1H,
d, J=5Hz), 5.87(1H, dd, J=and8
Hz), 7.77 (1H, d, J = 10Hz), 8.17 (2H,
broad s), 8.60 (1H, d, J=10Hz), 9.57
(1H, d, J=8Hz) (4) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido-3-[1-(2-a
(minoethyl)-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
(Syn isomer), mp185-190℃ (decomposition) IR (Nudyol): 3250, 1755, 1660, 1590,
1520cm ^-1 NMR(d ₆ −DMSO, δ) 3.23−2.67 (4H, m), 4.07and4.35 (2H,
ABq, J=13Hz), 4.23−4.80 (4H, m),
5.03 (1H, d, J = 5Hz), 5.70 (1H, dd, J
=5and8Hz), 8.15 (2H, broad s), 11.03
(1H, d, J = 8Hz) (5) 7-[2-carboxy flash imino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-fe)
Nyl-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
mp155-160℃ (decomposition) IR (nujiol): 3400, 3300, 3180, 1765,
1720, 1680, 1615, 1520, 1495cm ^-1 NMR(d ₆ -DMSO, δ) 3.65 (2H, broad s), 4.28and4.52 (2H,
ABq, J=13Hz), 4.63 (2H, s), 5.07 (1H,
d, J=5Hz), 5.80 (1H, dd, J=5and8
Hz), 7.63 (5H, s), 8.10 (2H, broad s),
9.47 (1H, d, J = 8Hz) Example 28 7-[2-trityloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(5-methyl-1,
3,4-thiadiazol-2-yl)thiomethyl
-3-Cefem-4-carboxylic acid (syn isomer:
4.5g), concentrated hydrochloric acid (4.5ml) and methanol (45ml)
The mixture was stirred at room temperature for an hour. Retains methanol
Add ethyl acetate and aqueous sodium hydrogen carbonate to the residue.
The pH was adjusted to 5 by adding liquid. Add ethyl acetate to the separated aqueous layer.
The pH was adjusted to 2 with 10% hydrochloric acid. separated
The ethyl acetate layer was dried with magnesium sulfate and then reduced.
Concentrate to 10ml under pressure. The precipitate is removed and acetic acid
After washing with ethyl and diethyl ethyl, drying
Then, 7-[2-hydroxyimino-2-(5
-amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(5-methyl-1,
3,4-thiadiazol-2-yl)thiomethyl
-3-Cefem-4-carboxylic acid (syn isomer:
1.4 g), mp 153-162°C (decomposition) was obtained. IR (Nujiyor): 3260, 3160, 1763, 1665,
1608, 1520cm ^-1 NMR(d ₆ −DMSO, δ) 2.67 (3H, s), 3.67 (2H, broad s),
4.23and4.53 (2H, ABq, J=13Hz), 5, 12
(1H, d, J = 4.5Hz), 5.82 (1H, dd, J =
4, 5anp8.5Hz), 7.98 (2H, broad s),
9.37 (1H, d, J = 8.5Hz) Example 29 7-[2-hydroxyimino-2-(5-amino)
No-1,2,4-thiadiazol-3-yl)a
Cetamido]-3-(5-methyl-1,3,4-
Thiadiazol-2-yl)thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer: 257.3mg)
and sodium bicarbonate (42 mg) in water (10 ml).
The resulting mixture was lyophilized. The product is N,N-di
Dissolve pivalin in methylformamide (5 ml).
N,N-dimethylphosate of methyl acid iodide (142.5mg)
Added lumamide (1 ml) solution and continued stirring for 20 minutes.
The reaction mixture was washed with water three times and then soaked in magnesium sulfate.
The solvent was distilled off. Residue diethyl ethyl ether
7-[2-hydro]
Roximino-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-3
-(5-methyl-1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-cal
Pivaloyloxymethyl bonate (syn isomer:
240mg), mp132-135℃ (decomposition) was obtained. IR (Nujiyor): 3270, 3160, 1775, 1745,
1675, 1610, 1520, 1115cm ^-1 NMR(d ₆ −DMSO, δ) 1.09 (9H, s), 2.70 (3H, s), 3.66and3.82
(2H, ABq, J=15Hz), 4.18and4.58 (2H,
ABq, J = 14Hz), 5.20 (1H, d, J = 4.5
Hz), 5.80−3.2 (3H, m), 8.04 (2H, broad
s), 9.47 (1H, d, J = 7.5Hz) Example 30 The following compound was prepared according to the same method as Example 29.
Obtained. (1) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-cephe
4-nitrobenzyl mu-4-carboxylate (syn)
isomer), mp155-160℃ (decomposition) IR (Nudiyol): 3300, 3180, 1770, 1720,
1680, 1625, 1600, 1580, 1520, 1480cm ^-1 (2) 7-[2-phenoxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
) Acetamide]-3-cephem-4-cal
4-nitrobenzyl bonate (syn isomer),
mp140~145℃ (decomposition) IR (nujiol): 3300, 1775, 1720, 1680,
1625, 1600, 1590, 1520cm ^-1 (3) 7-[2-(3-trifluoromethylphenol)
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-Cefem-4-carboxylic acid 4-nitrobe
Njiru (syn isomer), mp136-140℃ (decomposition) IR (Nujiol): 3370, 3200, 1780, 1730,
1690, 1630, 1610, 1520, 1450, 1325,
1280, 1125, 975, 850, 740cm ^-1 (4) 7-[2-(4-fluorophenoxyimide)
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
4-nitrobenzyl fem-4-carboxylate
(Syn isomer), mp135-140℃ (decomposition) IR (Nudyol): 3300, 3200, 1770, 1720,
1680, 1625, 1605, 1500, 1495cm ^-1 (5) 7-[2-{3-(N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamido]-3-chloro-cephem
4-Nitrobenzyl-4-carboxylate
mp91~100℃ (decomposition) NMR (d ₆ −DMSO＋D ₂ O, δ) 1.38 (9H, s), 1.80 (2H, m), 3.06 (2H,
m), 3.7-4.3 (4H, m), 5.33 (1H, d, J
= 5Hz), 5.49 (2H, s), 5.95 (1H, d, J
= 5Hz), 7.74 (2H, d, J = 9Hz), 8.92
(2H, d, J=9Hz) (6) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-cephem-4-cal
4-nitrobenzyl bonate (syn isomer),
mp125-130℃ (decomposition) IR (nujiol): 3300, 1700, 1720, 1680,
1630, 1610, 1520cm ^-1 Example 31 2-allyloxyimino-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetic acid
(syn isomer, 1.37 g) and phosphorus oxychloride (3.67 g)
in methylene chloride (30 ml) at room temperature.
Stir for 2 hours and cool to -12 to -15°C. cold mix
Add dimethylformamide (2.4 ml) to the mixture, -8
Stirred at ~-10°C for 42 minutes. On the other hand, 7-amino-3-
(1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid (2.9g)
and trimethylsilylacetamide (8 g)
Warm the mixture in methylene (40ml) to create a solution.
It was made into a state. Cool this to -25℃ and mix the above active mixture.
Add to the mixture and stir at -8 to -10℃ for 30 minutes to remove hydrogen carbonate.
Poured into a cold aqueous solution of sodium. this mixture
Stirred at room temperature for 30 minutes and separated the aqueous layer. 10% hydrochloric acid
The mixture was added to the aqueous layer to adjust the pH to 1, and extracted with ethyl acetate.
The extract was dried with magnesium sulfate and evaporated to dryness.
I set it. The residue was crystallized by treatment with diethyl ether.
When the crude 7-[2-allyloxyimino
-2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1,3,
4-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer, 2.1
g) was obtained. Dissolve this in sodium bicarbonate water.
When added to the solution and 10% hydrochloric acid to precipitate again,
Purification target (1.15g), mp138-140℃ (decomposition)
Obtained. IR (Nujiyor): 3350.3230, 1780, 1680,
1620, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 3.63 (2H, broad
s), 4.27 and 4.52 (2H, ABq, J=14
Hz), 4.5-4.8 (2H, m), 5.10 (1H, d, J
=5Hz), 5.0-5.5 (2H, m), 5.78 (1H, dd,
J = 5 and 9Hz), 5.7-6.3 (1H, m),
8.09 (2H, broad s), 9.48 (1H, s), 9.53
(1H, d, J=9Hz) Example 32 2-(2,2,2-trifluoroethoxyimide
-2-(5-amino-1,2,4-thiasia)
sol-3-yl)acetic acid (syn isomer, 1.62g)
and phosphorus oxychloride (3.67 g) in methylene chloride (30
ml) and the mixture was stirred at room temperature for 1.5 h.
Cooled to -12 to 615°C. Add dimethylform to this
Add amide (2.4ml) and stir at -8 to -10℃ for 45 minutes.
Stirred. On the other hand, 7-amino-3-(1,3,4-thi
Asiazol-2-yl)thiomethyl-3-ceph
M-4-carboxylic acid (2.9g) and trimethylsilica
Lylacetamide (8g) was dissolved in methylene chloride (40g).
ml) was heated to form a solution. child
The solution was cooled to −25°C and added to the above active mixture.
I got it. The reaction mixture was stirred at −10°C for 30 min and then diluted with carbonated water.
and poured into a cold aqueous solution of sodium chloride. Do this at room temperature
After stirring for 30 minutes, the aqueous layer was separated. Salt the aqueous layer with 10%
The pH was adjusted to 2 with acid and extracted with ethyl acetate. extract liquid
Dry with magnesium sulfate and evaporate to dryness. residue
Crystallization by treatment with diethyl ethyl results in purification
7-[2-(2,2,2-trifluoroethoxy)
(shiimino)-2-(5-amino-1,2,4-thi)
Asiazol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid
2.45 g) was obtained. Add this to sodium bicarbonate
Dissolve in aqueous solution of aluminum and add 10% hydrochloric acid to re-precipitate.
The purified target substance (1.42g)
mp153-158°C (decomposition) was obtained. IR (Nujiyor): 3350, 3250, 1780, 1680,
1625cm ^-1 NMR(d ₆ −DMSO, δ): 3.70 (2H, broad
s), 4.33 and 4.58 (2H, ABq, J=13
Hz), 4.70 and 4.92 (2H, ABq, J=9
Hz), 5.17 (1H, d, J = 5Hz), 5.82 (1H,
dd, J = 5 and 8Hz), 8.18 (2H, broad
s), 9.55 (1H, S), 9.70 (1H, d, J=8
Hz) Example 33 Dimethylformamide (6 ml) and phosphorus oxychloride
(918 mg) was stirred at room temperature for 30 minutes. Add methylene chloride (6 ml) to this and add 2-
Dichloroacetimino-2-(5-formamide
-1,2,4-thiadiazol-3-yl)acetic acid
(Syn isomer, 1.6 g) was added at -20 to -25°C.
This mixture was stirred at -10 to -15°C for 30 minutes. This mixture
7-amino-3-(1,3,4-thiadiazine)
Azol-2-yl)thiomethyl-3-cephem
-4-carboxylic acid (2.0g) and trimethylsilyl
Acetamide (6g) dissolved in methylene chloride (30ml)
The solution was added at -5 to -15°C. Chloride from reaction mixture
Distill the methylene and add the residue, ice water and ethyl acetate.
I got it. 7-[2-dichloroacetoxyimino-2
-(5-formamide-1,2,4-thiadiazo
-3-yl)acetamide]-3-(1,
3,4-thiadiazole-2-)thiomethyl-3
-Contains cefem-4-carboxylic acid (syn isomer)
The mixture was adjusted to pH 5 with an aqueous sodium bicarbonate solution.
The aqueous layer was separated and ethyl acetate was added. This mixture
Add 10% hydrochloric acid to the mixture to adjust the pH to 2 and remove insoluble matter.
did. The liquid was extracted three times with ethyl acetate, and the extract was
After drying with magnesium sulfate, it was evaporated to dryness.
The residue was treated with diethyl ethyl and crystallized.
When washed with diethyl ethyl, 7-[2-
Hydroxyimino-2-(5-formamide-
1,2,4-thiadiazol-3-yl)aceto
Amide]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer, 0.9g), mp155-160℃
(decomposition) was obtained. IR (nujiyor): 3200, 1780, 1680, 1620cm
^-1 NMR(d ₆ −DMSO, δ): 3.67 (2H, broad
s), 4.27 and 4.73 (2H, ABq, J=13
Hz), 5.13 (1H, d, J = 4Hz), 5.83 (1H,
dd, J = 4 and 8Hz), 8.80 (1H, s,),
9.50 (1H, d, J=8Hz), 9.53 (1H, s),
12.22 (1H, s) Example 34 Following a method similar to Examples 31-33, the following compounds were prepared.
manufactured something. (1) 7-[2-(2-propyloxyimino)-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body) mp140~~145℃ (decomposition). IR (Nujiyor): 3330, 3250, 1780, 1680,
1620, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 3.47 (1H, t, J
= 2Hz), 3.67 (2H, broad s), 4.28 and
4.53 (2H, ABq, J=13Hz), 4.77 (2H, d,
J=2Hz), 5.12 (1H, d, J=5Hz), 5.78
(1H, dd, J=5 and 8Hz), 8.13 (2H,
broad s), 9.55 (1H, s), 9.67 (1H, d,
J=8Hz) (2) 7-[2-benzyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1,3,4-thi)
Asiazol-2-yl)thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer) mp130
~135℃ (decomposition). IR (Nujiyor): 3360, 3250, 1780, 1680,
1625, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 3.63 (2H, broad
s), 4,35 and 4.58 (2H, ABq, J=13
Hz), 5.13 (1H, d, J = 5Hz), 5.23 (2H,
s), 5.80 (1H, dd, J=5 and 8Hz),
7.38 (5H, s), 8.13 (2H, broad s), 9.57
(1H, s), 9.63 (1H, d, J = 8Hz) (3) 7-[2-(2-phenoxyethoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(isomer) mp163-167℃ (decomposition) IR (Nujiol): 3350, 3250, 1780, 1680,
1630, 1600, 1530, 1500cm ^-1 NMR(d ₆ −DMSO, δ): 3.30 and 3.60
(2H, ABq, J=18Hz), 4.0−4.70 (6H,
m), 5.10 (1H, d, J=4Hz), 5.93 (1H,
dd, J = 4 and 8 Hz), 6.7-7.5 (5H,
m), 8.13 (2H, s), 9.50 (1H, s), 9.57
(1H, d, J=8Hz) (4) 7-[2-methylthiomethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer)
mp168-170℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 2.17 (3H, s),
3.65 (2H, borad s), 4.30 and 4.57 (2H,
ABq, J = 14Hz), 5.12 (1H, d, J = 4
Hz), 5.20 (2H, s), 5.80 (1H, dd, J=4
and 8Hz), 8.17 (2H, s), 9.53 (1H,
s), 9.62 (1H, d, J = 8Hz) (5) 7-[2-(2-methylthioethoxyimide
-2-yl(5-amino-1,2,4-th)
Asiazol-3-yl)acetamide]-3
-(1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(Syn isomer) mp125-130℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1625, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 2.08 (3H, s),
2.72 (2H, t, J = 7Hz) 3.68 (2H, broad
s), 4.28 (2H, t, J=7Hz), 4.30 and
4.55 (2H, ABq, J=13Hz), 5.13 (1H, d,
J=5Hz), 5.82(1H, dd, J=5 and 8
Hz), 8.15 (2H, broad s), 9.52 (1H, d,
J = 8Hz), 9.53 (1H, s) (6) 7-[2-phenoxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4-thia
diazol-2-yl)thiomethyl-3-cef
M-4-carboxylic acid (syn isomer) mp145~
150℃ (decomposition). IR (Nujiyor): 3350, 3230, 1780, 1680,
1620, 1590, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 3.70 (2H, broad
s), 4.30 and 4.60 (2H, ABq, J=14
Hz), 5.23 (1H, d, J = 5Hz), 5.92 (1H,
dd, J = 5 and 8 Hz)), 7.0−7.6 (5H,
m), 8.30 (2H, broad s), 9.52 (1H, s),
9.83 (1H, d, J = 8Hz) (7) 7-[2-cyanomethoxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1,3,4-thi)
Asiazol-2-yl)thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer) mp105
~110℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 3.6 and 3.76 (2H,
ABq, J=18Hz), 4.3 and 4.56 (2H,
ABq, J=13Hz), 5.12 (2H, s), 5.14 (1H,
d, J=5Hz), 5.80 (1H, dd, J=5 and
and 8Hz), 8.20 (2H, broad s), 9.52 (1H,
s), 9.78 (1H, d, J = 8Hz) (8) 7-[2-(N,N-diethylcarbamoy
) methoxyimino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer) mp175-180℃ (min
solution). IR (Nujiyor): 3480, 3310, 3200, 1775,
1740, 1680, 1630, 1610, 1515cm ^-1 NMR(d ₆ −DMSO, δ): 1.00 (3H, t, J
= 7Hz), 1.08 (3H, t, J = 7Hz), 3.27
(4H, q, = 7Hz), 3.62 and 3.72 (2H,
ABq, J=18Hz), 4.33 and 4.55 (2H,
ABq, J=14Hz), 4.88 (2H, s), 5.15 (1H,
d, J=5Hz), 5.83(1H, dd, J=5 and
and 9Hz), 8.13 (2H, broad s), 9.55 (1H,
s), 9.62 (1H, d, J = 9Hz) (9) 7-[2-(1-ethoxycarboxy-1-
methylethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-(1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer) mp130-135℃
(Disassembly). IR (Nujiyor): 3360, 3240, 1780, 1730,
1690, 1630, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 1.18 (3H, t, J
=7Hz), 1.50 (6H, s), 3.72 (2H, broad
s), 4.13 (2H, q, J = 7Hz), 4, 33 and
and 4.58 (2H, ABq, J=13Hz), 5.18 (1H,
d, J=5Hz), 5.85(1H, dd, J=5 and
and 8Hz), 8.18 (2H, broad s), 9.48 (1H,
d, J = 8Hz), 9.57 (1H, s) (10) 7-[2-ethoxycarbonylmethoxyimide
No-2-(5-amino1,2,4-thiadiazo
-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body) mp120-125℃ (decomposition). IR (Nujiyor): 3370, 3250, 1780, 1690,
1625, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.23 (3H, t, J
=7Hz), 3.72 (2H, broad s), 4.20 (2H,
q, J=7Hz), 4.35 and 4.58 (2H, ABq,
J = 13Hz), 4.78 (2H, s), 5.17 (1Hd, J =
5Hz), 5.83 (1H, dd, J=5 and 8Hz),
8.20 (2H, broad s), 8.58 (1H, d, J=8
Hz), 9.60 (1H, s) (11) 7-[2-hydroxyimino-2-(5-ho)
Lumamide-1,2,4-thiadiazole-3
-yl)acetamide]-3-(1,3,4-
Thiadiazol-2-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer)
mp155-160℃ (decomposition). IR (nujiyor): 3200, 1780, 1680, 1620cm
^-1 (12) 7-[2-{2-(2-hexyloxyeth
xy)ethoxyimino}-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-(1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer) mp100-105℃
(Disassembly). IR (Nujiyor): 3340, 3210, 1785, 1685,
1620, 1525cm ^-1 NMR(d ₆ −DMSO, δ): 0.87 (3H, t, J
=5Hz), 0.87-1.73 (8H, m), 3.10-3.92
(10H, m), 4.10−4.47 (2H, m), 4.30 and
and 4.58 (2H, ABq, J = 13Hz), 5, 17 (1H,
d, J=5Hz), 5.83(1H, dd, J=5 and
and 8Hz), 8.12 (2H, broad s), 9.55 (1H,
d, J = 8Hz), 9.57 (1H, s) (13) 7-[2-Mesylmethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer)
mp164-167℃ (decomposed). IR (Nujiyor): 3360, 3230, 1780, 1690,
1620, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 3.02 (3H, s),
3.72 (2H, broad s), 4.33 and 4.57 (2H,
ABq, J = 13Hz), 5.15 (1H, d, J = 5
Hz), 5.30 (2H, s), 5,83 (1H, dd, J=
5 and 8Hz), 8.20 (2H, broad s), 9.55
(1H, s), 9.78 (1H, d, J=8Hz) (14) 7-[2-trityloxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(1-methyl
-1H-tetrazol-5-yl)thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body) mp163-167℃ (decomposition). IR (Nujiyor): 3480, 3350, 3250, 1785,
1690, 1620, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 3.64 and 3.72
(2H, ABq, J=18Hz), 3.90 (3H, s),
4.24 and 4.38 (2H, ABq, J=14Hz), 5.18
(1H, d, J=4Hz), 5.98 (1H, dd, J=
4 and 8Hz), 7.30 (15H, s), 8.08 (2H,
s), 9.84 (1H, d, J = 8Hz) (15) 7-[2-trityloxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer)
mp175-178℃ (decomposition). IR (Nujiyor): 3450, 3350, 3200, 1790,
1690, 1620, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 3.73 (2H, broad
s), 4.33 and 4.63 (2H, ABq, J=13
Hz), 5, 10 (1H, d, J = 4Hz), 6, 03
(1H, dd, J=4 and 8Hz), 7.37 (15H,
s), 8.13 (2H, s), 9.60 (1H, s), 9.87
(1H, d, J=8Hz) (16) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl) acetamide] cephalosporanic acid (cephalosporanic acid)
isomers), mp131-133°C (decomposition). IR (Nujiyor): 3350, 3240, 1780, 1730,
1680, 1530, 1240cm ^-1 NMR(d ₆ −DMSO, δ): 2.07 (3H, s),
3.57 (2H, broad s), 4.5−5.1 (2H, m),
4.7 (2H, broad s), 5.1~5.6 (2H, m),
5.15 (1H, d, J = 4Hz), 5.6-6.4 (1H,
m), 5.84 (1H, dd, J = 4.5 and 9Hz),
8.13 (2H, broad s), 9.67 (1H, d, J=9
Hz) (17) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp154-156℃ (decomposition). IR (Nujiyor): 3380, 3245, 1780, 1680,
1625, 1527cm ^-1 NMR(d ₆ −DMSO, δ): 3.53 and 3.77
(2H, ABq, J=14Hz), 3.90 (3H, s),
4.27 (2H, broad s), 4.5-4.8 (2H.m), 5.0
-5.6 (2H, m), 5.15 (1H, d, J = 4.5Hz),
5.6−6.3 (1H, m), 5.85 (1H, dd, J = 4.5
and 9Hz), 7.23 (2H, broad s), 9.77 (1H,
d, J=9Hz) (18) 7-[2-trityloxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (anti-isomer),
mp165-170℃ (decomposition). IR (Nujiyor): 3350, 3200, 1785, 1690,
1620, 1515cm ^-1 NMR(d ₆ −DMSO, δ): 3.70 (2H, broad
s), 4.33 and 4.60 (2H, ABq, J=13
Hz), 5.10 (1H, d, J = 4Hz), 5.73 (1H,
dd, J=4 and 8Hz), 7.33 (15H, s),
8.17 (1H, d, J = 8Hz), 8.23 (2H, s),
9.60 (1H, s) (19) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl) acetamido]-3-(5-aminomethy
(1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp161-164℃ (decomposition). IR (Nujiyor): 3350, 3220, 1770, 1670,
1620, 1525cm ^-1 (20) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl) acetamide]-3-[1-{2-N-
tertiary-butoxycarbonylamino)ethyl}-
1H-tetrazol-5yl]thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer) powder
The end. (21) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-[1-(2-amido)
Noethyl)-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp165-169℃ (decomposed). IR (Nujiyor): 3350, 3200, 1768, 1670,
1610, 1522cm ^-1 (22) 7-[2-hydroxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-methyl-1H
-tetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp165-170℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1230cm ^-1 (23) 7-[2-hydroxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4-thia
diazol-2-yl)thiomethyl-3-ceph
M-4-carboxylic acid (syn isomer), mp170
~175℃ (decomposition). IR (Nujiyor): 3480, 3350, 1770, 1690,
1620, 1530cm ^-1 (24) 7-[2-hydroxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4-thia
diazol-2-yl)thiomethyl-3-cef
M-4-carboxylic acid (anti-isomer),
mp155-160℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1520cm ^-1 Example 35 The following compounds were prepared by a method similar to Examples 14 to 16.
manufactured something. (1) 7-[2-hydroxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4-thia
diazol-2-yl)thiomethyl-3-cef
M-4-carboxylic acid (syn isomer), mp155
~160℃ (decomposition). IR (nujiyor): 3200, 1780, 1680, 1620cm
^-1 (2) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4-thia
diazol-2-yl)thiomethyl-3-ceph
M-4-carboxylic acid (syn isomer), mp138
~140℃ (decomposition). IR (Nujiyor): 3350, 3230, 1780, 1680,
1620, 1530cm ^-1 (3) 7-[2-(2,2,2-trifluoroethane
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-(1,3,4-thiadiazole-2-i)
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp153-158℃ IR (Nujiol): 3350, 3250, 1780, 1680,
1625cm ^-1 (4) 7-[2-(2-propynyloxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), mp140-145℃ (decomposition). IR (Nujiyor): 3330, 3250, 1780, 1680,
1620, 1530cm ^-1 (5) 7-[2-benzyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1,3,4-thi)
Asiazol-2-yl)thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp130-135℃ (decomposition). IR (Nujiyor): 3360, 1780, 1680, 1625,
1530cm ^-1 (6) 7-[2-(2-phenoxyethoxyimine)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomers), mp163-167°C (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1630, 1600, 1530, 1500cm ^-1 (7) 7-[2-methylthiomethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer),
mp168-170℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1530cm ^-1 (8) 7-[2-(2-methylthioethoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomer), mp125-130℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1625, 1530cm ^-1 (9) 7-[2-phenoxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4-thia
diazol-2-yl)thiomethyl-3-cef
M-4-carboxylic acid (syn isomer), mp145
~150℃ (decomposition). IR (Nujiyor): 3350, 3230, 1780, 1680,
1620, 1590, 1530cm ^-1 (10) 7-[2-cyanomethoxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1,3,4-thi)
Asiazol-2-yl)thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp105-110℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1530cm ^-1 (11) 7-[2-(N,N-diethylcarbamoy
) methoxyimino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp175-180℃ (min
solution). IR (Nujiyor): 3480, 3310, 3200, 1775,
1740, 1680, 1630, 1610, 1515cm ^-1 (12) 7-[2-(1-ethoxycarbonyl-1-
methylethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-(1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp130-135℃
(Disassembly). IR (Nujiyor): 3360, 3240, 1780, 1730,
1690, 1630, 1530cm ^-1 (13) 7-[2-ethoxycarbonylmethoxy
mino-2-(5-amino-1,2,4-thiazi
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomers), mp120-125°C (decomposition). IR (Nujiyor): 3370, 3250, 1780, 1690,
1625, 1530cm ^-1 (14) 7-[2-{2-(2-hexyloxye
Toxy)ethoxyimino}-2-(5-amino
-1,2,4-thiadiazol-3-yl)a
cetamide]-3-(1,3,4,-thiadia
zol-2-yl)thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp100-105
°C (decomposition). IR (Nujiyor): 3340, 3210, 1785, 1685,
1620, 1525cm ^-1 (15) 7-[2-Mesylmethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,
4,-thiadiazol-2-yl)thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp164-167℃ (decomposition). IR (Nujiyor): 3360, 3230, 1780, 1690,
1620, 1530cm ^-1 (16) 7-[2-trityloxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(1-methyl
-1H-tetrazol-5-yl)thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp163-167℃ (decomposition). IR (Nujiyor): 3480, 3350, 3250, 1785,
1690, 1620, 1530cm ^-1 (17) 7-[2-trityloxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,
4,-thiadiazol-2-yl)thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp175-178℃ (decomposition). IR (Nujiyor): 3450, 3350, 3200, 1790,
1690, 1620, 1530cm ^-1 (18) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1methyl-1H
-tetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp154-156℃ (decomposition). IR (Nujiyor): 3380, 3245, 1780, 1680,
1625, 1527cm ^-1 (19) 7-[2-trityloxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,
4,-thiadiazol-2-yl)thiomethyl
-3cefem-4-carboxylic acid (anti-isomer
body), mp165-170℃ (decomposition). IR (Nujiyor): 3350, 3200, 1785, 1690,
1620, 1515cm ^-1 (20) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl) acetamido]-3-(5-aminomethy
(1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp161-164℃ (decomposition). IR (Nujiyor): 3350, 3220, 1770, 1670,
1620, 1525cm ^-1 NMR(d ₆ −DMSO＋D ₂ O, δ): 3.6 (2H,
broad s), 4.35 and 4.58 (2H, ABq, J
= 15Hz), 4.2-4.8 (4H, m), 5.0-5.5 (2H,
m), 5.05 (1H, d, J=5Hz), 5.75 (1H,
d, J = 5Hz), 5.7.6.4 (1H, m) (21) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl) acetamide]-3-[1-{2-(N
-Tertiary butoxycarbonylamino)ethyl}
-1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body) powder. (22) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-[1-(2-amido)
Noethyl)-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp165-169℃ (decomposed). IR (Nujiyor): 3350, 3200, 1768, 1670,
1610, 1522cm ^-1 (23) 7-[2-hydroxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-methyl-1H
-tetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp165-170℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1530cm ^-1 (24) 7-[2-hydroxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4,-ch)
Asiazol-2-yl)thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp170-175℃ (decomposition). IR (Nujiyor): 3480, 3350, 1770, 1690,
1620, 1520cm ^-1 (25) 7-[2-hydroxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4,-ch)
Asiazol-2-yl)thiomethyl-3-ce
fem-4-carboxylic acid (anti-isomer),
mp155-160℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1520cm ^-1 Example 36 The following compounds were prepared according to a method similar to Examples 21-24.
manufactured something. (1) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(5-aminomethyl
-1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomers), mp161-164°C (decomposition). IR (Nujiyor): 3350, 3220, 1770, 1670,
1620, 1520cm ^-1 (2) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-[1-(2-amino
ethyl)-1H-tetrazol-5-yl)
Omethyl-3-cephem-4-carboxylic acid
mp165-167℃ (decomposition). IR (Nujiyor): 3350, 3200, 1768, 1670,
1610, 1255cm ^-1 NMR(d ₆ −DMSO＋D ₂ O, δ): 3.41 (2H,
broad s), 3.60 (2H, broad s), 4.3−5.0
(4H, m), 5.05 (1H, d, J=4.5Hz), 5.73
(1H, d, J=4.5Hz), 4.9−5.6 (2H, m),
5.7-6.4 (1H, m) Example 37 7-[2-trityloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4,-thia
diazol-2-yl)thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer, 0.95g), concentrated
Add a mixture of hydrochloric acid (0.6 ml) and methanol (10 ml) to the room.
