JPH10152490A - Production of cephem compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To profitably obtain the subject compound useful as a medicine, especially an antibiotic, in water solvent having no problem on safety by reacting a specific 3-cephem-4-carboxylate (salt) with an acid chloride in the water. SOLUTION: This method for producing a cephem compound of formula IV comprises reacting a 3-cephem-4-carboxylate (salt) of formula I (R<2> is carboxyl, carboxyl anion; R<3> is a lower alkyl, a halogen, a lower acyloxyalkyl, etc.,) with an acid chloride of the formula: R<1> COCl R<1> is a group of formula II [A is N, methine; B is a lower alkoxy, a halogenated lower alkoxy, triphenylmethoxy, a lower alkyl, a lower acyloxy, a group of the formula: C(CH3 )2 COOR (R is H, an alkali metal, an alkaline earth metal, an organic cation)] or a group of formula III} in water. Thus, the objective cephem compound of formula IV especially useful as an antibiotic can profitably be obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel industrially excellent method for producing a cephem compound useful as a medicine, especially as an antibiotic.

[0002]

2. Description of the Related Art Conventionally, a cephem compound is prepared by reacting a 7-amino-3-cephem-4-carboxylate derivative or a 7-aminocephalosporanic acid derivative with a carboxylic acid chloride or carboxylic acid in an organic solvent. Amidation,
Has been manufactured.

[0003]

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For example, Japanese Patent Application Laid-Open No. 52-125,190,
53-68,795 and JP-A-53-68,796 disclose 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid and 7-aminocephalosporanic acid. An example of a reaction for producing ceftizoxime by condensation in the presence of phosphorus chloride is described.

[0005]

[Problems to be solved by the present invention] However, 7-amino
Many of the -3-cephem-4-carboxylate derivatives are hardly soluble in organic solvents and require a large amount of solvent for the reaction, which is extremely disadvantageous in production cost. Also,
Generally, organic solvents are toxic or flammable, so that a sufficient countermeasure is required for equipment and the like in the working environment. As described above, the conventional production method using an organic solvent has problems in raw material cost and production equipment.

[0006] Further, since cephem compounds are used as medicines, products of extremely high purity are required. For this reason, it is finally purified by column chromatography, but since the cephem compound itself is a highly polar substance,
Reverse-phase chromatography is used for its purification effect. However, when the reaction is carried out using an organic solvent, it is necessary to concentrate and remove a large amount of the reaction solvent and replace the solvent with a chromatography solvent (polar solvent). There was also a problem that purification efficiency was reduced.

[0007]

Means for Solving the Problems The present inventors have intensively studied to improve the above problems. as a result,
The present inventors have found that water having high solubility in a 7-amino-3-cephem-4-carboxylate derivative, inexpensive, and having no problem in safety is suitable as a solvent, and completed the present invention.

[0008] In addition, the present invention has an advantage that it can be charged as it is without solvent replacement in the subsequent chromatographic purification, and is an industrially excellent method for producing a cephem compound.

Next, a method for producing the cephem compound according to the present invention will be described in detail. First, the cephem-based compound (III) targeted in the present invention is represented by the following general formula.

[0010]

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In the formula, R ¹ represents any of the groups represented by the following general formula.

[0012]

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Wherein A is a nitrogen atom or a methine group,
B is a lower alkoxy group, a halogenated lower alkoxy group,
A triphenylmethoxy group or a lower alkyl group or a lower acyloxy group, a group represented by the formula —C (CH ₃ ) ₂ COOR (wherein
R represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom or an organic cation. ) Means a group selected from Further, A and B may be any of the (E) and (Z) geometric isomers. ] R ² denotes a carboxyl group or a carboxyl anion. R ³ represents a lower alkyl group, a halogen atom, a lower acyloxyalkyl group, or a group represented by the following general formula.

[0014]

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Here, the lower alkoxy group in the definition of B in R ¹ of the present invention means a linear or branched alkoxy group having 1 to 6 carbon atoms, and specifically, for example, methoxy group, ethoxy group Groups, propoxy group, butoxy group, pentyloxy group, hexyloxy group, etc., and methoxy group and isopropoxy group are more preferable. The halogenated lower alkoxy group means a group in which the lower alkoxy group is substituted with one or more halogen atoms, and specifically, for example, a chloromethoxy group, a fluoromethoxy group,
Examples thereof include a dichloromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a fluoroethoxy group, and a difluoroethoxy group, and a fluoromethoxy group and a 2-fluoroethoxy group are more preferable. The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Although it is possible, a methyl group or an ethyl group is more preferable. The lower acyloxy group means a linear or branched aliphatic acyloxy group having 1 to 6 carbon atoms, and specific examples include an acetoxy group, a propionyloxy group, and a butyryloxy group. More preferred.

