JP3214866B2 - Method for producing cephem derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a cephem derivative. More specifically, the present invention relates to an improved method for producing a cephem derivative or an intermediate thereof useful as an antibacterial agent.

[0002]

2. Description of the Related Art The following general formula (3) which is an object of the present invention is shown below.
As a method for producing the compound of the formula (1) and salts thereof,
A method described in US Pat. No. 15,56984 is known.

[0003]

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That is, in the compound of the general formula (3), the compound in which the 3-position of the cephem skeleton is 3-chloropropenyl is first converted to a compound having 3-iodopropenyl, followed by reacting with an amine. It is a way to get things.

[0005]

The present inventors have studied to carry out the above two-step reaction in one step. That is, as shown in Reference Example, a method in which a compound having a 3-chloropropenyl group at the 3-position is reacted with an amine in the presence of an alkali metal salt of iodine. It has been found that it can only be obtained in the form of a mixture of trans forms (E) (with regard to the double bond in the propenyl group). Considering the use of the final compound as an antibacterial agent, the trans form has a higher antibacterial activity, and therefore, a method for selectively obtaining the trans form in one step was further studied.

[0006]

The inventors of the present invention have investigated the cause of the mixture of the cis-form and the trans-form, and surprisingly found that the carboxyl group at the 4-position of the cephem skeleton in the starting compound was protected with a protecting group. The inventors have found that the above-mentioned phenomenon occurs, and that the trans-isomer can be selectively obtained unless protected by a protecting group, thereby completing the present invention.

That is, the present invention provides a compound represented by the general formula (1):

Embedded image (Wherein, R ¹ represents an amino group or an acylamino group)
Or a salt thereof, in the presence of an alkali metal iodine, a compound of the general formula (2)

Embedded image Wherein R ² and R ^{3 each} represent a lower alkyl group, and R ⁴ represents a carbamoyl lower alkyl group, or a salt thereof,

Embedded image (Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above) or a method for producing a cephem derivative or a salt thereof.

Examples of the acylamino group for R ¹ include the following groups. (1) General formula (4)

Embedded image (Wherein R ⁵ is a lower alkyl group which may be substituted,
R ⁶ is an amino group or a protected amino group) R ⁵
Examples of the optionally substituted lower alkyl group include: lower alkyl halides such as fluoromethyl, 2,2,2-trifluoroethyl and difluoromethyl; lower alkyl groups such as methyl and ethyl; cyanomethyl such as cyanomethyl and cyanoethyl Lower alkyl; and carboxy lower alkyl such as carboxymethyl, carboxyethyl, and carboxypropyl. Examples of the protecting group in the protected amino group of R ⁶ include a formyl group, an acetyl group, a chloroacetyl group, a t-butoxycarbonyl group,
Commonly used amino-protecting groups such as p-methoxybenzyl group, trityl group and diphenylmethyl group are exemplified.

(2) General formula (5)

Embedded image (Wherein, R ⁵ and R ⁶ are the same as defined above). Specific examples of R ⁵ and R ⁶ are the same as described above.

(3) A lower alkanoylamino group which may be substituted A formylamino group, an acetylamino group, a chloroacetylamino group, a dichloroacetylamino group, a phenylacetylamino group, a thienylacetylamino group and the like.

Examples of the lower alkyl group for R ² and R ³ include a methyl group, an ethyl group, a propyl group and a butyl group. Examples of the carbamoyl lower alkyl group for R ⁴ include a carbamoylmethyl group and a carbamoylethyl group.

The salts of the compounds of the general formulas (1), (2) and (3) are selected according to groups capable of forming salts of the respective compounds, for example, amino groups, carboxyl groups and the like. For example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; hydrochloride, hydrobromide, hydroiodide, sulfate, carbonate, bicarbonate and the like Organic carboxylate such as acetate, maleate, lactate, tartrate; organic sulfonate such as methanesulfonate, hydroxymethanesulfonate, tauric acid, benzenesulfonate, etc. It can be selected as appropriate.

The present reaction is carried out at a reaction temperature of 0 ° C. to 50 ° C., preferably
It can be performed at 10 ° C to 30 ° C. The reaction solvent is selected from solvents having a sufficient solubility for inducing the reaction with the compound of the general formula (1) or a salt thereof, and an alkali metal iodine salt. Examples of such a solvent include acetone, dimethylformamide, acetonitrile, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide and the like.

