JPS6034978A - Cephalosporin derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is formyl, t-butoxycarbonyl, chloroacetyl, trityl, silyl, etc.; R<2> is H or hydroxy). EXAMPLE:(5-Methyl-1,3-dioxol-2-on-4-yl)methyl 7-[D-O-(N-formyl-L-alanyl )mandelamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4- carboxylate. USE:Useful as a preventive and remedy for bacteriosis for oral administration and a synthetic intermediate of the cephalosporin derivative of formula II. It has high antibacterial activity. PREPARATION:The compound of formula I is prepared by reacting the compound of formula III or its reactive derivative with the compound of formula IVor its reactive derivative in the presence of a condensation agent such as N,N'- disubstituted-carbodiimide, etc. in a solvent such as acetone, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R1 is formyl, t-butoxycarbonyl, 1
-Methyl-2-methoxycarbonylvinyl, 1-methyl-2-ethoxycarbonylvinyl, henzyloxycarbonyl, p-methoxybenzyloxycarbonyl, chloroacetyl, trityl, silyl, 2,2.2-1-lichloroethoxycarbonyl R2 represents hydrogen or hydroxy. ), a method for producing the same, and a prophylactic/therapeutic agent for bacterial infections.

[Prior art]

Cephalosporins are generally poorly absorbed from the gastrointestinal tract and are administered by injection.

For example, a cephalosporin represented by the formula (wherein R2 has the same meaning as above) has an excellent antibacterial effect, but is not absorbed from the gastrointestinal tract, so it is administered by injection.

The present inventors have conducted extensive research in order to obtain a cephalosporin agent for oral administration, and have found that the cephalosporin derivative (1) has excellent absorbability from the gastrointestinal tract and, after absorption,
The carboxylic acid ester moiety at the 4-position of the cephem ring and the amino acid ester moiety at the α-position of the side chain at the 7-position are rapidly hydrolyzed by in vivo enzymes to form a cephalosporin derivative (1).
A non-ester corresponding to the cephalosporin, that is, a cephalosporin represented by the above formula (Ila) [hereinafter referred to as a non-ester (■a)]
In other words, by orally administering the cephalosporin derivative (1), a high blood concentration of the non-ester form (I[a) with excellent antibacterial activity can be obtained. (5-Methyl-1,3-dioxol-2-one-4-yl)methyl 7 ( D-0-(
L-alanyl)mandelamide)-3-(5-methyl-
It has been found that it is useful as a synthetic intermediate for a cephalosporin derivative (IIb) represented by the general formula containing 1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem (KY-109), and also as a cephalosporin derivative (IIb). The present invention was completed by establishing a method for producing derivative (I).

[Object of the present invention]

The first object of the present invention is to provide a novel cephalosporin derivative that is orally administrable and has high antibacterial activity.

A second object of the present invention is to obtain the cephalosporin derivative (
The object of the present invention is to provide a method for producing I).

The third object of the present invention is to provide oral administration for the prevention and prevention of bacterial infections.
The objective is to provide therapeutic agents.

The fourth object of the present invention is to obtain cephalosporin derivatives (II
b) to provide a synthetic intermediate.

[Disclosure of the invention]

The present invention relates to a cephalosporin derivative (1) and a method for producing the cephalosporin derivative (1) by the method described below.

Cephalosporin derivative (1) can be produced, for example, by the following method.

(Production method 1) A method of reacting a compound represented by the general formula (wherein R1 and R2 have the same meanings as above) and a compound represented by the general formula.

Compound (Ill) is used in this reaction as a free carboxylic acid or as a reactive derivative thereof. That is, free acids or salts of sodium, potassium, calcium, triethylamine, pyridine, etc., or their acid halides (acid chlorides, acid bromides, etc.), acid anhydrides, mixed acid anhydrides [substituted phosphoric acids (dialkyl phosphoric acids, etc.)] , alkyl carbon M
(monoethyl carbonate, etc.), activated amides (amides with imidazole, etc.), esters (cyanomethyl ester,
4-nitrophenyl ester, etc.) is used in the acylation reaction.

Silyl in relation to R refers to trialkylsilyl, dialkylalkoxysilyl, trialkoxysilyl, etc., and alkyl refers to methyl, ethyl, propyl, etc. with 1 carbon number.
-4 lower alkyl is preferred.

When compound (nl) is used in the form of a free acid or a salt, it is preferable to use a suitable condensing agent, such as N,N'- such as N,N'-dicyclohexylcarbodiimide. Disubstituted carbodiimides, N, N
Dehydrating agents such as azolide compounds such as '-carbonyldiimidazole and N,N'-thionyldiimidazole are used. When these condensing agents are used, the reaction is believed to proceed via reactive derivatives of carboxylic acids.

The reaction is carried out in a lightning inert solvent. Specific examples of the solvent include organic solvents such as water, acetone, dioxane, acetonitrile, chloroform, Hensen, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, and mixtures thereof. It will be done.

This reaction is preferably carried out at room temperature or under cooling (-20°C to 0°C).
℃).