Stir at room temperature for 7 hours. methanol from reaction mixture
is distilled off, and the residue contains ethyl acetate and sodium hydrogen carbonate.
The pH was adjusted to 2 by adding an aqueous solution of phlegm. Separated ethyl acetate
Dry the layer with magnesium sulfate and reduce to 10 ml under reduced pressure.
It was concentrated until it became. Collect the precipitate and add it to ethyl acetate.
After washing with diethyl ethyl and drying, 7-
[2-hydroxyimino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetamide
]-3-(1,3,4,-thiadiazole-2
-yl)thiomethyl-3-cephem-4-carbo
acid (syn isomer, 0.3 g), mp170-175°C (min.
solution) was obtained. IR (Nujiyor): 3480, 3350, 1770, 1690,
1620, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 3.61 and 3.73
(2H, ABq, J=18Hz), 4.30 and 4.57
(2H, ABq, J = 13Hz), 5.13 (1H, d, J
= 4Hz), 5.83 (1H, dd, J = 4 and 8
Hz), 8.03 (2H, s), 9.40 (1H, d, J=8
Hz), 9.57 (1H, s), 11.93 (1H, s) Example 38 The following compound was prepared according to the same method as Example 37.
Manufactured. (1) 7-[2-hydroxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-methyl-1H
-tetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp165-170℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 3.70 (2H, broad
s), 3.97 (3H, s), 4.33 (2H, broad s),
5.13 (1H, d, J = 4Hz), 5.83 (1H, dd, J
= 4 and 8Hz), 8.03 (2H, s), 9.43 (1H,
d, J = 8Hz), 11.93 (1H, s) (2) 7-[2-hydroxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4,-ch)
Asiazol-2-yl)thiomethyl-3-ce
fem-4-carboxylic acid (anti-isomer),
mp155-160℃ (decomposition). IR (Nujiyor): 3350, 3250, 1780, 1680,
1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 3.70 (2H, broad
s), 4.35 and 4.53 (2H, ABq, J=13
Hz), 5.13 (1H, d, J = 4Hz), 5.73 (1H,
dd, J=4 and 8Hz), 8.03 (2H, s),
8.92 (1H, d, J = 8Hz), 9.53 (1H, s) Example 39 Phosphorus pentachloride (1.89g) and methylene dichloride (20
ml) mixture for 15 hours at room temperature. 2-
(1-tertiary butoxycarbonylethoxyimino)
-2-(5-amino-1,2,4-thiadiazole
-3-yl)acetic acid (syn isomer) (2.2g) -
Add at 15°C, then stir at -10 to -15°C for 30 min.
After that, 7-amino-3-cephem-4-carvone
Acid (1.4g) and trimethylsilylacetamide
(8.4 g) in methylene chloride (20 ml) at -20
Add at °C. The resulting mixture was heated at -10 to -15℃ for 30 minutes.
for 30 minutes at 0-5°C. reaction solution
The solvent is distilled off. Add ethyl acetate and a small amount to the residue.
After adding a volume of water, the resulting solution was diluted with sodium bicarbonate.
Add to the lium aqueous solution. Separate the aqueous layer and add vinegar to this
After adding ethyl chloride, acidify the mixture with 6N hydrochloric acid.
and then extracted twice with ethyl acetate. extract liquid
After washing with water and drying with magnesium sulfate, the active
Treat with charcoal and then concentrate. Diisopropylene concentrate
Powder it with pill ether and take it, 7
-[2-(1-tertiary butoxycarbonylethoxy)
siimino)-(5-amino-1,2,4-thiazi
Azol-3-yl)acetamide]-3-ceph
Pale yellow color of em-4-carboxylic acid (syn isomer)
A powder (2.5 g) was obtained. Decomposes below 250℃. IR (Nujiyor): 3400, 3250, 3150, 1770,
1720, 1680, 1610, 1520, 1290, 1240,
1150, 980, 740cm ^-1 NMR (DMSO-d ₆ , δ): 1.50 (12H, droad
s), 3.63 (2H, m), 4.73 (1H, q, J=7
Hz), 5.17 (1H, d, J = 5Hz), 5.92 (1H,
dd, J=5 and 8Hz), 6.53 (1H, m),
8.17 (2H, m), 9.4 and 9.6 (1H, d, J=
8Hz) Example 40 Examples 1-3, 5, 7-12, 31-33 and 39
Following a similar method, the following compounds were obtained. (1) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(1-
Allyl-1H-tetrazol-5-yl)thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp120-125℃ (decomposition). IR (Nujiyor): 3290, 3180, 1770, 1680,
1615, 1580, 1520, 1480cm ^-1 NMR (DMSO-d ₆ , δ): 3.73 (2H, broad
s), 4.40 (2H, broad s), 5.17 (1H, d,
J = 5Hz), 4.87-5.20 (2H, m) 5.20-5.60
(2H, m), 5.90 (1H, dd, J=5 and 8
Hz), 5.60-6.30 (1H, m), 7.32 (2H, d,
J=9Hz), 7.48 (2H, d, J=9Hz), 8.32
(2H, broad s), 9.90 (1H, d, J=8Hz) (2) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(1-
Methyl-1H-tetrazol-5-yl)thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp130-135℃ (decomposition). IR (Nujiyor): 3400, 3300, 3280, 1770,
1670, 1615, 1580, 1520, 1480cm ^-1 NMR (DMSO-d ₆ , δ): 3.72 (2H, broad
s), 3.92 (3H, s), 4.32 (2H, broad s),
5.18 (1H, d, J = 5Hz), 5.87 (1H, dd, J
= 5 and 8 Hz), 7.25 (2H, d, J = 9
Hz), 7.42 (2H, d, J = 9Hz), 8.25 (2H,
borad s), 9.85 (1H, d, J = 8Hz) (3) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
[R-3-yl)acetamide] Cephalospo
Lanic acid (syn isomer), mp120-125°C (decomposed). IR (Nujiyor): 3400, 3300, 3190, 1770,
1720, 1650, 1620, 15880, 1520, 1480cm ^-1 NMR (DMSO-d ₆ , δ): 2.02 (3H, s),
3.58 (2H, broad s), 4.75 and 4.98 (2H,
ABq, J = 13Hz), 5.22 (2H, d, J = 5
Hz), 5.87 (1H, dd, J=5 and 8Hz),
7.27 (2H, d, J = 9Hz), 7.42 (2H, d, J
= 9Hz), 8.28 (2H, broad s), 9.85 (1H,
d, J=8Hz) (4) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
(2-carboxyethyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp135-140℃ (min
solution). IR (Nujiyor): 3400, 3270, 3190, 1770,
1680, 1620, 1585, 1520, 1480cm ^-1 NMR (DMSO-d ₆ , δ): 2.70−3.10 (2H,
m), 3.70 (2H, broad s), 4.10−4.60 (4H,
m), 5.20 (1H, d, J=5Hz), 5.87 (1H,
dd, J = 5 and 8 Hz), 7.28 (2H, d, J
= 9Hz), 7.45 (2H, d, J = 9Hz), 8.30
(2H, broad s), 9.85 (1H, d, J=8Hz) (5) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[2-
Carboxymethyl-3-oxy-2,3-dihy
Dro-1,2,4-triazolo [4,3,b]
Pyridazin-6-yl]thiomethyl-3-cef
M-4-carboxylic acid (syn isomer), mp140
~145℃ (decomposition). IR (Nujiyor): 3400, 3300, 3190, 1765,
1700, 1620, 1580, 1540, 1520, 1480cm ^-1 NMR (DMSO-d ₆ , δ): 3.80 (2H, broad
s), 4.28 (2H, broad s), 4.73 (2H, s),
5.27 (1H, d, J = 5Hz), 5.90 (1H, dd, J
= 5 and 8 Hz), 7.12 (1H, d, J = 10
Hz), 7.32 (2H, d, J = 9Hz), 7.47 (2H,
d, J = 9Hz), 7.72 (1H, d, J = 10Hz),
8.30 (2H, broad s), 9.92 (1H, d, J=8
Hz) (6) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(tet)
lazolo[1,5-b]pyridazin-6-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp140-145℃ (decomposed). IR (Nujiyor): 3350, 3240, 1780, 1685,
1625, 1530, 1490cm ^-1 NMR (DMSO-d ₆ , δ): 3.70 (2H, broad
s), 4.22 and 4.62 (2H, ABq, J=13
Hz), 5.22 (1H, d, J = 5Hz), 5.93 (1H,
dd, J = 5 and 8 Hz), 7.27 (2H, d, J
= 9Hz), 7.42 (2H, d, J = 9Hz), 7.73
(1H, d, J = 9Hz), 8.28 (2H, broad
s), 8.59 (1H, d, J=9Hz), 9.87 (1H,
d, J=8Hz) (7) 7-[2-(α-tertiary butoxycarbonyl
benzyloxyimino)-2-(5-amino
-1,2,4-thiadiazol-3-yl)a
cetamide]-3-(1,3,4,-thiadia
zol-2-yl)thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp105-110
°C (decomposition). IR (Nujiyor): 3400, 3300, 3180, 1780,
1720, 1680, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.40 (9H, s),
3.50−3.83 (2H, m), 4, 37 and 4.60
(2H, ABq, J=13Hz), 5.10 and 5.18
(1H, d, J=5Hz), 5.63 (1H, s), 5.67
-6.0 (1H, m), 7.47 (5H, s), 8.20 (2H,
broad s), 9.62 (1/2H, s), 9.64 (1/2H,
s), 9.47−9.77 (1H, m) (8) 7-[2-(α-tertiary butoxycarbonyl
benzyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-cephem-4-carboxylic acid
(syn isomer), mp90-95℃ (decomposition). IR (Nujiyor): 3400, 3380, 3230, 1780,
1730, 1685, 1635, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.38 (8H, s),
3.60 (2H, broad s), 5.0−5.20 (1H, m),
5.63 (1H, s), 5.72−6.03 (1H, m), 6.37−
6.67 (1H, m), 7.47 (5H, s), 8.18 (2H,
broad s), 9.43−9.70 (1H, m) (9) 7-[2-(α-tertiary butoxycarbonyl
benzyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-[1-{2-(N-tertiary block)
Toxycarbonylamino)ethyl}-1H-te
Torazol-5-yl]thiomethyl-3-cef
M-4-carboxylic acid (syn isomer), mp105
~110℃ (decomposition). IR (Nujiyor): 3360, 3220, 1785, 1690,
1625, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 1.38 (18H, s),
3.1−3.87 (4H, m), 4.17−4.65 (4H, m),
5.0−5.28 (1H, m), 5.12 (1H, s), 5.58−
6.0 (1H, m), 7.47 (5H, s), 8.17 (2H,
broad s), 9.45-9.75 (1H, m) (10) 7-[2-(2-propynyloxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
(2-carboxyethyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp125-130℃ (min
solution). IR (Nujiyor): 3400, 3260, 3190, 2580,
1765, 1710, 1670, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 2.92 (2H, t, J
= 6Hz), 3.47 (1H, t, J = 2Hz), 3.67
(2H, broad s), 4.17−4.60 (4H, m),
4.77 (2H, d, J = 2Hz), 5.08 (1H, d, J
= 5Hz), 5.77 (1H, dd, J = 5 and 8
Hz), 8.08 (2H, broad s), 9.57 (1H, d,
J=8Hz) (11) 7-[2-(2-propynyloxyimino)
-2-(5-amino-1,2,4-thiadiazo
[R-3-yl)acetamide] Cephalospo
Ranic acid (syn isomer). IR (Nujiyor): 3400, 3270, 3180, 1770,
1720, 1655, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.98 (3H, s),
2.45 (1H, t, J = 2Hz), 3.48 (2H, broad
s), 4.72 (2H, d, J=2Hz), 4.67 and
4.92 (2H, ABq, J=13Hz), 5.08 (1H, d,
J=5Hz), 5.77(1H, dd, J=5 and 8
Hz), 8.07 (2H, broad s), 9.55 (1H, d,
J=8Hz) (12) 7-[2-tertiary butoxycarbonyl methoxy
Shiimino-2-(5-amino-1,2,4-thi)
Asiazol-3-yl)acetamide]-3
-Cefem-4-carboxylic acid (syn isomer),
mp165-170℃ (decomposition). IR (Nujiyor): 3350, 3250, 3180, 1790,
1720, 1660, 1630, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.40 (9H, s),
3.57 (2H, broad s), 4.60 (2H, s) 5.07
(1H, d, J = 4Hz), 5.83 (1H, dd, J =
4 and 8Hz), 6.47 (1H, broad s), 8.13
(2H, s), 9.50 (1H, d, J=8Hz) (13) 7-[2-(thiolane-1,1-dioxa
ido-3-yl)oxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4,-ch)
Asiazol-2-yl)thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp170-175℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 2.30−2.50 (2H,
m) 3.0−3.57 (4H, m), 3.70 (2H, broad
s), 4.33 and 4.57 (2H, ABq, J=13
Hz), 5.0-5.15 (1H, m), 5.17 (1H, d, J
= 4Hz), 5.83 (1H, dd, J = 4 and 8
Hz), 8.23 (2H, s), 9.60 (1H, s), 9.67
(1H, d, J=8Hz) (14) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1-carboxy
Methyl-1H-tetrazol-5-yl)thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp140-145℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 3.63 (2H, broad
s), 4.23 and 4.43 (2H, ABq, J=14
Hz), 4.60−1.73 (2H, m), 5.10 (1H, d,
J=4Hz), 5.30 (2H, s), 5.07−5.50 (2H,
m), 5.67-6.20 (2H, m), 8.15 (2H, s),
9.63 (1H, d, J = 8Hz) (15) 7-[2-(2-propynyloxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-carboxymethyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp135-140℃ (min
solution). IR (Nujiyor): 3250, 3150, 1770, 1720,
1670, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 3.47 (1H, t, J
= 2Hz), 3.63 (2H, broad s), 4.22 and
4.43 (2H, ABq, J=14Hz), 5.07 (1H, d,
J=4Hz), 5.28 (2H, s), 5.80 (1H, dd,
J=4 and 8Hz), 8.15 (2H, s), 9.63
(1H, d, J=8Hz) (16) 7-[2-allyloxyimino-2-(5
-amino-1,2,4-thiazizole-3-i
)acetamide]-3-[1-(2-carbo
xyethyl)-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp140-145℃ (decomposed). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 2.87 (2H, t, J
= 6 Hz), 3.63 (2H, broad s), 4, 37
(2H, t, J=6Hz), 4.20 and 4.47 (2H,
ABq, J=14Hz), 4.57-4.67 (2H, m),
5.07 (1H, d, J = 4Hz), 5.10-5.43 (2H,
m), 5.67-6.13 (2H, m), 8.10 (2H, s),
9.58 (1H, d, J = 8Hz) (17) 7-[2-[tertiary butoxycarbonyl
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-[1-(2-carboxyethyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp150~155℃ (decomposition) IR (nujiol): 3300, 3200, 1770, 1720,
1700, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.50 (9H, s),
3.00 (2H, t, J=6Hz), 3.73 (2H, broad
s), 4.43 (2H, broad s), 4.50 (2H, t,
J = 6Hz), 4.67 (2H, s), 5.17 (1H, d,
J=4Hz), 5.87(1H, dd, J=4 and 8
Hz), 8, 18 (2H, s), 9.53 (1H, d, J=
8Hz) (18) 7-[2-(tertiary butoxycarbonyl)
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-[1-{3-(4-methyl-1-p
perazinyl)propyl}-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp220-225℃ (min
solution). IR (Nujiyor): 3300, 1700, 1680, 1605,
1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.40 (9H, s),
1.96-2.10 (2H, m), 2.38-2.50 (4H, m),
2.60 (3H, s), 2.95-3.10 (6H.m), 3.52 and
and 3.65 (2H, ABq, J=16Hz), 4.20–4.40
(4H, m), 4.60 (2H, s), 5.06 (1H, d,
J=4Hz), 5.70(1H, dd, J=4 and 8
Hz), 8.12 (2H, s), 9.44 (1H, d, J=8
Hz) (19) 7-[2-(1-tertiary butoxycarbonyl
-2-methylpropoxyimino)-2-(5
-Amino-1,2,4-thiadiazole-3-
yl) acetamide] cephalosporanic acid (cephalosporanic acid)
isomer), mp130-140℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1780,
1720―1680, 1620, 1520, 1460, 1370,
1230, 1150, 1030, 730cm ^-1 NMR (DMSO-d ₆ , δ): 1.03 (6H, d, J
=7Hz), 1.43 (9H, s), 2.03 (3H, s),
1.9-2.2 (1H, m), 3.6 (2H, m), 4.26 and
and 4.34 (1H, d, J = 6Hz), 4.68 and 5.05
(2H, ABq, J = 13Hz), 5.19 (1H, d, J
= 5Hz), 5.87 (1H, dd, J = 5 and 8
Hz), 8.10 (2H, broad s), 9.48 (1H, d,
J=8Hz) (20) 7-[2-(1-tertiary butoxycarbonyl
lupropoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-(1,3,4-thiazizole
-2-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp101-105℃ (min
solution). IR (Nujiyor): 3300, 3150, 1770, 1720,
1620, 1520, 1450, 1370, 1250, 1150,
1010, 900, 840, 720cm ^-1 NMR (DMSO-d ₆ , δ): 0.93 (3H, t, J
=7Hz), 1.42 (9H, s), 1.8 (2H, m), 3.7
(2H, m), 4.6 (3H, m), 5.18 (1H, d, J
= 5Hz), 5.87 (1H, dd, J = 5 and 8
Hz), 8.20 (2H, broad s), 9.5 (1H, m),
9.58 (1H, s) (21) 7-[2-(1-tertiary butoxycarbonyl
lupropoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide] cephalosporanic acid (syn isomer),
mp95-105℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1780,
1720, 1620, 1530, 1230, 1150, 1010, 890,
840, 740cm ^-1 NMR (DMSO-d ₆ , δ): 0.95 (3H, t, J
=7Hz), 1.39 (9H, s), 1.8 (2H, m),
2.02 (3H, s) 3.5 (2H, m), 4.47 (1H, m),
4.67 and 5.03 (2H, ABq, J=13Hz), 5.14
(1H, d, J=5Hz), 5.83 (1H, dd, J=
5 and 8Hz), 8.07 (2H, broad s), 9.37
and 9.43 (1H, d, J = 8Hz) (22) 7-[2-(1-tertiary butoxycarbonyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-(1,3,4-thiazizole-2
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp120-128°C (decomposed). IR (Nujiyor): 3280, 3180, 1770, 1720,
1680, 1620, 1520, 1240, 1150, 1000, 740,
720cm ^-1 NMR (DMSO-d ₆ , δ): 1.4 (12H, m),
3.76 (2H, m), 4.30 and 4.67 (2H, ABq,
J=13Hz), 4.70 (1H, q, J=7Hz), 5.22
(1H, d, J=5Hz), 5.88 (1H, dd, J=
5 and 8Hz), 8.20 (2H, broad s), 9.74
(1H, m), 9.60 (1H, s) (23) 7-[2-(1-tertiary butoxycarbonyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]cephalosporanic acid (syn isomer),
mp138-145℃ (decomposition). IR (Nujiyor): 3280, 3180, 1780, 1720,
1680, 1620, 1520, 1230, 1150, 840cm ^-1 NMR (DMSO-d ₆ , δ): 1.47 (12H, m),
2.07 (3H, s), 3.58 (2H, m), 4.5-5.1
(3H, m), 5.19 (1H, d, J=5Hz), 5.87
(1H, dd, J=5 and 8Hz), 8.10 (2H,
broad s), 9.40 and 9.50 (1H, d, J=
8Hz) (24) 7-[2-(1-methyl-1-tertiary buto
oxycarbonylethoxyimino)-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4-thia
disol-2-yl)thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp115~
120℃ (decomposition). IR (Nujiyor): 3280, 3170, 1780, 1720,
1680, 1520, 1140, 990, 750cm ^-1 NMR (DMSO-d ₆ , δ): 1.40 (9H, s),
1.46 (6H, s), 3.7 (2H, m), 4.26 and
4.63 (2H, ABq, J=13Hz), 5.18 (1H, d,
J=5Hz) 5.83 (1H, dd, J=5 and 8
Hz), 8.13 (2H, broad s), 9.40 (1H, d,
J = 8Hz), 9.53 (1H, s) (25) 7-[2-(1-tertiary butoxycarbonyl
Ru-1-cyclopentyloxyimino)-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer),
mp140-143℃ (decomposition). IR (Nujiyor): 3300, 3180, 1770, 1720―
1670, 1620, 1520, 1245, 1150, 1060, 995,
840cm ^-1 NMR (DMSO-d ₆ , δ): 1.40 (9H, s), 1.8
(4H, m), 2.1 (4H, m), 3.7 (2H, m),
4.27 and 4.68 (2H, ABq, J=13Hz), 5.18
(1H, d, J=5Hz), 5.85 (1H, dd, J=
5 and 8Hz), 8.1 (2H, broad s), 9.39
(1H, d, J = 8Hz), 9.53 (1H, s) (26) 7-[2-(1-methyl-1-tertiary but
oxycarbonylethoxyimino)-2-(5-
Amino-1,2,4-thiadiazole-3-i
) acetamide] cephalosporanic acid (sin)
isomers), mp135-140℃ (decomposition). IR (Nujiyor): 3400, 3300, 3180, 1780,
1720, 1690, 1620, 1540, 1300, 1220,
1140, 1030, 990, 840, 740cm ^-1 NMR (DMSO-d ₆ , δ): 1.57 (9H, s),
1.62 (6H, s), 2.03 (3H, s), 3.57 (2H,
m), 4.69 and 5.06 (2H, ABq, J=13Hz)
5.19 (1H, d, J = 5Hz) 5.89 (1H, dd, J
= 5 and 8 Hz), 8.21 (2H, broad s),
9.32 (1H, d, J = 8Hz) (27) 7-[2-(1-tertiary butoxycarbonyl
Ru-1-cyclopentyloxyimino)-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]cephalosporanic acid
(syn isomer), mp98-102℃ (decomposed). IR (Nujiyor): 3350, 3230, 1790, 1730,
1630, 1530, 1340, 1160, 1070, 1040, 1000
cm ^-1 NMR (DMSO-d ₆ , δ): 1.47 (9H, s),
1.80 (4H, m), 2.10 (4H, m), 2.13 (3H,
s), 3,60 (2H, m), 4.73 and 5.1 (2H,
ABq, J = 14Hz), 5.22 (1H, d, J = 5
Hz), 5.88 (1H, dd, J=5 and 8Hz),
8.15 (2H, m), 9.43 (1H, d, J = 8Hz) (28) 7-[2-(1-methyl-1-tertiary but
oxycarbonylethoxyimino)-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-[1-{2-(N-
tertiary-butoxycarbonylamino)ethyl}-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp96~100℃ (decomposition). IR (Nujiyor): 3300, 3150, 1780, 1680,
1570, 1240, 1160, 990cm ^-1 NMR (DMSO-d ₆ , δ): 1.45 (18H, s),
1.52 (6H, s), 3.33 (2H, m), 3.67 (2H,
m), 4.30 (4H, m), 5.10 (1H, d, J=5
Hz), 5.85 (1H, dd, J=5 and 8Hz),
6.92 (1H, m), 8.13 (2H, m), 9.40 (1H,
d, J=8Hz) (29) 7-[2-(1-methyl-1-tertiary but
oxycarbonylethoxyimino)-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-cephem-4-cal
Bonic acid (syn isomer), decomposes below 215℃. IR (Nujiyor): 3400, 3300, 3150, 1780,
1710, 1690, 1620, 1520, 1240, 1140, 980
cm ^-1 NMR (DMSO-d ₆ , δ): 1.40 (9H, s),
1.47 (6H, s), 3.60 (2H, m), 5.17 (1H,
d, J=5Hz), 5.92(1H, dd, J=5 and
and 8Hz), 6.50 (1H, m), 8.22 (2H, m),
9.50 ((1H, d, J=8Hz) (30) 7-[2-(1-tertiary butoxycarbonyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(1-allyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp96-100℃
(Disassembly). IR (Nujiyor): 3300, 3150, 1780, 1720,
1680, 1620, 1520, 1240, 1150, 1090, 1000
cm ^-1 NMR (DMSO-d ₆ , δ): 1.40 (2H, broad
s), 3.67 (2H, m), 4.2 and 4.50 (2H,
ABq, J = 13Hz), 4.67 (1H, q, J = 6
Hz), 4.93 (2H, m), 5.07 (1H, q, J=5
Hz), 5.13-5.37 (2H, m), 5.83 (1H, dd,
J=5 and 8Hz), 5.83−6.22 (1H, m),
8.10 (2H, broad s), 9.40 and 9.52 (1H,
d, J=8Hz) (31) 7-[2-(1-phenylethoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadizol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid
isomers), separated below 175℃. IR (Nujiyor): 3400, 3250, 3150, 1750,
1650, 1610, 1520, 1400, 1240, 1160,
1060, 1000, 700cm ^-1 NMR (DMSO-d ₆ , δ): 1.57 (3H, d, J
=8Hz), 3.73 (2H, m), 4.32 and 4.72
(2H, ABq, J = 13Hz), 5.22 (1H, d, J
=5Hz), 5.3-5.5 (1H, m), 5.93 (2H, dd,
J=5 and 8Hz), 7.36 (5H, m), 8.13
(2H, m), 9.57 (1H, s), 9.72 (1H, d,
J=8Hz) (32) 7-[2-(3,4-dichlorophenoxy
imino)-2-(5-amino-1,2,4-thi
Asiazol-3-yl)acetamide]-3
-Cefem-4-carboxylic acid (syn isomer),
Decomposes below 210℃. IR (Nujiyor): 3450, 3300, 3200, 1760,
1660, 1560, 1290, 1210, 1000, 970, 940,
730cm ^-1 NMR (DMSO-d ₆ , δ): 3.63 (2H, m),
5.17 (1H, d, J = 5Hz), 5.91 (1H, dd, J
=5 and 8Hz), 6.41 (1H, m), 7.13−
7.73 (3H, m), 8.28 (2H, broad s), 9.87
(1H, d, J=8Hz) (33) 7-[2-(p-tolyloxyimino)-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
3,4-thiadizol-2-yl)thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), decomposes below 150℃. This one is O-tril
It is a mixture of isomers. IR (Nujiyor): 3350, 3250, 1780, 1680,
1630, 1530, 1510, 1230, 1050, 910, 820cm
^-1 NMR (DMSO-d ₆ , δ): 2.23 (1/5H, s),
2.27 (9/5H, s), 3.71 (2H, m), 4.21 and
and 4.61 (2H, ABq, J=13Hz), 5.23 (1H,
d, J=5Hz), 5.90 (1H, m), 7.16 (4H,
m), 8.23 (2H, m), 9.56 (1H, s), 9.86
(1H, d, J=8Hz) (34) 7-[2-(3-trifluoromethylphene
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-(1-allyl-1H-tetrazole
-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), decomposes below 155°C. IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1320, 1160, 1120, 1060, 980,
930,700cm ^-1 NMR (DMSO-d ₆ , δ): 3.56 and 3.82
(2H, ABq, J=18Hz), 4.20 and 4.60
(2H, ABq, J=14Hz), 4.95 (2H, m),
5.18 (1H, d, J = 5Hz), 5.12-5.24 (2H,
m), 5.92 (1H, dd, J=5 and 8Hz),
5.72−6.12 (1H, m), 7.50 (4H, m), 8.26
(2H, m), 9.84 (1H, d, J = 8Hz) (35) 7-[2-(3-trifluoromethylphenylene)
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
[do]-3-(1-methyl-1H-tetrazole
-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), decomposes below 170℃. IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1320, 1160, 1120, 1060, 930,
790,700cm ^-1 NMR (DMSO-d ₆ , δ): 3.77 (2H, m),
3.97 (3H, s), 4.37 (2H, m), 5.27 (1H,
d, J=5Hz), 5.95(1H, dd, J=5 and
and 8Hz), 7.60 (4H, m), 8.33 (2H, m),
9.97 (1H, d, J = 8Hz) (36) 7-[2-(4-Fluorophenoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), decomposes below 170℃. IR (Nujiyor): 3450, 3350, 3200, 1780,
1710, 1680, 1610, 1510, 1590, 1240,
1200, 1170, 1090, 990, 910, 840cm ^-1 NMR (DMSO-d ₆ , δ): 3.73 (2H, m),
3.93 (3H, s), 4.33 (2H, m), 5.23 (1H,
d, J=5Hz), 5.90(1H, dd, J=5 and
and 8Hz), 7.17-7.28 (4H, m), 8.37 (2H,
m), 9.87 (1H, d, J = 8Hz) (37) 7-[2-(2,4-dichlorophenoxy
imino)-2-(5-amino-1,2,4-thi
Asiazol-3-yl)acetamide]-3
-Cefem-4-carboxylic acid (syn isomer),
Decomposes below 240℃. IR (Nujiyor): 3250, 1770, 1660, 1620,
1540, 1520, 1280, 1230, 1100, 1050, 970,
920, 810, 750cm ^-1 NMR (DMSO-d ₆ , δ): 3.56 (2H, m),
5.11 (1H, d, J = 5Hz), 5.91 (1H, dd, J
=5 and 8Hz), 6.47 (1H, m), 7.47−
7.63 (3H, m), 8.21 (2H, m), 9.81 (1H,
d, J=8Hz) (38) 7-[2-(2,4-dichlorophenoxy
imino)-2-(5-amino-1,2,4-thi
Asiazol-3-yl)acetamide]-3
-(1,3,4-thiazizol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
decomposes below 165°C. IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1250, 1230, 1100, 1060, 960,
910, 810cm ^-1 NMR (DMSO-d ₆ , δ): 3.71 (2H, m),
4.23 and 4.67 (2H, ABq, J=14Hz), 5.25
(1H, d, J = 5Hz), 5.93 (1H, dd, J =
5 and 8Hz), 7.50-7.67 (3H, m), 8.25
(2H, m), 9.57 (1H, s), 9.88 (1H, d,
J=8Hz) (39) 7-[2-(2-cyclopentene-1-i
ruoxiimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-methyl-3-cephem-4-cal
Bonic acid (syn isomer), mp165-218°C (decomposed). IR (Nujiyor): 3350, 3250, 3140, 3050,
1750, 1705, 1665, 1625, 1550, 1535cm ^-1 NMR (DMSO-d ₆ +D ₂ Oδ): 1.6−2.6 (4H,
m), 2.00 (3H, s), 3.0−3.9 (2H, m),
5.05 (1H, d, J = 4.5Hz), 5.2-5.5 (1H,
m), 5.70 (1H, d, J = 4.5Hz), 5.7−6.3
(2H, m) (40) 7-[2-cyclopentyloxyimino]
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamido]-3-methyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp170-21℃ (decomposition). IR (Nujiyor): 3350, 3120, 3050, 1750,
1705, 1668, 1625, 1556, 1534cm ^-1 NMR (DMSO-d ₆ +D ₂ Oδ): 1.3−2.2 (8H,
m), 2.03 (3H, s), 3.0-3.9 (2H, m),
4.77 (1H, broad s), 5.10 (1H, d, J=
4.5Hz), 5.73 (1H, d, J = 4.5Hz) (41) 7-[2-(2-cyclohexene-1-i
ruoxiimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-methyl-3-cephem-4-cal
Bonic acid (syn isomer), mp180-205°C (decomposition). IR (Nujiyor): 3340, 3250, 3210, 3050,
1750, 1705, 1665, 1625, 1535cm ^-1 NMR (DMSO-d ₆ +D ₂ Oδ): 1.3−2.4 (6H,
m), 2.03 (3H, s), 3.1-3.7 (2H, m),
4.70 (1H, broad s), 5.10 (1H, d, J=
4.5Hz), 5.73 (1H, d, J = 4.5Hz), 5.7−6.0
(2H, m) (42) 7-[2-(2-cyclopentene-1-i
ruoxiimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
Bonic acid (syn isomer), mp142-148°C (decomposed). IR (Nujiyor): 3300, 3200, 1775, 1650,
1630, 1520cm ^-1 NMR (DMSO-d ₆ +D ₂ Oδ): 1.41 (3H, d,
J=7.5Hz), 1.9-2.6 (4H, m), 3.5-4.1
(1H, m), 5.16 (1H, d, J=4.5Hz), 5.2
-5.5 (1H, m), 5.6-6.4 (3H, m), 6.62
(1H, d, J=6Hz) (43) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3200, 3160, 1773, 1685,
1620cm ^-1 NMR (DMSO-d ₆ +D ₂ Oδ): 1.41 (9H, s),
1.6-2.1 (2H, m), 2.8-3.3 (2H, m), 3.75
(2H, broad s), 4.0−4.5 (2H, m), 4.35
and 4.65 (2H, ABq, J=14Hz), 5.20
(1H, d, J = 5Hz), 5.83 (1H, d, J =