[0014]

Next, the present invention will be described in more detail with reference to Examples, Experimental Examples and Reference Examples. PMB in the formula represents a paramethoxybenzyl group.

Experimental Example 1 (Synthesis of Starting Compound) p-methoxybenzyl 7β- [2- (5-amino-
1,2,4-thiadiazol-3-yl)-(Z) -2
-Fluoromethoxyiminoacetamide] -3-
[(Z) -3-chloro-1-propenyl] -3-cephem-4-carboxylate

[0016]

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P-methoxybenzyl 7β-amino-3
N, O-bistrimethylsilylacetamide (3.4 ml) was added to a suspension of [(Z) -3-chloro-1-propenyl] -3-cephem-4-carboxylate hydrochloride (2.0 g) in tetrahydrofuran (20 ml). Was added at room temperature and stirred for 10 minutes. Next, 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid chloride (1.2 g) was added, and the mixture was stirred at room temperature for 50 minutes. Methanol (2.0 ml) was added to the reaction solution, and the precipitated insoluble material was removed by filtration. The filtrate was diluted with diisopropyl ether (50 m
l) and the resulting precipitate was collected by filtration to obtain the desired product (2.8 g).

Infrared absorption spectrum (cm ^-1 , Nujol): 3150, 1775, 1715, 1675 ¹ H-NMR spectrum (δ, DMSO-d ₆ ): 3.48 (1H, d, J = 18 Hz), 3.66 (1H, d, J = 18Hz), 3.
75 (3H, s), 3.96 (1H, dd, J = 7.6Hz, 12Hz), 4.13 (1H, dd, J = 7.
6Hz, 12Hz), 5.08 (1H, d, J = 12Hz), 5.14 (1H, d,
J = 12Hz), 5.28 (1H, d, J = 5.2Hz), 5.70 (1H, dt, J = 11Hz, 8.0H
z), 5.79 (2H, d, J = 55Hz), 5.89 (1H, dd, J = 5.2Hz, 8.
4Hz), 6.27 (1H, d, J = 11Hz), 6.94 (1H, d, J = 8.0Hz), 7.32 (1H, d, J = 8.0Hz), 8.25 (2H, brs), 9.80 (1H, d , J = 8.4Hz)

Experimental Example 2 (Synthesis of Starting Compound) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide] -3- [ (Z) -3-Chloro-1-propenyl] -3-cephem-4-carboxylic acid

[0020]

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To a solution of the compound of Experimental Example 1 (200 mg) in dichloromethane (2 ml) was added trifluoroacetic acid (0.2 ml) at room temperature, and the mixture was stirred for 1 hour and 30 minutes. The reaction mixture was added to diethyl ether (20 ml), and the resulting precipitate was collected by filtration to obtain the desired product (137 mg).

Infrared absorption spectrum (cm ⁻¹ , Nujol): 3280, 3180, 1770, 1675 ¹ H-NMR spectrum (δ, DMSO-d ₆ ): 3.42 (1H, d, J = 18 Hz), 3.65 (1H, d, J = 18Hz), 4.07 (1H, dd, J = 8.0Hz, 12Hz), 4.17 (1H, dd, J = 8.
0Hz, 12Hz), 5.20 (1H, d, J = 5.0Hz), 5.60 to 5.72 (1H, m), 5.74 (2H, d, J = 55Hz), 5.75 to 5.82 (1H, m), 6.30 (1H, d, J = 11Hz), 8.25 (2H, brs), 9.74 (1H, d
, J = 8.4Hz)

Experimental Example 3 (Synthesis of Starting Compound) 7β-amino-3-[(Z) -3-chloro-1-propenyl] -3-cephem-4-carboxylic acid trifluoroacetate

[0024]

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P-methoxybenzyl 7β-amino-3-
To a suspension of [(Z) -3-chloro-1-propenyl] -3-cephem-4-carboxylate hydrochloride (20 g) in dichloromethane (40 ml) was added trifluoroacetic acid (10.7 ml) at room temperature. The mixture was stirred for 1 hour and 15 minutes. The reaction mixture was added dropwise to ethyl acetate (400 ml), and the resulting precipitate was collected by filtration.
(17.2 g) was obtained.