Compound (IV) is, for example, a compound represented by the general formula (wherein R3 represents hydrogen or an amino group protecting group) and a compound represented by the general formula 0 (wherein, X represents a carboxyl group (reactive group thereof)). It is produced by reacting with a compound represented by "reactive group").

Regarding R3 in general formula (V), the amino group-protecting group includes known amino group-protecting groups, such as benzylcarbonyl, 2-chenylacetyl, 2-furylacetyl, D-5-amino-5-carboxy Valeryl, trityl, phthalimide, formyl, t-butoxycarbonyl,
Examples include 1-methyl-2-methoxycarbonylvinyl and -methyl-2-ethoxycarbonylvinyl.

Regarding the general formula (Vl), examples of "a group reactive with a carboxyl group (its reactive group)" represented by X include halogen (bromo, chlor, iodo, etc.), alkylsulfonyloxy (methanesulfonyloxy, etc.), Examples include arylsulfonyloxy (p-toluenesulfonyloxy, etc.) and hydroxy.

Compound (V) is used in this reaction as a free carboxylic acid or as a reactive derivative thereof.

That is, free acids or salts of sodium, potassium, calcium, triethylamine, and lysine, or their acid halides (acid chlorides, acid bromides, etc.);
Acid anhydrides, mixed acid anhydrides [substituted phosphoric acids (dialkyl phosphoric acids, etc.), alkyl carbonates (monoethyl carbonates, etc.)]
, active amides (amides with imidazole, etc.), esters (cyanomethyl ester, 4-nitrophenyl ester, etc.), and the like are subjected to the acylation reaction as reactive derivatives.

When X in compound (Vl) is used in a hydroxy form, it is preferable to use a suitable condensing agent, and examples of the condensing agent include N,N'-dicyclohexylcarbodiimide, etc. Dehydrating agents such as substituted carbodiimides, azolide compounds such as N,N"-carbonyldiimidazole, and N,N'-thionyldiimidazole are used. When these condensing agents are used, the reaction is caused by It is thought to proceed via reactive derivatives.

This reaction is preferably carried out at room temperature or under cooling (-2θ°C to θ
℃).

The protecting group (R3) can be removed by a method known per se.

(Production method 2) general formula ) (In the formula, 1.R2 has the same meaning as above) Compounds and general formulas represented by %formula%) ( A method of reacting with a compound represented by

Compound (■) is subjected to this reaction as a free carboxylic acid or as a reactive derivative thereof.

That is, free acids or salts of sodium, potassium, calcium, triethylamine, pyridine, etc., or their acid halides (acid chlorides, acid bromides, etc.);
Acid anhydrides, mixed acid anhydrides [substituted phosphoric acids (dialkyl phosphoric acids, etc.), alkyl carbonates (monoethyl carbonates, etc.)]
, active amides (amides with imidazole, etc.), esters (cyanomethyl ester, 4-nitrophenyl ester, etc.), and the like are subjected to the acylation reaction as reactive derivatives.

When compound (■) is used in the form of free acid or salt,
It is preferable to use a suitable condensing agent, such as N,N'-disubstituted carbodiimides such as N,N'-dicyclohexylcarbodiimide, N,N'
-carbonyldiimidazole, N,N'-thionyldiimidazole. When these condensing agents are used, the reaction is believed to proceed via reactive derivatives of carboxylic acids. In this reaction, it is preferable to use a base such as 4-dimethylaminopyridine as a catalyst.

This reaction is usually carried out in an inert solvent. Examples of the solvent include organic solvents such as water, acetone, dioxane, acetonitrile, chloroform, Hensen, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylbormamide, pyridine, and mixtures thereof. can give.

Compound (■) can be obtained by reacting compound (na) with compound (Vl), or by reacting compound (IV) with the general formula (in the formula, R2
is the same meaning as above).

Regarding this reaction, compound (Ila) can be subjected to the reaction as its reactive derivative (for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, triethylamine salts, pyridine salts, etc.). preferable.

In order to avoid the by-product of the Δ2-isomer, this reaction is preferably carried out under cooling, and a solvent that does not inhibit the reaction (
For example, the reaction can be easily carried out in the presence of N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide, acetone, acetonitrile, dimethyl sulfoxide, chloroform, methylene chloride, etc.).

(Production method 3) A method of reacting a compound represented by the general formula (wherein R1 and R2 have the same meanings as above) and compound (Vl).

Regarding this reaction, compound (X) is subjected to this reaction as a free carboxylic acid or as a reactive derivative thereof. That is, as a free acid or a salt of sodium, potassium, calcium, triethylamine, pyridine, etc.
Or their acid halides (acid chlorides, acid bromides, etc.), acid anhydrides, mixed acid anhydrides [substituted phosphoric acids (dialkyl phosphoric acids, etc.), alkyl carbonates (monoethyl carbonates, etc.)], activated amides (amidazole, etc.) )
, esters (cyanomethyl ester, 4-nitrophenyl ester, etc.) and the like are used in the acylation reaction.

When X in compound (Vl) is used in a hydroxy form, it is preferable to use a suitable condensing agent, and examples of the condensing agent include N,N'-dicyclohexylcarbodiimide, etc. Dehydrating agents such as substituted carbodiimides and azolide compounds such as N,N'-carbonyldiimidazole and N,N'-thionyldiimidazole are used. When these condensing agents are used, the reaction is believed to proceed via reactive derivatives of carboxylic acids. In this reaction, it is preferable to use a base such as 4-dimethylaminopyridine as a catalyst.