5Hz), 9.58 (1H, s) (44) 7-[2-{3-N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-[1-(2-hydro)
(loxyethyl)-1H-tetrazole-5-i
]Thiomethyl-3-cephem-4-carvone
acid (syn isomer). IR (Nujiyor): 3200, 3160, 1775, 1720,
1700, 1675, 1675, 1620cm ^-1 NMR (DMSO-d ₆ +D ₂ Oδ): 1.37 (9H, s),
1.5-1.9 (2H, m), 2.6-3.2 (2H, m), 3.4
-3.9 (4H, m), 3.9-4.4 (6H, m), 5.10
(1H, d, J=5Hz), 5.80 (1H, d, J=
5Hz) (45) 7-[2-{3-(N-Tertiary Butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(5-methyl
-1,3,4-thiadizol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid,
isomers). IR (Nujiyor): 3300, 3150, 1775, 1710,
1700, 1670, 1650, 1620cm ^-1 NMR (DMSO-d ₆ +D ₂ Oδ): 1.40 (9H, s),
1.6-2.1 (2H, m), 2.71 (3H, s), 2.9-3.3
(2H, m), 3.71 (2H, broad s), 4.0−4.8
(4H, m), 5.18 (1H, d, J=4.5Hz), 5.88
(1H, d, J=4.5Hz) (46) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(1-methyl
-1H-tetrazol-5-yl)thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp81-119℃ (decomposition). IR (Nujiyor): 3300, 3180, 1770, 1715,
1700, 1670, 1620cm ^-1 NMR (DMSO-d ₆ +D ₂ Oδ): 1.35 (9H, s),
1.5-2.0 (2H, m), 2.7-3.2 (2H, m), 3.68
(2H, broad s), 3.9−4.5 (4H, m), 3.92
(3H, s), 5.12 (1H, d, J=4.5Hz), 5.83
(1H, d, J=4.5Hz) (47) 7-[2-{4-(N-tertiary butoxyca
(rubonylaminomethyl)benzyloxyimide
No}-2-(5-amino-1,2,4-thiazi
Azol-3-yl)acetamide]-3-meth
Chill-3-cefem-4-carboxylic acid
gender body). IR (nujiyor): 3300, 3170, 1760, 1680cm
^-1 NMR (DMSO-d ₆ , δ): 1.65 (9H, s), 2.0
(3H, s), 3.4 (2H, m), 4.14 (2H, d, J
= 6Hz), 5.1 (1H, d, J = 4.5Hz, 5.2 (2H,
s), 5.75 (1H, dd, J = 4.5 and 8Hz) (48) 7-[2-{1-(cyclohexoxyoxycarbon
(rubonyl)ethoxyimino}-2-(5-amino)
(n-1,2,4-thiadiazol-3-yl)
Acetamide]-3-cephem-4-carvone
Acid (syn isomer), mp160-163°C (decomposition). IR (Nujiyor): 3420, 3300, 3180, 1775,
1720, 1685, 1610, 1520, 1290, 1230,
1040, 980, 740cm ^-1 NMR (DMSO-d ₆ , δ): 1.50 (3H, d, J
= 6Hz), 1.0-2.1 (10H, m), 3.62 (2H,
m), 4.80 (1H, q, J = 6Hz) 4.6-5.0
(1H, m), 5.15 (1H, d, J=5Hz), 5.90
(1H, dd, J=5 and 8Hz), 6.50 (1H,
m), 8.13 (2H, broad s), 9.39 (1/2H,
d, J = 8Hz), 9.53 (1/2H, d, J = 8Hz) (49) 7-[2-(1-tertiary butoxycarbonyl
Ru-1-cyclopentyloxyimino)-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-cephem-4
-Carboxylic acid (syn isomer), mp165-169℃
(Disassembly). IR (Nujiyor): 3400, 3300, 3200, 1770,
1710, 1680, 1610, 1520, 1290, 1240,
1150, 1000, 970, 740cm ^-1 NMR (DMSO-d ₆ , δ): 1.42 (9H, s),
1.77 (4H, m), 2.05 (4H, m), 3.60 (2H,
m), 5.13 (1H, d, J=5Hz), 5.87 (1H,
dd, J=5 and 8Hz), 6.47 (1H, m),
8.13 (2H, m), 9.33 (1H, d, J = 8Hz) (50) 7-[2-galboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{2
-N,N-dimethylamino)ethyl}-1H-
Tetrazol-5-yl]thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp170-173℃ (decomposition). IR (Nujiyor): 3400, 3280, 3150, 1760,
1665, 1610, 1520cm ^-1 (51) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{3
-(N,N-dimethylamino)propyl}-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp170-175℃ (decomposition). IR (Nujiyor): 3400, 3280, 3160, 1760,
1665, 1610, 1520cm ^-1 (52) 7-[2-(2-propyloxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
{3-(N-tertiary butoxycarbonylamino)
propyl}-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp85-90℃ (decomposed). IR (Nujiyor): 3400, 3290, 3200, 1770,
1680, 1620, 1520cm ^-1 (53) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{3
-N-tertiary butoxycarbonylamino)pro
pill}-1H-tetrazol-5-yl]thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp185-190℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520cm ^-1 (54) 7-[2-(2,2,2-trifluoroe
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
[do]-3-(1-carboxymethyl-1H-te)
Torazol-5-yl)thiomethyl-3-ceph
M-4-carboxylic acid (syn isomer), mp130
~132℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 (55) 7-[2-(1-carboxy-2-methyl
propoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{3-(N-Third Class Butoki
cyclocarbonylamino)propyl}-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp192~
195℃ (decomposition). IR (Nujiyor): 3400-3200, 1780, 1680,
1520, 1450, 1360, 1240, 1160, 1620,
1020,730cm ^-1 (56) 7-[2-(1-carboxypropoxy)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
[1-{3-(N-tertiary butoxycarbonyl
Amino)propyl}-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp185-192°C (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1450, 1360, 1250, 1160,
1000, 730−710cm ^-1 (57) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-{3-
(N-tertiary butoxycarbonylamino)pro
pill}-1H-tetrazol-5-yl]thio
Methyl-3-cephem-4-carboxylic acid
isomers). IR (Nujiyor): 3300, 3150, 1770, 1715,
1675, 1650, 1615cm ^-1 (58) 7-[2-(1-carboxyethoxyimi
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-{3-(N-tertiary butoxycarbonyl
Amino)propyl}-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp110-115°C (separated). IR (Nujiyor): 3300, 3200, 1770, 1680,
1600, 1520, 1250, 1000, 720cm ^-1 (59) 7-[2-(1-carboxy-1-cyclo
pentyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-[1-{3-(N-tertiary block)
Toxycarbonylamino)propyl}-1H-
Tetrazol-5-yl]thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp200-205℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1680,
1520, 1250, 1160, 1000cm ^-1 (60) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(3
-morpholinopropyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp190-194℃ (min
solution). IR (Nujiyor): 3300, 3200, 1770, 1680,
1610, 1530, 1240, 1180, 1090, 1060, 880,
760cm ^-1 (61) 7-[2-(1-carboxy-1-methyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{3-(N-Third Class Butoki
cyclocarbonylamino)propyl}-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer). IR (Nujiyor): 3300, 3150, 1770, 1680,
1520, 1240, 1160, 990cm ^-1 (62) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(4-methy
Ru-5-oxo-6-hydroxy-4,5-di
hydro-1,2,4-triazin-3-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp210-214℃ (decomposed). IR (Nujiyor): 3250, 3180, 1760, 1720―
1660, 1590, 1520, 1240, 1090, 1050, 720
cm ^-1 (63) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{4
-(N-tertiary butoxycarbonylamino)butylene
Thiol}-1H-tetrazol-5-yl]thio
Methyl-3-cephem-4-carboxylic acid
isomers). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1240, 1160, 1090, 1060, 890
cm ^-1 (64) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(3
-piperidinopropyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp223-228℃ (min
solution). IR (Nujiyor): 3300, 3200, 1770, 1670,
1610, 1520cm ^-1 (65) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-cal)
boxymethyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp170-175℃ (decomposed). IR (Nujiyor): 3300, 3200, 1765, 1720,
1660, 1620, 1520cm ^-1 (66) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{6
-(N-tertiary butoxycarbonylamino)he
xyl}-1H-tetrazol-5-yl]
Omethyl-3-cephem-4-carboxylic acid
isomer), pale yellow powder. (67) 7-[2-(1-carboxyethoxyimi
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[5-(N-tertiary butoxycarbonylamino)
Methyl-1,3,4-thiazizole-2-y
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp210-215°C (decomposed). IR (Nujiyor): 3300, 1770, 1680, 1620,
1520, 1240, 1140cm ^-1 (68) 7-[2-(2-propyloxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
(3-aminopropyl)-1H-tetrazole-
5-yl]thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp165-170℃ (min
solution). IR (Nujiyor): 3450, 3300, 3210, 1700,
1670, 1620, 1525cm ^-1 (69) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(3
-aminopropyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp195-200℃ (decomposition). IR (Nujiyor): 3150, 1760, 1660, 1640,
1520cm ^-1 (70) 7-[2-(1-carboxy-2-methyl
propylpoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-[1-(3-aminopropylene)
)-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
sex body), mp183-189℃ (decomposition). IR (Nujiyor): 3400-3100, 3150, 1770,
1670, 1620, 1520, 1380, 1280, 1230,
1180, 1100, 1020, 900, 730cm ^-1 (71) 7-[2-(1-carboxypropoxy)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
[1-(aminopropyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp183-188℃ (min
solution). IR (Nujiyor): 3400, 3150, 1770, 1670,
1620, 1530, 1380, 1280, 1230, 1180,
1100, 1050, 1010, 730cm ^-1 (72) 7-[2-(1-carboxyethoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(3-aminopropyl)-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp185-188℃
(Disassembly). IR (Nujiyor): 3300, 3150, 1760, 1660,
1620, 1520, 1230, 1000, 720cm ^-1 (73) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(4
-aminobutyl)-1H-tetrazole-5-
yl]thiomethyl-3-cephem-4-carbo
acid (syn isomer), mp191-194°C (decomposed). IR (Nujiyor): 3300, 3150, 1760, 1670,
1620, 1520, 1230, 1170, 1050, 890, 740,
720cm ^-1 (74) 7-[2-(1-carboxy-1-methyl
Ethoxyimino-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-[1-(3-aminopropyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp200-203℃ (decomposition). IR (Nujiyor): 3300, 3150, 1760, 1660,
1620, 1520, 1160, 990cm ^-1 (76) 7-[2-(1-carboxy-1-cyclo
pentyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-[1-(3-aminopropylene)
)-1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp202-205℃ (decomposition). IR (Nujiyor): 3300, 3200, 1760, 1660,
1620, 1520, 1180, 1060, 1000, 730cm ^-1 (76) 7-[2-(1-carboxyethoxyimine)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(5-aminomethyl-1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp207-210℃
(Disassembly). IR (Nujiyor): 3300, 3150, 1760, 1660,
1620, 1520, 1230, 1170, 1090, 1060,
1040,990cm ^-1 (77) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(6
-aminohexyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp185-188℃. (Decomposition) IR (nujiol): 3300, 3200, 1760, 1670,
1620, 1520, 1240, 1180, 1060cm ^-1 (78) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2yl)thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp165-183℃ (decomposition). IR (Nujiyor): 3150, 1765, 1660, 1630,
1570, 1520cm ^-1 (79) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(2-hydroxyethyl)-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp170-185
°C (decomposition). IR (Nujiyor): 3140, 1760, 1660, 1610,
1580, 1520cm ^-1 (80) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(5-methyl-1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp192-195°C (min
solution). IR (Nujiyor): 3250, 3140, 1760, 1640,
1620, 1585, 1525cm ^-1 (81) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp180-184℃ (decomposed). IR (nujiyor): 3160, 1760, 1660, 1590cm
^-1 (82) 7-[2-(4-aminomethylbenzyl)
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-methyl-3-cephem-4-carboxylic acid
sine salt (syn isomer), mp230-240℃ (min.
solution). IR (nujiyor): 1750cm ^-1 (83) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(aminopropyl)-1H-tetrazole
-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer). IR (Nujiyor): 3300, 3150, 1760, 1660,
1607, 1595, 1520cm ^-1 (84) 7-[2-(α-carboxybenzyloxy)
(shiimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-(1,3,4-thiadiazole-2-i)
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp150-155℃ (decomposition). IR (Nujiyor): 3400, 3290, 3160, 2500,
1770, 1720, 1615, 1520cm ^-1 (85) 7-[2-(α-carboxybenzyloxy)
(shiimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-cefem-4-carboxylic acid (syn isomer),
mp170-175℃ (decomposition). IR (Nujiyor): 3400, 3280, 3160, 2600,
1770, 1720, 1670, 1625, 1520cm ^-1 (86) 7-[2-(α-carboxybenzyloxy)
(shiimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-[1-(2-aminoethyl)-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp190~
195℃ (decomposition). IR (Nujiyor): 3400, 3300, 3150, 1765,
1670, 1620, 1610, 1520cm ^-1 (87) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide] -3-Cefem-
4-Carboxylic acid (syn isomer), mp180-185℃
(Disassembly). IR (Nujiyor): 3350, 3250, 1770, 1720,
1680, 1630, 1530cm ^-1 (88) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{3
-(4-methyl-1-piperazinyl)propyl
1-day-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
mp185-190℃ (decomposition). IR (Nujiyor): 3300, 1760, 1670, 1600,
1520cm ^-1 (89) 7-[2-(1-carboxy-2-methyl
propoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]cephalosporanic acid (syn isomer). IR (Nujiyor): 3400-3150, 1770, 1730-
1670, 1720, 1620, 1460, 1370, 1230,
1030,730cm ^-1 (90) 7-[2-(1-carboxypropylpoki)
(shiimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-(1,4,4-thiadiazole-2-i
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp153-158°C (decomposed). IR (Nujiyor): 3300, 3180, 1770, 1720―
1670, 1620, 1520, 1220, 1060, 1000, 900,
730cm ^-1 (91) 7-[2-(1-carboxypropylpoki)
(shiimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide
Phalosporanic acid (syn isomer), mp115-120
°C (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1720−1670, 1620, 1520, 1230, 1030−
1010, 890, 740−720cm ^-1 (92) 7-[2-(1-carboxyethoxyimi
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomers), mp165-168°C (decomposition). IR (Nujiyor): 3400-3200, 1700, 1710,
1670, 1620, 1520, 1230, 1170, 1000, 900,
720cm ^-1 (93) 7-[2-(1-carboxy-1-methyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp164-167°C (min
solution). IR (Nujiyor): 3300, 3200, 2800−2300,
1770, 1720−1660, 1620, 1520, 1160,
1060, 990, 800cm ^-1 (94) 7-[2-(1-carboxy-1-cyclo
pentyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-(1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp165-169℃
(Disassembly). IR (Nujiyor): 3300, 3180, 1770, 1720−
1660, 1620, 1520, 1240, 1180, 1060,
1000, 720cm ^-1 (95) 7-[2-(1-carboxy-1-methyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-cephem-4-carboxylic acid (sin
isomers), mp215-220℃ (decomposition). IR (Nujiyor): 3400, 3250, 3200, 1770,
1670, 1520, 1290, 1240, 1160, 1000, 980,
740cm ^-1 (96) 7-[2-(1-carboxyethoxyimi
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-allyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), decomposes below 180℃. IR (Nujiyor): 3300, 3150, 1770, 1680,
1610, 1520, 1260, 1100, 1040, 1000cm ^-1 (97) 7-[2-(1-carboxyethoxyimi
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
fem-4-carboxylic acid (syn isomer),
mp230-235℃ (decomposition). IR (Nujiyor): 3400, 3250, 3150, 1760,
1720, 1660, 1610, 1550, 1290, 1240,
1170, 970, 740cm ^-1 (98) 7-[2-(1-carboxy-1-cyclo
pentyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-cephem-4-carboxylic acid
(syn isomer), mp212-217℃ (decomposed). IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1520, 1280, 1240, 1180, 1000, 970,
730cm ^-1 (99) 7-[2-(1-carboxyethoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide] Cephalo
Sporanic acid (syn isomer). IR (Nujiyor): 3300, 3200, 1770, 1710,
1670, 1520, 1230, 1040cm ^-1 (100) 7-[2-(1-carboxy-1-methy)
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mid]-3-[1-(2-aminoethyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp195~200℃ (decomposition). IR (Nujiyor): 3150, 1760, 1670, 1620,
1520, 1170, 990cm ^-1 (101) 7-[2-cyclopentyloxyimino]
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
{4-methyl-1-piperazinyl)propyl}
-1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp175-180℃ (decomposition). IR (Nujiyor): 3300, 1770, 1650, 1610,
1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.50−1.80 (8H,
m), 1.80-2.10 (2H, m), 2.30-2.50 (4H,
m), 2.60 (3H, s), 2.8-3.3 (6H, m),
3.60 (2H, broad s), 4.30−4.50 (4H, m),
4.67−4.83 (1H, m), 5.10 (1H, d, J=4
Hz), 5.77 (1H, dd, J=4 and 8Hz),
8.17 (2H, s), 9.50 (1H, d, J = 8Hz) (102) 7-[2-Cyclopentyloxyimino
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-carba
Moyloxymethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp175-180℃ (decomposed). IR (Nujiyor): 3400, 3300, 3180, 1770,
1710, 1670, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.40−2.0 (8H,
m), 3.53 (2H, broad s), 4.67 and 4.86
(2H, ABq, J=13Hz), 4.67−5.07 (1H,
m), 5.15 (1H, d, J=5Hz), 5.78 (1H,
dd, J = 5 and 8Hz), 6.55 (2H, broad
s), 8.08 (2H, broad s), 9.45 (1H, d,
J=8Hz) (103) 7-[2-(2-cyclopentene-1-
yloxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-carbamoyloxymethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp165-170℃ (decomposition). IR (Nujiyor): 3400, 3300, 3180, 1770,
1710, 1670, 1615, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.97−2.47 (4H,
m), 3.50 (2H, broad s), 4.65 and 4.85
(2H, ABq, J = 13Hz), 5.12 (1H, d, J
=5Hz), 5.17-5.50 (1H, m), 5.67-6.27
(3H, m), 6.55 (2H, broad s), 8.10 (2H,
broad s), 9.47 (1H, d, J=8Hz) (104) 7-[2-cyclopentyloxyimino
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamido]-2-methyl
-3-Cefem-4-carboxylic acid (synisomer
body). IR (Nujiyor): 3420, 3400, 3270, 3180,
2430, 1790, 1775, 1690, 1675, 1640,
1615, 1600, 1495cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (3H, d, J
=7Hz), 1.5-2.1 (8H, m), 3.73 (1H, q,
J=7Hz), 4.5-4.9 (1H, m), 5.07 (1H,
d, J=5Hz), 5.84(1H, dd, J=5 and
and 9Hz), 6.50 (1H, d, J = 6Hz), 8.02
(2H, broad s), 9.38 (1H, d, J = 9Hz) (105) 7-[2-(2-oxo-3-tetrahydrogen
Drofuryloxyimino)-2-(5-amino
-1,2,4-thiadiazol-3-yl)a
Cetamide]-3-(1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp165-170℃
(Disassembly). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 2.27−2.70 (2H,
m), 3.70 (2H, broad s), 4.17−4.73 (4H,
m), 5.15 (1H, d, J = 4Hz), 5.18 (1H,
t, J=7Hz), 5.83(1H, dd, J=4 and
and 8Hz), 8.13 (2H, broad s), 9.50 (1H,
s), 9.60 (1H, d, J = 8Hz) (106) 7-[2-(2-oxo-3-tetrahydryl
Drofuryloxyimino)-2-(5-amino
-1,2,4-thiadiazol-3-yl)a
Cetamide]-3-Cefem-4-carboxylic acid
(syn isomer), mp175-180℃. IR (Nujiyor): 3300, 3200, 1775, 1670,
1620, 1530cm ^-1 NMR (DMSO-d ₆ , δ): 2.35−2.67 (2H,
m), 3.57 (2H, broad s), 4.17−4.50 (2H,
m), 5.07 (1H, d, J = 4Hz), 5.15 (1H,
t, J = 8Hz), 5.82 (1H, dd, J = 4 and
and 8Hz), 6.43 (1H, t, J = 5Hz), 8.17
(2H, broad s), 9.60 (1H, d, J=8Hz) (107) 7-[2-(1 cyclohexyl oxycarbonate)
(rubonylethoxyimino)-2-(5-amino
-1,2,4-thiadiazol-3-yl)a
Cetamide]-3-[1-{3-(N-tertiary
Butoxycarbonylamino)propyl}-1H
-tetrazol-5-yl]thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp145-150℃ (decomposition). IR (Nujiyor): 3400-3250, 1780, 1680,
1620, 1520, 1240, 1220, 1160, 1100,
1000, 740, 720cm ^-1 NMR (DMSO-d ₆ , δ): 1.0−2.3 (15H,
m), 1.40 (9H, s), 3.0 (2H, m), 3.7 (2H,
m), 4.3 (4H, m), 4.5-5.0 (1H, m), 4.77
(1H, q, J = 7Hz), 5.13 (1H, d, J =
5Hz) 5.86 (1H, m), 6.83 (1H, m), 8.12
(2H, broad s), 9.37 (1/2H, d, J=8
Hz), 9.51 (1/2H, d, J = 8Hz) (108) 7-[2-(1-benzyloxycarbo
Nyloxyethoxyimino)-2-(5-amino)
(n-1,2,4-thiadiazol-3-yl)
Acetamide]-3-cephem-4-carvone
Acid (syn isomer), mp177-180℃ (decomposed). IR (Nujiyor): 3400, 3300, 3200, 1770,
1730, 1680, 1610, 1520, 1240, 1160,
1040, 980, 740cm ^-1 NMR (DMSO-d ₆ , δ): 1.47 (3H, d, J
=7Hz), 3.57 (2H, m), 4.88 (1H, q, J
=7Hz), 5.10 (1H, d, J = 5Hz), 5.18
(2H, s), 5.87 (1H, dd, J=5 and 8
Hz), 6..45 (1H, m), 7.31 (5H, broad s),
8.10 (2H, broad s), 9.40 and 9.55 (1H,
d, J=8Hz) (109) 7-[2-(1-benzyloxycarbo
Nylethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-[1-{3-(N-tertiary block)
Toxicarbonylimino)propyl}-1H-
Tetrazol-5-yl]thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp113-117℃ (decomposed). IR (Nujiyor): 3300, 3200, 1780, 1680,
1620, 1520, 1250, 1160, 1100, 1040,
1000, 740, 700cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (9H, s),
1.53 (3H, d, J=6Hz), 2.0 (2H, m),
3.03 (2H, m), 3.70 (2H, m), 4.10−4.67
(4H, m), 4.88 (1H, q, J=6Hz), 5.10
(1H, d, J=5Hz), 5.17 (2H, s), 5.80
(1H, dd, J=5 and 8Hz), 6.53 (1H,
m), 7.30 (5H, s), 8.10 (2H, broad s),
9.40 and 9.55 (1H, d, J = 8Hz) (110) 7-[2-(1-butoxycarbonyl ester
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-cephem-4-carboxylic acid
sex body), mp147-151℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1720, 1680, 1610, 1520, 1280, 1235,
1155, 1045, 980, 740cm ^-1 NMR (DMSO-d ₆ , δ): 0.87 (3H, t, J
= 6Hz), 1.46 (3H, d, J = 7Hz), 0.8-
1.8 (4H, m), 3.6 (2H, m), 4.08 (2H, t,
J=6Hz), 4.74 (1H, q, J=7Hz), 5.08
(1H, d, J=5Hz), 5.83 (1H, dd, J=
5 and 8Hz), 6.4 (1H, m), 8.07 (2H,
broad s), 9.39 and 9.44 (1H, d, J=
6Hz) (111) 7-[2-(1-butoxycarbonyl ether)
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
[do]-3-[1-{3-(N-tertiary butoxy
carbonylamino)propyl}-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp149-155
°C (decomposition). IR (Nujiyor): 3300, 3200, 1780, 1700,
1620, 1520, 1250, 1160, 1100, 1040,
1000, 740, 720cm ^-1 NMR (DMSO-d ₆ , δ): 0.26 (3H, t, J
=7Hz), 1.40 (9H, s), 1.0−1.7 (4H,
m), 1.43 (3H, d, J = 7Hz), 1.7-2.3
(2H, m), 3.0 (2H, m), 3.7 (2H, m), 4.0
-4.5 (6H, m), 4.77 (1H, q, J = 7Hz),
5.15 (1H, d, J=6Hz), 5.8 (1H, m),
6.9 (1H, m), 8.13 (2H, broad s), 9.5
(1H, m) (112) 7-[2-(2-D-phenylglycyl
aminoethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-2-methyl-3-cephem-4-
Carboxylic acid (syn isomer), mp204-222℃ (min
solution). IR (Nujiyor): 3260, 3150, 1760, 1665,
1616, 1512, 1400, 1045cm ^-1 (113) 7-[2-(3-D-phenylglycyl
Aminopropoxyimino)-2-(5-amino
-1,2,4-thiadiazol-3-yl)a
Cetamide]-2-methyl-3-cefuem-4
-Carboxylic acid (syn isomer), mp203-231℃
(Disassembly). IR (Nujiyor): 3280, 1170, 1760, 1660,
1600, 1520, 1400cm ^-1 NMR(D ₂ O+DCl, δ): 1.47 (3H, d, J=
7.5Hz), 1.7-2.3 (2H, m), 3.40 (2H, t,
J=7Hz), 3.88 (1H, q, J=7.5Hz), 4.33
(2H, t, J=6Hz), 5.18 (1H, d, J=
4.5Hz), 5.20 (1H, s), 5.95 (1H, d, J=
4.5Hz), 6.90 (1H, d, J = 6.0Hz), 7.57
(5H,s) (114) 7-[2-(1-cyclohexyloxy
Carbonylethoxyimino)-2-(5-amino)
(n-1,2,4-thiadiazol-3-yl)
Acetamide]-3-[1-(3-aminopro
pill)-1H-tetrazol-5-yl]thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp175-178℃ (decomposition). IR (Nujiyor): 3400-3200, 1760, 1680,
1610, 1520, 1220, 1100, 1000, 890, 790cm
^-1 NMR (DMSO-d ₆ , δ): 0.9−2.0 (13H,
m), 2.2 (2H, m), 2.9 (2H, m), 3.6 (2H,
m), 4.0−5.1 (5H, m), 4.76 (1H, q, J
=7Hz), 5.03 (1H, d, J = 5Hz), 5.77
(1H, m), 8.17 (2H, broad s), 9.45 (1H,
m) (115) 7-[2-(1-benzyloxycarbo
Nylethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-[1-(3-aminopropylene)
)-1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
sex body), mp162-166℃ (decomposition). IR (Nujiyor): 3300, 3200, 1760, 1680,
1620, 1520, 1100, 1040, 1000, 740cm ^-1 NMR (DMSO-d ₆ , δ): 1.47 (3H, d, J
=6Hz), 2.23 (2H, m), 2.90 (2H, m),
3.60 (2H, m), 4.43 (4H, m), 4.90 (1H,
q, J = 6Hz), 5.07 (1H, d, J = 5Hz),
(2H, s), 5.77 (1H, m), 7.43 (5H, s),
8.23 (2H, m), 9.57 (1H, m) (116) 7-[2-(1-butoxycarbonyl ether)
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-[1-(3-aminopropyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp158-163℃ (decomposition). IR (Nujiyor): 3400-3200, 1770, 1680,
1610, 1530, 1300, 1290, 1050, 1040,
1000, 960, 900, 790, 740, 720cm ^-1 (117) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-2-meth
pivalo of chill-3-cephem-4-carboxylic acid
hydrochloride of yloxymethyl ester (syn isomer
body), mp91-156℃ (decomposition). IR (Nujiyor): 3150, 1780, 1745, 1670,
1625, 1525cm ^-1 (118) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
Pivaloyloxymethyl ester hydrochloride (silica
isomers), mp110-125°C (decomposition). IR (Nujiyor): 1780, 1745, 1670, 1625,
1525cm ^-1 (119) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(5-methyl-1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
of pivaloyloxymethyl ester of rubonic acid
Hydrochloride (syn isomer), mp88-153°C (decomposed). IR (Nujiyor): 2150, 1780, 1745, 1650,