Infrared absorption spectrum (cm ^-1 , Nujol): 3400, 1775, 1705 ¹ H-NMR spectrum (δ, DMSO-d ₆ ): 3.69 (2H, s), 4.15 (1H, dd, J = 8.0 Hz) , 12Hz), 4.23 (1H, dd, J = 8.0Hz, 12Hz), 5.18 (1H, d, J = 4.
8Hz), 5.30 (1H, d, J = 4.8Hz), 5.80 (1H, dt, J = 12Hz, 8.0H
z), 6.45 (2H, d, J = 12Hz)

Experimental Example 4 (Synthesis of Starting Compound) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide] -3- [ (Z) -3-Chloro-1-propenyl] -3-cephem-4-carboxylic acid

[0028]

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To a solution of the compound of Experimental Example 3 (1.56 g) in tetrahydrofuran (20 ml) was added N, O-bistrimethylsilylacetamide (3.0 ml) at room temperature, and the mixture was stirred for 10 minutes. To this was added 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid chloride (1.0 g), and the mixture was stirred at room temperature for 40 minutes. Methanol (2.0 ml) was added to the reaction solution, and the precipitated insoluble material was removed by filtration. The filtrate was added to diethyl ether (50 ml), and the resulting precipitate was collected by filtration to obtain the desired product (1.62 g).
The physical properties matched those of Experimental Example 2.

Example 1 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (Carbamoylmethylethylmethylammonio) -1-propenyl] -3
-Cephem-4-carboxylate

[0031]

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7β- [2- (5-amino-1,2,4-
Thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(Z) -3-chloro-1-propenyl] -3-cephem-4-carboxylic acid
(1.0 g) in a solution of acetone (10 ml) in 2-ethylmethylaminoacetamide (0.73 g) and sodium iodide (0.47
g) was added at room temperature and stirred for 30 minutes. The resulting precipitate was collected by filtration, suspended in water, and adjusted to pH 6 with sodium acetate.
The insoluble material was removed by filtration, and the filtrate was purified by reversed-phase silica gel column chromatography, and lyophilized to give the desired product (0.83 g,
Yield 71%). In HPLC analysis, this product did not contain any isomers in which the double bond of the propenyl group at the 3-position of cephem was the cis-form (Z). The same analysis was performed on the reaction solution after the completion of the reaction, but no cis-form (Z) was found.

[0033] Infrared absorption spectrum (cm ^-1, nujol): 1760,1675,1590,1520 ¹ H-NMR spectrum _{(δ, DMSO-d 6)} : 1.26 (3H, t, J = 7.2Hz), 3.08 and 3.09 (Together
3H, s), 3.4-3.6 (2H, m), 3.47 (1H, d, J = 16.8Hz), 3.65 (1H, d, J = 16.8Hz), 4.01 (2H, s), 4.05-4.2 (2H , M), 5.60 (1H, d, J = 4.8Hz), 5.6-5.75 (2H, m), 5.79 (2H, br, d, J = 55.3Hz)
, 7.17 (1H, d, J = 15.8Hz), 7.66 (1H, s), 8.23 (2H, s), 8.33 (1H, s), 9.71 (1H, d, J = 8.4Hz)

Example 2 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (Carbamoylmethylethylmethylammonio) -1-propenyl] -3
-Cephem-4-carboxylate

[0035]

Embedded image

In the same manner as in Example 2 except that the solvent acetone in Example 1 was changed to dimethylformamide, 0.71 g of the desired product was obtained. In HPLC analysis, this product contains
No mixture of isomers in which the double bond at the 3-position of the propenyl group of cephem was the cis-form (Z) was found. Similarly, the cis form (Z) was not observed in the reaction solution after the completion of the reaction. The physical properties were consistent with those of Example 1.

Experimental Example 5 (Synthesis of Starting Compound) 7β- (2-phenylacetamido) -3-[(Z)-
3-chloro-1-propenyl] -3-cephem-4-carboxylic acid 1/2 diisopropyl ether solvate.