Compound (X) is 7-amino-3-(5-methyl-1,
3,4-thiadiazol-2-yl)thiomethyl-3-
Cephem-4-carboxylic acid (7-ACTD) and the compound (
III).

Compound (III) is preferably used as its acid halide (acid chloride, acid bromide, etc.), acid anhydride, mixed acid anhydride [substituted phosphoric acid (dialkyl phosphoric acid, etc.), alkyl carbonate (
monoethyl carbonate, etc.), activated amides (amides with imidazole, etc.), esters (cyanomethyl ester,
(4-nitrophenyl ester, etc.) is used in the acylation reaction.

In the cephalosporin derivative (1), a D monomer at the asymmetric carbon marked with * in the general formula (I) is preferable.

Furthermore, the cephalosporin derivative (1) may form a salt depending on the case, and the present invention also includes such salt forms.

? -ACTD may be used in the reaction with some or all of the functional groups blocked by a silyl group.

The cephalosporin derivative (I) thus produced is useful as an intermediate raw material for oral cephalosporin drugs (II b>. That is, R1 of compound (1) is eliminated by a known elimination means. Compound (If b) can be obtained.

In addition, the cephalosporin derivative (1) itself is useful as an oral cephalosporin drug, that is, as a prophylactic/therapeutic agent for bacterial infections, and can be used for oral administration by diluting it with a pharmaceutical excipient according to a known method. A prophylactic/therapeutic agent for bacterial infections can be produced. Dilution is carried out by means known per se, such as mixing. Specific examples of excipients include starch, lactose, sugar, calcium carbonate, calcium phosphate, and the like. After mixing the various components, the mixture can be formulated into a dosage form suitable for oral administration, such as capsules, powders, fine granules, granules, dry tablets, etc., by means known per se.

When the agent for preventing and treating bacterial infections of the present invention is orally administered, the cephalosporin derivative (1) as an active ingredient is rapidly absorbed from the gastrointestinal tract, and immediately hydrolyzed by enzymes in the body after absorption. Non-esterified form (I [
a).

By the way, this non-ester form (Ila) and its salts have excellent antibacterial activity, and are effective against Staphylococcus aureus (Staphylococcus aureus).
Durham-positive bacteria such as Escherichia coli and Klebsiella pneumonia
moniae), Proteus vulgaris (Pro
teus vulgaris), Proteus mirabilis, Proteus morganii
It has excellent antibacterial activity against Gram-negative bacteria such as Nii). Moreover, the non-esterified (Ila) salt thereof has extremely low toxicity.

Therefore, the cephalosporin derivative CI) of the present invention can be used to treat diseases caused by bacteria (e.g., purulent diseases, respiratory infections, etc.) in warm-blooded animals (dogs, cats, cows, horses, rats, mice, etc.) including humans. , biliary tract infections, urinary tract infections), etc.

The dosage of the cephalosporin derivative (1) is determined by the administration target,
Although it varies depending on the symptoms and other factors, for example, when administering to purulent diseases in adults, cephalosporin derivatives (1
) is orally administered at a dose of about 1 to 40 mg/kg body weight per dose, for example, about 1 to 4 times a day.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

In addition, in the following examples, Boc means t-butoxycarbonyl.

Example 1 D-0-(N-Boc-L-alanyl)mandelic acid 49
．． 7 g, (5-methyl-1゜3-dioxol-2-one-4-yl)methyl 7-amino-3 obtained in Reference Example 1
62 g of -(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate are dissolved in 600 ml of methylene chloride. 80 ml of 2N-N,N'-dicyclohexylcarbodiimide methylene chloride solution was added dropwise at -5°C, followed by stirring at the same temperature for 1 hour. Insoluble materials were filtered off, the filtrate was distilled off under reduced pressure, ethyl acetate was added to the residue, and the filtrate was filtered off again, the filtrate was distilled off under reduced pressure, methanol was added to the residue, and the precipitated crystals were collected by filtration and dried.
5-Methyl-1,3-dioxol-2-one-4-yl)methyl 7-CD-0-(N-Boc-L-alanyl)mandelamide]-3-(5-methyl-1,3,
72 g of 4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate are obtained. Melting point: 15
6℃ (decomposition) I R (nujol, c+n-'); 3340, 1
820. 17B0. 1750. 168ONMR(
CD (, s, δ value); 1.40 (d, 3H, J=711z, -CH-Cl+
3) 1.41 (s, 9H, -C(C113)3)2
．． 22 (s, 3tl, dioxole CI+3)2
．． 73 (s, 311. Thiadiazole-CI (3
)3.42.3.82 (d, d, 2H, J=171
1z, 2nd place -82) 3, +39.4.91 (d, d,
2+1. J=14Hz, 3rd position-CII, 5-)4.
1 to 4.55 (m, III, -C1l-CH3)5
．． 0 (br, III, -Nll-)5.0j (d,
IH, J=5Hz, 6th-H)5.05 (s, 2
11. Dioxo-ru〇〇2-)5.69 (d x
d, IH, J=5 and 911z, 7th position-II)6.
19 (s, Ill, -CH-C0NH-)7.4 (
s+ 58. phenyl) 7.68(d, Ill, J = 911z, -C
ONII-) Example 2 D-0-(N-Boc-L-alanyl)mandelic acid 3.
55 g, (5-methyl-1,3-dioxo-2-
4.56 g of methyl 7-amino-3-(5-methyl-1,3,4-thiacyazol-2-yl)thiomethyl-3-cephem-4-carboxylate,
A solution of 3.5 ml of pyridine and 90 ml of methylene chloride was cooled to -20°C, and 1.69 g of phosphorus oxychloride was stirred.
dropwise while maintaining the same temperature. Then -20℃~0℃
Stir for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from methanol, filtered, and dried to obtain 4.1 g of the compound of Example 1.