1625, 1525cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.16 (9H,
s), 1.6-2.2 (2H, m), 2.6-3.1 (2H, m),
2.68 (3H, s), 3.76 (2H, broad s), 4.20
and 4.53 (2H, ABq, J=18Hz), 4.24
(2H, broad s), 5.18 (1H, d, J=4.5
Hz), 5.6-6.0 (3H, m) (120) 7-[2-(3-aminopropoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(2-hydroxyethyl)-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid pivaloyloxymethyl ester
Stell's hydrochloride (syn isomer), mp150-175℃
(Disassembly). IR (Nujiyor): 3150, 1780, 1740, 1670,
1630, 1520cm ^-1 (121) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
Baloyloxymethyl ester hydrochloride (sin
isomers), mp96-155℃ (decomposition). IR (Nujiyor): 3300, 3150, 1775, 1730,
1670, 1625, 1530cm ^-1 (122) 7-[2-(4-aminomethylbenzyl
Oximino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-methyl-3-cephem-4-carbo
Hydrochloric acid of pivaloyloxymethyl ester of phosphoric acid
Salt (syn isomer), mp160-168°C (decomposed). IR (nujiyor): 1780, 1745, 1670, 1628cm
^-1 (123) 7-[2-allyloxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-(2-
aminoethyl)-1H-tetrazole-5-i
]Thiomethyl-3-cephem-4-carvone
Synthetic acid salt of pivaloyloxymethyl ester of acid
(syn isomer), mp95-105℃ (decomposed). IR (Nujiyor): 1790, 1735, 1452, 1370,
1118,990cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.2 (9H,
s), 3.2−3.35 (2H, m), 3.7 (2H, broad
s), 4.2-4.6 (2H, m), 4.1-4.6 (2H, m),
4.7 (2H, broad s), 4.8−5.2 (1H, m),
5.25 (1H, d, J = 4.5Hz), 5.45 (2H, m),
5.7−6.25 (2H, m), 5.8 (1H, d, J = 4.5
Hz) (124) 7-[2-cyclopentyloxyimino
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamido]-2-methyl
-1-aceto of 3-cephem-4-carboxylic acid
Xyethyl ester (syn isomer). IR (Nujiyor): 3400, 3310, 3150, 1780,
1770, 1750, 1675cm ^-1 (125) 7-[2-cyclopentyloxyimino
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamido]-2-methyl
1-isobu of 3-cephem-4-carboxylic acid
Tyryloxyethyl ester (syn isomer),
Amorphous powder IR (nujiol): 3400, 3300, 3170, 1780,
1745, 1675, 1620, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 1.08 (6H, d, J
=7Hz), 1.2-2.2 (14H, m), 2.2-2.9 (1H,
m), 3.88 (1H, q, J = 7Hz), 4.6-5.0
(1H, m), 5.12 (1H, d, J=4.5Hz), 5.90
(1H, dd, J = 4.5 and 8Hz), 6.63 (1H,
d, J=7Hz), 8.06 (2H, broad s), 9.43
(1H, d, J=8Hz) (126) 7-[2-(2-cyclopentene-1-
yloxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
1-acetoxypropyl ester of bonic acid
isomer), mp110-128℃ (decomposition). IR (Nujiyor): 3400, 3280, 3150, 1780,
1750, 1730, 1620cm ^-1 (127) 7-[2-(2-cyclopentene-1-
yloxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
1-(2-azidoethoxycarbonyl of bonic acid)
oxy)ethyl ester (syn isomer), mp85
~100℃ (decomposition). IR (Nujiyor): 3310, 2200, 1760-1785,
1680cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.48 (3H,
d, J = 6Hz), 1.5 (3H, d, J = 4.5Hz),
2.0−2.5 (4H, m), 3.5−4.1 (1H, m), 3.63
(2H, t, J = 4Hz), 4.30 (2H, t, J =
4Hz), 5.16 (1H, d, J = 4.5Hz), 5.2-5.45
(1H, m), 5.7-6.2 (2H, m), 6-6.2 (1H,
m), 6.6−6.8 (1H, m), 6.7 (1H, d, J=
6Hz) (128) 7-[2-(2-cyclopentene-1-
yloxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
1-ethoxycarbonyloxyethyl bonic acid
Ester (syn isomer). IR (Nujiyor): 3420-3300, 3150, 1780,
1760, 1675, 1620cm ^-1 (129) 7-[2-{3-(N-tertiary butoxy)
carbonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-2-methyl-3-
Pivaloyloxy of cefem-4-carboxylic acid
Methyl ester (syn isomer) powder, mp66~
75℃ (decomposition). IR (Nujiyor): 3300, 1780, 1745, 1680,
1620cm ^-1 (130) 7-[2-{3(N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-
Pivaloluo of 3-cephem-4-carboxylic acid
Oxymethyl ester (syn isomer), powder. IR (Nujiyor): 3300, 1780, 1745, 1680,
1620cm ^-1 (131) 7-[2-{3-(N-tertiary butoxy)
carbonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(5-methyl
-1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
Baloyloxymethyl ester (syn isomer). IR (Nujiyor): 3300, 3150, 1785, 1745,
1675, 1615cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.15 (9H,
s), 1.37 (9H, s), 1.5-2.0 (2H, m),
2.65 (3H, s), 2.8-3.2 (2H, m), 3.5-3.8
(2H, m), 3.9-4, 3 (2H, m), 41.6 and
and 4.53 (2H, ABq, J=13Hz), 5.17 (1H,
d, J = 4.5Hz), 5.6-6.0 (3H, m) (132) 7-[2-{3-(N-tertiary butoxy
carbonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-(2-
Hydroxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Pivaloyloxymethyl ester of bonic acid (cyanic acid)
(isomer), powder, mp88-101°C (decomposition). IR (Nujiyor): 3300, 1780, 1750, 1675,
1620cm ^-1 (133) 7-[2-{3-(N-tertiary butoxy)
carbonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid pivaloyloxy
dimethyl ester (syn isomer), powder, mp71
~84℃ (decomposition). IR (Nujiyor): 3300, 1780, 1745, 1680,
1615cm ^-1 (134) 7-[2-(2-cyclohexene-1-
yloxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
pivaloyloxy of cephalosporanic acid
Methyl ester (syn isomer), mp93~101℃
(Disassembly). IR (Nujiyor): 3400, 3300, 3180, 1780,
1740, 1675, 1615, 1525cm ^-1 (135) 7-[2-(2-cyclopetene-1-i)
ruoxiimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
Phthalid-3-yl ester of bonic acid
sex body), mp131-144℃ (decomposition). IR (Nujiyor): 3420, 3210, 3150, 1780,
1740, 1675, 1620, 1525cm ^-1 (136) 7-[2-(2-cyclopentene-1-
yloxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
Pivaloyloxymethyl ester of bonic acid (cyanic acid)
isomers), mp111-124°C (decomposition). IR (Nujiyor): 3400, 3300, 3270, 1775,
1740, 1670, 1620, 1520cm ^-1 (137) 7-[2-(2-cyclopentene-1-
yloxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
1-benzoyloxyethyl ester of bonic acid
(syn isomer), mp132-137℃ (decomposition). IR (Nujiyor): 3400, 3300, 3160, 1780,
1738, 1680, 1620cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1,43(3H,
d, J = 7Hz), 1.62 (3H, d, J = 5Hz),
1.7−2.4 (4H, m), 3.84 (1H, q, J=7
Hz), 5.0-5.4 (1H, m), 5.13 (1H, d, J
= 4.5Hz), 5.6-6.3 (3H, m), 6.70 (1H, d,
J=6Hz), 7.16 (1H, q, J=5Hz), 7.3−
8.2 (5H, m) (138) 7-[2-{4-(N-tertiary butoxy
carbonylamino) methylbenzyloxyimide
No}-2-(5-amino-1,2,4-thiazi
Azol-3-yl)acetamide]-3-meth
pivalo of chill-3-cephem-4-carboxylic acid
yloxymethyl ester (syn isomer) powder
The end. IR (nujiyor): 3300, 1780, 1750, 1680cm
^-1 (139) 7-[2-allyloxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-{2-
N-tertiary butoxycarbonylamino)ethyl
1H-tetrazol-5-yl]thiome
pivalo of chill-3-cephem-4-carboxylic acid
yloxymethyl ester (syn isomer), powder
The end. IR (nujiyor): 3300, 1780, 1750, 1680cm
^-1 (140) 7-[2-{2-(N-(N-Third class block)
Toxicarbonyl)-D-phenylglycyrrha
(mino)ethoxyimino}-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-2-methyl-3-cephem-4-
Carboxylic acid (syn isomer), mp77-91℃ (min
Solution) IR (Nujiyor): 3300, 3160, 1770, 1680,
1660, 1630, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 1.37 (9H, s),
1.40 (3H, d, J = 8Hz), 3.1-4.2 (5H,
m), 5.08 (1H, d, J = 4.5Hz), 5.10 (1H,
d, J = 8Hz), 5.90 (1H, dd, J = 4.5 and
and 9Hz), 6.53 (1H, d, J = 7.5Hz), 7.32
(5H, s), 8.13 (2H, broad s), 9.48 (1H,
d, J=9Hz) (141) 7-[2-{3-(N-(2-(1-A)
mino-1-cyclohexyl)acetyl)amino
Proboximino}-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
Bonic acid (syn isomer), mp198-224°C (decomposition). IR (Nujiyor): 3250, 3150, 1760, 1640,
1580, 1520cm ^-1 (142) 7-[2-{3-(N-(N-Third class block)
Toxicarbonyl-D-phenylglycylamide
g) Propoxyimino}-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-2-methyl-3-cephem-4-
Carboxylic acid (syn isomer). IR (Nujiyor): 3300, 3200, 1750, 1700,
1650, 1525cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.3−1.6
(12H, m), 1.6-2.0 (2H, m), 2.8-3.4
(2H, m), 3.82 (1H, q, J = 7.5Hz), 3.9
-4.3 (2H, m), 5.05 ((1H, d, J = 4.5
Hz), 5.83 (1H, d, J = 4.5Hz), 6.48 (1H,
d, J=6Hz) Example 41 7-[2-(1-tertiary butoxycarbonyl ester
Toxiimino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
Phalosporanic acid (syn isomer) (5.7g), 1-
[3-(N-tertiary butoxycarbonylamino)
Propyl]-1H-tetrazole-5-thiol
(3.9g) and sodium bicarbonate (2.5g)
70% of the solution mixed with phosphate buffer (PH6.8: 150ml)
Stir for 4.6 hours at °C. After cooling the reaction solution on ice, add acetic acid to
Wash with chill several times and then add ethyl acetate on top of the aqueous layer.
Add ru. The resulting mixture was acidified with hydrochloric acid.
Then, extract with ethyl acetate. Add the extract to water and salt.
Wash with sodium sulfate aqueous solution and rinse with magnesium sulfate solution.
After drying with a vacuum, the solvent is distilled off. Diethyl the residue
When powdered with ether and taken, 7-
[2-(1-carboxyethoxyimino)-2-
(5-amino-1,2,4-thiadiazole-3
-yl)acetamide]-3-[1-{3-(N
-Tertiary butoxycarbonylamino)propyl}
-1H-tetrazol-5-yl]thiomethyl-
3-Cefem-4-carboxylic acid (syn isomer)
A brown powder (3.5g) was obtained. mp110-115℃ (decomposition). IR (Nujol): 3300, 3200, 1770, 1680, 1600,
1520, 1250, 1000, 720cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.4 (12H,
m), 2.02 (2H, m), 2.98 (2H, t, J=6
Hz), 3.70 (2H, m), 4.1-4.5 (4H, m),
4.70 (1H, q, J = 7Hz), 5.13 (1H, d, J
= 5 Hz), 5.85 (1H, d, J = 5 Hz) Example 42 Following the same method as Examples 14 to 17 and 41.
The following compound was obtained. (1) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(1-
Allyl-1H-tetrazol-5-yl)thio
Methyl-3-cephem-4-carboxylic acid
Isomers) mp120-125℃ (decomposition). IR (Nujiyor): 3290, 3180, 1770, 1680,
1615, 1580, 1520, 1480cm ^-1 (2) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(1-
Methyl-1H-tetrazol-5-yl)thio
Methyl-3-cephem-4-carboxylic acid. (Syn isomer) mp130-135℃ (decomposition) IR (Nudiyol): 3400, 3300, 3280, 1770,
1670, 1615, 1580, 1520, 1480cm ^-1 (3) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
[2-carboxyethyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp135-140℃ (decomposed). IR (Nujiyor): 3400, 3270, 3190, 1770,
1680, 1620, 1585, 1520, 1480cm ^-1 (4) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[2-
Carboxymethyl-3-oxo-2,3-dihydrogen
Dro-1,2,4-triazolo [4,3,-
b]Pyridazin-6-yl]thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer),
mp140-145℃ (decomposition). IR (Nujiyor): 3400, 3300, 3190, 1765,
1700, 1620, 1580, 1540, 1520, 1480cm ^-1 (5) 7-[2-(4-chlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(tet)
lazolo[1,5-b]pyridazin-6-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp140-145℃ (decomposition). IR (Nujiyor): 3350, 3240, 1780, 1685,
1625, 1530, 1490cm ^-1 (6) 7-[2-(α-tertiary butoxycarbonyl
benzyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-(13,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer) mp105-110℃ (min
Solution). IR (Nujiyor): 3400, 3300, 3180, 1780,
1720, 1680, 1620, 1520cm ^-1 (7) 7-[2-(α-tertiary butoxycarbonyl
benzyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-[1-{2-(N-tertiary block)
Toxycarbonylamino)ethyl}-1H-te
Torazol-5-yl)thiomethyl-3-ceph
M-4-carboxylic acid (syn isomer) mp105-110℃ (decomposed). IR (Nujiyor): 3360, 3220, 1780, 1690,
1625, 1525cm ^-1 (8) 7-[2-(2-propynyloxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
(2-carboxyethyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp125-130℃ (min.
Solution). IR (Nujiyor): 3400, 3260, 3190, 2580,
1765, 1710, 1670, 1620, 1520cm ^-1 (9) 7-[2-(thiolane-1,1-dioxai
(do-3-yl)oxyimino-2-(5-amino)
(n-1,2,4-thiadiazol-3-yl)
acetamide]-3-(1,3,4-thiadia
zol-2-yl)thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp170-175
°C (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1520cm ^-1 (10) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-carboxyme)
Chil-1H-tetrazol-5-yl)thiome
Chill-3-cefem-4-carboxylic acid
mp140-145℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 (11) 7-[2-(2-propyloxyimino)-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-ka)
ruboxymethyl-1H-tetrazole-5-i
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp135-140℃ (decomposition) IR (Nudyol): 3250, 3150, 1770, 1720,
1670, 1620, 1520cm ^-1 (12) 7-[2-allyloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-[1-(2-carbo
xyethyl)-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp140-145℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 (13) 7-[2-(tertiary butoxycarbonyl)
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-[1-(2-carboxyethyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp150-155℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1700, 1620, 1520cm ^-1 (14) 7-[2-(tertiary butoxycarbonyl)
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-[1-{3-(4-methyl-1-p
perazinyl)propyl}-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp220-225℃ (min.
solution). IR (Nujiyor): 3300, 1700, 1680, 1605,
1520cm ^-1 (15) 7-[2-(1-tertiary butoxycarbonylate)
lupropoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-(1,3,4-thiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp101-105℃ (min.
solution). IR (Nujiyor): 3300, 3150, 1770, 1720,
1620, 1520, 1450, 1370, 1250, 1150,
1010, 900, 840, 720cm ^-1 (16) 7-[2-(1-tertiary butoxycarbonylate)
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp120-128℃ (min.
solution). IR (Nujiyor): 3280, 3180, 1770, 1720,
1680, 1620, 1520, 1240, 1150, 1000, 740,
720cm ^-1 (17) 7-[2-(1-methyl-1-tertiary buto
oxycarbonylethoxyimino)-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-(1,3,4-thia
diazol-2-yl)thiomethyl-3-ceph
M-4-carboxylic acid (syn isomer), mp115-120℃ (decomposition). IR (Nujiyor): 3280, 3170, 1780, 1720,
1680, 1520, 1140, 990, 750cm ^-1 (18) 7-[2-(1-tertiary butoxycarbonylate)
Ru-1-cyclopentyloxyimino)-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer),
mp140-143℃ (decomposition). IR (Nujiyor): 3300, 3180, 1770, 1720―
1670, 1620, 1520, 1245, 1150, 1060, 995,
840cm ^-1 (19) 7-[2-(1-methyl-1-tertiary buto)
oxycarbonylethoxyimino)-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-[1-{2-(N-
tertiary-butoxycarbonylamino)ethyl}-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp96~100℃ (decomposition). IR (Nujiyor): 3300, 3150, 1780, 1680,
1570, 1240, 1160, 990cm ^-1 (20) 7-[2-(1-tertiary butoxycarbonyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(1-allyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp96-100℃
(Disassembly). IR (Nujiyor): 3300, 3150, 1780, 1720,
1680, 1620, 1520, 1240, 1150, 1090, 1000
cm ^-1 (21) 7-[2-(1-phenylethoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
decomposes below 175℃. IR (Nujiyor): 3400, 3250, 3150, 1750,
1650, 1610, 1520, 1400, 1240, 1160,
1060, 1000, 700cm ^-1 (22) 7-[2-(p-tolyloxyimino)-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), decomposes below 150℃. This one is O-tril
It is a mixture of isomers. IR (Nujiyor): 3350, 3250, 1780, 1680,
1630, 1530, 1510, 1230, 1050, 910, 820cm
^-1 (23) 7-[2-(3-trifluoromethylphene
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-(1-allyl-1H-tetrazole
-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), decomposes below 155℃. IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1320, 1160, 1120, 1060, 980,
930,700cm ^-1 (24) 7-[2-(3-trifluoromethylphene
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
[do]-3-(1-methyl-1H-tetrazole
-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), decomposes below 170℃. IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1320, 1160, 1120, 1060, 930,
790,700cm ^-1 (25) 7-[2-(4-fluorophenoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(Syn isomer), decomposes below 170℃. IR (Nujiyor): 3450, 3350, 3200, 1780,
1710, 1680, 1610, 1510, 1590, 1240,
1200, 1170, 1090, 990, 910, 840cm ^-1 (26) 7-[2-(2,4-dichlorophenoxy
imino)-2-(5-amino-1,2,4-thi
Asiazol-3-yl)acetamide]-3
-(1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(Syn isomer), decomposes below 165℃. IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1250, 1230, 1100, 1060, 960,
910, 810cm ^-1 (27) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer), IR (Nudiyol): 3200, 3160, 1773, 1685,
1620cm ^-1 (28) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-(2-
Hydroxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). IR (Nujiyor): 3200, 3160, 1775, 1720,
1700, 1675, 1620cm ^-1 (29) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(5-methyl
-1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomers). IR (Nujiyor): 3300, 3150, 1775, 1710,
1700, 1670, 1650, 1620cm ^-1 (30) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(1-methyl
-1H-tetrazol-5-yl)thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp81-119℃ (decomposition). IR (Nujiyor): 3300, 3180, 1773, 1715,
1700, 1670, 1620cm ^-1 (31) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{2
-(N,N-dimethylamino)ethyl}-1H
-tetrazol-5-yl]thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer), mp170-173℃ (decomposition). IR (Nujiyor): 3400, 3280, 3150, 1760,
1665, 1610, 1520cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 2.53 (6H,
s), 3.07-3.37 (2H, m), 3.50-3.77 (2H,
m), 4.10-4.37 (2H, m), 4.43-4.83 (4H,
m), 5.10 (1H, d, J=5Hz), 5.80 (1H,
d, J=5Hz) (32) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{3
-N,N-dimethylamino)propyl}-1H
-tetrazol-5-yl]thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer), mp170-175℃ (decomposition). IR (Nujiyor): 3400, 3280, 3160, 1760,
1665, 1610, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 2.10−2.43 (2H,
m), 2.70 (6H, s), 2.92−3.28 (2H, m),
3.45-3.80 (2H, m), 4.17-4.80 (6H, m),
5.10 (1H, d, J = 5Hz), 5.84 (1H, dd, J
=5and8Hz), 8.15 (2H, broad s), 10.1
(1H, d, J=8Hz) (33) 7-[2-(2-propynyloxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-{3-(N-tertiary butoxycarbonyl
Amino)propyl}-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp85-90℃ (decomposed). IR (Nujiyor): 3400, 3290, 3200, 1770,
1680, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.40 (9H, s), 1.77
-2.17 (2H, m), 2.78 - 3.23 (2H, m), 3.50
(1H, t, J = 2Hz), 3.73 (2H, broad
s), 4.07-4.53 (4H, m), 4.82 (2H, d,
J=2Hz), 5.15 (1H, d, J=5Hz), 5.85
(1H, dd, J=5and8Hz), 8.17 (2H, broad
s), 9.65 (1H, d, J = 8Hz) (34) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{3
-(N-tertiary butoxycarbonylamino)
lopyl}-1H-tetrazol-5-yl]
Omethyl-3-cephem-4-carboxylic acid
(isomer), mp185-190℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.33 (9H, s), 1.67
-2.12 (2H, m), 2.77 - 3.07 (2H, m), 3.63
(2H, broad s), 4.07−4.43 (4H, m),
4.60 (2H, s), 5.05 (1H, d, J=4Hz),
5.77 (1H, dd, J=4and8Hz), 8.08 (2H,
s), 9.47 (1H, d, J = 8Hz) (35) 7-[2-(2,2,2-trifluoroethylene
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-(1-carboxymethyl-1H-te)
Torazol-5-yl)thiomethyl-3-ceph
M-4-carboxylic acid (syn isomer), mp130-132℃ (decomposed). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 3.73 (2H, broad
s), 4.30and4.53 (2H, ABq, J=14Hz),
4.73and4.97 (2H, ABq, J=8Hz), 5.10
(1H, d, J=4Hz), 5.35 (2H, s), 5.87
(1H, dd, J=4and8Hz), 8.23 (2H, s)
9.80 (1H, d, J = 8Hz) (36) 7-[2-(1-carboxy-2-methyl
propoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{3-(N-Third Class Butoki
cyclocarbonylamino)propyl}-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp192-195℃ (decomposition). IR (Nujiyor): 3400-3200, 1780, 1680,
1520, 1450, 1360, 1240, 1160, 1020, 730
cm ^-1 NMR (DMSO-d ₆ , δ): 0.98 (6H, d, J=
7Hz), 1.38 (9H, s), 1.8-2.2 (3H, m),
2.8-3.2 (2H, m), 3.7 (2H, m), 4.1-4.7
(5H, m), 5.12 (1H, d, J=5Hz), 5.7−
6.9 (1H, m), 6.7-6.9 (1H, m), 8.03 (2H,
broad s), 9.42 (1H, d, J = 8Hz) (37) 7-[2-(1-carboxypropoxyi
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
[1-{3-(N-tertiary butoxycarbonyl
Amino)propyl}-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp185-192℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1450, 1360, 1250, 1160,
1000, 730−710cm ^-1 NMR (DMSO-d ₆ , δ): 1.08 (3H, t, J=
7Hz), 1.35 (9H, s), 1.6-2.1 (4H, m),
2.6-3.1 (2H, m), 3.7 (2H, m), 4.1-4.6
(5H, m), 5.10 (1H, d, J = 6Hz) 5.81
(1H, dd, J=5and8Hz), 6.8 (1H, m),
8.1 (2H, broad s), 9.45and9.47 (1H, d,
J=8Hz) (38) 7-[2-{3-(N-tertiary butoxica
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-{3-
(N-tertiary butoxycarbonylamino)pro
pill}-1H-tetrazol-5-yl]thio
Methyl-3-cephem-4-carboxylic acid
isomer), IR (Nudiyol): 3300, 3150, 1775, 1715,
1675, 1650, 1615cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.37 (18H,
s), 1.5-2.1 (4H, m), 2.7-3.3 (4H, m),
3.5-3.9 (2H, m), 3.9-4.5 (6H, m), 5.13
(1H, d, J = 4.5Hz), 5.83 (1H, d, J =
4.5Hz) (39) 7-[2-(1-carboxyethoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-{3-(N-tertiary butoxycarbonyl
Amino)propyl}-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp110-115℃ (decomposed). IR (Nujiyor): 3300, 3200, 1770, 1680,
1600, 1520, 1250, 1000, 720cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.4 (12H, m)
2.02 (2H, m), 2.98 (2H, t, J=6Hz),
3.70 (2H, m), 4.1-4.5 (4H, m), 4.70
(1H, q, J = 7Hz), 5.13 (1H, d, J =
5Hz), 5.85 (1H, d, J = 5Hz) (40) 7-[2-(1-carboxy-1-cyclo
pentyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-[1-{3-(N-tertiary block)
Toxycarbonylamino)propyl}-1H-
Tetrazol-5-yl]thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer), mp200-205℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1680,
1520, 1250, 1160, 1000cm ^-1 NMR (DMSO-d ₆ , δ): 1.38 (9H, s), 1.68
(4H, m), 2.0 (6H, m), 2.96 (2H, m),
3.70 (2H, m), 4.26 (4H, m), 5.12 (1H,
d, J = 5Hz), 5.82 (1H, dd, J = 5and8
Hz), 6.86 (1H, m), 8.14 (2H, m), 9.40
(1H, d, J=8Hz) (41) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(3
-morpholinopropyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp190-194℃ (min.
solution). IR (Nujiyor): 3300, 3200, 1770, 1680,
1610, 1530, 1240, 1180, 1090, 1060, 880,
760cm ^-1 NMR (DMSO-d ₆ , δ): 2.17 (2H, m), 2.63
(6H, m), 3.67 (6H, m), 4.37 (4H, m),
4.67 (2H, broad s), 5.15 (1H, d, J=5
Hz), 5.83 (1H, dd, J=5and8Hz), 8.17
(2H, m), 9.73 (1H, d, J=8Hz) (42) 7-[2-(1-carboxy-1-methyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{3-(N-Third Class Butoki
cyclocarbonylamino)propyl}-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer). IR (Nujiyor): 3300, 3150, 1770, 1680,
1520, 1240, 1160, 990cm ^-1 NMR (DMSO-d ₆ , δ): 1.45 (15H, broad
s), 2.0 (2H, m), 3.0 (2H, m), 3.77 (2H,
m), 4.10-4.40 (4H, m), 5.20 (1H, d,
J=5Hz) 5.87 (1H, dd, J=5and8Hz),
6.87 (1H, m), 8.20 (2H, broad s), 9.47
(1H, d, J=8Hz) (43) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(4-methy
Ru-5-oxo-6-hydroxy-4,5-di
hydro-1,2,4-triazin-3-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(Syn isomer) mp210-214℃ (decomposition). IR (Nujiyor): 3250, 3180, 1760, 1720−
1660, 1590, 1520, 1240, 1090, 1050, 720
cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 3.30 (3H,
s), 3.65 (2H, m), 4.10 (2H, m), 4.65
(2H, broad s), 5.11 (1H, d, J=5
Hz), 5.82 (1H, dd, J=5and8Hz) (44) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{4
-(N-tertiary butoxycarbonylamino)butylene
Thiol}-1H-tetrazol-5-yl]thio
Methyl-3-cephem-4-carboxylic acid
isomers). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1240, 1160, 1090, 1060, 890
cm ^-1 NMR (DMSO-d ₆ , δ): 1.0−2.0 (4H, m),
1.33 (9H, s), 2.90 (2H, m), 3.66 (2H,
m), 4.0−4.5 (4H, m), 4.62 (2H, broad
s), 5.10 (1H, d, J=5Hz), 5.80 (1H,
dd, J=5and8Hz), 6.75 (1H, m), 8.13
(2H, broad s), 9.55 (1H, d, J = 8Hz) (45) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(3
-piperidinopropyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp223-228℃ (min.
