JPS5943477B2 - Method for producing cephalosporins - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a solvent in a method for producing 7-methoxycephalosporins by a ring expansion reaction.

More specifically, the present invention relates to the general formula HOCH3? to / one soil]: Ju.

,,\R_, (wherein, R_1 represents a phenylacetyl group or a thienylacetyl group, and R_.

represents a hydrogen atom, an acetoxy group or a carbamoyloxy group, and R_3, R_4 and R_5 are the same or different and represent a hydrogen atom, a phenyl group or a halogenomethyl group. ) by heating a penicillin derivative represented by the general formula R_'-H in a solvent in the presence of a salt of phosphoric acid or organic phosphonic acid and an organic nitrogen base with pKB4 or higher.
□H, -R_.

/R_3 [■] COOC-R_4 \R_, (wherein, R_,, R_,, R_3, R_4 and R_,
means the same as above.

) In the method for producing cephalosporins represented by
The present invention relates to a method characterized in that an organic halogen compound having a boiling point of 100° C. or higher is used as a solvent.

Here, specific examples of organic halogen compounds having a boiling point of 100°C or higher include alkyl halides such as 1,1,2,2-atrachloroethane (boiling point 146°C), bromobenzene (boiling point 156°C), Chlorbenzene (boiling point 1
73-180℃), chlorotoluene (boiling point 158-16
Examples include aryl halides such as FC). Specific examples of salts of phosphoric acid or organic phosphonic acid and organic nitrogen bases with PKb4 or higher that act as catalysts for the ring expansion reaction include pyridium, dichloromethanephosphonic acid, and the like.

In recent years, as a method for producing 7-methoxycephalosporin antibiotics, which have been attracting attention as a new derivative of cephalosporin, a penicillin derivative with a methoxy group introduced at the 6-position is ring-expanded to produce a 7-methoxycephalosporin derivative. There are two known methods.

One of them is the method disclosed in JP-A-48-10094, in which a penicillin derivative is heated in the presence of an acid. (boiling point: 101°C), isobutyl methyl ketone (boiling point: 116°C), etc., and requires refluxing for as long as 18 hours, making it difficult to say that this is a useful method.

Additionally, 6-
It cannot be said that it is preferable to use an acid catalyst for a methoxypenicillin derivative.

The other is Journal of the American Chemical Society, Volume 95, Page 2401 (197
The ring expansion was carried out in dioxane using a dipyridine phosphoric acid salt as a catalyst using the method disclosed in 1993).

This method is similar to the present invention in that a salt of phosphoric acid is used as a catalyst, but as a result of additional trials by the present inventors,
It was found that heating for several hours or more was required to complete the ring expansion reaction.

Therefore, as a result of repeated research in order to carry out the ring expansion reaction from 6-methoxypenicillin derivatives to 7-methoxycephalosporin in a short time and with good yield, we found that the same heating conditions However, if an organic halogen compound with a boiling point of 100°C or higher is used as a solvent,
The present invention was completed based on the finding that the reaction is completed in a much shorter time than when dioxane or the like is used as a solvent. In order to carry out the method of the present invention, the penicillin derivative represented by the general formula [1] may be dissolved in an organic halogen compound having a boiling point of 100° C. or higher, and a catalyst may be added thereto and heated.

This reaction is carried out at 80-170°C, preferably at 100-150°C.
Generally, it is heated for several minutes to several hours.

After the ring expansion reaction, if necessary, the ester moiety can be hydrolyzed to give a carboxylic acid or even a salt of a carboxylic acid.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. Example 1 6α-methoxy-6β-phenylacetamide 2,2-
Dimethylpenam-3-carboxylic acid trichloroethyl ester-1-oxide (500mv) was dissolved in the solvent (107111) listed in the following table, pyridinium chloromethanephosphonate (200m7) was added, and the mixture was heated at 100°C.

After a certain period of time from the start of heating, each reaction mixture was spotted on a silica gel sheet and developed with a mixture of benzene (3) and ethyl acetate (1). The progress of the expansion reaction was observed and the following results were obtained. As shown in the previous table, boiling point 100℃
When the above organic halogen compound was used as a solvent, spots of the target product appeared 30 minutes after the start of heating, and spots of the raw material completely disappeared after 1 hour, and the ring expansion reaction was completed.

On the other hand, when dioxane was used as a solvent, the target product spot was weaker than the raw material spot after 3 hours, and the reaction was not completed even after 8 hours. Example 2 Process for producing 7α-methoxy 7β-phenylacetamide 3-methynole-3-cephem-4-carboxylic acid trichloroethyl ester 6α-methoxy-6β-phenylacetamide 2,2-dimethylpenam-3-carboxylic acid trichloroethyl ester Ester-1-oxide (1.09) to 1,1,2,2-tetrachloroethane (201TLI)
Pyridinium dichloromethanephosphonate (
0.49) and heat at 145°C for 30 minutes.

The solvent was distilled off under reduced pressure, the residue was extracted with alcohol, and the alcohol was distilled off to obtain 0.99% of crude crystals. Wash this product with ethyl acetate to obtain the desired product (0.43 g). The melting point of the sample for analysis is 205-207°C. Example 3 Method for producing 7α-methoxy7β-phenylacetamide-13-methynole-3-cephem-4-carboxylic acid trichloroethyl ester.