Example 3 D-0-(N-formyl-alanyl)mandelic acid 5
g, (5-methyl-1,3-dioxol-2-one-
4-yl)methyl 7-amino-3-(5-methyl-1
,3,4-thiadiazol-2-yl)thiomethyl-3
- 9.1 g of Cephem-4 to carboxylate are dissolved in 60 ml of methylene chloride. IN-N, N'- at -5℃
Dicyclohexylcarbodiimide methylene chloride solution 20
ml was added dropwise, and the mixture was stirred at the same temperature for 2 hours. Insoluble materials were removed by filtration, the filtrate was distilled off under reduced pressure, and ethyl acetate was added to the residue.
Insoluble matters were again filtered off, and isopropyl ether was added to the filtrate to give (5-methyl-1,3-dioxol-2-one-4
-yl)methyl 7-CD-0-(N-pormyl-alanyl)mandelamide)-3-(5-methyl-1
,3,4-thiadiazol-2-yl)thiomethyl-3
11.2 g of -cephem-4-carboxylate are obtained.

I R (nujol, cm-1); 1B20.17
B0.1735.1675NMR ((CD3)230
．． δ value); 1.33 (d, 3H, J=7Hz, -
CIl-CIl3) 2.17 (s, 311. Dioxo-Cl+3) 2.64 (s, 3H, thiadiazole-C113) 3.61 (br, s, 2
11.2nd-H2) 4.06.4.66 (d, d,
2H, J=14Hz, 3rd place -CIl□S->4.35~
4.85 (m, III, -(jj-C1h)5.
01 (d, 18. J=5Hz, 6th-1st place 5.
12 (s, 2H, dioxo-CH2-)5.7
2 (d x d, 18. J=5 and 911z, 7
-II) 5.99 (s, IH, -CI(-CON
H-)7.38 (s, 511. phenyl)8.0
1 (s, 1B, -CIIO) 8.52 (d, III, J=8Hz, -CH-N
i1-)9.29 (d, Ill, J-911z, -C
ONII-) Example 4 D-α-(N-Boc-L-alanyloxy)-p-hydroxyphenylacetic acid 0.88 g, (5-methyl-1,
3-dioxol-2-one-4-yl)methyl 7-
To 1 g of amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate, 30 ml of methylene chloride and 1 ml of ethyl acetate.
Add 5ml. IN-N, N at -5℃ under suspension stirring
” -dicyclohexylcarbodiimide methylene chloride,
2.8 ml of the solution was added dropwise, followed by IW stirring at the same temperature for 1 hour. The insoluble matter was filtered off, the filtrate was distilled off under reduced pressure, ethyl acetate was added to the residue, the insoluble matter was filtered off again, isopropyl ether was added to the filtrate, the precipitated solid was collected by filtration and dried, (5-
methyl-1,3-dioxol-2-one-4-yl)
Methyl 7-CD-α-(N-Boc-L-alanyloxy)-p-hydroxyphenylacetamide)-3-(
5-methyl-1゜3.4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylate 1.
Obtain 45 g.

NMR (CDC7!3. δ value); 1.39 (s, 91L -C(Cll3)3) 1.40 (d, 311. J=711z, -Cll
-哄3) 2.19 (s, 311. Dioxo-Cl+3) 2.70 (s, 311. Thiadiazole-Cll3) 3.38.3.80 (d, d, 2H
, J=17Hz, 2nd place - 112) 3.89.4.90
(d, d, 2H, J=14Hz, 3rd position -CH,S-)
4-4.4 (m, IH, -CI-CH3) 4.95
(d, 1)1. J=511z, 6th place-■5.0
5-5.25 (m, 311.-Nll-, dioxo-Cl2-
)5.70 (d x d, ill, J=5 and 9
11z, 7th place - ■) 6.06 (s, ill, -C
i-CONH-)6.75.7.23 (d, d, 4
11. J-811z, phenyl) 7.25 (br, I
ll, -Of amount) 7.75 (d, IH, J=9Hz -CONII-)
Example 5 +11 (5-Methyl-1,3-dioxol-2-one-4-yl)methyl 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl- 3-cephem-4-carboxyleh 45.6 g
was dissolved in 500 ml of methylene chloride, 17.8 g of anhydro-0-carboxymandelic acid was added over 15 minutes at 0°C, and the mixture was stirred at the same temperature for 2 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure, add isopropyl ether, collect the precipitated solid by filtration, and recrystallize from methanol to obtain (5-methyl-1,3-dioxo-
49 g of 7-D-mandelamido-3-(5-methyl-1.4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate are obtained. Melting point: 151°C (decomposed) IR (nujol, cm')'; Distilled off, methanol was added to the residue, and the mixture was heated overnight. The precipitated crystals were collected by filtration and dried, and 2.7 g of the compound of Example 1 was obtained.
get.