Next, the lower alkyl group in the definition of R ³ and the like has the same meaning as described above. Specific examples of the halogen atom include a chlorine atom, a bromine atom, an iodine atom and a fluorine atom, and a chlorine atom is more preferable. The lower acyloxyalkyl group means a lower alkyl group substituted with the lower acyloxy group, and specific examples include an acetoxymethyl group, an acetoxyethyl group, a propionyloxymethyl group, and a propionyloxyethyl group. However, an acetoxymethyl group is more preferred.

The cephem compound represented by the above general formula (I
As II), many compounds are conventionally known. More specifically, for example, the following compounds are known to have more excellent pharmacological effects. (1) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetamide] -3- (E) -3-
Carbamoylmethylethylmethylammonio-1-propenyl-3-cephem-4-carboxylate. Generic name: Cefluprenam (2) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (4-carbamoyl Quinuclidinio) methyl-3-cephem-4-carboxylate. Generic name: Cefclidine (3) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (imidazo [1 , 2-
b] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate. Generic name: Cefozopran (4) 7- (D-α-phenylglycylamino) -3-chloro-3-cephem-4-carboxylic acid. Generic name: Cefaclor (5) 7- (D-α-phenylglycylamino) -3-methyl-3-cephem-4-carboxylic acid. General name: Cephalexin (6) 7- (D-α-phenylglycylamino) -3-acetoxymethyl-3-cephem-4-carboxylic acid. Generic name: Cephaloglycin (7) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetamido] -3-methyl
-3-cephem-4-carboxylic acid. (8) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetamide] -3-[(E) -2
-(2,2-Dimethyl-5-isoxazolidinio) vinyl] -3-cephem-4-carboxylic acid. Generic name: YM-40220 (34th Interscience Conference o
n Antimicrobial Agentsand Chemotherapy, Paper No.
F103)

[0018]

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(9) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-
(Benzothiazol-2-yl) thio-3-cephem-4-carboxylic acid. Generic name; CP0467

[0020]

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(10) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (1-sodiumcarboxylate-1)
-Methoxyethoxy) iminoacetamide] -3- (imidazo
[1,2-b] pyridazinium-1-yl) methyl-3-cephem-4-
Carboxylate. (Japanese Patent Laid-Open No. 7-101,960, Example 2)

[0022]

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(11) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-fluoroethoxyimino) acetamido] -3- (imidazo [ 1,2-b] pyridazinium-1-yl)
Methyl-3-cephem-4-carboxylate. (Japanese Unexamined Patent Publication No. 7-10
No. 1,958, Example 1)

[0024]

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(12) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-isopropoxyiminoacetamide] -3- (3-aminoimidazo [1 , 2-b] Pyridazinium-1-yl) methyl-3-cephem-4-carboxylate. (JP 7
-133,280, Example 2)

[0026]

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The cephem compound (III) according to the present invention is not limited to the above-mentioned compounds, but exhibits particularly excellent effects as a method for producing the following compounds. (1) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetamide] -3- (E) -3-
Carbamoylmethylethylmethylammonio-1-propenyl) -3-cephem-4-carboxylate [generic name: Cefluprenam] (2) 7β-[(Z) -2- (5-amino-1,2, 4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (4-carbamoylquinuclidinio) methyl-3-cephem-4-carboxylate [generic name; cefclidine]

The cephem compound according to the present invention (I
II) may have an asymmetric carbon atom in the molecule,
It is not limited and may be any optical isomer,
It may be racemic. Further, it may be a hydrate, but is not limited thereto, and may be an anhydride or an n-hydrate [n means a real number (integer and decimal)].

Next, the 3-cephem-4-carboxylate (I) according to the present invention is represented by the following general formula.

[0030]

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In the formula, R ² and R ³ have the same meaning as described above. More specifically, examples of the 3-cephem-4-carboxylate (I) include, but are not limited to, the following compounds. It may be a salt. (1) 7β-amino-[(E) -3-carbamoylmethylethylammonio-1-propenyl] -3-cephem-4-carboxylate (2) 7β-amino-3- (4-carbamoylquinuclidinio ) Methyl-3-cephem-4-carboxylate (3) 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-
(Yl) methyl-3-cephem-4-carboxylate (4) 7-amino-3-chlorocephalosporanic acid (5) 7-amino-3-methylcephalosporanic acid (6) 7-aminocephalosporanic acid (7) 7-Amino-3-methylcephalosporanic acid The 3-cephem-4-carboxylate (I) according to the present invention is a known compound, and is generally available as an industrial raw material or a reagent.