[0038]

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P-methoxybenzyl 7β- (2-phenylacetamido) -3-[(Z) -3-chloro-1-
Propenyl] -3-cephem-4-carboxylate
(5.0 g) in dichloromethane (15 ml) and anisole (5 m
l). To this was added trifluoroacetic acid (5 ml) at room temperature, and the mixture was stirred for 1 hour. The reaction solution was added to diisopropyl ether (100 ml) and stirred at room temperature for 2 hours.
The crystals are collected by filtration and washed with diisopropyl ether to give the desired product.
(4.2 g) was obtained as crystals.

Infrared absorption spectrum (cm ^-1 , Nujol): 3290, 1780, 1715, 1660 ¹ H-NMR spectrum (δ, DMSO-d ₆ ): 1.02 (3H, d, J = 6.0 Hz), 3.49 (1H) , D, J = 18 Hz), 3.50 (1H, d, J = 14 Hz), 3.58 (1H, d, J = 14 Hz), 3.61 (1H, q, J = 6.0 Hz), 3.70 (1H, d, J = 18Hz), 4.13 (1H, dd, J = 8.4Hz, 12Hz), 4.22 (1H, dd, J = 8.
4Hz, 12Hz), 5.18 (1H, d, J = 5.2Hz), 5.70 (1H, dd,
J = 5.2Hz, 8.4Hz), 5.74 (1H, dt, J = 8.4Hz, 12Hz), 6.38 (1H, d, J = 12
Hz), 7.16-7.34 (5H, m), 9.14 (1H, d, J = 8.4Hz)

Example 3 7β- (2-phenylacetamido) -3-[(E)-
3- (carbamoylmethylethylmethylammonio)-
1-propenyl] -3-cephem-4-carboxylate

[0042]

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The compound of Experimental Example 5 (100 mg) was added to acetone (2 m
l) and suspended in 2-ethylmethylaminoacetamide (7
8 mg) and sodium iodide (51 mg) were added at room temperature.
After stirring at the same temperature for 30 minutes, diisopropyl ether (30 ml) was added to the reaction solution, and the resulting precipitate was collected by filtration. After suspending this in water, the insoluble matter was removed by filtration. The filtrate was purified by reverse phase silica gel column chromatography, and lyophilized to obtain the desired product (80 mg, yield: 75%). In the HPLC analysis of this product, no isomers in which the double bond of the propenyl group at the 3-position of cephem was the cis-form (Z) were mixed. Similarly, the reaction solution after the completion of the reaction did not show any mixture of the cis-form (Z).

[0044] Infrared absorption spectrum (cm ^-1, nujol): 3175,1780,1665,1635 ¹ H-NMR spectrum _{(δ, DMSO-d 6)} : 1.26 (3H, t, J = 7Hz), 3.07 (1.5H , S), 3.08 (1.5H
, S), 3.25 to 3.55 (2H, m), 3.49 (1H, d, J = 17 Hz), 3.56 (1
H, d, J = 14Hz), 3.59 (1H, d, J = 14Hz), 3.65 (1H
, D, J = 17 Hz), 4.00-4.08 (2H, m), 4.05-4.20 (2H, m), 4.98 (1H, d, J = 5 Hz), 5.48 (1H, dd, J = 5 Hz, 8 Hz), 5.68 (1H, dt, J = 16Hz, 7Hz), 7.15 to 7.37 (6H, m), 7.64 (1H, brs), 8.46 (1H, brs), 9.13 (1H, d, J = 8Hz)

Reference Example 1 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E, Z)- 3- (carbamoylmethylethylmethylammonio) -1-propenyl]
-3-Cephem-4-carboxylate

[0046]

Embedded image

P-methoxybenzyl 7β [2- (5-
Amino-1,2,4-thiadiazol-3-yl)-
(Z) -2-fluoromethoxyiminoacetamide]-
3-[(Z) -3-chloro-1-propenyl] -3-cephem-4-carboxylate (500 mg) in acetone (5 m
l) Add 2-ethylmethylaminoacetamide (195m
g) and sodium iodide (190 mg) were added at room temperature. After stirring at the same temperature for 40 minutes, the reaction solution was added dropwise to diethyl ether (50 ml). The resulting precipitate is collected by filtration and p-methoxybenzyl 7β [2- (5-amino-1,2,4
-Thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide] -3-[(E, Z) -3
-(Carbamoylmethylethylmethylammonio) -1
-Propenyl] -3-cephem-4-carboxylate iodide (641 mg) was obtained. To a solution of this compound (100 mg) in dichloromethane (1 ml) was added trifluoroacetic acid (0.2 ml).
) Was added at room temperature. After stirring at the same temperature for 25 minutes, the reaction solution was added dropwise to ethyl acetate (50 ml). The resulting precipitate was collected by filtration, suspended in water, and adjusted to pH 6 with sodium acetate. After filtering off the insoluble matter, the filtrate was purified by reverse phase silica gel column chromatography, and lyophilized to give the desired product (2
3 mg). In the HPLC analysis of this product, the double bond site of the propenyl group at the 3-position of cephem was found to be in trans form (E).
And the ratio of the compound being the cis form (Z) is 1:10
And the cis body was much more.