Example 6 5.9 g of the compound obtained in Example 5 (1), N-formyl-
1.2 g of di-alanine was dissolved in 150 ml of methylene chloride, and 2.1 g of N,N'-dicyclohexylcarbodiimide was dissolved at 0°C, followed by 0.1 g of 4-dimethylaminopyridine.
Add 3 g and react at the same temperature for 1 hour. Insoluble matters were removed by filtration, and the filtrate was washed with a 10% aqueous citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate. The mixture was distilled off under reduced pressure, ethyl acetate was added to the residue, insoluble matter was removed by filtration, isopropyl ether was added to the filtrate, and the precipitated solid was collected by filtration and dried to obtain 6.5 g of the compound of Example 3.

Example 7 - (1) Human fg: 21 g of D-0-(N-Boc-L-alanyl)mandelic acid was added to 540 m of anhydrous tetrahydrofuran.
1, add 9.0.7 ml of triethylamine, and cool to -15°C. Add 33% ethyl chloride to this solution.
50, 1B20. 1780. 1730. 168
ONMR ((CD3)2 So, δ value); 2.22
(s, 3H, dioxole CI3)2.70 (
s, 3H, thiadiazole-CH5) 3.59.3.
97 (d, d, 2H, J-171 (z, 2nd place -82
)4.07.4.87 (d, d, 2H, J=141
12. 3rd place - C2) 5.12 (d, III, J
-5Hz, 6th place - ■) 5.15 (s, 211.
Dioxo-CH2-)5.21 (d, IH, J=
6flz, -Cll-OR)5.11 (d, IH, J
=6Hz, -0H)5.81 (d x d, IH,
J=5 and 911z, 7th position-H) 7.42 (m, 5
)1. phenyl) 7.99 (d, IH, J-9Hz
, -CONII-)+21 fil Compound 2.7
5g of N-Boc-L-γ-lanine and 0.97g of N-Boc-L-γ-lanine were dissolved in 100ml of methylene chloride, and 1.15'g of N,N'-dicyclohexylcarbodiimide and then 0.06g of 4-dimethylaminopyridine were dissolved at 0°C. Add and react at the same temperature for 1 hour. Insoluble matters were removed by filtration, and the filtrate was washed with a 10% aqueous citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate. Add 41 ml of vacuum Lua and stir at the same temperature for 30 minutes. On the other hand, 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
22.4 g of carboxylic acid and 310 m of tetrahydrofuran
1, dissolved in a mixture of 230 ml of water and 9.5 ml of triethylamine, and added dropwise to the previously obtained solution at -10°C for 5 minutes.
The mixture is then stirred at 0° C. for 1 hour and at room temperature for 1 hour. Insoluble matter was filtered off, tetrahydrofuran was distilled off under reduced pressure, and the remaining liquid was adjusted to pH 2 using phosphoric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried with anhydrous sodium sulfate. Concentrate under reduced pressure, add petroleum ether, collect the precipitated solid by filtration, dry it, and... -CD-0-(N-Boc-L-alanyl)mandelamide)-3-(5-methyl-1°3.4
-thiadiazol-2-yl)thiomethyl-3-cephem-4-carvone rl! Obtain 36.1 g.

I R (nujol, am'); 3300.176
0.169ONMR ((CD3)2So, δ value);
1.30 (d, 3H, J=7Hz, -CIl-CH
3) 1.35 (s+ 9H, -C(CIl3)3)
2.67 (s+ 3H, thiadiazole-CH5)3
．． 41~3.70 (br, S+ 211.2nd -8
2) 3.91-4.75 (m, 41L 3rd position -CHZ S-, -C02I+,
-CIl-CH3)4.96 (d, III, J=
511z, 6th place-11) 5.64 (d x d,
IH, J=5 and 911z, 7th place - old 6.02 (s,
11(,-CnaC0NI+-)7.39 (s, 5
th phenyl)9.27 (d, III, J=9
11z -CONII-) Method B = 7-amino-3-(
5-methyl-1゜3.4-thiadiazol-2-yl)
3.44 g of thiomethyl-3-cephem-4-carboxylic acid
,, 2.62 g of N-1-limethylsilylacetamide was added to 35 g of tab-1 chloride. After stirring, D-0-(N-Boc-L-alanyl)mandel! was added to the reaction solution. 3.55g and Piri'2 7 3. 5 m
1 and cooled to -20°C. While maintaining the same temperature, 1.69 g of phosphorus oxychloride was added dropwise. Next time - under water cooling, 1
After stirring for an hour, the mixture was condensed under reduced pressure, the residue was dissolved in ethyl acetate, water was added, and after stirring, the ethyl acetate layer was further washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Isopropyl ether is added to the residue, and the precipitated solid is collected by filtration and dried to obtain 4 g of the compound of Method A.