Next, the acid chloride (II) according to the present invention is represented by the general formula R ¹ COCl. In the formula, R ¹ has the same meaning as described above. More specifically, examples of the acid chloride (II) include, but are not limited to, the following compounds. It may be a salt. (1) 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2
-Fluoromethoxyiminoacetic acid chloride (2) (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid chloride (3) phenylglycine chlorideAcid chloride (II) according to the present invention is It is a known compound and generally available as industrial raw materials or reagents.

The present invention is characterized in that 3-cephem-4-carboxylate (I) or a salt thereof is reacted with an acid chloride (II) in water. At this time, the reaction conditions are not limited, but usually, it is more preferable to carry out the reaction under the following conditions. (1) Reaction is performed while adjusting the pH to 3 to 7 by dropwise addition of a base. (Corresponding Examples; 1-8, 13-14, 16-21) (2) A required (calculated) amount of a base is initially charged and reacted.
(Corresponding embodiment; 9-12, 15)

The base under the above condition (1) is not limited as long as it is water-soluble and is not a primary or secondary amine, and may be an inorganic base or an organic base. Examples thereof include hydroxides, carbonates, phosphates, and tertiary amines. Among these, more preferred examples include sodium hydroxide, potassium hydroxide, aqueous ammonia, and triethylamine.
Note that these bases may be used alone or as a mixture of two or more.

The pH under the condition (1) is not particularly limited as long as it is within the range of 3 to 7, but it is usually preferably 3.5 to 3.5.
6.5, and more preferably 4-6. The reaction temperature is not limited as long as it is higher than the temperature at which the reaction solution does not freeze, but it can be usually carried out at room temperature. The reaction time at that time varies depending on the amount of the solvent and the like, but is usually completed in about 30 minutes to 6 hours.

The base under the above condition (2) is also not limited as long as it is water-soluble and is not a primary or secondary amine, and may be an inorganic base or an organic base. For example, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, disodium hydrogen phosphate, ammonium carbonate, ammonium carbamate and the like can be mentioned. Here, the amount of the base used under the condition (2) is not limited, but is usually 3-cephem-4-carboxylate.
It is 1 to 20 equivalents, preferably 1.5 to 10 equivalents, and more preferably 2 to 5 equivalents to (I). The reaction temperature is not limited as long as it is higher than the temperature at which the reaction solution does not freeze, but it can be usually carried out at room temperature. The reaction time at that time varies depending on the amount of the solvent and the like, but is usually completed in about 30 minutes to 6 hours.

In any of the above (1) and (2), the amount of water used as a solvent is not limited. However, from the viewpoint of reaction operability and reaction time, 1 g of 3-cephem-4-carboxylate (I) is used. Is preferably 1 to 100 ml, more preferably 2 to 50 ml, and still more preferably 3 to 20 ml.

In the present invention, after the completion of the reaction, it is possible to immediately purify by reverse phase chromatography without replacing the solvent. That is, after confirming the completion of the reaction, the reaction solution can be directly charged to reverse phase chromatography, followed by elution and separation operations. Therefore, not only the operability is improved, but also a solvent concentration step for solvent replacement becomes unnecessary, and even in a cephem-based compound which is unstable in temperature, a thermal decomposition product is generated, and the yield is reduced or purification is difficult.
(Poor purity) can be avoided.

Next, in order to specifically explain the present invention, examples and comparative examples are given below, but it goes without saying that the present invention is not limited to these.

EXAMPLES Example 1 7β-[(Z) -2- (5-amino-1,2,4-thiadiazo)
Ru-3-yl) -2-fluoromethoxyiminoacetamide] -3
-(E) -3-carbamoylmethylethylmethylammonio-1-
Synthesis of ( propenyl) -3-cephem-4-carboxylate (Cefluprenam)

[0040]

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In 97 ml of water cooled to 9 ° C., 7β-amino-
After dissolving 12.08 g (30.9 mmol) of [(E) -3-carbamoylmethylethylammonio-1-propenyl] -3-cephem-4-carboxylate.hydrochloride [hereinafter, compound (1)], a pH meter was used. Was set, and the pH was adjusted to 5 by dropwise addition of a 5N-NaOH aqueous solution. Where 2- (5-amino-1,2,4-thiadiazole-3-
8.33 g (30.3 mmol) of yl)-(Z) -2-fluoromethoxyiminoacetic acid chloride hydrochloride [hereinafter, compound (2)]
The mixture was stirred for 2 hours while adjusting with a 5N-NaOH aqueous solution so as to be maintained at 4.5 to 5.5. After confirming the completion of the reaction, the reaction solution was directly purified by reverse phase chromatography (ODS). Ethanol was added to the main fraction and cooled to -20 ° C. The precipitated crystals were separated, washed with ethanol, and dried to obtain 12.6 g of the title compound. (Yield; 73%, HPLC purity; 99.2%).