¹ H-NMR spectrum (δ, DMSO-d
₆ ): 1.24 (3H, t, J = 7Hz), 3.12 and 3.13 (3H,
s), 3.26 (1H, d, J = 17Hz), 3.4-3.63 (3H, m), 4.0-4.12 (3H, m), 4.18-4.28 (1H, m), 5.11 (1H, d, J = 6Hz) ), 5.61 (1H, m), 5.66 (1H, dd, J = 5Hz, 8Hz), 5.79 (2H, br-d, J = 56Hz)
, 6.69 and 6.71 (1H, d in total), 7.63 (1H, s), 8.25 (2H, s), 8.59 and 8.62 (1H, s in total)
, 9.74 (1H, d, J = 8Hz)

Reference Example 2 p-methoxybenzyl 7β- (2-phenylacetamido) -3-[(E, Z) -3- (carbamoylmethylethylmethylammonio) -1-propenyl] -3-cephem-4-carboxylate iodide

[0050]

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P-Methoxybenzyl 7β- (2-phenylacetamido) -3-[(Z) -3-chloro-1-propenyl] -3-cephem-4-carboxylate (1.0 g) suspended in acetone (10 ml) 2-Ethylmethylaminoacetamide (0.68 g) and sodium iodide (0.44 g) were added to the suspension at room temperature. After stirring at the same temperature for 30 minutes, diisopropyl ether
(30 ml) and ethyl acetate (30 ml) were added dropwise. The resulting precipitate was collected by filtration to obtain the desired product (1.4 g). In the HPLC analysis of this product, the ratio of the compound in which the double bond site of the propenyl group at the 3-position of cephem is trans-form (E) to cis-form (Z) is 1: 3, which is much higher in the cis-form. There were many.

¹ H-NMR spectrum (δ, DMSO-d
₆ ): 1.17 and 1.26 (3H, t, J = 7.2 Hz in total), 3.06 and 3.12 (3H, s in total), 3.44 to 3.69 (5H,
m), 3.76 (3H, s), 3.84-4.11 (3H, m), 4.15-4.33 (2H,
m), 5.12 and 5.17 (total 1H, d, J = 5.2Hz), 5.11 and 5.18 (total 1H, d J = 12Hz), 5.17 and
5.26 (1H, d, J = 12Hz in total), 5.70-5.78 (1H, m), 5.78-5.90 (1H, m), 5.58 (0.7H, d, J = 12Hz), 6.91
-7.00 (2.3H, m), 7.20-7.40 (7H, m), 7.75 (1H, brs), 7.90 and 7.93 (1H, brs in total), 9.15 and 9.17 (1H, d, J = 7.2Hz in total )

[0053]

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-1-156984 (JP, A) JP-A-62-228084 (JP, A) JP-A-1-308287 (JP, A) (58) Field (Int.Cl. ⁷ , DB name) C07D 501/00-501/62 A61K 31/00-31/80 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (1) (Wherein, R ¹ represents an amino group or an acylamino group)
Or a salt thereof, in the presence of an alkali metal iodide, a compound represented by the general formula (2): Wherein R ² and R ³ represent a lower alkyl group and R ⁴ represents a carbamoyl lower alkyl group, or a salt thereof, which is characterized by reacting a compound represented by the following general formula (3): (Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above) or a method for producing the cephem derivative or a salt thereof. Wherein R ¹ is an amino group, phenylacetylenyl
L- amino group or general formula (4) (Wherein R ⁵ is a lower alkyl group which may be substituted,
R ⁶ is an amino group or a protected amino group). The method for producing a cephem derivative according to claim 1, wherein