(2) 6.5 g of the compound obtained in Example 7 (1), 0.0 g of potassium acetate. 98 g was dissolved in 15 ml of N,N-dimethylformamide, and 4-bromomethyl-5 was dissolved at -10°C.
-Methyl-1,3-dioxol-2-one 2, 12g
A solution of 15 ml of N,N-dimethylborumamide was added dropwise thereto, and the mixture was stirred at the same temperature for 30 minutes. 100% water to reaction solution
ml and extracted twice with 50 ml each of ethyl acetate.

The ethyl acetate layers are combined, washed with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The mixture was distilled off under reduced pressure, methanol was added to the residue, and the precipitated crystals were collected by filtration and dried to obtain 5.9 g of the compound of Example 1.

Example 8 Compound 0. obtained in Example 7 (1). 65 g, 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one 0. 14 g was suspended in 2 ml of methylene chloride. At -20°C, 0.22 g of N,N'-dicyclohexylcarbodiimide and a catalytic amount of 4-dimethylaminopyridine are added, and the mixture is stirred at the same temperature for 1 hour. Insoluble matters were removed by filtration, and the filtrate was washed with a 10% aqueous citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate. Distillation was carried out under reduced pressure, methanol was added to the residue, and the precipitated crystals were collected by filtration and dried to obtain the compound 0 of Example 1.
．． Obtain 4 6 g.

Example 9 (11 Compound 1 of Example 7 (1) 3.2 5 g
was dissolved in 66 ml of formic acid, 33 ml of 4.9N hydrogen chloride isopropanol solution was added at room temperature, stirred for 5 minutes at the same temperature, and then pressurized into 500 ml of ethyl acetate. Next, the precipitated solid was collected by filtration, washed with ethyl acetate, dried, and
- CD-0- (L-alanyl)mandelamide]-
3-(5-methyl-1.3.4-thiadiazole-2
11.30 g of -yl)thiomethyl-3-cephem-4-carboxylic hydrochloride are obtained.

I R (nujoLcm'); 3270, 1770, 1740, 1710. 1
67ONMR ((CD3)2 SO, δ value); 1, 4
9 (d, 3H, J"7Hz, -CH-CH3
) 2.68 (s, 311. Thiadiazole-CD
5) 3.61 (br, s, 21L 2nd place - [2)
4.10~4.50 (m, LH, -CH-C1h
)4.17.4.52 (d, d, 2H, J-141
1z, 3rd position -C12S-)5.01 (d, IIL
, I=511z, 6th place - 11) 5.70 (d x
d, ill J=5 and 911z, 7th place - I7.42
(s+ 5N, phenyl) 8.18-9.94 (br, 4H, -Nl13"
, -CO, If )9.44 (d, 11(, J=9
7-CD- 0-(L-alanyl)mandelamide)
-3-(5-methyl-1,3,4-thiadiazole-2
-yl)thiomethyl-3-7femu-4-carboxylic acid 9
．． Obtain 50 g.

IR(nu3o1.cm-'); 3270.17
60.167ONMR ((CD3)2SO, δ value)
;1.41 (d, 3H, J=711z, -CH-C
Il3) 2.66 (s, 38. Thiadiazole-CD5) 3.45 (br, s, 211.2 position-
112) 3.8B, 4.39 (d, d, 211. J = 14Hz, 3rd place - C1l,
S-) 3.95-4.44 (m, 18. -CH-
C113) 4.8B, 4.96 (d, ill,
J=511z,, 6th place - 11) 5.50. 5.63 (d x d, ill, J=5 and 9Hz, 7th place -
II) 6.10 (s, 11(, -C8-CONll
-)6.48 Cbr-311, -NI+2, -C02
, H) 7.42 (s, 58. phenyl) 9.33
(d, LH, J-9Hz, -CONII-) (2)
1-CD'-0-(L-alanyl)mandelamide)-3-(5-methyl-1,3°4-thiadiazol-2-yl)thiomethyl-3-cephem-4 obtained in (1) above
- Add 23 ml of methanol to 1.7 g of carboxylic acid and 0.4 g of ethyl acetoacetate, and add ¥1! , Add a solution of 0.2 g of potassium hydroxide in 15 ml of methanol at room temperature under stirring, and stir for 4 hours. 350 ml of diethyl ether was added to the reaction solution, the precipitated solid was collected by filtration, and dried.
-(D-0-(N-(l-methyl-2-ethoxycarbonylvinyl)-L-alanyl)mandelamide)-3-
1.92 g of (5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid potassium salt are obtained.