HPLC analysis conditions Stationary phase; ODS (5 μm, 4.6 × 150 mm) Mobile phase; 0.5% -ammonium acetate / 7% -methanol water, flow rate; 1.0 ml / min Detector; UV254 nm

[0043] (physical properties of ^{E-1077) IR (cm -1} , ^{nujol);. 1768,1689,1681,1630,1602 1 H-NMR} (400MHz, DMSO-d 6); δ (ppm) 1.26 (3H , t, J = 7Hz),
3.08 & 3.09 (3H, s × 2), 3.47 (1H, d, J = 17Hz), 3.48 (2H, m), 3.
64 (1H, d, J = 17Hz), 4.02 (2H, s), 4.13 (2H, m), 5.06 (1H, d, J =
5Hz), 5.63-5.73 (1H, m), 5.64 (1H, dd, J = 8Hz, 5Hz), 5.78 (2
H, d, J = 55Hz), 7.18 (1H, d, J = 15Hz), 7.65 (1H, s), 8.23 (2H,
s), 8.37 (1H, s), 9.70 (1H, d, J = 8Hz).

Example 2 7β-[(Z)-(2- (5-amino-1,2,4-
(Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
Synthesis of citrate (Cefluprenam)

12.08 g of compound (1) was added to 97 ml of water cooled to 9 ° C.
After dissolving (30.9 mmol), set a pH meter, 2N-N
The pH was adjusted to 5 by dropwise addition of an aOH aqueous solution. Compound here
(2) 8.25 g (30.0 mmol) was added, and the mixture was adjusted with a 2N-NaOH aqueous solution to keep the pH at 4.5 to 5.5. After 2 hours, the completion of the reaction was confirmed, and the mixture was treated in the same manner as in Example 1 to obtain 12.0 g of the title compound.
I got (Yield; 70%)

Example 3 7β-[(Z) -2- (5-amino-1,2,4-
(Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
Synthesis of chromatography bets (Sefurupurenamu, Cefluprenam) water and cooled to 9 ° C. 97 ml
After dissolving 12.08 g (30.9 mmol) of compound (1) in the above, a pH meter was set, and a 5N-NaOH aqueous solution was added dropwise to adjust the pH to 6. After adding 8.33 g (30.3 mmol) of compound (2), pH
It was adjusted with a 5N-NaOH aqueous solution so as to be maintained at 5.5 to 6.5. After 2 hours, the completion of the reaction was confirmed, and the mixture was treated in the same manner as in Example 1 to obtain 12.8 g of the title compound. (Yield; 74%)

Example 4 7β-[(Z) -2- (5-amino-1,2,4-
(Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
Synthesis of chromatography bets (Sefurupurenamu, Cefluprenam) water and cooled to 9 ° C. 97 ml
After dissolving 12.08 g (30.9 mmol) of the compound (1) in the above, a pH meter was set, and the pH was adjusted to 6 by dropwise addition of a 2N-NaOH aqueous solution. After adding 8.33 g (30.3 mmol) of compound (2), pH
It was adjusted with a 2N-NaOH aqueous solution so as to be maintained at 5.5 to 6.5. After 2 hours, the completion of the reaction was confirmed, and the mixture was treated in the same manner as in Example 1 to obtain 11.9 g of the title compound. (Yield; 69%)

Example 5 7β-[(Z) -2- (5-amino-1,2,4-
(Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
Synthesis of chromatography bets (Sefurupurenamu, Cefluprenam) water and cooled to 9 ° C. 97 ml
After dissolving 12.08 g (30.9 mmol) of the compound (1) in the above, a pH meter was set, and a 2N-NaOH aqueous solution was added dropwise to adjust the pH to 3. After adding 9.55 g (34.7 mmol) of compound (2), the pH was
It was adjusted with a 2N-NaOH aqueous solution so as to be kept at 2.5 to 3.5. After 5 hours, the completion of the reaction was confirmed, and the mixture was treated in the same manner as in Example 1 to obtain 8.2 g of the title compound. (Yield; 48%)

Example 6 7β-[(Z) -2- (5-amino-1,2,4-
(Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
Synthesis of citrate (Cefluprenam)