6α-methoxy-6β-phenylacetamide 2,2-
Dimethylpenam-3-carboxylic acid trichloroethyl ester-1-oxide (1.09) was dissolved in bromobenzene (
20ml), add lyridinium dichloromethanephosphonate (0.29ml), and heat to 100°C for 1 hour.

The solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, and the ethyl acetate was distilled off to obtain 0.89 g of crude crystals. If this is washed with a small amount of ethyl acetate, the same target as in Example 2 (0.
459). Example 4 Process for producing 7α-methoxy 7β-phenylacetamide-13-methyl-3-cephem-14-carboxylic acid trichloroethyl ester 6α-methoxy-6β-phenylacetamide 2,2-dimethylpenam-13-carboxylic acid trichlor Dissolve ethyl ester-1-oxide (1.09) in m-chlorotoluene (20ml), add pyridinium dichloromethanephosphonate (0.4f1),
Heat at 145°C for 30 minutes.

The solvent is distilled off under reduced pressure, the residue is extracted with alcohol, and the alcohol is distilled off to obtain crude crystals. This product was washed with ethyl acetate to obtain the same desired product (0.449) as in Example 2. Example 5 Process for producing 7α-methoxy-7β-phenylacetamide-13-methyl-3-cephem-14-carboxylic acid benzyl ester 6α-methoxy-6β-phenylacetamide-12,2-dimethylpenam-13-carboxylic acid benzyl ester Ester-1-oxide (0.59) to 1,1,2,2
-Dissolved in tetrachloroethane (15ml) and added pyridinium dichloromethanephosphonate (0.19),
Heat to 145°C for 30 minutes.

The solvent was distilled off under reduced pressure, extracted with ethyl acetate, and the solvent was distilled off to obtain a residue of 0.99%. If this residue is treated by silica gel chromatography, the melting point is 181-182.
Obtain the desired product (0.16 g) at ℃. Example 67 α-methoxy 7β-phenylacetamide 3-methyl-3-
Production method of Cefem-4-carboxylic acid methyl ester 6α
-Methoxy-6β-phenylacetamide-2,2-dimethylpenam-3-carboxylic acid methyl ester-1-oxide (1.49) was dissolved in 1,1,2,2-tetrachloroethane (20ml) and pyridinium dichloromethane was added. Add phosphonate (0.39) and heat at 100°C for 2 hours.

The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and purified by silica gel column talomatography. From the mixed solution of benzene (5) and ethyl acetate (1), 0.689 of the desired product in the form of carmela is obtained. Example 7 7α-methoxy 7β-(2-thienylacetamide)
-Production method of 3-acetoxymethyl-3-cephem-4-carboxylic acid benzhydryl ester 6α-methoxy-6
β-(2-thienylacetamido)-2-methyl-2-
Acetoxymethylpenam-3-carboxylic acid benzhydryl ester 1-oxide (1.09) was converted into 1,1,2,
2-Tetrachloroethane (dissolved in 20m0, add pyridinium dichloromethanephosphonate (0.29),
Heat to 100°C for 1 hour.

The solvent was distilled off under reduced pressure, extracted with ethyl acetate, and the solvent was distilled off to obtain a residue. This residue was treated with silica gel chromatography to obtain a caramel-like target product (0.349).
get. Example 8 Method for producing 7α-methoxy 7β-phenylacetamide 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid benzhydryl ester 6α-methoxy-6
β-acetamido-2-methyl-2-carbamoyloxymethylpenam-3-carboxylic acid benzhydryester-1-oxide (1.09) was dissolved in 1,1,2,2-tetrachloroethane (20ml), Add pyridinium dichloromethanephosphonate (0.29) and add 145
Heat at ℃ for 30 minutes.

The solvent was distilled off under reduced pressure, extracted with ethyl acetate, and then the solvent was distilled off under reduced pressure to obtain a yellow oil. This was treated with silica gel talomatography to give a caramel-like object (0.3
69) is obtained. Reference example 1 6α-methoxy-6β-phenylacetamide 2,2-
Dimethylpenam-3-carboxylic acid trichloroethyl ester-1-oxide, Journal of the American Chemical Society, Vol. 95, 2401
(1973) from 6β-phenylacetamide-2,2-dimethylpenam-3-carboxylic acid trichloroethyl ester-1-oxide.

Melting point 147-148°C.

IR (KBr, crl): 1795, 1765, 167
0NMR (CDCl3, δ): 130 (3H,S)1.
72 (3H, S) 3.39 (3H, S) 3.68 (2H
, S) 4.67 (1H, d, j = 12HZ) 4.74 (
1H, S) 5.01 (1H, S) 5.02 (1H, d,
j=12HZ)7.32(5H,S) Reference Example 2 The following compound was obtained in the same manner as in Reference Example 1.

6α-methoxy-6β-phenylacetamide-2,2
-Dimethylpenam-3-carboxylic acid benzyl ester-1-oxide.

Melting point 74-77°C.

IR(KBr,a'ri: 1795

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ and R_5 are the same or different and mean a hydrogen atom, a phenyl group, or a halogenomethyl group. By heating, there are general formulas▲mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1, R_2, R_3, R_4 and R_5
means the same as above. ) In the method for producing cephalosporins represented by
A method characterized in that an organic halogen compound having a boiling point of 100° C. or higher is used as a solvent.