solution). IR (Nujiyor): 3300, 3200, 1770, 1670,
1610, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.30−1.83 (6H,
m), 2.1-2.3 (2H, m), 2,8-3.3 (6H,
m), 3.60 (2H, broad s), 4.0−4.50 (4H,
m), 4.60 (2H, s), 5.06 (1H, d, J=4
Hz), 5.80 (1H, dd, J=4and8Hz), 8.15
(2H, s), 10.1 (1H, d, J = 8Hz) (46) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-cal)
boxymethyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp170-175℃ (decomposition). IR (Nujiyor): 3300, 3200, 1765, 1720,
1660, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 3.67 (2H, broad
s), 4.27and4.47 (2H, ABq, J=13Hz),
4.67 (2H, s), 5.13 (1H, d, J=4Hz),
5.33 (2H, s), 5.87 (1H, dd, J=4and8
Hz), 8.20 (2H, s), 9.60 (1H, d, J=8
Hz) (47) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{6
-(N-tertiary butoxycarbonylamino)he
xyl}-1H-tetrazol-5-yl]
Omethyl-3-cephem-4-carboxylic acid
(isomer), pale yellow powder (48) 7-[2-(1carboxyethoxyimer)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[5-(N-tertiary butoxycarbonylamino)
Methyl-1,3,4-thiadiazole-2-y
]Thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp210-215℃ (decomposition). IR (Nujiyor): 3300, 1770, 1680, 1620,
1520, 1240, 1140cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (12H, broad
s), 3.70 (2H, m), 4.27-4.87 (5H, m),
5.20 (1H, d, J = 5Hz), 5.87 (1H, dd, J
=5and8Hz), 7.70 (1H, m), 8.17 (2H,
broad s), 9.50 (1H, d, J = 8Hz) (49) 7-[2-(2-propynyloxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(3-aminopropyl)-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp165-170℃
(Disassembly). IR (Nujiyor): 3450, 3300, 3210, 1770,
1670, 1620, 1525cm ^-1 (50) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(3
-aminopropyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp195-200℃ (decomposed). IR (Nujiyor): 3150, 1760, 1660, 1640,
1520cm ^-1 (51) 7-[2-(1-carboxy-2-methyl
propoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-(3-aminopropyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp183-189℃ (decomposition). IR (Nujiyor): 3400-3100, 3150, 1770,
1670, 1620, 1520, 1380, 1280, 1230,
1180, 1100, 1020, 900, 730cm ^-1 (52) 7-[2-(1-carboxypropoxy)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
[1-(3-aminopropyl)-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp183-188℃ (decomposition). IR (Nujiyor): 3400-3150, 1770, 1670,
1620, 1530, 1380, 1280, 1230, 1180,
1100, 1050, 1010, 730cm ^-1 (53) 7-[2-(1-carboxyethoxyimine)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(3-aminopropyl)-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-Carboxylic acid (syn isomer), mp185-188℃
(Disassembly). IR (Nujiyor): 3300, 3150, 1760, 1660,
1620, 1520, 1230, 1000, 720cm ^-1 (54) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(4
-aminobutyl)-1H-tetrazole-5-
yl]thiomethyl-3-cephem-4-carbo
acid (syn isomer), mp191-194℃ (decomposed). IR (Nujiyor): 3300, 3150, 1760, 1670,
1620, 1520, 1230, 1170, 1050, 890, 740,
720cm ^-1 (55) 7-[2-(1-carboxy-1-methyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-(3-aminopropyl)-
1H-tetrazol-5-yl]thiomethyl-
3-Cefem-4-carboxylic acid (syn isomer), mp200-203℃ (decomposition). IR (Nujiyor): 3300, 3150, 1760, 1160,
1620, 1520, 1660, 990cm ^-1 (56) 7-[2-(1-carboxy-1-cyclo
pentyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-[1-(3-aminopropylene)
)-1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp202-205℃ (decomposition). IR (Nujiyor): 3300, 3200, 1760, 1660,
1620, 1520, 1180, 1060, 1000, 730cm ^-1 (57) 7-[2-(1-carboxyethoxyimi
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(5-aminomethyl-1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp207-210℃
(Disassembly). IR (Nujiyor): 3300, 3150, 1760, 1660,
1620, 1520, 1230, 1170, 1090, 1060,
1040,990cm ^-1 (58) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(6
-aminohexyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp185-188℃ (decomposed). IR (Nujiyor): 3300, 3200, 1760, 1670,
1620, 1520, 1240, 1180, 1060cm ^-1 (59) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(isomer), mp165-183℃ (decomposition). IR (Nujiyor): 3150, 1765, 1660, 1630,
1570, 1520cm ^-1 (60) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(2-hydroxyethyl)-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp170-185
°C (decomposition). IR (Nujiyor): 3140, 1760, 1660, 1610,
1580, 1520cm ^-1 (61) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(5-methyl-1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp192-195℃ (min.
solution). IR (Nujiyor): 3250, 3140, 1760, 1640,
1620, 1585, 1525cm ^-1 (62) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp180-184°C (decomposition). IR (nujiyor): 3160, 1760, 1660, 1590cm
^-1 (63) 7-[2-(3-aminopropoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(3-aminopropyl)-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer). IR (Nujiyor): 3300, 3150, 1760, 1660,
1607, 1595, 1520cm ^-1 (64) 7-[2-(α-carboxybenzyloxy)
(shiimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-(1,3,4-thiadiazole-2-i)
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp150-155℃ (decomposition). IR (Nujiyor): 3400, 3290, 3160, 2500,
1770, 1720, 1615, 1520cm ^-1 (65) 7-[2-(α-carboxybenzyloxy)
(shiimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-[1-(2-aminoethyl)-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp190-195℃ (decomposition). IR (Nujiyor): 3400, 3300, 3150, 1765,
1670, 1610, 1520cm ^-1 (66) 7-[2-carboxymethoxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-{3
-(4-methyl-1-piperazinyl)propyl
1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp185-190℃ (decomposition). IR (Nujiyor): 3300, 1760, 1670, 1600,
1520cm ^-1 (67) 7-[2-(1-carboxypropoxy)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(isomer), mp153-158℃ (decomposition). IR (Nujiyor): 3300, 3180, 1770, 1720−
1670, 1620, 1520, 1220, 1060, 1000, 900,
730cm ^-1 (68) 7-[2-(1-carboxyethoxyimine)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomers), mp165-168℃ (decomposition). IR (Nujiyor): 3400-3200, 1770, 1710,
1670, 1620, 1520, 1230, 1170, 1000, 900,
720cm ^-1 (69) 7-[2-(1-carboxy-1-methyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp164-167℃ (min.
solution). IR (Nujiyor): 3300, 3200, 2800−2300,
1770, 1720−1660, 1620, 1520, 1160,
1060, 990, 800cm ^-1 (70) 7-[2-(1-carboxy-1-cyclo
pentyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-(1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp165-169℃
(Disassembly). IR (Nujiyor): 3300, 3180, 1770, 1720−
1660, 1620, 1520, 1240, 1180, 1060,
1000, 720cm ^-1 (71) 7-[2-(1-carboxyethoxyimine)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-allyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(Syn isomer), decomposes below 180℃. IR (Nujiyor): 3300, 3150, 1770, 1680,
1610, 1520, 1260, 1100, 1040, 1000cm ^-1 (72) 7-[2-(1-carboxy-1-methyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mid]-3-[1-(2-aminoethyl)-
1H-tetrazol-5-yl]thiomethyl-
3-Cefem-4-carboxylic acid (syn isomer), mp195-200℃ (decomposition). IR (Nujiyor): 3150, 1760, 1670, 1620,
1520, 1170, 990cm ^-1 (73) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
{3-(4-methyl-1-piperazinyl)pyro
pill}-1H-tetrazol-5-yl]thio
Methyl-3-cephem-4-carboxylic acid
isomer), mp175-180℃ (decomposition). IR (Nujiyor): 3300, 1770, 1650, 1610,
1520cm ^-1 (74) 7-[2-(2-oxo-3-tetrahydride
lofuryloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-(1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp165-170℃
(Disassembly). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1525cm ^-1 (75) 7-[2-(1-cyclohexyloxyca
(rubonylethoxyimino)-2-(5-amino
-1,2,4-thiadiazol-3-yl)a
Cetamide]-3-[1-{3-(N-tertiary
Butoxycarbonylamino)propyl}-1H
-tetrazol-5-yl]thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer), mp145-150°C (decomposition). IR (Nujiyor): 3400-3250, 1780, 1680,
1620, 1520, 1240, 1160, 1220, 1100,
1000, 740, 720cm ^-1 (76) 7-[2-(1-benzyloxycarboni
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{3-(N-Third Class Butoki
cyclocarbonylamino)propyl}-1H-tet
Lazol-5-yl]thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp113-117°C (decomposed). IR (Nujiyor): 3300, 3200, 1780, 1680,
1620, 1520, 1250, 1160, 1100, 1040,
1000, 740, 700cm ^-1 (77) 7-[2-(1-butoxycarbonyleth)
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-[1-{3-(N-tertiary butoxylic
Bonylamino)propyl}-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp149-155℃
(Disassembly). IR (Nujiyor):: 3300, 3200, 1780, 1700,
1620, 1520, 1250, 1160, 1100, 1040,
1000, 740, 720cm ^-1 (78) 7-[2-(1-cyclohexyloxyca)
(rubonylethoxyimino)-2-(5-amino
-1,2,4-thiadiazol-3-yl)a
Cetamide]-3-[1-(3-aminopropylene)
)-1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
mp175-178℃ (decomposition). IR (Nujiyor): 3400-3200, 1765, 1680,
1610, 1520, 1220, 1100, 1000, 890, 790cm
^-1 (79) 7-[2-(1-benzyloxycarboni
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-(3-aminopropyl)-
1H-tetrazol-5-yl]thiomethyl-
3-Cefem-4-carboxylic acid (syn isomer), mp162-166°C (decomposition). IR (Nujiyor): 3300, 3200, 1760, 1680,
1620, 1520, 1100, 1040, 1000, 740cm ^-1 (80) 7-[2-(1-butoxycarbonyleth)
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-[1-(3-aminopropyl)-1H-
Tetrazol-5-yl]thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer), mp158-163°C (decomposed). IR (Nujiyor): 3400-3200, 1770, 1680,
1610, 1530, 1300, 1290, 1050, 1040,
1000, 960, 900, 790, 740, 720cm ^-1 (81) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
Pivaloyloxymethyl ester hydrochloride (silica
isomers), mp110-1250℃ (decomposition). IR (Nujiyor): 1780, 1745, 1670, 1625,
1525cm ^-1 (82) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(5-methyl-1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
of pivaloyloxymethyl ester of rubonic acid
Hydrochloride (syn isomer), mp88-153°C (decomposed). IR (Nujiyor): 2150, 1780, 1745, 1650,
1625, 1525cm ^-1 (83) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(2-hydroxyethyl)-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid pivaloyloxymethyl ester
Stell's hydrochloride (syn isomer), mp150-175℃
(Disassembly). IR (Nujiyor): 3150, 1780, 1740, 1670,
1630, 1520cm ^-1 (84) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
Baloyloxymethyl ester hydrochloride (sin
isomers), mp96-155℃ (decomposition). IR (Nujiyor): 3300, 3150, 1775, 1730,
1670, 1625, 1530cm ^-1 (85) 7-[2-aloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
)acetamide]-3-[1-(2-amino
ethyl)-1H-tetrazol-5-yl]
Omethyl-3-cephem-4-carboxylic acid
Paroyloxymethyl ester ester
isomers), mp95-105℃ (decomposition). IR (Nujiyor): 1790, 1735, 1452, 1370,
1118,990cm ^-1 (86) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(1-methyl
-1H-tetrazol-5-yl]thiomethyl
-3-cephem-4-carboxylic acid pivaloyl
Oxymethyl ester (syn isomer), powder. IR (Nujiyor): 3300, 1780, 1745, 1680,
1620cm ^-1 (87) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(5-methyl
-1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
Baloyloxymethyl ester (syn isomer). IR (Nujiyor): 3300, 3150, 1783, 1745,
1675, 1615cm ^-1 (88) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-(2-
Hydroxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Pivaloyloxymethyl ester of bonic acid
((Syn isomer), powder, mp88-101℃ (decomposition). IR (Nujiol): 3300, 1780, 1750, 1675,
1620cm ^-1 (89) 7-[2-{3-(N-tertiary butoxyca
Rubonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid pivaloyloxy
dimethyl ester (syn isomer), powder, mp71
~84℃ (decomposition). IR (Nujiyor): 3300, 1780, 1745, 1680,
1615cm ^-1 (90) 7-[2-aloxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-[1-{2-(N-
tertiary-butoxycarbonylamino)ethyl}-
1H-tetrazol-5-yl]thiomethyl-
Pivaloluo of 3-cephem-4-carboxylic acid
Oxymethyl ester ((syn isomer), powder. IR (Nudiyol): 3300, 1780, 1750, 1680cm
^-1 (91) 7-[2-(4-chlorophenoximine)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomer), mp150-155℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1520cm ^-1 (92) 7-[2-(4-fluorophenoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomers), mp140-154°C (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520cm ^-1 (93) 7-[2-phenoxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-carboxyme)
Chil-1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp175-180℃ (decomposition). IR (Nujiyor): 3400, 3200, 1770, 1700,
1660, 1620, 1580, 1510cm ^-1 (94) 7-[2-Phenoxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-allyl-1H
-tetrazol-5-yl]thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer), mp145-150°C (decomposition). IR (Nujiyor): 3450, 3350, 3180, 1780,
1710, 1680, 1610, 1590, 1510cm ^-1 (95) 7-[2-phenoxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-(1-methyl-1H
-tetrazol-5-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer), mp155-158°C (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1720, 1680, 1620, 1590, 1520cm ^-1 (96) 7-[2-(2-methoxy-5-nitroph)
enoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp160-169℃ (min
solution). IR (Nujiyor): 3380, 3220, 3100, 1780,
1690, 1620, 1600, 1520, 1340, 1280,
1085, 1065, 820, 750cm ^-1 (97) 7-[2-(4-fluorophenoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(Tetrazolo[1,5-b]pyridazine-6-
yl]thiomethyl-3-cephem-4-carbo
acid (syn isomer), mp125-130°C (decomposition). IR (Nujiyor): 3300, 3190, 1770, 1670,
1615, 1520, 1495cm ^-1 (98) 7-[2-(4-chlorophenoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(5-hydroxymethyl-1,3,4-thiazidi
azol-2-yl)thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp135~
140℃ (decomposition). IR (Nujiyor): 3450, 3280, 3180, 1760,
1720, 1660, 1620, 1580, 1520, 1480cm ^-1 (99) 7-[2-(4-chlorophenoximine)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-carboxymethyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp135-140℃ (min
solution). IR (Nujiyor): 3400, 3250, 3170, 1765,
1700, 1680, 1650, 1615, 1580, 1510, 1480
cm ^-1 (100) 7-[2-(4-chlorophenoximine)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-2-hydroxyethyl)-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp120-1250°C (decomposition). IR (Nujiyor): 3400, 3300, 3180, 1765,
1670, 1615, 1580, 1520, 1480cm ^-1 (101) 7-[2-(3,4-dichlorophenox
(shiimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-(1,3,4-thiadiazole-2-i)
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), decomposes below 160℃. IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520, 1250, 1205, 1060cm ^-1 (102) 7-[2-(3-trifluoromethyl fluoride)
enoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), decomposes below 164°C. IR (Nujiyor): 3300, 3180, 1765, 1670,
1610, 1520, 1320, 1165, 1120, 1060, 930,
790,700cm ^-1 (103) 7-[2-(3-ethoxycarbonylph)
enoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), decomposes below 162°C. IR (Nujiyor): 3350-3150, 1770, 1720-
1660, 1620, 1520, 1290, 1270, 1100,
1060, 900, 760cm ^-1 (104) 7-[2-(4-fluorophenoxyi)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
[1-(2-hydroxyethyl)-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp145-150℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1670,
1610, 1520cm ^-1 (105) 7-[2-(4-fluorophenoxy)
imino)-2-(5-amino-1,2,4-thi
Asiazol-3-yl)acetamide]-3
-(1-carboxymethyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp150-155℃
(Disassembly). IR (Nujiyor): 3300, 3200, 1770, 1720,
1670, 1620, 1520, 1500cm ^-1 (106) 7-[2-(4-fluorophenoxyi)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
[2-carboxymethyl-3-oxo-2,3
-dihydro-1,2,4-triazolo[4,3
-b]pyridazin-6-yl]thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer), mp165-170℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1710,
1620, 1540, 1520, 1500cm ^-1 (107) 7-[2-(4-fluorophenoxyi)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
[1-(2-carboxyethyl)-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-Carboxylic acid (syn isomer), mp140-145℃ (decomposed). IR (Nujiyor): 3300, 3200, 1770, 1700,
1620, 1520, 1500cm ^-1 (108) 7-[2-(4-fluorophenoxyi)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
(1-allyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp145-150℃ (decomposed). IR (Nujiyor): 3450, 3350, 3150, 1780,
1705, 1670, 1610, 1510cm ^-1 (109) 7-[2-phenoxy-2-(5-ami
(n-1,2,4-thiadiazol-3-yl)
Acetamide]-3-[1-(2-aminoethyl
)-1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp180-185℃ (decomposition). IR (Nujiyor): 3300, 3250, 1760, 1670,
1620, 1590, 1520cm ^-1 (110) 7-[2-(tertiary butoxycarbonyl
methoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(tetrazolo[1,5-b]pyri
dazin-6-yl)thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp125-130
°C (decomposition). IR (Nujiyor): 3400, 3300, 3180, 1770,
1720, 1680, 1620, 1525cm ^-1 (111) 7-[2-{3-(N-tertiary butoxy
carbonylamino)propoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-{2-
(N-tertiary butoxycarbonylamino)ethyl
1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
sex body), mp107-112℃ (decomposition). (112) 7-[2-(2,2,2-trifluoro
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(1-allyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp125-130℃
(Disassembly). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1520cm ^-1 (113) 7-[2-(2,2,2-trifluoro
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-(1-methyl-1H-tetrazo
(ru-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp145-150℃
(Disassembly). IR (Nujiyor): 3300, 3200, 1770, 1680,
1620, 1525cm ^-1 (114) 7-[2-{2-(N-tertiary butoxy
carbonylamino)ethoxyimino}-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-{2-
(N-tertiary butoxycarbonylamino)ethyl
1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp181-186℃ (decomposition). IR (Nujiyor): 3320, 1780, 1680, 1620,
1520, 1165cm ^-1 (115) 7-[2-trityloxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamido]-3-(5-methyl
-1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomer), mp147-161℃ (decomposition). IR (Nujiyor): 3420, 1780, 1680, 1615,
1525cm ^-1 (116) 7-[2-{2-(N-tertiary butoxy
carbonylaminoethoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1-carboxy
Methyl-1H-tetrazol-5-yl)thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp105℃ (decomposition). IR (Nujiyor): 3305, 3160, 1770, 1670,
1520, 1245cm ^-1 (117) 7-[2-(tertiary butoxycarbonyl
methoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-(1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp140-145℃ (min
solution). IR (Nujiyor): 3300, 3175, 1770, 1720,
1680, 1620, 1520cm ^-1 (118) 7-[2-(tertiary butoxycarbonyl
methoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-(1-allyl-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp130-135℃
(Disassembly). IR (Nujiyor): 3400, 3280, 3180, 1770,
1720, 1680, 1620, 1520cm ^-1 (119) 7-[2-(tertiary butoxycarbonyl
methoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-{2-(N-Third Class Butoki
cyclocarbonylamino) ether}-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid (syn isomer), mp110-115
℃. IR (Nujiyor): 3300, 3200, 1775, 1680,
1620, 1520cm ^-1 (120) 7-[2-(tertiary butoxycarbonyl
methoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-3-(1-phenyl-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp135-140℃
(Disassembly). IR (Nujiyor): 3400, 3300, 3200, 1775,
1720, 1685, 1620, 1525, 1500cm ^-1 (121) 7-[2-(3-aminopropoxyimide)
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3[1
-(2-aminoethyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp184-196℃ (min
solution). IR (Nujiyor): 3400-3100, 1760, 1660,
1610, 1520, 1170, 1060, 1010cm ^-1 (122) 7-[2-(2-aminoethoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(1-
Carboxymethyl-1H-tetrazole-5-
yl)thiomethyl-3-cephem-4-carbo
acid (syn isomer), mp190-198°C (decomposition). IR (Nujiyor): 3250, 3160, 1760, 1650,
1615, 1522, 1020cm ^-1 (123) 7-[2-carboxymethoxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), mp170-175℃ (decomposition). IR (Nujiyor): 3250, 3150, 1770, 1710,
1680, 1610, 1520cm ^-1 (124) 7-[2-carboxymethoxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-a
Lyle-1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp145-150℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1765,
1720, 1680, 1620, 1520cm ^-1 (125) 7-[2-carboxymethoxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(tetra
Zolo[1,5-b]pyridazin-6-yl)
Omethyl-3-cephem-4-carboxylic acid
isomer), mp170-175℃ (decomposition). IR (Nujiyor): 3400, 3300, 3180, 1765,
1720, 1680, 1615, 1520cm ^-1 (126) 7-[2-(2-aminoethoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
(2-aminoethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp182-187°C (decomposed). IR (Nujiyor): 3350, 3150, 1760, 1660,
1625, 1565, 1520cm ^-1 (127) 7-[2-carboxymethoxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-[1-
(2-aminoethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp185-190°C (decomposition). IR (Nujiyor): 3250, 1755, 1660, 1590,
1520cm ^-1 (128) 7-[2-(2,2,2-trifluoro
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mid]-3-[1-(2-aminoethyl)-
1H-tetrazol-5-yl]thiomethyl-
3-Cefem-4-carboxylic acid (syn isomer), mp185-190°C (decomposed). IR (Nujiyor): 3300, 3170, 1760, 1670,
1615, 1500cm ^-1 (129) 7-[2-carboxymethoxyimino-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-ph)
enyl-1H-tetrazol-5-yl)thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp155-160℃ (decomposition). IR (Nujiyor): 3400, 3300, 3180, 1765,
1720, 1680, 1615, 1520, 1495cm ^-1 (130) 7-[2-hydroxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(5-methyl-
1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid
isomers), mp153-162℃ (decomposition). IR (Nujiyor): 3260, 3160, 1763, 1665,
1608, 1520cm ^-1 (131) 7-[2-hydroxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(5-methyl-
1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid piva
Loyloxymethyl ester (syn isomer), mp132-135°C (decomposition). IR (Nujiyor): 3270, 3160, 1775, 1745,
1675, 1610, 1520, 1115cm ^-1 Example 43 7-[2-(1-carboxymethoxyimino)
-2-(5-amino-1,2,4-thiadiazole
ru-3-yl)acetamide]-3-[1-{3
-(N-tertiary butoxycarbonylamino)pro
pill}-1H-tetrazol-5-yl]thiome
Chil-3-cephem-4-carboxylic acid (synisomer
(3.4 g) and formic acid (34 ml) at room temperature.
Stir for 2 hours. Work up the reaction mixture in the usual manner.
Then, 7-[2-(1
-Carboxyethoxyimino)-2-(5-amino)
No-1,2,4-thiadiazol-3-yl)a
Cetamide]-3-[1-(3-aminopropylene)
)-1H-tetrazol-5-yl]thiomethi
Leu-3-cephem-4-carboxylic acid (synisomer
body) (1.1g). IR (Nujiyor): 3300, 3150, 1760, 1660,
1620, 1520, 1230, 1000, 720cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.48 (3H, d,
J=7Hz), 2.3 (2H, m), 2.9 (2H, m),
3.6 (2H, m), 4.1-5.0 (4H, m) 4.70 (1H,
q, J = 7Hz), 5.10 (1H, d, J = 5Hz),
5.85 (1H, m) Example 44 7-[2-{3-(N-tertiary butoxycarbo
nylamino)propoxyimino}-2-(5-a
mino-1,2,4-thiadiazol-3-yl)
Acetamide]-3-(1,3,4-thiadiazole
(2-yl)-thiomethyl-3-cephem-
4-Carboxylic acid pivaloyloxymethyl ester
(Syn isomer) (2.7g), Anisole (24 drops),
of 0.6N hydrochloric acid (26.6ml) and dioxane (18ml)
The solution is stirred for 30 minutes at room temperature. Tilt the insoluble matter
Collect and dissolve in water. The aqueous solution was diluted with ethyl acetate twice.
When washed and lyophilized, mp90~155℃ (decomposed)
7-[2-(3-aminopropoxyimino)-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1,3,4
-thiadiazol-2-yl)thiomethyl-3-
Cefem-4-carboxylic acid pivaloyloxymethylate
ester hydrochloride (syn isomer) (1.8g) was obtained.