Compound (1) 12.0 was added to 120 ml of water cooled to 10 ° C.
After dissolving 8 g (30.9 mmol), set a pH meter and 6.
The pH was adjusted to 5 by dropwise addition of 25% -ammonia water. 8.07 g (29.3 mmol) of the compound (2) was added thereto, and the mixture was stirred for 2 hours while adjusting with 6.25% -aqueous ammonia so as to keep the pH at 4.5 to 5.5. After confirming the completion of the reaction, the mixture was treated in the same manner as in Example 1 to obtain 12.4 g of the title compound. (Yield; 72%)

Example 7 7β-[(Z) -2- (5-amino-1,2,4-
(Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
Synthesis of chromatography bets (Sefurupurenamu, Cefluprenam) water 120ml was cooled to 9 ° C.
After dissolving 12.08 g (30.9 mmol) of compound (1) in the above, a pH meter was set, and the pH was adjusted to 6 by dropwise addition of 6.25% -aqueous ammonia. After 8.07 g (29.3 mmol) of the compound (2) was added thereto, the mixture was adjusted with 6.25% -aqueous ammonia so as to keep the pH at 5.5 to 6.5. After 2 hours, the completion of the reaction was confirmed.
In the same manner as described above, 12.2 g of the title compound was obtained. (yield;
71%)

Example 8 7β-[(Z) -2- (5-amino-1,2,4-
(Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
Synthesis of citrate (Cefluprenam)

8.0 g (16.6 mmol) of 7β-amino-[(E) -3-carbamoylmethylethylmethylammonio-1-propenyl] -3-cephem-4-carboxylate hydroiodide was added to water.
Dissolve in 215 ml, set the pH meter, and
The pH was adjusted to 5 with an aqueous NaOH solution. Under ice-cooling, while maintaining the pH at 4.5 to 5.5 with a 5N-NaOH aqueous solution, (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic chloride 4.0 g (16.8 mmol) and stirred for 2 hours. After confirming the completion of the reaction, the same treatment as in Example 1 was carried out to give the title compound
6.6 g were obtained. (Yield; 71%, HPLC purity; 98.5%)

Example 9 7β-[(Z) -2- (5-amino-1,2,4-
(Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
Synthesis of citrate (Cefluprenam)

At room temperature, 0.78 g (2.0 mmol) of compound (1) was added to water 1
After dissolving in 0 ml, sodium hydrogen carbonate 0.56 g (6.6 mmol)
Was added. Under ice cooling, 0.55 g (2.0 mmol) of compound (2) was added. After completion of the reaction, the mixture was treated in the same manner as in Example 1 to obtain 0.75 g of the title compound. (Yield; 68%)

Example 10 7β-[(Z) -2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
Synthesis of citrate (Cefluprenam)

At room temperature, 18.22 g (50.9 mmol) of disodium hydrogen phosphate dodecahydrate were dissolved in 72 ml of water. After dissolving 5.67 g (14.5 mmol) of compound (1), 4.24 g of compound (2)
(15.4 mmol) was added. After completion of the reaction, the mixture was treated in the same manner as in Example 1 to obtain 5.5 g of the title compound. (Yield; 68%)

Example 11 7β-[(Z) -2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
Synthesis of citrate (Cefluprenam)

At room temperature, 4.17 g (50.9 mmol) of sodium acetate
Was dissolved in 72 ml of water, and 5.67 g (14.5 mmol) of compound (1) was added thereto.
After dissolving, 4.24 g (15.4 mmol) of compound (2) was added.
After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 to give the title compound
5.4 g were obtained. (Yield; 67%)

Example 12 7β-[(Z) -2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Cetamide] -3- (E) -3-carbamoylmethylethylmethyl
(Ammonio-1-propenyl) -3-cephem-4-carboxyle
At room temperature, 6.33 g (77.2 mmol) of sodium acetate was dissolved in 72 ml of water, and 6.01 g (15.4 mmol) of compound (1) was dissolved therein, and then compound (2) 4.25 g
(15.4 mmol) was added. After 2 hours, the completion of the reaction was confirmed, and the mixture was treated in the same manner as in Example 1 to obtain 5.2 g of the title compound.
(Yield; 61%)

Example 13 7β-[(Z) -2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-methoxyiminoacetami
Do] -3- (4-carbamoylquinuclidinio) methyl-3-cef
Synthesis of hem-4-carboxylate (Cefclidine)

[0062]