NMR ((CD3)2So, δ value); 1.15 (
t, 3H, J=711z, -CO2-CI2-C1
13) 1.41 (d, 311. J=711z, -
CH-Cl+3)1.92 (s, 3+1. CI
l3-to) 2.66 (s, 311. Thiadiazole-C113) 3.4 (br, s, 211.2
-112) 3.9 to 4.8 (m, 311.3 -
CIl2S-, -CIl-CH3)3.98 (Q,
21L J-7Hz, -CO2-Cl+2-CIl
3)4.43 (s, IH, -C-Cll-)4.
94 (d, III, J = 511z, 6th place -
11) 5.5 (L(d x d, ill, J=5 and 911z, 7th place - 11) 6.01 (s, III,
-Cll-CONll-)7.36 (s, 511
．． phenyl) 8.67 (d, Ill, J=9+
1z, -CONI(-)9.25 (d, III,
J=9Hz, -NH-) (3) 1 g of the compound obtained in (2) above was added to 20 ml of N,N-dimethylformamide.
4-bromomethyl-5-methyl-
1,3-dioxo-2-one 0.37 g N,N
- Add 2 ml of dimethylformamide solution dropwise and stir at the same temperature for 30 minutes. Add 100 ml of water to the reaction solution, and extract twice with 50 ml each of ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the precipitated solid was collected by filtration and dried to give (5-methyl-1,3-dioxol-2-one-4-yl)methyl 7-CD.
-0-+N-(1-methyl-2-ethoxycarbonylvinyl)-L-alanyl)mandelamide)-3-(5-
Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate 0.6g
get.

NMR ((CD3)2So, δ value); 1.16 (t
, 311. J=711z, -CO2-C112-
CIl3) 1.41 (d, 3tl, J=711
z, -CIl-C113) 1.92 (s, 3H,C
H31c=)2.18 (s, 3tl, dioxo-J
Ii-C)13) 2.65 (s, 311. Thiadiazole-CD5) 3.65 (br, s, 2
11.2nd place -) 12) 4.0 (q, 2H, J=7t
lz, -CO2CIl2-C! 13) 4.0-4.
8 (m, 311.3 position -CIly-5-, -Ct
l-CH3)4.42 (s, 1)! , -C=C)I
-) 5.10 (d, IH, J-5!Iz, 6th place -
11) 5.13 (s, 2H, dioxo-ru C11
2-)5.72 (d x d, III, J=5 and 911z, 7th place-11)5.98 (s, III,
-Cll-CONII-)7.38 (s, 511
．． phenyl) 8.70 (d, III, J-91
1z, -CONH-)9.35 (d, Ill,
J-911z, -Nll-) Example 10 (1) 7-CD-0- in the same manner as in Example 7(l)
(N-formyl-L-alanyl)mandelamide]-3
-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-4-carboxylic acid is obtained.

NMR ((CD3)2SO, δ value); 1.33 (
d, 311. J=711z, -C1l-C113)2
．． 67 (s, 3H, thiadiazole-Cl13)3
．． 62 (br, s, 211.2nd-112)4.
05.4.66 (d, d, 211. J=1411
z, 3rd position -CH123-)4.33-4.82 (m,
211. -Cdan-CIl3, -C(12II)5
．． 00 (d, IH, J=511z, 6th-11th)
5.70 (d x d, IH, J=5 and 9Hz,
7th position-II) 6.01 (s, III, -C1l-CO
NI(-)7.39 (s, 511. phenyl)8
．． 01 (s, III, JCIIO) 8.53 (d,
1B, J=811z, -C1l-Nll-)9.28
(d, ill, J=911z, -CONII-) (2)
The compound of Example 3 (5
~Methyl-1,3-dioxol-2-one-4-yl)methyl 7-CD-0-(N-pormyl~L-alanyl)mandelamide]-3-(5-methyl-1,3,
4'-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate is obtained.

Reference example 1 (5-methyl-1,3-dioxo-2-one-4-
yl)methyl 7-amino-3-(5-methyl-1,3
Synthesis of ,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (1) 7-amino-3-(5-methyl-1,3°4-thiadiazol-2-yl)thiontyl-3 =Cephem-
Add 100 g of 4-carvone m to methanol 21, and heat at 0°C.
250 ml of methanol containing 19.2 g of potassium hydroxide was added dropwise over 30 minutes. Filter the insoluble matter, 1
1, added isopropyl ether 11, and filtered the precipitate. Potassium 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxy Obtain rate 94g.

I R (nujol, cm-1); 3400.175
5.159ONMR<<CD3)2So, δ value)
;2.67 (s, 3H, thiadiazole-C113
)2.50~3.40 (br,, 211.-NH2
)3.22.3.63 (d, d, 211. J-1
811z, 2nd place-82) 4.24.4.54 (cl,
d, 2)1. J=13112. 3rd place -CH2S-
)4.56 (d, IIl, J=5.5Hz, 6
-11) 4.83 (d, III, J=5.51
1z, 7-11) (93.5 g of the potassium salt obtained in 21fil was added to 470 ml of ethyl acetoacetate,
Stir overnight at room temperature.

Diethyl ether 11! When you add potassium and filter it out, potassium? 120 g of -N-(1-methyl-2-ethoxycarbonylvinyl)amino-3-(5-methyl-1°3.4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate are obtained.