Ru. IR (Nujiyor): 3300, 3150, 1775, 1730,
1670, 1625, 1530cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.20 (9H,
s), 1.9-2.5 (2H, m), 2.9-3.5 (2H, m),
3.78 (2H, broad s), 4.27 and 4.63 (2H,
ABq, J=14Hz), 4.2-4.8 (2H, m), 5.25
(1H, d, J=2.5Hz), 5.6~6.1 (3H, m),
9.42 (1H, s) Example 45 In the same manner as Examples 21-24, 43 and 44, the following formula
I got a compound. (1) 7-[2-(2-propynyloxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
(3-aminopropyl)-1H-tetrazole-
5-yl]thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp165-170℃ (min
solution). IR (Nujiyor): 3450, 3300, 3210, 1770,
1670, 1620, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 1.90−2.37 (2H,
m), 2.67-3.03 (2H, m), 3.47 (1H, t,
J=2Hz), 3.37-3.53 (2H, m), 3.93-4.60
(4H, m), 4.75 (2H, d, J=2Hz), 5.0
(1H, d, J=5Hz), 5.68 (1H, dd, J=
5 and 8Hz), 8.12 (2H, broad s), 9.50
(1H, d, J=8Hz) (2) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)-acetamide]-3-[1-(3
-aminopropyl)-1H-tetrazole-5
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp195-200℃ (decomposed). IR (Nujiyor): 3150, 1760, 1660, 1640,
1520cm ^-1 NMR (DMSO-d ₆ , δ): 2.0−2.30 (2H, m),
2.73−3.0 (2H, m), 3.60 (2H, broad s),
4.20−4.50 (4H, m), 4.60 (2H, s), 5.08
(1H, d, J = 4Hz), 5.83 (1H, dd, J =
4 and 8Hz), 8.23 (2H, s), 10.20 (1H,
d, J=8Hz) (3) 7-[2-(1-carboxy-2-methylbutylene)
Ropoxiimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-(3-aminopropyl)-
1H-tetrazol-5-yl)thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp183-189℃ (decomposition). IR (Nujiyor): 3400-3100, 3150, 1770,
1670, 1620, 1520, 1380, 1280, 1230,
1180, 1100, 1020, 900, 730cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 0.98 (6H, d,
J=7Hz), 2,2 (3H, m), 3.6 (2H,
m), 3.9 (2H, m), 4.3 (5H, m), 5.06 (1H,
d, J=5Hz), 5.70 (1/2H, d, J=5
Hz), 5.82 (1/2H, d, J = 5Hz) (4) 7-[2-(1-carboxypropoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(3-aminopropyl)-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp183-188℃
(Disassembly). IR (Nujiyor): 3400-3150, 1770, 1670,
1620, 1530, 1380, 1280, 1230, 1180,
1100, 1050, 1010, 730cm ^-1 NMR (DMSO-d ₆ , δ): 0.98 (3H, t, J=
7Hz), 1.7-2.3 (4H, m), 2.7-3.1 (2H,
m), 3.4-3.7 (2H, m), 4.2-4.8 (5H, m),
5.07 (1H, d, J = 5Hz), 5.6-5.9 (1H,
m), 8.13 (2H, broad s), 10.08 (1H, m) (5) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-(4-
aminobutyl)-1H-tetrazole-5-i
]Thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp191-194°C (decomposed). IR (Nujiyor):: 3300, 3150, 1760, 1670,
1620, 1520, 1230, 1170, 1050, 890, 740,
720cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.2−2.1 (4H,
m), 2.80 (2H, t, J=6Hz), 3.6 (2H,
m), 4.3 (4H, m), 4.60 (2H, broad s),
5.10 (1H, d, J = 5Hz), 5.82 (1H, d, J
=5Hz) (6) 7-[2-(1-carboxy-1-methyl ester
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-[1-(3-aminopropyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp200−203℃ (decomposition). IR (Nujiyor): 3300, 3150, 1760, 1660,
1620, 1520, 1160, 990cm ^-1 NMR (DMSO-d ₆ , δ): 1.50 (6H, s), 2.20
(2H, m), 2.90 (2H, m), 3.60 (2H, m),
4.30 (4H, m), 5.10 (1H, d, J=5Hz),
5.83 (1H, m), 8.20 (2H, broad s), 9.87
(1H, d, J=8Hz) (7) 7-[2-(1-carboxy-1-cyclope
methyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-[1-(3-aminoprop
)-1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp202−205℃ (decomposition). IR (Nujiyor): 3300, 3200, 1760, 1660,
1620, 1520, 1180, 1060, 1000, 730cm ^-1 NMR (DMSO-d ₆ , δ): 1.70 (4H, m), 2.10
(6H, m), 2.90 (2H, m), 3.11 and 3.60
(2H, ABq, J=18Hz), 4.40 (4H, m),
5.08 (1H, d, J = 5Hz), 5.80 (1H, dd, J
= 5 and 8Hz), 8.23 (2H, m), 9.78 (1H,
m) (8) 7-[2-(1-carboxyethoxyimi
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(5-aminomethyl-1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), mp207-210℃
(Disassembly). IR (Nujiyor): 3300, 3150, 1760, 1660,
1620, 1520, 1230, 1170, 1090, 1060,
1040,990cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.43 (3H, d,
J=5Hz) 3.60 (2H, m), 4.0−4.93 (5H,
m), 5.05 and 5.15 (1H, d, J = 5Hz),
5.70 (1H, m), 8.1 (2H, broad s), 9.5
(1H, d, J=8Hz) (9) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-(6-
aminohexyl)-1H-tetrazole-5-
yl]-thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp185-188°C (decomposition). IR (Nujiyor): 3300, 3200, 1760, 1670,
1620, 1520, 1240, 1180, 1060cm ^-1 NMR (DMSO-d ₆ , δ): 1.10−1.57 (6H,
m), 1.57-1.97 (2H, m), 2.70 (2H, m),
3.83 (2H, m), 4.27 (4H, m), 4.57 (2H,
broad s), 5.03 (1H, d, J=5Hz), 5.72
(1H, dd, J=5 and 8Hz), 8.13 (2H,
m), 9.80 (1H, d, J = 8PH) (10) 7-[2-(3-aminopropoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), mp165-183℃ (decomposition). IR (Nujiyor): 3150, 1765, 1660, 1630,
1570, 1520cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.6−2.3 (2H,
m), 2..6-3.2 (2H, m), 3.2-3.7 (2H,
m), 3.9-4.7 (4H, m), 4.97 (1H, d, J
= 4.5Hz), 5.68 (1H, d, J = 4.5Hz), 9.50
(1H,s) (11) 7-[2-(3-aminopropoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-[1-
(2-hydroxyethyl)-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer), mp170-185℃ (min
solution). IR (Nujiyor): 3140, 1760, 1660, 1610,
1580, 1520cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.6−2.4 (2H,
m), 2.7-3.4 (2H, m), 3.3-3.9 (4H, m),
3.9−4.7 (6H, m), 4.97 (1H, d, J = 4.5
Hz), 5.67 (1H, d, J = 5Hz) (12) 7-[2-(3-aminopropoxyimino)
-2-(5-amino-1,2,4-thiadiazo
-3-yl)acetamide]-3-(5-
Methyl-1,3,4-thiadiazole-2-y
) thiomethyl-3-cephem-4-carvone
Acid (syn isomer), mp192-195°C (decomposition). IR (Nujiyor): 3250, 3140, 1760, 1640,
1620, 1585, 1525cm ^-1 NMR(D ₂ O + DCl, δ): 2.0−3.4 (2H, m),
3.00 (3H, s), 3.22 (2H, t, J=7Hz),
3.74 and 3.92 (2H, ABq, J=18Hz), 4.36
and 4.53 (2H, ABq, J=14Hz), 4.54
(2H, t, J = 7Hz), 5.28 (1H, d, J =
4.5Hz), 5.82 (1H, d, J = 4.5Hz) (13) 7-[2-(3-aminopropoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp180-184℃ (decomposed). IR (nujiyor): 3160, 1760, 1660, 1590cm
^-1 NMR(D ₂ O + DCl, δ): 1.9−2.4 (2H, m),
3.20 (3H, t, J=8Hz), 3.80 (2H, broad
s), 4.02 (3H, s), 4.22 (2H, broad s),
4.52 (2H, t, J = 6Hz), 5.25 (1H, d, J
= 5Hz), 5.85 (1H, d, J = 5Hz) (14) 7-[2-(4-aminomethylbenzyl)
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-methyl-3-cephem-4-carboxylic acid
Formate (syn isomer), mp230-240°C (decomposition). IR (nujiyor): 1750cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.86 (3H,
s), 3.25 (2H, m), 3.97 (2H, s), 4.94
(1H, d, J=4.5Hz), 5.16 (2H, s), 5.6
(1H, d, J=4.5Hz), 7.35 (4H, s), 8.20
(1H, s) (15) 7-[2-(3-aminopropoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(3-aminopropyl)-1H-tetrazo
[R-5-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer). IR (Nujiyor): 3300, 3150, 1760, 1660,
1607, 1595, 1520cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 2.0−2.7 (4H,
m), 3.0-3.5 (4H, m), 3.4-4.0 (2H, m),
4.0−4.9 (6H, m), 5.20 (1H, d, J = 4.5
Hz), 5.81 (1H, d, J = 4.5Hz) (16) 7-[2-(2-D-phenylglycyrrha
(minoethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-2-methyl-3-cephem-4-
Carboxylic acid (syn isomer), mp204-222℃ (min
solution). IR (Nujiyor): 3260, 3150, 1760, 1665,
1615, 1512, 1400, 1045cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.43 (3H, d,
J=7Hz), 3.13-4.45 (5H, m), 4.98 (1H,
s), 5.02 (1H, d, J=4.5Hz), 5.85 (1H,
d, J = 4.5Hz), 6.27 (1H, d, J = 6Hz),
7.43 (5H, s) (17) 7-[2-(3-D-phenylglycyrrha
Minopropoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-2-methyl-3-cephem-4-
Carboxylic acid (syn isomer), mp203-231℃ (min
solution). IR (Nujiyor): 3280, 1170, 1760, 1660,
1600, 1525, 1400cm ^-1 NMR(D ₂ O+DCl, δ): 1.47 (3H, d, J=
7.5Hz), 17-2.3 (2H, m), 3.40 (2H, t,
J=7Hz), 3.88 (1H, q, J=7.5Hz), 4.33
(2H, t, J=6Hz), 5.18 (1H, d, J=
4.5Hz), 5.20 (1H, s), 5.95 (1H, d, J=
4.5Hz), 6.90 (1H, d, J = 6.0Hz), 7.57
(5H, s) (18) 7-[2-(1-cyclohexyloxyca
(rubonylethoxyimino)-2-(5-amino
-1,2,4-thiadiazol-3-yl)a
Cetamide]-3-[1-(3-aminopropylene)
)-1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
sex body), mp175-178℃ (decomposition). IR (Nujiyor): 3400-3200, 1765, 1680,
1610, 1520, 1220, 1100, 1000, 890, 790cm
^-1 NMR (DMSO-d ₆ , δ): 0.9−2.0 (13H, m),
2.2 (2H, m), 2.9 (2H, m), 3.6 (2H, m),
4.0−5.1 (5H, m), 4.76 (1H, q, J=7
Hz), 5.03 (1H, d, J = 5Hz), 5.77 (1H,
m), 8.17 (2H, broad s), 9.45 (1H, m) (19) 7-[2-(1-benzyloxycarbonyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mid]-3-[1-(3-aminopropyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp162-166℃ (decomposition). IR (Nujiyor): 3300, 3200, 1760, 1680,
1620, 1520, 1100, 1040, 1000, 740cm ^-1 NMR (DMSO-d ₆ δ): 1.47 (3H, d, J=6
Hz), 2.23 (2H, m), 2.90 (2H, m), 3.60
(2H, m), 4.43 (4H, m), 4.90 (1H, q,
J=6Hz), 5.07 (1H, d, J=5Hz), 5.20
(2H, s), 5.77 (1H, m), 7.43 (5H, s),
8.23 (2H, m), 9.57 (1H, m) (20) 7-[2-(1-butoxycarbonyleth)
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-[1-(3-aminopropyl)-1H-
Tetrazol-5-yl]thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp158-163℃ (decomposition). IR (Nujiyor): 3400-3200, 1770, 1680,
1610, 1530, 1300, 1290, 1050, 1040,
1000, 960, 900, 790, 740, 720cm ^-1 NMR (DMSO-d ₆ δ): 0.85 (3H, t, J=6
Hz), 1.1-1.8 (4H, m), 1.43 (3H, d, J
= 6Hz), 1.9-2.4 (2H, m), 2.7-3.1 (2H,
m), 3.5 (2H, m), 3.9-4.4 (2H, m), 4.10
(2H, t, J=6Hz), 4.3−4.6 (2H, m),
4.78 (1H, q, J = 7Hz), 5.02 (1H, d, J
=5Hz), 5.7 (1H, m), 8.2 (2H, broad
s), 10.1 (1H, m) (21) 7-[2-(3-aminopropoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-2-meth
Chil-3-cephem-4-carboxylic acid pivaloy
hydrochloride of hydroxymethyl ester (syn isomer)
body), mp91-156℃ (decomposition). IR (Nujiyor): 3150, 1780, 1745, 1670,
1625, 1525cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.13 (9H,
s), 1.43 (3H, d, J=7Hz), 1.7−2.3
(2H, m), 2.5-3.2 (2H, m), 3.5-4.5
(3H, m), 5.10 (1H, d, J=5Hz), 5.6−
6.1 (3H, m), 6.63 (1H, d, J = 7Hz) (22) 7-[2-(3-aminopropoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid pyridine
Baloyloxymethyl ester hydrochloride (sin
isomers), mp110-125℃ (decomposition). IR (Nujiyor): 1780, 1745, 1670, 1625,
1525cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.13 (9H,
s), 1.7-2.3 (2H, m), 2.6-3.2 (2H, m),
3.75 (2H, broad s), 3.90 (3H, s), 4.0−
4.7 (4H, m), 5.12 (1H, d, J = 4.5Hz),
5.6-6.1 (3H, m) (23) 7-[2-(3-aminopropoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(5-methyl-1,3,4-thiadiazole-
2-yl)thiomethyl-3-cephem-4-ka
Rubonic acid pivaloyloxymethyl ester hydrochloric acid
Salt (syn isomer), mp88-153°C (decomposition). IR (Nujiyor): 2150, 1780, 1745, 1650,
1625, 1525cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.16 (9H,
s), 1.6-2.2 (2H, m), 2.6-3.1 (2H, m),
2.68 (3H, s), 3.76 (2H, broad s), 4.20
and 4.53 (2H, ABq, J=18Hz), 4.24
(2H, broad s), 5.18 (1H, d, J=4.5
Hz), 5.6-6.0 (3H, m) (24) 7-[2-(3-aminopropoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[1-(2-hydroxyethyl)-1H-tetra
Zol-5-yl]thiomethyl-3-cephem
-4-carboxylic acid pivaloyloxymethyl s
Tel hydrochloride (syn isomer), mp150-175℃ (min
solution). IR (Nujiyor): 3150, 1780, 1740, 1670,
1630, 1520cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.20 (9H,
s), 1.7-2.3 (2H, m), 2.6-3.2 (2H, m),
3.5-4.0 (4H, m), 4.0-4.6 (6H, m), 5.17
(1H, d, J = 5Hz), 5.6-6.1 (3H, m) (25) 7-[2-(4-aminomethylbenzyl)
Kiimino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetamide]-
3-Methyl-3-cephem-4-carboxylic acid pi
Baloyloxymethyl ester hydrochloride
(decomposition), mp160-168℃ (decomposition). IR (nujiyor): 1780, 1745, 1670, 1628cm
^-1 (26) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-[1-(2-amido)
Noethyl)-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid pyridine
Baloyloxymethyl ester formate
(decomposition), mp95-105℃ (decomposition). IR (Nujiyor): 1790, 1735, 1452, 1370,
1118,990cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.2 (9H, s),
3.2−3.35 (2H, m), 3.7 (2H, broad s),
4.2-4.6 (2H, m), 4.1-4.6 (2H, m), 4.7
(2H, broad s), 4.8-5.2 (1H, m), 5.25
(1H, d, J=4.5Hz), 5.45 (2H, m), 5.7
-6.25 (2H, m), 5.8 (1H, d, J = 4.5Hz) Example 46 7-[2-(1-tertiary butoxycarbonyl ester
Toxiimino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]-
3-Cefem-4-carboxylic acid (syn isomer)
(2.35g), tofluoroacetic acid (16ml) and aniso
(3 ml) was stirred at room temperature for 40 minutes.
Ru. Concentrate the reaction mixture and dissolve the residue in diisopropylene.
Powdered with diisopropyl ether and diisopropyl ether
When washed with white powder, 7-[2-(1-ka)
ruboxyethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)aceto
Amide]-3-cephem-4-carboxylic acid (synamide)
isomer) (2.3 g) is obtained. This powder (2.3g)
Mixture of sodium bicarbonate (0.44g) and water (50ml)
When reprecipitated from the compound, removed the precipitate, and washed with water,
mp230-235℃ (decomposition), the above compound in the form of a light brown powder
(1.1g). IR (Nujiyor): 3400, 3250, 3150, 1760,
1720, 1660, 1610, 1550, 1290, 1240,
1170, 970, 740cm ^-1 NMR (DMSO-d ₆ , δ): 1.46 (3H, d, J=
8Hz), 3.46 (2H, m), 4.72 (1H, q, J=
7Hz), 5.15 (1H, d, J=5Hz), 5.58 (1H,
dd, J=5 and 8Hz), 6.50 (1H, m),
8.20 (2H, m), 9.40 and 9.57 (1H, d, J
= 8 Hz) Example 47 7-[2-(α-tertiary butoxycarbonylbenzene)
ndyloxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetamide
Do]-3-[1-{2-(N-tertiary butoxyca
Rubonylamino)ethyl}-1H-tetrazole
-5-yl]thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer) (3.0g), trifluoro
Mixture of acetic acid (30ml) and anisole (6ml)
Stir for 1 hour at room temperature. Prepare the reaction mixture in a conventional manner.
When processed further, mp190-195℃ (decomposition) 7-
[2-(α-carboxybenzyloxyimino)-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-[1-(2-
aminoethyl)-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
obtained (1.16 g). IR (Nujiyor): 3400, 3300, 3150, 1765,
1670, 1610, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 3.10−3.77 (4H,
m), 4.13-4.37 (2H, m), 4.40-4.77 (2H,
m), 5.0-5.23 (1H, m), 5.57 (1/2H,
s), 5.65 (1/2H, s), 5.53−5..93 (1H,
m), 7.27-7.80 (5H, m), 8.28 (2H, broad
s) Example 48 The following compounds were prepared in the same manner as in Examples 26, 46 and 47.
I got it. (1) 7-[2-(α-carboxybenzyloxy
imino)-2-amino-1,2,4-thiasia
zol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomer), mp150-155℃ (decomposition). IR (Nujiyor): 3400, 3290, 3160, 2500,
1770, 1720, 1615, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 3.12−3.88 (2H,
m), 4.08-4.68 (2H, m), 5.04 (1/2H,
d, J=5Hz), 5.10 (1/2H, d, J=5
Hz), 5.62 (1H, s), 5.64-5.88 (1H, m),
7.12−7.68 (5H, m), 8.14 (2H, broad s),
9.52 (1/2H, s), 9.54 (1/2H, s),
9.36−9.72 (1H, m) (2) 7-[2-(α-carboxybenzyloxy
imino)-2-(5-amino-1,2,4-thi
Asiazol-3-yl)acetamide]-3
-Cefem-4-carboxylic acid (syn isomer),
mp170-175℃ (decomposition). IR (Nujiyor): 3400, 3280, 3160, 2600,
1770, 1720, 1670, 1625, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 3.24−3.68 (2H,
m), 5.02 (1/2H, d, J = 5Hz), 5.08
(1/2H, d, J=5Hz), 5.64 (1H, s),
5.68-5.96 (1H, m), 6.28-6.60 (1H, m),
7.16−7.64 (5H, m), 8.16 (2H, broad s),
9.54 (1/2H, d, J = 8Hz), 9.62 (1/2H, d, J = 8Hz),
2H, d, J=8Hz) (3) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-cephem-4
-Carboxylic acid (syn isomer), mp180-185℃
(Disassembly). IR (Nujiyor): 3350, 3250, 1770, 1720,
1680, 1630, 1530cm ^-1 NMR (DMSO-d ₆ , δ): 3.53 (2H, d, J=
3Hz), 4.63 (2H, s), 5.07 (1H, d, J=
4Hz), 5.85 (1H, dd, J=4 and 8Hz),
6.45 (1H, t, J=3Hz), 8.13 (2H, s),
9.50 (1H, d, J = 8Hz) (4) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-[1-{3-
(4-methyl-1-piperazinyl)propyl}
-1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (synisomer
body), mp185-190℃ (decomposition). IR (Nujiyor): 3300, 1760, 1670, 1600,
1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.80−2.10 (2H,
m), 2.30−2.50 (4H, m), 2.60 (3H, s),
2.8−3.3 (6H, m), 3.60 (2H, broad s),
4.20−4.50 (4H, m), 4.60 (2H, s), 5.10
(1H, d, J = 4Hz), 5.83 (1H, dd, J =
4 and 8Hz), 8.15 (2H, s), 10.17 (1H,
d, J = 8Hz) (5) 7-[2-(1-carboxy-2-methylpropylene)
Ropoxiimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
Mido]-cephalosboranic acid (syn isomer). IR (Nujiyor): 3400-3150, 1770, 1730-
1670，1720，1620，、1460，1370，1230，
1030,,730cm ^-1 NMR (DMSO-d ₆ , δ): 0.97 (6H, d, J=
7Hz), 2.03 (3H, s), 1.9-2.3 (1H, m),
3.6 (2H, m) 4.27 and 4.35 (1H, d, J=
6Hz), 4.65 and 5.02 (2H, ABq, J=13
Hz), 5.15 (1H, d, J = 5Hz), 5.7-6.0
(1H, m), 8.03 (2H, broad s), 9.42 (1H,
d, J = 8Hz) (6) 7-[2-(1-carboxyproboximide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazole-2-thiomethy
Leu-3-cephem-4-carboxylic acid (synisomer
body), mp153-158℃ (decomposition). IR (Nujiyor): 3300, 3180, 1770, 1720−
1670, 1620, 1520, 1220, 1060, 1000, 900,
730cm ^-1 NMR (DMSO-d ₆ , δ): 0.97 (3H, t, J=
7Hz), 1.83 (2H, m), 3.56 and 3.80 (2H,
ABq, J=18Hz), 4.25 and 4.55 (2H,
ABq, J = 14Hz), 4.52 (1H, t, J = 7
Hz), 5.14 (1H, d, J = 5Hz), 5.82 (1H,
dd, J = 5 and 8Hz), 8.1 (2H, broad
s), 9.46 (1H, d, J=8Hz), 9.52 (1H,
s) (7) 7-[2-(1-carboxypropoxyimide)
-(5-amino-1,2,4-thiadiazole)
[R-3-yl)acetamide] Cephalospo
Lanic acid (syn isomer), mp115-120°C (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1720−1670, 1620, 1520, 1230, 1030−
1010, 890, 740−720cm ^-1 NMR (DMSO-d ₆ , δ): 1.07 (3H, t, J=
6Hz), 1.8 (2H, m), 2.00 (3H, s), 3.5
(2H, s), 4.63 and 5.02 (2H, ABq, J=
14Hz), 4.5 (1H, m), 5.14 (2H, d, J=5
Hz), 5.84 (1H, dd, J=5 and 9Hz),
8.11 (2H, broad s), 9.5 (1H, m) (8) 7-[2-(1-carboxyethoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
isomers), mp165-168°C (decomposition). IR (Nujiyor): 3400-3200, 1770, 1710,
1670, 1620, 1520, 1230, 1170, 1000, 900,
720cm ^-1 NMR (DMSO-d ₆ , δ): 1.43 (3H, d, J=
7Hz), 3.7 (2H, m), 4.23 and 4.60 (2H,
ABq, J = 14Hz), 4.68 (1H, q, J = 7
Hz), 5.15 (1H, d, J = 5Hz), 5.83 (1H,
dd, J = 5 and 8Hz), 8.1 (2H, broad
s), 9.3-9.6 (1H, m), 9.50 (1H, s) (9) 7-[2-(1-carboxy-1-methyl ether
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
]-3-(1,3,4-thiadiazole-2
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer), mp164-167°C (decomposition). IR (Nujiyor): 3300, 3200, 2800−2300,
1770, 1720−1660, 1620, 1520, 1160,
1060, 990, 800cm ^-1 NMR (DMSO-d ₆ , δ): 1.47 (6H, s), 3.53
and 3..87 (2H, ABq, J = 20Hz), 4.24
and 4.63 (2H, ABq, J=14Hz), 5.17 (1H,
d, J=5Hz), 5.83(1H, dd, J=5 and
and 8Hz), 8.2 (2H, broad s), 9.44 (1H,
d, J = 8Hz), 9.50 (1H, s) (10) 7-[2-(1-carboxy-1-cyclope
methyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
Toamide]-3-(1,3,4-thiadiazole
(2-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer), mp165-169℃
(Disassembly). IR (Nujiyor): 3300, 3180, 1770, 1720−
1660, 1620, 1520, 1240, 1180, 1060,
1000, 720cm ^-1 NMR (DMSO-d ₆ , δ): 1.8 (4H, m), 2.1
(4H, m), 3.7 (2H, m), 4.30 and 4.68
(2H, ABq, J = 13Hz), 5.20 (1H, d, J
= 5Hz), 5.87 (1H, dd, J = 5 and 8
Hz), 8.3 (2H, broad s), 9.48 (1H, d, J
= 8Hz), 9.60 (1H, s) (11) 7-[2-(1-carboxy-1-methylethyl
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-cephem-4-carboxylic acid
(decomposition), mp215-220℃ (decomposition). IR (Nujiyor): 3400, 3250, 3200, 1770,
1670, 1520, 1290, 1240, 1160, 1000, 980,
740cm ^-1 NMR (DMSO-d ₆ , δ): 1.57 (6H, s), 3.70
(2H, m), 5.22 (1H, d, J=5Hz), 5.97
(1H, dd, J=5 and 8Hz), 6.58 (1H,
m), 8.25 (2H, broad s), 9.52 (1H, d,
J=8Hz) (12) 7-[2-(1-carboxyethoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
(1-allyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(Syn isomer), this product decomposes up to 180℃. IR (Nujiyor): 3300, 3150, 1770, 1680,
1610, 1520, 1260, 1100, 1040, 1000cm ^-1 NMR (DMSO-d ₆ , δ): 1.46 (3H, d, J=
8Hz), 3.50 and 3.74 (2H, ABq, J=18
Hz), 4.2 and 4.46 (2H, ABq, J=14Hz),
4.72 (1H, q, J=8Hz), 4.98 (2H, m),
5.15 (1H, d, J = 5Hz), 5.2-5.36 (2H,
m), 5.76-6.1 (3H, m), 8.12 (2H, m),
9.48 and 9.56 (1H, d, J = 8Hz) (13) 7-[2-(1-carboxy-1-cyclo
pentyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-cephem-4-carboxylic acid
(syn isomer), mp212-217℃ (decomposed). IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1520, 1280, 1240, 1180, 1000, 970,
730cm ^-1 NMR (DMSO-d ₆ , δ): 1.70 (4H, m), 2.30
(4H, m), 3.60 (2H, m), 5.10 ((1H, d,
J=5Hz), 5.87(1H, dd, J=5 and 8
Hz), 6.47 (1H, m), 8.20 (2H, m), 9.50
(1H, d, J=8Hz) (14) 7-[2-(1-carboxyethoxyimide
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide] Cephalo
Sporanic acid (syn isomer). IR (Nujiyor): 3300, 3200, 1770, 1710,
1670, 1520, 1230, 1040cm ^-1 NMR (DMSO-d ₆ , δ): 1.47 (3H, d, J=
8Hz), 2.03 (3H, s), 3.58 (2H, m), 4.13
-5.00 (1H, m), 4.68 and 5.03 (2H,
ABq, J = 8Hz), 5.26 (1H, d, J = 5
Hz), 5.87 (1H, dd, J=5 and 8Hz),
8.15 (2H, broad s), 9.42 and 9.55 (1H,
d, J=8Hz) (15) 7-[2-(1-carboxy-1-methyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mid]-3-[1-(2-aminoethyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp195~200℃ (decomposition). IR (Nujiyor): 3150, 1760, 1670, 1620,
1520, 1170, 990cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.50 (6H,
s), 3.27 (2H, m), 3.60 (2H, m), 4.17
(2H, m), 4.57 (2H, m), 5, 10 (1H, d,
J=5Hz), 5.80 (1H, d, J=5Hz) Example 49 7-[2-cyclopentyloxyimino-2-
(5-amino-1,2,4-thiadiazole-3
-yl)acetamide]-3-hydroxycefa
Mu-4-carboxylic acid (syn isomer) (115mg)
Add piva chloride to a solution of trahydrofuran (1.5 ml).
Roil (66 mg) is added at room temperature under stirring. 5 minutes later,
Add sodium acetate (82) mg and stir at room temperature for 10 hours.
Stir. Concentrate the reaction mixture and add ethyl acetate to the residue.
and dilute aqueous sodium bicarbonate solution.
Add ethyl acetate to the aqueous layer, adjust the pH to 1 with hydrochloric acid, and extract.
put out Add the extract to water and aqueous sodium chloride solution.
Wash with water, dry with magnesium sulfate, and concentrate.
Ru. When the residue is triturated with diethyl ether,
mp170-175℃ (decomposition), white powder 7-[2-
Cyclopentyloxyimino-2-(5-amino
-1,2,4-thiadiazol-3-yl)acetate
toamide]-3-cephem-4-carboxylic acid
obtained (70 mg). IR (Nujiyor): 3520, 3420, 3320, 3160,
1770, 1685, 1655, 1635, 1625, 1570, 1505
cm ^-1 NMR (DMSO-d ₆ , δ): 1.33−2.07 (8H,
m), 3.43-3.77 (2H, m), 4.60-4.93 (1H,
m), 5.15 (1H, d, J=5Hz), 5.90 (1H,
dd, J = 5 and 8Hz), 6.43−6.67 (1H,
m), 8.23 (2H, broad s), 9.63 (1H, d,
J=8Hz) Example 50 The following compound was obtained in the same manner as in Example 49. (1) 7-[2-(α-tertiary butoxycarbonyl
benzyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-cephem-4-carboxylic acid
(syn isomer), mp90-95℃ (decomposed). IR (Nujiyor): 3400, 3380, 3230, 1780,
1730, 1685, 1635, 1530cm ^-1 (2) 7-[2-tertiary butoxycarbonylmethoxy
Shiimino-2-(5-amino-1,2,4-thi)
Asiazol-3-yl)acetamide]-3
-Cefem-4-carboxylic acid (syn isomer),
mp165-170℃ (decomposition). IR (Nujiyor): 3350, 3250, 3180, 1790,
1720, 1660, 1630, 1620, 1520cm ^-1 (3) 7-[2-(1-methyl-1-tertiary butoki)
cycarbonylethoxyimino)-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
) Acetamide]-3-cephem-4-cal
Bonic acid (syn isomer). This product decomposes up to 215℃
do. IR (Nujiyor): 3400, 3300, 3150, 1780,
1710, 1690, 1620, 1520, 1240, 1140, 980
cm ^-1 (4) 7-[2-(1-tertiary butoxycarbonyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-cephem-4-carboxylic acid (sin
isomers). This product decomposes up to 250℃. IR (Nujiyor): 3400, 3250, 3150, 1770,
1720, 1680, 1610, 1520, 1290, 1240,
1150, 980, 740cm ^-1 (5) 7-[2-(3,4-dichlorophenoxy)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
Cefem-4-carboxylic acid (syn isomer). Book
The product decomposes by 210℃. IR (Nujiyor): 3450, 3300, 3200, 1760,
1660, 1560, 1290, 1210, 1000, 970, 940,
730cm ^-1 (6) 7-[2-(2,4-dichlorophenoxy)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetamide]-3-
Cefem-4-carboxylic acid (syn isomer). Book
The product decomposes up to 240℃. IR (Nujiyor): 3250, 1770, 1660, 1620,
1540, 1520, 1280, 1230, 1100, 1050, 970,
920, 810, 750cm ^-1 (7) 7-[2-{1-(cyclohexyloxyca)
(rubonyl)ethoxyimino}-2-(5-amino)
(n-1,2,4-thiadiazol-3-yl)
Acetamide]-3-cephem-4-carvone
Acid (syn isomer), mp160-163°C (decomposition). IR (Nujiyor): 3420, 3300, 3180, 1775,
1720, 1685, 1610, 1520, 1290, 1230,
1040, 980, 740cm ^-1 (8) 7-[2-(1-tertiary butoxycarbonyl
-1-cyclopentyloxyimino)-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-cephem-4
-Carboxylic acid (syn isomer), mp165-169℃
(Disassembly). IR (Nujiyor): 3400, 3300, 3200, 1770,
1710, 1680, 1610, 1520, 1290, 1240,
1150, 1000, 970, 740cm ^-1 (9) 7-[2-(α-carboxybenzyloxy
imino)-2-(5-amino-1,2,4-thi
Asiazol-3-yl)acetamide]-3
-Cefem-4-carboxylic acid (syn isomer),
mp170-175℃ (decomposition). IR (Nujiyor): 3400, 3280, 3160, 2600,
1770, 1720, 1670, 1625, 1520cm ^-1 (10) 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetamide]-3-cephem-4
-Carboxylic acid (syn isomer), mp180-185℃
(Disassembly). IR (Nujiyor): 3350, 3250, 1770, 1720,
1680, 1630, 1530cm ^-1 (11) 7-[2-(1-carboxy-1-methyl ester
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-cephem-4-carboxylic acid
(decomposition), mp215-220℃ (decomposition). IR (Nujiyor): 3400, 3250, 3200, 1770,
1670,, 1520, 1290, 1240, 1160, 1000,
980,740cm ^-1 (12) 7-[2-(1-carboxyethoxyimi
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
fem-4-carboxylic acid (syn isomer),
mp230-235℃ (decomposition). IR (Nujiyor): 3400, 3250, 3150, 1760,
1720, 1660, 1610, 1550, 1290, 1240,,
1170, 970, 740cm ^-1 (13) 7-[2-(1-carboxy-1-cyclo
pentyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-cephem-4-carboxylic acid
(syn isomer), mp212-217℃ (decomposed). IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1520, 1280, 1240, 1180, 1000, 970,
730cm ^-1 (14) 7-[2-(2-oxo-3-tetrahydride
lofuryloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-cephem-4-carboxylic acid
(syn isomer), mp175-180℃ (decomposed). IR (Nujiyor): 3300, 3200, 1775, 1670,
1620, 1530cm ^-1 (15) 7-[2-(1-benzyloxycarboni
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-cephem-4-carboxylic acid (sin
isomers), mp177-180℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1730, 1680, 1610, 1520, 1240, 1160,
1040, 980, 740cm ^-1 (16) 7-[2-(1-butoxycarbonyleth)
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-3-Cefem-4-carboxylic acid (synisomer
body), mp147-151℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1720, 1680, 1610, 1520, 1280, 1235,
1155, 1045, 980, 740cm ^-1 (17) 7-[2-phenoxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-cephem-4-cal
Bonic acid 4-nitrobenzyl ester (synisomer
body), mp140-145℃ (decomposition). IR (Nujiyor): 3300, 1774, 1720, 1680,
1625, 1600, 1590, 1520cm ^-1 (18) 7-[2-(4-fluorophenoxyimide)
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
Fem-4-carboxylic acid 4-nitrobenzyl
Stell (syn isomer), mp135-140℃ (decomposed). IR (Nujiyor): 3300, 3200, 1770, 1720,
1680, 1625, 1605, 1500, 1495cm ^-1 (19) 7-[2-(4-chlorophenoxyimide)
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
Fem-4-carboxylic acid-4-nitrobenzyl
Ester (syn isomer), mp155-160℃ (min
solution). IR (Nujiyor): 3300, 3180, 1770, 1720,
1680, 1625, 1600, 1580, 1520, 1480cm ^-1 (20) 7-[2-(3-trifluoromethylphene
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
[do]-3-cephem-4-carboxylic acid 4-nito
lobenzyl ester (syn isomer), mp136~
140℃ (decomposition). IR (Nujiyor): 3370, 3200, 1780, 1730,
1690, 1680, 1630, 1610, 1520, 1450,
1325, 1280, 1160, 1125, 975, 850, 740cm
^-1 (21) 7-[2-(3-trifluoromethylphene
noxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-cephem-4-carboxylic acid
gender body). This product decomposes up to 193℃. IR (Nujiyor): 3450, 3320, 3200, 1770,
1710, 1665, 1630, 1560, 1515, 1325,
1170, 1110, 940cm ^-1 (22) 7-[2-phenoxyimino-2-(5-
Amino-1,2,4-thiadiazole-3-i
) Acetamide]-3-cephem-4-cal
Bonic acid (syn isomer), mp168-170°C (decomposed). IR (Nujiyor): 3400, 3200, 1780, 1660,
1620, 1600, 1590, 1540cm ^-1 (23) 7-[2-(4-chlorophenoximine)
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
fem-4-carboxylic acid (syn isomer),
mp145-150℃ (decomposition). IR (Nujiyor): 3400, 3260, 3180, 1775,
1675, 1625, 1600, 1520, 1480cm ^-1 (24) 7-[2-(4-fluorophenoxyimide)
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamide]-3-ce
fem-4-carboxylic acid (syn isomer),
mp130-135℃ (decomposition). IR (Nujiyor): 3400, 3270, 3180, 1765,
1675, 1605, 1500cm ^-1 (25) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
il) Acetamide]-3-Cefem-4-ka
Rubonic acid (4-nitrobenzyl ester)
isomers), mp125-130℃ (decomposition). IR (Nujiyor): 3300, 1770, 1720, 1680,
1630, 1610, 1520cm ^-1 (26) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
il) Acetamide]-3-Cefem-4-ka
Rubonic acid (syn isomer), mp160-165℃ (min
solution). (27) 7-[2-(2-cyclopentene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-cephem-4-carboxylic acid (sin
isomers), mp180-185℃ (decomposition). IR (Nujiyor): 3500, 3430, 3300, 3200,
1770, 1690, 1660, 1640, 1620, 1580, 1510
cm ^-1 (28) 7-[2-cyclopentyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-cephem
-4-carboxylic acid (syn isomer), mp170-175
℃ IR (nujiol): 3520, 3420, 3320, 3220,
3160, 1770, 1685, 1655, 1635, 1625,
1570, 1505cm ^-1 (29) 7-[2-(2-cyclohexene-1-i)
)oximino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-3-cephem-4-carboxylic acid (sin
isomers), mp175-180℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1670,
1630, 1520cm ^-1 (30) 7-[2-cycloheptyloxyimino-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamide]-3-cephem
-4-carboxylic acid (syn isomer). White powder.