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7β-amino-3- (4-carbamoylquinuclidinio) methyl-3-cephem-4-carboxylate [hereinafter, referred to as
Compound (3)] 7.4 g (20.2 mmol) was dissolved in 180 ml of water,
Set the H meter, and pH 5 with 5N-NaOH aqueous solution under ice-cooling.
Adjusted to 5. Under ice cooling, while maintaining the pH at 5.0 to 6.0 with a 5N-NaOH aqueous solution, (5-amino-1,2,4-thiadiazol-3-yl)
-(Z) -2-methoxyiminoacetic chloride [hereinafter, compound
(4)], and stirred for 1 hour. After completion of the reaction, the reaction solution was directly purified by reverse phase chromatography (ODS),
Ethanol was added dropwise to the main fraction and left in a refrigerator overnight. The precipitated crystals were separated, washed with ethanol and dried to obtain 7.5 g of the title compound. (Yield; 67
%, HPLC purity; 98.7%)

(HPLC analysis conditions) Stationary phase: ODS (5 μm, 6.0 × 150 mm) Mobile phase: 0.1% -ammonium acetate / 10% -methanol water,
Flow rate; 1.5ml / min Detector; UV254nm

(Physical properties of E-1040) Infrared absorption spectrum (cm ^-1 , Nujol); 3408, 1776,
1672, 1613, 1529, 132.1 ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 1.98 (6H, m), 3.27 (1
H, d, J = 16.5Hz), 3.31 (3H, m), 3.44 (3H, m), 3.75 (1H, d, J = 1
6.5Hz), 3.78 (1H, d, J = 12.8Hz), 3.91 (3H, s), 4.91 (1H, d, J =
12.8Hz), 5.09 (1H, d, J = 4.8Hz), 5.67 (1H, dd, J = 8.4Hz, 4.8H
z), 7.12 (1H, s), 7.29 (1H, s), 8.11 (2H, s), 9.50 (1H, d, J = 8.
Four).

Example 14 7β-[(Z) -2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-methoxyiminoacetami
Do] -3- (4-carbamoylquinuclidinio) methyl-3-cef
Synthesis of hem-4-carboxylate (Cefclidine) Compound (3) 9.35 g (25.5mmo
After l) was dissolved in 250 ml of water, a pH meter was set, and the pH was adjusted to 5.5 with a 1N-NaOH aqueous solution under ice-cooling. Under ice cooling, 5.9 g of compound (4) was added, and the mixture was stirred for 1 hour while adjusting the pH to 5.0 to 6.0 with a 1N-NaOH aqueous solution. After completion of the reaction, the mixture was treated in the same manner as in Example 13 to obtain 8.6 g of the title compound. (Yield; 61
%)

Comparative Example 1 7β-[(Z) -2- (5-amino-1,2,4-
Thiadiazol-3-yl) -2-methoxyiminoacetami
Do] -3- (4-carbamoylquinuclidinio) methyl-3-cef
Synthesis of hem-4-carboxylate (conventional method) (Cefclidine)
It was dissolved in a mixture of 42 ml of water and 126 ml of methanol, and 10.5 g of compound (3) was dissolved therein under ice cooling. Further, 126 ml of methanol was added, and 7.4 g of compound (4) was added. below freezing,
Stirring was continued for 2 hours. After completion of the reaction, insolubles were filtered.
Methanol was added dropwise thereto, and the mixture was allowed to stand under ice cooling overnight. The precipitated crystals were separated, washed with methanol, dissolved in water, recrystallized from ethanol, and the obtained crystals were dried to obtain 10.0 g of the title compound. (Yield; 63%, HPLC purity; 99.5%).

Example 15 7β-[(Z) -2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-methoxyiminoacetami
Do] -3- (imidazo [1,2-b] pyridazinium-1-yl) methyl
Synthesis of -3-cephem-4-carboxylate (Cefozopran, Cefozopran, SCE-2787)

[0069]

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Under ice-cooling, 7β-amino-3- (imidazo [1,2-b] pyridazinium-1-yl) methyl-3-cephem was added to 220 ml of water.
-4-carboxylate [hereinafter, compound (5)] 14.7 g (40.0 mm
ol), 16.4 g (200.0 mmol) of sodium acetate was added. To this, 11.3 g (44.1 mmol) of compound (4) was added.
After the completion of the reaction, the insolubles were filtered and purified as it was by reverse phase chromatography (ODS). The main fraction was lyophilized to give 11.5 g of the title compound. (Yield: 56
%, HPLC purity; 97.5%).