I R (nujol, cm') 13250.1760
．． 1660.161ONMR((CD3)2So,
δ(a); 1.17 (t, 3H, J=711z,
-C113) 1.97 (s+ 311.Cth -
C=)2.67 (s, 311. Thiadiazole-Bv
-C113) 3.32.3.71 (d, d, 211
．． J-1811z, 2nd place -112) 4.00 (q+
21L J=711z, -CH2-)4.30.
4.59 (d, d', 21 amount, J-1311z, 3
(St-CHS-)E4.57 (s, IH, -C=CH-)5.03 (d
, III, J-5,5Hz, 6th position-H) 5.53
(d x d, 1)1. J=5.5 and 911z
, 7th place - ■) 8.87 (d, IH, J-9Hz, =
Cl1-N11-) (3) 51.2 g of 4-bromomethyl-5-methyl-1,3-thioxol-2-one was mixed with N,
Dissolved in 360 ml of N-dimethylformamide and cooled to 5°C. 118.5 g of the compound obtained in (2) above was dissolved in 15
The mixture was added for 35 minutes and stirred at the same temperature for 35 minutes. Ice water 3.
61, poured into a mixture of 360 ml of methanol, collected the precipitate by filtration, and added (5-methyl-1,3-dioxol-2-one-4-yl)methyl 7-N-(1-methyl-2-ethoxy carbonylvinyl)amino-3-(5-methyl-
1,3,4-thiadiazol-2-yl)thiomethyl-
109 g of 3-cephem-4-carboxylate are obtained.

IR(nujol+cm-'); 1820, 1780.1725.1640.161ON
MR ((CD3)2So, δ value); 1.16 (t
, 3H, J-7Hz, -CH3)1.96 (s,
3H, Cll3-C-)2.19 (s, 311.
Dioxol-C113) 2.67 (s, 3+1.
Thiadiazole-C113) 3.60.3.93 (
d, d, 211. J=1811z, 2nd place -112)
4.00 (Q1211. J=7Hz, -Cll2-
)4.08.4.73 (d, d, 21+, J=
1311z, 3rd position -CIlLS-)4.61 (s, I
II, -C=CII-)5.13 (s, 211.
Dioxole CI+2-) 5.18 (d, III
, J=5.5+1z, 6th place - 11) 5.78 (d
x d, III, J=5.5 and 911z, 7th position -I+) 8.91 (d, III, J=911z, -C
Compound 10 obtained with ll-Nll-)+41 +31
Add 8.5 g to a mixture of 11 methanol and 4 ml of water,
190 ml of 5N hydrogen chloride ituburobanol solution was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Add acetone 11,
Filter, (5-methyl-1,3-dioxol-2-one-4-yl)methyl 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3 -Cephem-4-carboxylate hydrochloride at 90%
Get g゛.

I R (nujol+cm-'): 3400, 2600. 1810. 1780. 17
2ONMR ((CD3)2So, δ value); 2.19
(s, 3H, dioxo-CH3)2.67 (
s, 3H, thiadiazole-cn3) 3.81 (
br, s, 2H, 2nd position-112) 4.17.4.7
4 (d, d, 2H, J=1311z, 3rd place - CIl
□5-) 5.18 (br, s, 411. Dioxo-Cl2-16-II, 7-11) 6.20-10. OO(br,, 311.-NH3
)+51 (49 g of the compound obtained in 41 was added to 2 ml of water.
60 ml, add 110 ml of methylene chloride, neutralize by gradually adding 22 g of sodium bicarbonate powder under stirring, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and leave a residue. 25 ml of ethyl acetate was added to the solution, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried. -Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-Cal Shimoto Pano 1 Note 29.8 g are obtained.

I R (nujol, cm'); 3400, 3350.1810.1780.173ON
MR (CDC7!3. δ value); 1.83 (s, 211. -NH2) 2.22 (s
, 311. Dioxo-Cl1a) 2.71 (
s, 311. Thiadiazole-C113) 3.33
．． 3.86 (d, d, 2H, J=18Hz, 2nd place -
CH, 7) 3.91.4.88 (d, d, 2H, J
-1411z, 3rd place -CIILS-) 4.78-4.9
5 (m, 21L 6th position-〇, 7th position-H) 4.90.
5.19 (d, d, 211. J=1511z, dioxo-
Ru0112→Patent applicant: Kyoto Pharmaceutical Industry Co., Ltd.

Claims (1)

[Claims] 11) General formula (wherein R1 is formyl, t-butoxycarbonyl, 1
-Methyl-2-methoxycarbonylvinyl, 1-methyl-2-ethoxycarbonylvinyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, chloroacetyl, trityl, silyl, 2.2.2-1-lichloroethoxyl R2 represents hydrogen or hydroxy. ) A cephalosporin derivative represented by (2) Reacting the general formula with a compound represented by the general formula (wherein R1 and R2 have the same meanings as above) or a reactive derivative thereof; or or a compound represented by the general formula (wherein R1 has the same meaning as above) or a reactive derivative thereof, or a compound represented by the general formula (wherein R1 and R2 have the same meaning as above) or its reactive derivative. The cephalocarbon compound according to claim fl), characterized in that the derivative is reacted with a compound represented by the general formula (wherein, X represents a group reactive with a carboxyl group (its reactive group)). Method for producing a sporin derivative.