JPS5943476B2 - Method for producing cephalosporin derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION A feature of the present invention lies in the selection of a specific catalyst and solvent when ring-expanding a 6-methoxypenicillin derivative to lead to 7-methoxycephalosporin.

The present invention relates to the general formula (wherein R1 represents a phenylacetyl group or a thienylacetyl group, R2 represents a hydrogen atom, an acetoxy group or a carbamoyloxy group, and R3, R4 and R5 are the same or different and are a hydrogen atom, a phenyl group or Each means a trihalogenomethyl group.

) by heating a penicillin derivative represented by the general formula (wherein R,,R2,R
3, R4 and R, li have the same meanings as above.

) In the method for producing a cephalosporin derivative represented by the general formula (wherein R represents a lower alkyl group, Y
represents a hydrogen atom or a halogen atom, and n represents an integer of 1 to 7.

), and in the ring expansion reaction, a phosphorus compound represented by the general formula [] is used as a catalyst, and an organic halogen compound having a boiling point of 100°C or higher is used as a solvent. Relating to a method characterized by:

In this case, the phosphorus compound represented by the general formula [] acts as a catalyst for the ring expansion reaction, and a specific example thereof is diethylmethylphosphonate [CH3PO(0C2H
5)2], dimethyl-n-butylphosphonate [C4H
9PO(0CH3)2], diethyl-n butylphosphonate [C4H, PO(0C2H5)2], diethyl-n
-pentylphosphonate [C5HllPO(0C2H5
)2], diethyl-n-hexylphosphonate [C6H
13PO(0C2H,)2], diethyl-2-chloroethylphosphonate [ClCH2CH2PO(0C2H,
)2] etc.

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 form a 7-methoxycephalosporin derivative. The methods of deriving the ring expansion include a method of ring expansion in dioxane in the presence of an acid (Japanese Patent Application Laid-open No. 10094/1983) and a method of ring expansion in dioxane in the presence of dipyridine phosphate, which belongs to the salt catalyst (Journal of the American Chemical Society). Volume 95, page 2401 1
973) is already known. Japanese Patent Publication No. 48-100
The method disclosed in No. 94 requires heating for as long as 18 hours, and it is a useful method to use an acid catalyst for the 6-methoxypenicillin derivative, which is said to be very sensitive to acids. It's hard to say.

In addition, the method disclosed in Journal of the American Chemical Society, Vol. 95, p. 2401 (1973) was repeated by the present inventors, and as a result,
It was found that heating for several hours or more was required to complete the ring expansion reaction.

Therefore, the present inventors selected a neutral catalyst represented by the general formula [ ] that does not belong to either acid catalysts or salt catalysts used in known methods, and thereby converted 7-methoxycephalosporin from 6-methoxypenicillin derivatives. The present invention was completed based on the knowledge that ring expansion reactions to derivatives can be carried out in good yields and in a short time, and that the reaction can be dramatically slowed down by using a combination of this catalyst and a specific solvent. . To carry out the method of the present invention, a penicillin derivative represented by general formula [1] is dissolved in a solvent, a catalyst represented by general formula [] is added thereto, and the temperature is 80 to 170°C, preferably 120°C.
It may be heated at 0 to 150°C for several minutes to several hours. Further preferred embodiments include alkyl halides such as 1,1,2,2-tetrachloroethane (boiling point 146°C), bromobenzene (boiling point 156°C), dichlorobenzene (boiling point 173-180°C), chlorobenzene (boiling point 173-180°C), Toluene (boiling point 15
Boiling point 10 of aryl halide such as 8-161℃)
``It is preferable to use an organic halogen compound of C or higher as a solvent.

After the reaction, if necessary, the ester moiety can be hydrolyzed to lead to 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-meI-xy-6β-phenylacetamide-2,
2-Dimethylpenam-3-carboxylic acid trichloroethyl ester-1-oxide (500m9) was dissolved in each solvent (10m0) listed in the following table, and diethyl-n-hexylphosphonate (250m7) was added to each solution.
Heat at 5°C.