mp170-175℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1670, 1620, 1520, 1280, 1240, 1160,
1000, 980, 730cm ^-1 Example 51 The following compound was obtained in the same manner as in Example 29. (1) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamido]-2-methyl-3
-Cefem-4-carboxylic acid 1-acetoxye
Tyl ester (syn isomer). IR (Nujiyor): 3400, 3310, 3150, 1780,
1750, 1675cm ^-1 NMR (DMSO-d ₆ , δ): 1.2−1.6 (6H, m),
1.5-2.1 (8H, m), 2.07 (3H, s), 3.6-4.1
(1H, m), 4.6-5.0 (1H, m), 5.17 (1H,
d, J = 4.5Hz), 5.95 (1H, dd, J = 4.5 and
and 8Hz), 6.67 (1H, d, J = 6Hz), 6.90
(1H, q, J = 5Hz), 8.12 (2H, broad
s), 9.45 (1H, d, J = 8Hz) (2) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamido]-2-methyl-3
-Cefem-4-carboxylic acid 1-isobutyryl
Oxyethyl ester (syn isomer), amorphous
powder. IR (Nujiyor): 3400, 3300, 3170, 1780,
1745, 1675, 1620, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 1.08 (6H, d, J=
7Hz), 1.2-2.2 (14H, m), 2.2-2.9 (1H,
m), 3.88 (1H, q, J = 7Hz), 4.6-5.0
(1H, m), 5.12 (1H, d, J=4.5Hz), 5.90
(1H, dd, J = 4.5 and 8Hz), 6.63 (1H,
d, J=7Hz), 8.06 (2H, broad s), 9.43
(1H, d, J=8Hz) (3) 7-[2-(2cyclopentene-1-yl)
ximino)-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-2-methyl-3-cephem-4-carboxylic acid
1-acetoxypropyl ester (synisomer
body), mp110-128℃ (decomposition). IR (Nujiyor): 3400, 3280, 3150, 1780,
1750, 1730, 1620cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 0.92 (3H, t,
J=7.5Hz), 1.42 (3H, d, J=7Hz), 1.8
-2.5 (4H, m), 1.5-2.3 (2H, m), 2.05
(3H, s), 3.6-4.1 (1H, m), 5.10 (1H,
d, J = 4.5Hz), 5.1-5.5 (1H, m), 5.7-
6.3 (3H, m), 6.4−6.9 (2H, m) (4) 7-[2-(2-cyclopenten-1-yl
Oximino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-2-Metel-3-Cefem-4-Carbo
1-(2-azidoethoxycarbonyloxy)
c) Ethyl ester (syn isomer), mp85~
100℃ (decomposition). IR (Nujiyor): 3310, 2200, 1760-1785,
1680cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.48 (3H, d,
J=6Hz), 1.5 (3H, d, J=4.5Hz), 2.0−
2.5 (4H, m), 3.5-4.1 (1H, m), 3.63 (2H,
t, J = 4Hz), 4.30 (2H, t, J = 4Hz),
5.16 (1H, d, J = 4.5Hz), 5.2-5.45 (1H,
m), 5.7-6.2 (2H, m), 6-6.2 (1H, m),
6.6-6.8 (1H, m), 6.7 (1H, d, J = 6Hz) (5) 7-[2-(2-cyclopenten-1-yl
Oxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
1-Ethoxycarbonyloxyethyl ester
Stell (syn isomer). IR (Nujiyor): 3420, 3300, 3150, 1780,
1760, 1675, 1620cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.23 (3H, t,
J=8Hz), 1.42 (3H, d, J=7Hz), 1.88
(3H, d, J=5Hz), 1.8-2.5 (4H, m),
3.6−4.1 (1H, m), 4.19 (2H, q, J=8
Hz), 5.18 (1H, d, J = 5Hz), 5.2-5.6
(1H, m), 5.9-6.3 (2H, m), 5.95 (1H,
d, J = 5Hz), 6.8 (1H, q, J = 5Hz) (6) 7-{3-(N-tertiary butoxycarbonyl
amino) propoxyimino}-2-(5-amino)
(n-1,2,4-thiadiazol-3-yl)
Acetamide]-2-methyl-3-cephem-
4-Carboxylic acid pivaloyloxymethyl ester
(syn isomer), powder. mp66-75℃ (decomposed). IR (Nujiyor): 3300, 1780, 1745, 1680,
1620cm ^-1 (7) 7-[2-{3-(N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-
3-Cefem-4-carboxylic acid pivaloyloki
Dimethyl ester (syn isomer), powder. IR (Nujiyor): 3300, 1780, 1745, 1680,
1620cm ^-1 (8) 7-[2-{3-(N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(5-methyl-
1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid pivalo
yloxymethyl ester (syn isomer). IR (Nujiyor): 3300, 3150, 1783, 1745,
1675, 1615cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.15 (9H,
s), 1.37 (9H, s), 1.5-2.0 (2H, m),
2.63 (3H, s), 2.8-3.2 (2H, m), 3.5-3.8
(2H, m), 3.9−4.3 (2H, m), 4.16 and
4.53 (2H, ABq, J=13Hz), 5.17 (1H, d,
J = 4.5Hz), 5.6-6.0 (3H, m) (9) 7-[2-{3-(N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-[1-(2-hydro)
(loxyethyl)-1H-tetrazole-5-i
]Thiomethyl-3-cephem-4-carvone
Acid pivaloyloxymethyl ester (syn isomer
body), powder, mp88-101℃ (decomposed). IR (Nujiyor): 3300, 1780, 1750, 1675,
1620cm ^-1 (10) 7-[2-{3-(N-tertiary butoxylic
Bonylamino) propoxyimino}-2-(5
-Amino-1,2,4-thiadiazole-3-
yl)acetamide]-3-(1,3,4-thi)
Asiazol-2-yl)-thiomethyl-3-
Cefem-4-carboxylic acid pivaloyloxime
Tyl ester (syn isomer), powder, mp71-84
°C (decomposition). IR (Nujiyor): 3300, 1780, 1745, 1680,
1615cm ^-1 (11) 7-[2-(2-cyclohexen-1-yl
Oximino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
]--Pivaloyloxime cephalosporanate
Tyl ester (syn isomer), mp93~101℃
(Disassembly). IR (Nujiyor): 3400, 3300, 3180, 1780,
1740, 1675, 1615, 1525cm NMR (DMSO―d ₆ +D ₂ O, δ): 1.13 (9H,
s), 1.4.2.2 (6H, m), 2.02 (3H, s), 3.58
(2H, s), 4.50−4.93 (1H, m), 4.68 and
and 4.90 (2H, ABq, J=13.5Hz), 5.18 (1H,
d, J = 4.5Hz), 5.6-6.2 (5H, m) (12) 7-[2-(2-cyclopenten-1-yl
Oximino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-2-methyl-3-cephem-4-carbo
phthalid-3-yl ester of phosphoric acid (synisomer
body), mp131-144℃ (decomposition). IR (Nujiyor): 3420, 3210, 3150, 1780,
1740, 1675, 1620, 1525cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.45 (3H, d,
J = 7Hz), 1.9-2.5 (4H, m), 5.13 (1H,
d, J = 4.5Hz), 5.2-5.5 (1H, m), 5.7-
6.3 (3H, m), 6.75 (1/2H, d, J=6
Hz), 6.77 (1/2H, d, J = 6Hz), 7.62
(1/2H, s), 7.65 (1/2H, s), 7.83
(4H, broad s) (13) 7-[2-(2-cyclopentene-1-i
ruoxiimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
Bonic acid pivaloyloxymethyl ester (sin
isomers), mp111-124℃ (decomposition). IR (Nujiyor): 3400, 3300, 3270, 1775,
1740, 1670, 1620, 1520cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.17 (9H,
s), 1.45 (3H, d, J=7Hz), 1.9−2.4
(4H, m), 3.7-4.0 (1H, m), 5.1-5.6
(1H, m), 5.13 (1H, d, J=4.5Hz), 5.7
-6.3 (5H, m), 6.65 (1H, d, J = 7Hz) (14) 7-[2-(2-cyclopentene-1-i)
ruoxiimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetoa
mido]-2-methyl-3-cephem-4-cal
Bonic acid 1-benzoyloxyethyl ester
(syn isomer), mp132-137 (degraded). IR (Nujiyor): 3400, 3300, 3160, 1780,
1738, 1680, 1620cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.43 (3H, d,
J=7Hz), 1.62 (3H, d, J=5Hz), 1.7−
2.4 (4H, m), 3.84 (1H, q, J=7Hz),
5.0−5.4 (1H, m), 5.13 (1H, d, J = 4.5
Hz), 5.6-6.3 (3H, m), 6.70 (1H, d, J
= 6Hz), 7.16 (1H, q, J = 5Hz), 7.3−
8.2 (5H, m) (15) 7-[2-{4-(N-tertiary butoxyca
(rubonylamino) methylbenzyloxyimide
No}-2-(5-amino-1,2,4-thiazi
Azol-3-yl)acetamide]-3-meth
Chil-3-cephem-4-carboxylic acid pivaloy
oxymethyl ester (syn isomer), powder. IR (nujiyor): 3300, 1780, 1750, 1680cm
^-1 (16) 7-[2-allyloxyimino-2-(5
-Amino-1,2,4-thiadiazole-3-
yl) acetamide]-3-[1-{2-(N
-Tertiary butoxycarbonylamino)ethyl}
-1H-tetrazol-5-yl]thiomethyl
-3-cephem-4-carboxylic acid pivaloyloki
Dimethyl ester (syn isomer), powder. IR (nujiyor): 3300, 1780, 1750, 1680cm
^-1 Example 52 7-[2-(3-aminopropoxyimino)-
2-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-2-methyl-3-
Cefem-4-carboxylic acid (syn isomer) (132
mg), bis(trimethylsilyl)acetamide
(0.6 ml) and methylene chloride (6 ml).
Add 2-(1-amino-1-cyclohexychloride) to the solution.
) Acetyl hydrochloride (127.2 mg) and methylene
A solution of chloride (2 ml) was stirred at -30℃ for 5 minutes.
Add the mixture dropwise for 30 minutes at -30 to -35℃.
Stir for a minute. Sodium carbon hydrogen saturated aqueous solution
The mixture was added and further stirred, and the reaction mixture was washed in a conventional manner.
When processed, 7-[2
-{3-(N-(2-1-amino-1-cyclohe
xyl)acetyl)amino)propoxyimino}
-2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetamido]-2-methyl-3
-Cefem-4-carboxylic acid (syn isomer) (85
mg). IR (Nujiyor): 3250, 3150, 1760, 1640,
1580, 1520cm ^-1 NMR(D ₂ O + DCl, δ): 1.0−2.2 (15H, m),
2.65 (2H, s), 3.1-3.6 (2H, m), 3.6-4.1
(1H, m), 4.1-4.6 (2H, m), 5.0-5.3
(1H, m), 5.95 (1H, d, J=4.5Hz), 6.82
(1H, d, J=6Hz) Example 53 The following compound was obtained in the same manner as in Example 52. (1) 7-[2-{2-(N-tertiary butoxylic
(bonyl)-D-phenylglycylamino)eth
ximino}-2-(5-amino-1,2,4
-Thiadiazol-3-yl)acetamide]
-2-methyl-3-cephem-4-carboxylic acid
(syn isomer), mp77-91℃ (degraded). IR (Nujiyor): 3300, 3160, 1775, 1680,
1660, 1630, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 1.37 (9H, s), 1.40
(3H, d, J=8Hz), 3.1-4.2 (5H, m),
5.08 (1H, d, J = 4.5Hz), 5.10 (1H, d,
J = 8Hz), 5.90 (1H, dd, J = 4.5 and 9
Hz), 6.58 (1H, d, J = 7.5Hz), 7.32 (5H,
s), 8.13 (2H, broad s), 9.48 (1H, d,
J=9Hz) (2) 7-[2-{3-(N-(N-tertiary butoki)
(cycarbonyl)-D-phenylglycylamide
g) Propoxyimino}-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-2-methyl-3-cephem-4-
Carboxylic acid (syn isomer) IR (Nudiyol): 3300, 3200, 1775, 1700,
1650, 1525cm ^-1 NMR (DMSO−D ₂ O, δ): 1.3−1.6 (12H,
m), 1.6-2.0 (2H, m), 2.8-3.4 (2H, m),
3.82 (1H, q, J = 7.5Hz), 3.9−4.3 (2H,
m), 5.05 (1H, d, J = 4.5Hz), 5..83 (1H,
d, J = 4.5Hz), 6.48 (1H, d, J = 6Hz) Production example 23 Solution of iodine (7.7g) and concentrated sulfuric acid (70ml)
Then, add potassium iodate (20.0 g) at room temperature with stirring.
and stir the mixture for 1.5 hours at 35-40°C.
Acetic anhydride (30ml) was added for 0.5 hours at below 10℃.
and then 1,2-dichlorobenzene (44.69
g) is added over a period of 0.5 hour at a temperature below 10°C. mixture
The mixture was stirred at the same temperature for 1 hour, then at room temperature for 19 hours.
Stir. Pour the reaction mixture into ice water (500ml)
and wash with diethyl ether. Sodium chloride in the aqueous layer
Add thorium (8.9g) aqueous solution (50ml) and precipitate.
When taken and washed with ice water, mp183~186℃
(Decomposition) of 3,4,3',4'-tetrachlorodiphene
Niliodonium chloride (58 g) is obtained. IR (Nujiyor): 1555, 1450, 1250, 1210,
11701125, 1030cm ^-1 Production Example 24 The following compound was obtained in the same manner as Production Example 23. (1) 3.3′-di(trifluoromethyl)diphenyl
Iodonium chloride IR (nujiol): 3600, 3200, 1600, 1420,
1320, 1310, 1190, 1170, 1120, 1095,
1085, 1055, 800, 700, 658cm ^-1 (2) 3,3′-dicarboxydiphenyliodonium
Mubromide IR (Nujiol): 3400, 1700, 1290, 1250,
1210, 1170, 1050, 750cm ^-1 (3) 3,3′-di(ethoxycarbonyl)dipheni
Ruiodonium bromide mp154-157℃. IR (Nujiyor): 1730, 1295, 1280, 1250,
1110, 1020, 750cm ^-1 Production Example 25 In the same manner as Production Example 1-(1) and 1-(2), the following
I got a compound. (1) N-(3-phthalimidopropoxy)phthal
Imide, mp168-170℃. IR (Nujiyor): 1790, 1770, 1730, 1710,
1390, 1060, 725, 705cm ^-1 (2) N-(1-cyclohexyloxycarbonyl
ethoxy) phthalimide, mp50-54℃. NMR(d ₆ −DMSO, δ): 1.51 (3H, d, J=
7Hz), 0.9-2.1 (10H, m), 4.7 (1H, m),
4.82 (1H, q, J = 7Hz), 7.87 (4H, s) (3) N-(α-tertiary butoxycarbonylbenzi
ruoxy) phthalimide. (4) N-(1-tertiary butoxycarbonyl-2-
Methylpropoxy)phthalimide. mp84~87
℃. IR (Nujiyor): 1790, 1730, 1360, 1160,
1140, 1000, 880, 780, 700cm ^-1 (5) N-(1-tertiary butoxycarbonylpropo
xy) phthalimide, mp49-52℃. NMR(d ₆ −DMSO, δ): 1.02 (3H, t, J=
7Hz), 1.40 (9H, s), 1.9 (2H, m), 4.55
(1H, t, J = 6Hz), 7.82 (4H, s) (6) N-(1-tert-butoxycarbonyl ethoxy
c) Phthalimide, mp80-82℃. NMR(d ₆ −DMSO, δ): 1.42 (9H, S), 1.48
(3H, d, J = 7Hz), 4.72 (1H, q, J =
7Hz), 7.86 (4H, s) (7) N-(1-tertiary butoxycarbonyl-1-
Methyl ethoxy) phthalimide, mp96~100
℃. NMR(d ₆ −DMSO, δ): 1.42 (9H, S), 1.48
(6H, s), 7.87 (4H, s) (8) N-(1-butoxycarbonylethoxy) fluoride
Talimide, mp48-53℃. IR (Nujiyor): 1755, 1720, 1210, 1140,
1110, 1080, 875, 695cm ^-1 (9) N-(1-benzyloxycarbonylethoxy)
c) Phthalimide, mp65-68℃. IR (Nujiyor): 1790, 1740, 1450, 1210,
1190, 1110, 1080, 980, 880, 735, 700cm ^-1 (10) N-(2-oxo-3-tetrahydrofuryl
Oxy) phthalimide, mp140-142℃ IR (Nudiyol): 1785, 1760, 1720, 1605,
1215, 1185, 870, 695cm ^-1 Production Example 26 The following compound was obtained in the same manner as Production Example 2. (1) 3-Aminopropoxyamine dihydrochloride NMR (D ₂ O, δ): 2.20 (2H, m), 3.27 (2H,
t, J = 7Hz), 4.33 (2H, t, J = 6Hz) (2) 1-phenylethoxyamine (3) 1-tertiary butoxycarbonyl-2-methyl
Propoxyamine (4) α-tertiary butoxycarbonylbenzyl oxychloride
Cyamine (5) 1-Butoxycarbonylethoxyamine Production Example 27 The following compound was obtained in the same manner as Production Example 17. (1) 2-(tertiary butoxycarbonylmethoxy)
mino)-2-(5-amino-1,2,4-thia
diazol-3-yl)acetic acid (syn isomer),
mp150-155℃ (decomposition). IR (Nujiyor): 3420, 3230, 3100, 1725,
1610, 1530cm ^-1 NMR (DMSO-d ₆ , δ): 1.45 (9H, s), 4.70
(2H, s), 8.12 (2H, broad s) (2) 2-(1-cyclohexyloxycarbonyl
ethoxyimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetic acid
isomers). mp175-180℃ (decomposition). IR (Nujiyor): 3380, 3260, 3170, 1720,
1610, 1520, 1220, 990, 710cm ^-1 NMR(d ₆ −DMSO, δ): 0.99−2.1 (13H,
m), 4.7 (1H, m), 4.85 (1H, q, J=6
Hz) 8.13 (2H, broad s) (3) 2-(thiolane-1,1-dioxide-3
-yloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetic acid
(Syn isomer) mp200-205℃ (decomposition). IR (nujiyor): 3300, 1720, 1620, 1530cm
^-1 NMR(d ₆ −DMSO, δ): 2.20−2.50 (2H,
m), 3.00-3.50 (4H, m), 5.00-5.27 (1H,
m), 8.20 (2H, s) (4) 2-(α-tertiary butoxycarbonylbenzi
ruoxiimino)-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetic acid
mp155-160℃ (decomposition). IR (Nujiyor): 3440, 3350, 3250, 1750,
1730, 1640, 1535cm ^-1 NMR(d ₆ −DMSO, δ): 1.37 (9H, s), 5.67
(1H, s), 7.45 (5H, s), 8.25 (2H, broad
s) (5) 2-(1-tertiary butoxycarbonyl)-2
-methylpropoxyimino)-2-(5-amino)
(n-1,2,4-thiadiazol-3-yl)
Acetic acid (syn isomer) mp158-162℃ (decomposition). IR (Nujiyor): 3600, 3400, 1740, 1720,
1630cm ^-1 NMR(d ₆ −DMSO, δ): 0.95 (6H, d, J=
7Hz), 1.8-2.4 (1H, m), 4.33 (1H, d,
J = 6 Hz), 8.13 (2H, broad s) (6) 2-(1-tertiary butoxycarbonylpropo
ximino)-2-(5-amino-1,2,4
-thiadiazol-3-yl)acetic acid (synisomer
body) mp152-155℃ decomposition. NMR(d ₆ −DMSO, δ): 0.94 (3H, t, J=
7Hz), 1.42 (9H, s), 1.80 (2H, m), 4.51
(1H, t, J = 6Hz), 8.16 (2H, broad s) (7) 2-(1-tertiary butoxycarbonyl ethoxy
(shiimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetic acid (synisomer
body), mp155-156℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1720,
1710, 1620, 1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.2−1.7 (12H, m),
4.72 (1H, q, J = 7Hz), 8.2 (2H, broad
s) (8) 2-(1-tertiary butoxycarbonyl-1-
methylethoxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetic acid
(syn isomer), mp180-181℃ (decomposed). IR (Nujiyor): 3400, 3300, 3200, 1745,
1715, 1630, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 1.38 (9H, s), 1.43
(6H, s), 8.15 (2H, broad s) (9) 2-(1-butoxycarbonyl ethoxyimide
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetic acid (syn isomer),
mp120-123℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1725,
1615, 1510, 1410, 1210, 1170, 1135,
1100, 1040, 990, 870, 720cm ^-1 NMR (DMSO−d ₆ , δ): 0.85 (3H, t, J=
6Hz), 1.43 (3H, d, J=7Hz), 1.0−1.74
(4H, m), 4.12 (2H, t, J=6Hz), 4.85
(1H, q, J = 7Hz), 8.04 (2H, broad s) (10) 2-(1-benzyloxycarbonyl ethoxy
(shiimino)-2-(5-amino-1,2,4-
thiadiazol-3-yl)acetic acid (synisomer
body) mp129-133℃ (decomposition). IR (Nujiyor): 3300, 3200, 1720, 1620,
1530cm ^-1 NMR (DMSO−d ₆ , δ): 1.45 (3H, d, J=
6Hz), 4.97 (1H, q, J = 6Hz), 5.13 (2H,
s), 7.31 (5H, s), 8.17 (2H, broad s) Production Example 28 The following compound was obtained in the same manner as Production Example 15. (1) 2-(thiolane-1,1-dioxide-3
-yloxyimino)-2-(5-formamide)
Do-1,2,4-thiadiazole-3-i
) Acetic acid (syn isomer), mp214°C (decomposed). IR (Nujiyor): 3200, 1720, 1680, 1600,
1530cm ^-1 NMR (DMSO−d ₆ , δ): 2.30−2.50 (2H,
m), 2.90-3.83 (4H, m), 5.10-5.50 (1H,
m), 8.92 (1H, s) (2) 2-(1-phenylethoxyimino)-2-
(5-formamide-1,2,4-thiadia
zol-3-yl)acetic acid (syn isomer),
mp174-175℃ (decomposition). IR (nujiyor): 3100, 1720, 1690, 1550cm
^-1 NMR(d ₆ −DMSO, δ): 1.58 (3H, d, J=
6Hz), 5.44 (1H, q, J = 6Hz), 7.32 (5H,
m), 8.78 (1H, m), 13.34 (1H, broad s) Production Example 29 2-(3-amidium) produced in the same manner as Production Example 15
nopropoxyimino)-2-(5-formamino)
-1,2,4-thiadiazol-3-yl)acetic acid
In an aqueous solution containing sodium (syn isomer),
Thylamine (20g) and 2-tertiary butoxyca
Rubonylmethoxyimino-2-phenylacetoni
A solution of tolyl (27g) and dioxane (270ml)
Add dropwise and stir the mixture for 2 hours at room temperature. Geoki
After distilling off the san, adjust the aqueous layer to PH6 with 10% hydrochloric acid.
and wash with ethyl acetate. Add ethyl acetate to the aqueous layer.
and adjust the mixture to PH3 with 10% hydrochloric acid. organic
The layer was washed with brine and dried with magnesium sulfate.
and concentrate to dryness. Diisopropyl ether
When ground in tel, mp115-117℃ (decomposition)
2-[3-(N-tertiary butoxycarbonyla)
Mino) propoxyimino]-2-(5-formua)
mino-1,2,4-thiadiazol-3-yl)
Acetic acid (syn isomer) (14.2 g) is obtained. IR (Nujiyor): 3320, 3150, 1740, 1680,
1560−1530, 1400, 1230, 1140, 1040,
1030,890cm ^-1 NMR (DMSO−d ₆ , δ): 1.47 (9H, s), 1.97
(2H, m), 3.10 (2H, t, J=7Hz), 4.30
(2H, t, J = 7Hz), 8.80 (1H, s) Production Example 30 The following compound was obtained in the same manner as Production Examples 13 and 29.
Ta. (1) 2-[2-(N-tertiary butoxycarbonyl
amino)ethoxyimino]-2-(5-form
Amido-1,2,4-thiadiazole-3-y
) Acetic acid (syn isomer), mp139-154°C (min.
solution). IR (Nujiyor): 3400, 3150, 1748, 1700,
1690, 1540cm ^-1 NMR (DMSO−d ₆ +D ₂ O, δ): 1.45 (9H,
s), 3.40 (2H, t, J=6Hz), 4.32 (2H,
t, J = 6 Hz), 8.07 (1H, s) (2) 2-(4-tertiary butoxycarbonylamino
methyl)benzyloxyimino-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
) Acetic acid (syn isomer). IR (Nujiyor): 3300, 3150, 1700cm ^-1 NMR (DMSO−d ₆ , δ): 1.65 (9H, s), 4.12
(2H, d, J=5.5Hz), 5.19 (2H, s), 7.21
(4H,s) Production Example 31 The following compound was obtained in the same manner as in Production Example 4. (1) 2-(N-tertiary butoxycarbonylamine
) Ethoxyimino]-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetic acid
(syn isomer), mp172-177℃ (decomposed). IR (Nujiyor): 3300, 3140, 1738, 1680,
1628, 1595, 1550, 1527, 1285, 1245,
1165, 1120cm ^-1 NMR (DMSO-d ₆ +D ₂ O, δ): 1.42 (9H,
s), 3.35 (2H, t, J=6Hz), 4.22 (2H,
t, J=6Hz) (2) 2-[3-(N-tertiary butoxycarbonyl
(propoxyimino)-2-(5-amino)
-1,2,4-thiadiazol-3-yl) vinegar
acid (syn isomer). IR (Nujiyor): 3300, 3150, 2600-2400,
1720−1660, 1620, 1530, 1250, 1160,
1030, 720cm ^-1 NMR (DMSO-d ₆ , δ): 1.33 (9H, s), 1.82
(2H, m), 3.03 (2H, m), 4.17 (2H, t,
J = 6Hz), 6.73 (1H, broad s) 8.13 (2H,
broad s) (3) 2-(4-chlorophenoximino)-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetic acid (syn isomer), mp150-155℃
(Disassembly). IR (Nujiyur): 3300, 3200, 1710, 1640,
1580, 1530cm ^-1 NMR (DMSO-d ₆ , δ): 7.37 (2H, d, J=
9Hz), 7.67 (2H, d, J = 9Hz), 8.50 (2H,
broad s) (4) 2-(4-fluorophenoxyimino)-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetic acid (syn isomer), mp140-145
°C (decomposition). IR (Nujiyor): 3450, 3300, 3200, 1730,
1630, 1530, 150cm ^-1 NMR (DMSO-d ₆ , δ): 7.17 (2H, s), 7.27
(2H, s), 8.27 (2H, s) (5) 2-[1-tertiary butoxycarbonyl-1-
Cyclopentyloxyimino-2-(5-amino)
(n-1,2,4-thiadiazol-3-yl)
Acetic acid (syn isomer), mp174-175°C (decomposed). IR (Nujiyor): 3400, 3300, 3200, 1745,
1715, 1630, 1530cm ^-1 NMR(d ₆ −DMSO, δ): 1.37 (9H, s), 1.65
(4H, m), 1.97 (4H, m), 8.17 (2H, broad
s) (6) 2-(1-phenylethoxyimino)-2-
(5-amino-1,2,4-thiadiazole-
3-yl)acetic acid (syn isomer), mp103-107℃
(Disassembly). IR (Nujiyor): 3250, 3150, 1710, 1610,
1520cm ^-1 NMR(d ₆ −DMSO, δ): 1.57 (3H, d, J=
6Hz), 5.42 (1H, q, J = 6Hz), 7.40 (5H,
m), 8.20 (2H, m) Production example 32 2-hydroxyimino-2-(5-formamide
Do-1,2,4-thiadiazol-3-yl) vinegar
Acid (syn isomer) (7.2g) and methanol (83.7g)
ml) and 1N aqueous sodium hydroxide solution (83.7ml)
Hydrous methanolic sodium hydroxide made from
4,4'-difluorodiphenyl iodo in a solution of
Add nium chloride (11.8g) and bring the mixture to room temperature.