(HPLC analysis conditions) Stationary phase; ODS (5 μm, 4.6 × 150 mm) Mobile phase; 0.1% -ammonium acetate / 5% -methanol water, flow rate: 1.5 ml / min Detector; UV254 nm

(Physical properties of SCE-2787) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 3.03 & 3.41 (2H, ABq,
J = 17.4Hz), 3.84 (3H, s), 4.98 (1H, d, J = 5.2Hz), 5.25 & 5.47
(2H, ABq, J = 14.4Hz), 5.62 (1H, dd, J = 4.8Hz, 8.4Hz), 7.96 (1
(H, dd, J = 4.6Hz, 9.4Hz), 8.13 (2H, br-s), 8.77 (2H, s), 9.05
(1H, dd, J = 1.6Hz, 4.4Hz), 9.34 (1H, dd, J = 1.2Hz, 9.6Hz), 9.
50 (1H, d, 8.4Hz).

Example 16 7β-[(Z) -2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-methoxyiminoacetami
Do] -3- (imidazo [1,2-b] pyridazinium-1-yl) methyl
Synthesis of -3-cephem-4-carboxylate (Cefozopran, Cefozopran, SCE-2787) Under ice cooling, 14.7 g (40.0 mmol) of compound (5) was dissolved in 220 ml of water, and a pH meter was set. The pH was adjusted to 5 by dropwise addition of an aqueous NaOH solution. To this, 11.3 g (44.1 mmol) of compound (4) was added.
After completion of the reaction, the same treatment as in Example 15 was carried out to give the title compound 1
2.5 g were obtained. (Yield; 61%)

Example 17 7β- (D-α-phenylglycyl)
Synthesis of ( amino) -3-chloro-3-cephem-4-carboxylic acid (cefaclor)

[0075]

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7-amino-3-chlorocephalosporanic acid 2.
After dissolving 35 g in 80 ml of water, a pH meter was set, and the pH was adjusted to 8 with triethylamine under ice-cooling. Under ice cooling, p
While maintaining the H at 4.5 to 5.5, 2.65 g of (R)-(-)-2-phenylglycine chloride hydrochloride and triethylamine were alternately added, followed by stirring for 2 hours. After completion of the reaction, the reaction solution was directly purified by reverse phase chromatography, and the main fraction was concentrated under reduced pressure. After dissolving the concentrated residue in 1N-HCl (15 ml), the pH was adjusted to 4.5 with triethylamine for crystallization.
The precipitated crystals were separated, washed with ethanol, and dried to obtain 2.58 g of the title compound as a monohydrate. (Yield: 66.8
%, HPLC purity; 98.0%)

HPLC analysis conditions Stationary phase; Inertsil ODS-2 (4.6 × 150 mm) Mobile phase; 6% -CH ₃ CN / 50 mM-KH ₂ PO ₄ aqueous solution (pH 3.4), flow rate;
1.0ml / min detector; UV254nm internal standard reagent; p-aminoacetophenone

¹ H-NMR (400 MHz, D ₂ O / DCl); δ (ppm) 3.1 to
3.7 (ABq, 2H), 5.00 (d, 1H), 5.57 (d, 1H), 7.37 (s, 5H).

Example 18 7β- (D-α-phenylglycyl)
Synthesis of ( amino) -3-chloro-3-cephem-4-carboxylic acid (cefaclor) 14.1 g of 7-amino-3-chlorocephalosporanic acid was dissolved in 960 ml of water. Under cooling, the pH was adjusted to 8 with aqueous ammonia. While maintaining the pH at 4.5 to 5.5 under ice-cooling, the mixture was stirred for 2 hours while alternately adding 17.61 g of (R)-(-)-2-phenylglycine chloride hydrochloride and aqueous ammonia for adjustment. After completion of the reaction, the reaction solution was directly purified by reverse phase chromatography, and the main fraction was concentrated under reduced pressure. After dissolving the concentrated residue in 150 ml of 1N HCl, pH 4.5 with ammonia water.
And crystallized. The precipitated crystals were separated, washed with ethanol, and dried to obtain 16.7 g of the title compound as a monohydrate.
I got (Yield; 72.0%, HPLC purity; 98.3%)

Example 19 7β- (D-α-phenylglycyl)
Synthesis of ( amino) -3-chloro-3-cephem-4-carboxylic acid (cefaclor) 14.1 g of 7-amino-3-chlorocephalosporanic acid was dissolved in 960 ml of water. Under cooling, the pH was adjusted to 8 with an 8N-NaOH aqueous solution. Under ice cooling, while keeping the pH at 4.5 to 5.5, (R)-(-)-2-phenylglycine chloride hydrochloride (21.83 g) and an 8N-NaOH aqueous solution were alternately added, followed by stirring for 2 hours. After completion of the reaction, the reaction solution was directly purified by reverse phase chromatography, and the main fraction was concentrated under reduced pressure. Concentrate residue to 1N-HCl 150
After dissolving in water, the solution was adjusted to pH 4.5 with aqueous ammonia and crystallized. The precipitated crystals were separated, washed with ethanol, and dried to obtain 13.5 g of the title compound as a monohydrate.
(Yield; 58.2%, HPLC purity; 97.8%)