After a certain period of time from the start of heating, each reaction mixture was spotted on a silica gel sheet, developed with a mixed solution of benzene (3) and ethyl acetate (1), and the proportion of spots of the remaining raw material and target product at each time was observed. The progress of the ring expansion reaction was observed using the following methods, and the following results were obtained. As shown in the previous table, boiling point 100
When an organic halogen compound with a temperature of ℃ or higher is used as a solvent, the spot of the target product becomes large 30 minutes after the start of the reaction, the spot of the raw material becomes very small in comparison, and the spot of the raw material completely disappears after 1 hour. However, the ring expansion reaction was completed.

With the other solvents, even 2 hours after the start of the reaction, the spots of the target product were weak. Example 2 Method for producing 7α-methoxy7β-phenylacetamide 3-methyl-3-cephem-4-carboxylic acid trichloroethyl ester.

6α-methoxy-6β-phenylacetamide 2,2-
Dimethylpenam-3-carboxylic acid trichloroethyl ester-1-oxide (1.09) was converted into 1,1,2,2-
Dissolved in tetrachloroethane (20ml) and diluted with diethyl
Add n-hexylphosphonate (0.59) to 145
Heat at ℃ for 1.5 hours.

The solvent was distilled off under reduced pressure, ether was added to the residue, and the mixture was allowed to stand to obtain crystals (0.45 g) of the desired product. Melting point 205~2
07℃0IR (KBr, α'ri: 1760, 1725,
1695NMR (DMSO-D6, δ): 2.12 (3
H,S) 3.36 Example 37α-methoxy7β-phenylacetamide 3-methyl-3-cepheme-4-
Process for producing carboxylic acid trichloroethyl ester.

6α-methoxy-6β-phenylacetamide-2,2
-dimethylpenam-3-carboxylic acid trichloroethyl ester-1-oxide (1.09) to 1,1,2,2
-Tetrachloroethane (dissolved in 20m0, diethyl-
Add 2-chloroethylphosphonate (0.59) and add 1
Heat at 45°C for 2.5 hours.

The solvent was distilled off under reduced pressure, and the residue was purified by silica gel talomatography. Benzene (5) and ethyl acetate (1)
Crystals of the target substance (0.429) were obtained from the part eluted with the mixture of
get. Example 4 Method for producing 7α-methoxy7β-phenylacetamide-13-methyl-3-cephem-4-carboxylic acid benzyl ester.

6α-methoxy-6β-phenylacetamide-2,2
-Dimethylpenam-3-carboxylic acid benzyl ester-1-oxide (1.09) was dissolved in 1,1,2,2-tetrachloroethane (20ml), diethyl-n-hexylphosphonate (0.5g) was added, 1 at 145℃
．． Heat for 5 hours.

After cooling, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography. Crystals of the target product (0
．． 409). Melting point 181-182℃ o Example 5
A method for producing 7α-methoxy 7β-phenylacetamide 3-methyl-3-cephem-4-carboxylic acid methyl ester.

6α-methoxy-6β-phenylacetamide 2,2
-dimethylpenam-3-carboxylic acid methyl ester-1
-oxide (0.59) was dissolved in 1,1,2,2-tetrachloroethane (20ml), diethyl-n-hexylphosphonate (0.19) was added and heated to 145°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 chromatography. From the mixed solution of benzene (3) and ethyl acetate (1) flowing out, 0.219 of the target product in the form of carmela is obtained. Example 6 Method for producing 7α-methoxy7β-phenylacetamide-13-methyl-3-cephem-4-carboxylic acid benzyl ester.

6α-methoxy-6β-phenylacetamide 2,2-
Dimethylpenam-3-carboxylic acid benzyl ester-1
-Dissolve 1.09% of the oxide in bromobenzene (20ml) and add diethyl.

-Hexylphosphonate (0.59) is added and heated at 146°C for 1.5 hours. After cooling, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography. Crystals of the same target product as in Example 4 (0.399) were obtained from the outflowing portion of the mixed solution of benzene (5) and ethyl acetate (1).
get. Example 7 Method for producing 7α-methoxy 7β-phenylacetamide 3-methyl-3-cephem-4-carboxylic acid benzyl ester.