Stir at warm temperature for 1 hour. Remove the generated oil with a slope.
Then, concentrate the solution under reduced pressure to remove methanol. water soluble
Acidify the solution with 10% hydrochloric acid and extract with ethyl acetate.
Ru. Wash the extract with water and dry with magnesium sulfate.
and concentrate to dryness. Diisopropyl ether
When ground in tel, mp130-135℃ (decomposition)
2-(4-fluorophenoxyimino)-2-
(5-formamide-1,2,4-thiadiazole
Obtained (6.0 g)
Ru. IR (Nujiyor): 3100, 3050, 1730, 1690,
1530, 1500cm ^-1 NMR (DMSO-d ₆ , δ): 7.17 (2H, s), 7.27
(2H, s), 8.83 (1H, s), 13.43 (1H, s) Production Example 33 The following compound was obtained in the same manner as Production Example 32. (1) 2-(4-chlorophenoximino)-2-
(5-formamide-1,2,4-thiadiazole
R-3-yl)acetic acid (syn isomer), mp155
-160℃ (decomposition). IR (Nujiyor): 3180, 1725, 1690, 1580,
1530cm ^-1 NMR (DMSO-d ₆ , δ): 7.30 (2H, d, J=
9Hz), 7.57 (2H, d, J = 9Hz), 9.0 (1H,
s) (2) 2-(2-methoxy-5-nitrophenoxy
imino)-2-(5-amino-1,2,4-thi
adiazol-3-yl)acetic acid (syn isomer),
mp125-128℃ (decomposition). IR (Nujiyor): 3400, 3280, 1740, 1720,
1690, 1630, 1590, 1510, 1340, 1275, 970,
720cm ^-1 NMR (DMSO-d ₆ , δ): 3.93 (3H, s), 7.27
(1H, d, J=8Hz), 8.01 (1H, d, J=
8Hz), 8.07 (1H, s), 8.30 (2H, broad s) Production Example 34 The following compound was obtained in the same manner as Production Example 21. 2-(1-tert-butoxycarbonyl-1-cy
Clopentyloxyimino)-2-(5-form
Amido-1,2,4-thiadiazole-3-y
) Acetic acid (syn isomer), mp140-141°C (decomposition). IR (Nujiyor): 3550, 1730, 1670, 1550,
1540, 1280, 1255, 1150, 980, 720cm ^-1 NMR (DMSO-d ₆ , δ): 1.48 (9H, s), 1.83
(4H, m), 2.03 (4H, m), 8.87 (1H, s),
13.6 (1H, broad s) Production Example 35 In Production Example 32, Production Example 4 was used as the raw material compound.
2-hydroxyimino-2 produced in the same manner as
-(5-amino-1,2,4-thiadiazole-
Using 3-yl)acetic acid (syn isomer), perform the same operation.
The following compound was obtained. (1) 2-(O and P-tolyloxyimino)-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetic acid (syn isomer) NMR (d ₆ -DMSO, δ): 2.20 (1H, S), 2.27
(2H, s), 6.97-7.43 (4H, m), 8.33 (2H,
bs) (2) 2-(3,4-dichlorophenoximino)
-2-(5-amino-1,2,4-thiadiazo
R-3-yl)acetic acid (syn isomer), mp177
~178℃. IR (Nujiyor): 3300, 1710, 1625, 1585,
1530, 1300, 1210, 110, 980cm ^-1 NMR (DMSO-d ₆ , δ): 6.83−7.73 (3H,
m), 8.38 (2H, broad s) (3) 2-(3-trifluoromethylphenoxy)
mino)-2-(5-amino-1,2,4-thia
Diazol-3-yl)acetic acid (syn isomer)
mp167~168℃. (Disassembly). IR (Nujiyor): 3250, 1645, 1620, 1590,
1450, 1320, 1170, 1140, 1010, 995, 845,
730cm ^-1 NMR (DMSO-d ₆ , δ): 7.63 (4H, m), 8.44
(2H, broad s) (4) 2-(3-ethoxycarbonylphenoxy)
(mino)-2-(amino-1,2,4-thiasia)
zol-3-yl)acetic acid (syn isomer) mp161
~164℃ (decomposition). IR (NujOl): 3400, 3300, 3180, 1755, 1720,
1690, 1630, 1590, 1545, 1410, 1290,
1275, 970, 900, 755cm ^-1 NMR (DMSO-d ₆ , δ): 1.36 (3H, t, J=
7Hz), 4.40 (12H, q, J = 7Hz), 7.4-8.0
(3H, m), 8.5 (2H, broad s) (5) 2-(3-carboxyphenoximino)-
2-(5-amino-1,2,4-thiadiazole
(ru-3-yl)acetic acid (syn isomer), mp186~
188℃ (decomposition). IR (Nujiyor): 3420, 3150, 1735, 1690,
1620, 1580, 1265, 1200, 1000, 980, 760cm
^-1 NMR (DMSO-d ₆ , δ): 7.3−8.0 (4H, m),
8.30 (2H, broad s) (6) N-phenoximino-2-(5-amino-
1,2,4-thiadiazol-3-yl)-vinegar
Acid (syn isomer), mp145-147°C (decomposed). IR (Nujiyor): 3350, 3170, 2500, 1730,
1710, 1645, 1630, 1595, 1535cm ^-1 NMR (DMSO-d ₆ , δ): 7.0−7.5 (5H, m),
8.30 (2H, broad s) Production example 36 (5-formamide-1,2,4-thiadiazole
(3-yl) S-methyl thioglyoxylate
Ester (64.8g) and N-(2-oxo-3-
Tetrahydrofuryloxy)phthalimide (65.0
g) with concentrated hydrochloric acid (50 ml) and water (200 ml) for 1 hour.
1-carboxy-3-hyperoxygenate produced by heating under reflux for
and droxypropoxyamine in the same manner as in Production Example 17.
When treated with
(1-carboxy-3-hydroxypropoxy
(mino)-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetic acid (syn isomer) (33.2
g) is obtained. IR (Nujiyor): 3400, 3250, 3100, 1710,
1620, 1540cm ^-1 NMR (DMSO-d ₆ , δ): 1.73−2.10 (2H,
m), 3.50 (2H, t, J=6Hz), 4.73 (1H,
t, J = 6Hz), 8.13 (2H, s) Production example 37 2-(1-carboxy-3-hydroxypropo
ximino)-2-(5-amino-1,2,4-
Thiadiazol-3-yl)acetic acid (syn isomer)
(33.0 g) and methanol (2.8),
Anhydrous magnesium sulfate (120g) and acetic anhydride
(60g). The mixture was stirred at room temperature for 30 minutes,
Filter and concentrate the liquid to dryness. Acetone the residue
(200ml) and add ethyl acetate (1).
Add. The mixture was stirred at room temperature for 1 hour to remove the precipitate.
Separate and wash with ethyl acetate. Precipitate with water (200ml)
Dissolved in ethyl acetate (500ml), acetone (200ml)
ml) and 6N hydrochloric acid (40 ml). organic layer
Separate and extract the aqueous layer with ethyl acetate. organic layer
Combine, dry over anhydrous magnesium, and concentrate to dryness.
Ru. Triturate the residue in diethyl ether and set aside.
and washed with diisopropyl ether,
2-(2-oxo-3) at mp185-187℃ (decomposition)
-tetrahydrofuryloxyimino)-2-(5
-amino-1,2,4-thiadiazole-3-i
) Obtain acetic acid (syn isomer) (26.5 g). IR (Nujiyor): 3400, 3300, 3200, 1775,
1730, 1640, 1605, 1535cm ^-1 NMR(d ₆ -DMSO, δ): 2.27-2.70 (2H,
m), 4.17-4.50 (2H, m), 5.27 (1H, t,
J = 8Hz), 8.22 (2H, s) Production Example 38 (1) Obtain the following compound in the same manner as Production Example 22-(1).
Ta. N-(6-acetamidohexyl) dithioka
Rubamic acid methyl ester NMR (DMSO-d ₆ , δ): 1.33 (8H, broad
s), 1.80 (3H, s), 2.50 (3H, s), 3.07
(2H, m), 3.53, (2H, m), 7.77 (1H,
m), 9.80 (1H, m) (2) Obtain the following compound in the same manner as in Production Example 22-(2).
Ta. (a) 1-(4-acetamidobutyl)-1H-te
Torazol-5-thiol IR (Nudiyol): 3300, 1620, 1560, 1520
cm ^-1 NMR(d ₆ -DMSO, δ): 1.23-1.93 (4H,
m), 1.77 (3H, s), 3.10 (2H, m), 4.28
(2H, m), 7.80 (1H, broad s) (b) 1-(6-acetamidohexyl)-1H
-Tetrazole-5-thiol, oil. (3) The following compound was obtained in the same manner as in Production Example 22-(3).
Ta. (a) 1-(4-aminobutyl)-1H-tetra
Sol-5-thiol hydrochloride, white powder. (b) 1-(6-aminohexyl)-1H-tet
Lazole-5-thiol hydrochloride, red oil
thing. (4) The following compound was obtained in the same manner as in Production Example 22-(4).
Ta. (a) 1-[4-(N-tertiary butoxycarbonylate)
Ruamino)butyl]-1H-tetrazole-
5-thiol, mp107-108.5℃. IR (nujiyor): 3200, 1640, 1520cm ^-1 NMR(d ₆ -DMSO, δ): 1.37 (9H, s),
1.33−2.1 (4H, m), 2.97 (2H, m), 4.23
(2H, m), 6.73 (1H, broad s) (b) 1-[6-(N-tertiary butoxycarbonyl
Ruamino)hexyl]-1H-tetrazole
-5-thiol, oily substance. NMR (DMSO-d ₆ , δ): 1.40 (15H, m),
1.77 (2H, m), 2.93 (2H, m), 4.20 (2H,
m), 6.70 (1H, broad s) Production example 39 (1) N-(3-bromopropyl)phthalimide
(402g) and acetone (2.5), 1-
Methylpiperazine (225g) and potassium carbonate
Add mussels (415g). Stir the resulting mixture
Reflux for under 3.5 hours. Cool the mixture and strain
Ru. Wash the mass with acetone (500 ml).
Combine the liquid and washing liquid and concentrate under reduced pressure. residual oily
When raw materials in a substance are azeotropically removed with benzene, they become stateless.
N-[3-(4-methyl-1-piperazini)
[propyl]phthalimide (502 g) was obtained. IR (liquid film): 1770, 1700cm ^-1 (2) N-[3-(4-methyl-1-piperazini)
) propyl] phthalimide (502g) and eta
100% hydrazine hydrated in a solution of nol (3.0)
(187.6g). Stir the resulting mixture.
Heat to reflux for 1.5 hours while stirring. Cool the mixture;
pass Wash the mass with ethanol (1)
Ru. Combine the liquid and washing liquid and concentrate under reduced pressure. residual
When the oily substance is distilled under reduced pressure, bp (34 mmHg)
3-(4-methyl-1-piperazi) at 127-128℃
(146.6 g) of propylamine (146.6 g) is obtained. (3) Potassium hydroxide (57.3g) and methanol
(250 ml) of 3-(4-methyl-1-pi
Add perazinyl) propylamine (146g),
Furthermore, carbon disulfide (70.6 g) was added for 40 minutes under ice cooling and stirring.
Take your time and add. Cool the resulting mixture on ice.
Stir for 3.5 hours. The reaction mixture is concentrated under reduced pressure.
Dissolve the remaining oil in water (400ml) and
Wash twice with chill ether. The washed aqueous layer
Cool on ice and add methyl iodide (132.1g) while stirring.
Add. Stir the resulting mixture under ice cooling for 2 hours.
Then, add ethyl acetate (400ml x 3) and chlorophore.
Extract with Lum (400ml x 2). Combine the extracts
dried over magnesium sulfate, and concentrated under reduced pressure.
and N-[3-(4-methyl-1-piperazini)
) Propyl] methyl dithiocarbamate
Obtain tel (139.3 g). This product can be used without refining.
It was used in the process. (4) N-[3-(4-methyl-1-piperazini)
) Propyldithiocarbamate methyl ester
(obtained in Production Example 39(3)) (139.3g),
Solution of water (420ml) and ethanol (280ml)
Add sodium azide (47.6g) to the solution. Obtained
The mixture is heated under reflux for 3 hours while stirring. anti
The reaction mixture is concentrated under reduced pressure. Ethyl acetate concentrate
and diethyl ether and concentrated.
Ru. Add ethanol to the residue and filter the mixture.
do. Concentrate the liquid under reduced pressure to remove the remaining oil.
Add 6N hydrochloric acid. Concentrate the mixture under reduced pressure. Residue
Recrystallize the distillate from aqueous isopropyl alcohol
Then, mp239~243℃ 1-[3-(4-method)
Chyl-1piperazinyl)propyl]-1H-te
Torazol-5-thiol dihydrochloride (48.1g)
get. NMR(D ₂ O, δ): 2.3−2.8 (2H, m), 3.07
(3H, s), 3.3-3.7 (2H, m), 3.75 (8H,
s), 4.42 (2H, t, J=6Hz) Manufacturing example 40 Examples 1-3, 5, 7-12, 31-33 and 39
Following a similar method, 7-[2-cyclopentyloxyimino-2-
(5-amino-1,2,4-thiadiazole-3
-yl)acetamide]-3-hydroxycefa
Mu-4-carboxylic acid (syn isomer), mp169-173
°C (decomposition) was obtained. IR (Nujiyor): 3440, 3250, 1750, 1660,
1520, 1400, 1240, 1060, 990, 720cm ^-1 NMR (DMSO-d ₆ , δ): 1.7 (8H, m), 2.77
(1H, m), 3.0-3.5 (1H, m), 3.7-4.1
(1H, s), 4.43 (1H, d, J=6Hz), 4.73
(1H, m), 5.16 (1H, d, J=5Hz), 5.47
(1H, dd, J=5 and 8Hz), 8.02 (2H,
s), 9.33 (1H, d, J=8Hz) Example 54 The following compound was prepared in the same manner as in Example 39, 41 or 46.
I got it. 7-[2-carboxymethoxyimino-2-
(5-amino-1,2,4-thiadiazole-3
-yl)acetamide]-3-[1-(2-cal)
boxyethyl)-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
isomer), mp215-220℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1720,
1680, 1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 2.93 (2H, t, J=
6Hz), 3.67 (2H, broad s), 4.33 (2H,
broad s), 4.43 (2H, t, J=6Hz), 4.67
(2H, s), 5.10 (1H, d, J=4Hz), 5.83
(1H, dd, J=4 and 8Hz), 8.13 (2H,
s), 9.50 (1H, d, J = 8Hz) Example 55 Example 29, 39, 41, 43, 44, 46 or 47
The following compounds were obtained according to either method. (1) 7-[2-(2-oxo-3-tetrahydro
furyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-[1-(3-(N-tertiary block)
Toxycarbonylamino)propyl)-1H-
Tetrazol-5-yl]thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp130-135℃ (decomposition). IR (Nujiyor): 3300, 3200, 1780, 1680,
1620, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 1.53 (9H, s), 1.80
-2.10 (2H, m), 2.4-3.1 (4H, m), 3.73
(2H, broad s), 4.0−4.7 (6H, m), 5.13
(1H, d, J = 4Hz), 5.20 (1H, t, J =
7Hz), 5.83 (1H, dd, J=4 and 8Hz),
8.13 (2H, s), 9.57 (1H, d, J = 8Hz) (2) 7-[2-(2-oxo-3-tetrahydro
furyloxyimino)-2-(5-amino-
1,2,4-thiadiazol-3-yl)acetate
toamide]-3-[1-(3-aminopropylene)
)-1H-tetrazol-5-yl]thiome
Chill-3-cefem-4-carboxylic acid
(decomposition), mp210-215℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 2.0−2.5 (4H, m),
2.8−3.0 (2H, m), 3.93 (2H, broad s),
4.0−4.70 (6H, m), 5.03 (1H, d, J=4
Hz), 5.20 (1H, t, J=7Hz), 5.86 (1H,
dd, J=4 and 8Hz), 8.13 (2H, s),
9.50 (1H, d, J = 8Hz) (3) 7-[2-(1-methyl-1-carboxye
Toxiimino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Cephalosporanic acid (syn isomer),
mp210-220℃ (decomposition). IR (Nujiyor): 3400, 3300, 3200, 1770,
1720, 1700−1670, 1620, 1520, 1230,
1150, 1060, 1020, 995, 975, 920, 740,
720cm ^-1 NMR (DMSO-d ₆ , δ): 1.48 (6H, s), 2.05
(3H, s), 3.60 (2H, m), 4.73 and 5.11
(2H, ABq, J = 14Hz), 5.23 (1H, d, J
= 5Hz), 5.93 (1H, dd, J = 5 and 9
Hz), 8.30 (2H broad s), 9.57 (1H, d, J
=9Hz) (4) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamido]-2-methyl-3
-Cefem-4-carboxylic acid pivaloyloxy
Dimethyl ester (syn isomer), amorphous powder. IR (Nujiyor): 3450, 3360, 3200, 1790,
1750, 1680, 1625, 1530cm ^-1 NMR (DMSO-d ₆ , δ): 1.15 (9H, s), 1.43
(3H, d, J=7Hz), 1.2-2.0 (8H, m),
3.7-4.1 (1H, m), 4.4-4.9 (1H, m), 5.13
(1H, d, J=4.5Hz), 5.7−6.1 (3H, m),
6.63 (1H, d, J = 6Hz), 8.03 (2H, broad
s), 9.42 (1H, d, J = 8.5Hz) (5) 7-[2-(1-methyl-1-tertiary butoki
cycarbonylethoxyimino)-2-(5-a
Minnow-1,2,4-thiadiazole-3-i
)acetamide]-3-[1-(3-amino
propyl)-1H-tetrazol-5-yl]
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp198-203℃ (decomposition). IR (Nujiyor): 3450-3300, 3200, 1770,
1680, 1600−1615, 1525, 1140, 990, 970,
750, 720cm ^-1 NMR(D ₂ O, δ): 1.4 (15H, broad s), 2.3
(2H, m), 3.0 (2H, m), 3.7 (2H, m), 4.1
-4.7 (4H, m), 5.13 (1H, d, J=5Hz),
5.83 (1H, d, J = 5Hz) (6) 7-[2-(1-carboxyethoxyimide
-2-(5-amino-1,2,4-thiazidi)
azol-3-yl)acetamido-3-[5
-{2-(N-tertiary butoxycarbonylamine
) Ethyl}-1,3,4-thiadiazole-
2-yl]thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer), mp202-204℃ (min
solution). IR (Nujiyor): 3350, 3200, 1780, 1680,
1620, 1520, 1250, 1170, 1100, 1050, 1000
cm ^-1 NMR (DMSO-d ₆ , δ): 1.40 (9H, s), 1.48
(3H, d, J=6Hz), 3.17−3.43 (4H, m),
3.70 (2H, m), 4.25 and 4.60 (2H, ABq,
J=13Hz), 4.73 (1H, q, J=6Hz), 5.20
(1H, d, J=5Hz), 5.88 (1H, m), 6.97
(1H, m), 8.17 ((2H, broad s), 9.50
(1Hm) (7) 7-[2-(1-carboxyethoxyimide)
-2-(5-amino-1,2,4-thiazidi)
Azol-3-yl)acetamide]-3-
[5-(2-aminoethyl)-1,3,4-thi
Asiazol-2-yl]thiomethyl-3-ce
fem-4-carboxylic acid (syn isomer),
mp200-204℃ (decomposition). IR (Nujiyor): 3350, 3200, 1770, 1680,
1620, 1520, 1240, 1180, 1100, 1060,
1040, 1000cm ^-1 NMR (DMSO-d ₆ , δ): 1.45 (3H, d, J=
6Hz), 3.05-3.77 (6H, m), 4.13 (2H,
m), 4.67 (1H, q, J = 6Hz), 5.10 (1H,
d, J=5Hz), 5.83 (1H, m), 8.13 (2H,
broad s), 9.80 (1H, m) Example 56 The following compound was obtained in the same manner as in the previous example.
Ta. (1) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(5-methy
(1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp150-155℃ (decomposed). IR (Nujiyor): 3300, 3190, 1770, 1670,
1620, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.27−2.07 (8H,
m), 2.67 (3H, s), 3.68 (2H, broad s),
4.23 and 4.53 (2H, ABq, J=13Hz), 4.60
-4.93 (1H, m), 5.13 (1H, d, J=5Hz),
5.80 (1H, dd, J=5 and 8Hz), 8.10
(2H, broad s)9.47 (1H, d, J=8Hz) (2) 7-[2-(2-cyclopenten-1-yl
Oximino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
]-3-(5-methyl-1,3,4-thiazidi
azol-2-yl)thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer), mp150~
155℃ (decomposition). IR (Nujiyor): 3350, 3220, 1775, 1680,
1620, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 1.90−2.50 (4H,
m), 2.70 (3H, s), 3.68 (2H, broad s),
4.25 and 4.53 (2H, ABq, J=13Hz)),
5.15 (1H, d, J = 5Hz), 5.23−5.53 (1H,
m), 5.70−6.30 (3H, m), 8.15 (2H, broad
s), 9.52 (1H, d, J = 8Hz) (3) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1H-te)
Torazol-5-yl)thiomethyl-3-cef
M-4-carboxylic acid (syn isomer), mp150
~155℃ (decomposition). IR (Nujiyor): 3300, 3200, 1770, 1670,
1620, 1530cm ^-1 NMR (DMSO-d ₆ , δ): 1.5−2.0((8H,
m), 3.62 and 3.72 (2H, ABq, J=17
Hz), 4.20 and 4.42 (2H, ABq, J=14
Hz), 4.65-4.84 (1H, m), 5.15 (1H, d,
J=4Hz), 5.80(1H, dd, J=4 and 8
Hz), 8.10 (2H, s), 9.50 (1H, d, J=8
Hz) (4) 7-[2-cyclopentyloxyimino-2
-(5-amino-1,2,4-thiadiazole
-3-yl)acetamide]-3-(1-(2
-Hydroxyethyl)-1H-tetrazole-
5-yl]thiomethyl-3-cephem-4-ka
Rubonic acid (shicine isomer), mp145-150℃ (min
solution). IR (Nujiyor): 3350, 3220, 1775, 1670,
1620, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 1.22−2.15 (8H,
m), 3.47-4.00 (4H, m), 4.10-4.57 (4H,
m), 4.57-4.90 (1H, m), 5.12 (1H, d,
J=5Hz), 5.80(1H, dd, J=5 and 8
Hz), 8.10 (2H, broad s), 9.47 (1H, d,
J=8Hz) (5) 7-[2-(2-cyclopenten-1-yl
Oximino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-[1-(2-hydroxyethyl)-
1H-tetrazol-5-yl]thiomethyl-
3-cefem-4-carboxylic acid (syn isomer),
mp135-140℃ (decomposition). IR (Nujiyor): 3350, 3250, 1775, 1675,
1620, 1525cm ^-1 NMR (DMSO-d ₆ , δ): 1.90−2.47 (4H,
m), 3.53-3.90 (4H, m), 4.13-4.53 (4H,
m), 510 ((1H, q, J=5Hz), 5.20−5.50
(1H, m,), 5.63−6.23 (3H, m), 8.12 (2H,
broad s), 9.43 (1H, d, J=8Hz) (6) 7-[2-(2-cyclopenten-1-yl
Oximino)-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetamide
Do]-3-(1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer), mp150-155℃ (decomposed). IR (Nujol): 3350, 3200, 1780, 1680, 1620,
1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.8−2.5 (4H, m),
3.67 (2H, broad s), 4.20 and 4.43 (2H,
ABq, J = 15Hz), 5.13 (1H, d, J = 4
Hz), 5.3-5.5 (1H, m), 5.80 (1H, dd, J
=4 and 8Hz), 5.8-6.4 (2H, m), 8.13
(2H, s), 9.53 (1H, d, J=8Hz)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is an amino group or a protected amino group, R ² is hydrogen, halogen, lower alkoxy,
Aryl group optionally having a substituent selected from nitro, halo lower alkyl and protected carboxy, aryl optionally substituted with amino lower alkyl or protected amino lower alkyl, halogen, cyano, carboxy , protected carboxy, lower alkylthio, aryloxy, di-lower alkylcarbamoyl, lower alkanesulfonyl, lower alkoxy, lower alkoxy,
a lower alkyl group, a lower alkenyl group having a substituent selected from amino and protected amino;
a 5-membered heterocyclic group having a heteroatom selected from S and O, substituted with a lower alkynyl group, a cycloalkyl group optionally substituted with carboxy or protected carboxy, a cyclo-lower alkenyl group, or an oxo group; , R ³ is hydrogen or a lower alkyl group, R ⁴ is hydrogen, an acyloxy lower alkyl group, a substituted or unsubstituted thiadiazolylthio lower alkyl group, a substituted or unsubstituted tetrazolylthio lower alkyl group, a substituted or unsubstituted tetrazolopyrida dinylthio lower alkyl group, substituted or unsubstituted dihydrotriazolopyridazinylthio lower alkyl group, substituted or unsubstituted dihydrotriazinylthio lower alkyl group, lower alkyl group, or halogen, R ⁵ is a carboxy group,
or protected carboxy group] 7-substituted-3-cefem-4-carboxylic acid and its salts. 2. The compound according to claim 1, which is a syn isomer. 3. The compound according to claim 2, wherein the group represented by the formula [formula] is [formula]. 4 R ¹ is an amino group, R ² is hydrogen, an aryl group optionally having 1 to 3 substituents selected from halogen: lower alkoxy: nitro: halo lower alkyl and protected carboxy;
Al lower alkyl group, lower alkylthio lower alkyl group, halo lower alkyl group, aryloxy lower alkyl group, cyano lower alkyl group, protected carboxy lower alkyl group, di-lower alkylcarbamoyl lower alkyl group, lower alkoxy lower alkoxy lower alkyl group , lower alkanesulfonyl lower alkyl group, protected amino lower alkyl group, amino lower alkyl group, carboxy lower alkyl group, protected carboxy-substituted al-lower alkyl group, carboxy-substituted al-lower alkyl group, protected Al lower alkyl group substituted with amino lower alkyl, lower alkenyl group, lower alkynyl group, cycloalkyl group optionally substituted with carboxy or protected carboxy , a cyclo lower alkenyl group, a thiolanyl group substituted with two oxo, or a tetrahydrofuryl group substituted with oxo,
R ⁴ is hydrogen, acyloxy lower alkyl group, lower alkyl: hydroxy lower alkyl: thiadiazolylthio lower alkyl group, lower alkyl which may have a substituent selected from protected amino lower alkyl and amino lower alkyl : Hydroxy lower alkyl: Amino lower alkyl: Protected amino lower alkyl: Di-lower alkylamino lower alkyl: Lower alkenyl: Carboxy lower alkyl: Protected carboxy lower alkyl:
Aryl: Morpholino lower alkyl: Tetrazolylthio lower alkyl group optionally having a substituent selected from piperidino lower alkyl and lower alkyl-substituted piperazinyl lower alkyl, tetrazolopyridazinylthio lower alkyl group, oxo and carboxy dihydrotriazolopyridazinylthio lower alkyl group substituted with lower alkyl, oxo: dihydrotriazolopyridazinylthio lower alkyl group substituted with hydroxy and lower alkyl, lower alkyl group, or halogen, R ⁵ is a carboxy group, Al lower alkoxycarbonyl group substituted with nitro, lower alkanoyloxy lower alkoxycarbonyl group, lower alkoxycarbonyloxy lower alkoxycarbonyl group optionally substituted with azide, aroyloxy lower alkoxycarbonyl group, or phthalidyloxycarbonyl group A compound according to claim 3. 5 R ² is a carboxy lower alkyl group, a cycloalkyl group, or a cyclo lower alkenyl group, R ³ is hydrogen, and R ⁴ is substituted with hydrogen, a thiadiazolylthio lower alkyl group, a lower alkyl group, or an amino lower alkyl group. 5. The compound according to claim 4, which is a tetrazolylthio lower alkyl group or a tetrazolopyridazinylthio lower alkyl group, and R ⁵ is a carboxy group.