Example 20 7- (D-α-phenylglycylaria)
Synthesis of ( mino) -3-methyl-3-cephem-4-carboxylic acid (cephalexin, Cephalexin)

[0082]

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7-amino-3-methylcephalosporanic acid 3.
6 g was dissolved in 150 ml of water, and after setting a pH meter, the pH was adjusted to 8 with aqueous ammonia under ice cooling. Under ice-cooling and stirring, add 10.3 g of (R)-(-)-2-phenylglycine chloride and adjust with ammonia water to maintain pH8.
Stirred for hours. After completion of the reaction, add 1000 ml of acetone,
Leave in the refrigerator overnight. The precipitated crystals were separated, washed with acetone, and dried to obtain 3.8 g of the title compound. (Yield; 65%, HPLC purity; 81%)

Example 21 7β-[(Z) -2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-fluoromethoxyiminoa
Synthesis of [Cetamido] -3-methyl-3-cephem-4-carboxylic acid

[0085]

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7-amino-3-methylcephalosporanic acid 3.
After dissolving 5 g in 146 ml of water, a pH meter was set, and the pH was adjusted to 8 with aqueous ammonia under ice-cooling. Under ice-cooling and stirring, 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2
-Add 4.7 g of fluoromethoxyiminoacetic chloride and adjust the pH.
Adjust with ammonia water to keep it at 7.5 to 8.5
Stirred for hours. After completion of the reaction, the mixture was adjusted to pH 1 to 2 with 1N-HCl and extracted with 150 ml of ethyl acetate. After the extract was washed with water and dried, it was allowed to stand in a refrigerator overnight, and the precipitated crystals were separated. Washing with ethyl acetate and drying gave 5.1 g of the title compound. (Yield; 75%, HPLC purity; 98.3%)

¹ H-NMR (400 MHz, DMSO-D ₆ ); δ (ppm) 2.01
(3H, s), 3.33 (1H, d, J = 19Hz), 3.57 (1H, d, J = 19Hz), 5.10 (1
H, d, J = 5Hz), 5.74 (1H, dd, J = 8,5Hz), 5.79 (2H, d, J = 55Hz),
8.19 (2H, s), 9.70 (1H, d, J = 8Hz), 13.2 (1H, br-s).

Claims (6)

[Claims] 1. 3-Cephem-4-carboxylate (I) or a salt thereof represented by the following general formula: [Wherein, R ² represents a carboxyl group or a carboxyl anion, and R ³ represents a lower alkyl group, a halogen atom, a lower acyloxyalkyl group, or a group represented by the following general formula. Embedded image ] And the formula R ¹ acid chloride represented by COCl (II) {wherein, R ¹ is meant any group represented by the following formula. Embedded image Wherein A is a nitrogen atom or a methine group, B is a lower alkoxy group, a halogenated lower alkoxy group, a triphenylmethoxy group or a lower alkyl group or a lower acyloxy group, and a formula —C (CH ₃ ) ₂ COOR (Wherein R represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom or an organic cation).
Further, A and B may be any of the (E) and (Z) geometric isomers. ] A method for producing a cephem compound (III) represented by the following general formula, wherein｝ is reacted in water. Embedded image (In the formula, R ¹ , R ² and R ³ have the same meaning as described above.) 2. The process for producing a cephem compound (III) according to claim 1, wherein the reaction is carried out using a base under conditions of pH 3 to 7. 3. The method for producing a cephem compound (III) according to claim 1, wherein the base is at least one selected from sodium hydroxide, potassium hydroxide, aqueous ammonia and triethylamine. 4. The method for producing a cephem compound (III) according to claim 1, wherein the reaction is carried out in the presence of a base. 5. The method according to claim 1, wherein the base is sodium acetate, potassium acetate,
Sodium carbonate, potassium carbonate, sodium bicarbonate,
The method for producing a cephem compound (III) according to claim 1 or 4, wherein the compound is at least one selected from potassium hydrogen carbonate, disodium hydrogen phosphate, ammonium carbonate and ammonium carbamate. 6. The method according to claim 1, wherein the cephem compound (III) is 7β-[(Z) -2-
(5-Amino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetamide] -3- (E)-(3-carbamoylmethylethylmethylammonio-1-propenyl) -3-cephem -4-carboxylate or 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (4-carbamoylquinuclidinio ) Methyl
The method for producing a cephem compound (III) according to any one of claims 1 to 5, which is -3-cephem-4-carboxylate.