6α-methoxy-6β-phenylacetamide 2,2-
Dimethylpenam-3-carboxylic acid benzyl ester-1
- oxide (1.0g) mchlorotoluene (20m
1) and diethyl-n-hexylphosphonate (
0.59) and heated under reflux on an oil bath for 1.5 hours.

After cooling, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel talomatography. Crystals (0.399) of the same target product as in Example 4 are obtained from the mixed solution of benzene (5) and ethyl acetate (1) flowing out. Example 8 7α-methoxy 7β-(2-thienylacetamide)
-Production method of 3-acetoxymethyl-3-cephem-4-carboxylic acid benzhydryl ester.

6α-methoxy-6β-(2-thienylacetamide)
-2-Methyl-2-acetoxymethylpenam-3-carboxylic acid benzhydryl ester-11-oxide (1.
09) in 1,1,2,2-tetrachloroethane (20 m
1) and diethyl n-hexylphosphonate (0
．． Add 29) and heat at 145°C for 1.5 hours.

After cooling, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography. Crystals of the target product (0
．． 399) is obtained. R(αV): 1780, 1740,
1690NMR (CDCl3, δ): 2.00 (3H,
S) 336 (2H) 3.49 (3H, S) 3.89 (2
H, S) 4.96 (2H) 5.08 (1H, S) 6.8
~7.4 (13H,M) Example 9 Method for producing 7α-methoxy7β-phenylacetamide 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid benzhydryl ester.

6α-methoxy-6β-acetamido-2-methyl-2
-Carbamoyloxymethylpenam-3-carboxylic acid benzhydryl ester-1-oxide (1.09) was dissolved in 1,1,2,2-tetrathalolethane (20ml) and diethyl-n-hexylphosphonate (0 .29
) and heat at 145°C for 1.5 hours.

After cooling, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography. A glassy target product (0.329) was obtained from the outflowing portion of a mixed solution of benzene (3) and ethyl acetate (1). 1R(CHCl3, (T1):
1780, 1730, 1680NMR (CDCl3, δ
): 3.30 (2H, br) 3.40 (3H, S) 3.
60 (2H, S) 4.7-5.0 (4H, M) 5.0 (
1H, S) 6.85 (1H, S) 7,0 to 7.5 (15
H, M) 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.

Melt Point 147-148°C.

IR (KBr, a'ri: 1795, 1765, 167
0NMR(CDCl3,δ):1,30(3H,S)1
．． 72 (3H, S) 3.39 (3H, S) 3.68 (2
H, 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, ml): 1795 NMR (CDCl3, δ): 1,06 (3H, S) 15
9 (3H, S) 338 (3H, S) 366 (2H, S)
4.60 (1H, S) 4.94 (1H, S) 5.15 (
1H, d, J = 12HZ) 5.32 (1H, d, J = 1
2HZ) 7,2-7.5 (10H,M) 6α-methoxy-6β-phenylacetamide 2,2-dimethylpenam-3-carboxylic acid methyl ester-1-oxide.

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ , and R_5
are the same or different and each means a hydrogen atom, a phenyl group or a trihalogenomethyl group. ) by heating the penicillin derivative represented by the formula in a solvent in the presence of a catalyst ▲ There are mathematical formulas, chemical formulas, tables, etc.
means the same as above. ) In the method for producing cephalosporin derivatives, the catalyst is represented by the general formula ▲mathematical formula, chemical formula, table, etc. means an integer.) A method characterized by using a phosphorus compound represented by: 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 is a phenylacetyl group or thienylacetyl group, R_2 is a hydrogen atom, acetoxy group or carbamoyloxy group, and R_3, R_4 and R_5 are the same or different. A general formula ▲ There are 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 cephalosporin derivatives represented by the general formula ▲mathematical formula, chemical formula, table, etc. as a catalyst▼ (in the formula, R is a lower alkyl group, Y is a hydrogen atom or a halogen atom, and n is an atom of 1 to 7). ) is used as a solvent, and the boiling point is 10.
A method characterized by using an organic halogen compound having a temperature of 0°C or higher.