JPH0454674B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 3-alkoxymethylcephalosporin. More specifically, the present invention relates to the formula () 7-amino-3-acetoxymethyl-
3-cephem-4-carboxylic acid (hereinafter referred to as 7-
ACA) or a salt thereof is reacted with a lower alcohol in the presence of an alkyl sulfonic acid, an alkyl sulfuric acid, a halogen-substituted alkyl sulfonic acid, and sulfuric acid. [In the formula, R represents a lower alkyl group. ] The present invention relates to a method for producing 3-alkoxymethylcephalosporin or a salt thereof.

3-Alkoxymethylcephalosporin derivatives represented by the general formula () and salts thereof are important as raw materials for cephalosporin antibiotics having various antibacterial effects.

The method for producing the 3-alkoxymethylcephalosporin derivative represented by the general formula () is (a) a method in which a 3-acetoxymethyl compound is reacted with a lower alcohol (Japanese Patent Publication No. 10873/1987) (b) 3-hydroxymethyl (Japanese Patent Publication No. 50-10873) (c) Method of reacting a 3-halomethyl form with a lower alcohol (Japanese Patent Publication No. 50-10872) (d) Reacting a 3-haloacetoxymethyl form with a lower alcohol (Japanese Patent Publication No. 50-10872) (e) A method of isomerizing the Δ ² -3-halomethyl form with a lower alcohol and then isomerizing it to the Δ ³ form (J.Med.
Chem. 14 , 113 (1971)) are known, but none of them are satisfactory as production methods on an industrial scale. That is, method (a), as described in Example 1 of Japanese Patent Publication No. 50-10873, has an extremely low yield and is difficult to separate and disperse.

Method (b) can be obtained in good yield when diazomethane is reacted in the presence of boron trifluoride as an alkylating agent, but in this method, the 3-acetoxymethyl group must be first changed to 3-hydroxymethyl group; Problems include the need to protect the carboxyl group at the 4-position, and the use of large amounts of diazomethane poses problems in terms of toxicity and danger.

The method (c) requires two steps to produce the 3-halomethyl compound, which is the starting material, from the industrially available 3-acetoxymethyl compound, as described in Japanese Patent Publication No. 50-10872, page 218. This process essentially requires three steps (see Patent Example 8) to protect the carboxyl group, and the yield of the reaction between the 3-halomethyl compound and the alcohol is not necessarily good.

Similarly to method (c), method (d) requires 3 to 4 steps to produce the 3-haloacetoxymethyl compound as a raw material from the 3-acetoxymethyl compound, and the reaction yield with alcohol is poor.

Method (e) involves isomerizing the Δ ³ -3-methyl form to the Δ ² -3-methyl form, then halogenating it to form the Δ ² -3-halomethyl form, which is then used as a raw material to react with a lower alcohol. , the process is long because it returns to the 3-cephem form again.

Because of this situation, even if a useful compound is found among cephalosporins having an alkoxymethyl group at the 3-position, it is difficult to put it into practical use.

As a result of extensive research into this problem, the present inventors found that by reacting the raw material compound () or its salt with a lower alcohol in the presence of acids, the target compound () can be produced in a relatively high yield in one step. After discovering that it can be produced, and further studying this reaction, we have completed the present invention.

That is, the object of the present invention is to convert the compound having the above formula () or a salt thereof, which is an important intermediate of cephalosporin compounds having excellent antibacterial activity, into 7-ACA having the above formula () or a salt thereof. The object of the present invention is to provide a method for obtaining high purity with industrially easy operation.

The acids used in the method of the present invention are industrially readily available, and the method using them has less restrictions on reaction solvents and reaction equipment, and is easy to handle in the reaction process and post-treatment process. It also has the advantage of

The salts of the compounds represented by the above formulas () and () refer to salts at the free carboxyl group or acid addition salts at the amino group, and examples of salts at the carboxyl group include alkali metals such as sodium and potassium. Salts with alkaline earth metals such as calcium and magnesium; Ammonium salts; Examples include salts with nitrogenous organic bases; salts with amino groups include acid addition salts with mineral acids such as hydrochloric acid and sulfuric acid; oxalic acid, formic acid, trichloroacetic acid,
Examples include acid addition salts with carboxylic acids such as trifluoroacetic acid; acid addition salts with sulfonic acids such as methanesulfonic acid, toluenesulfonic acid, and naphthalenesulfonic acid. In short, any salt may be used as long as it dissolves in the solvent during the reaction or is suitable for collecting the target product after the reaction.

The most important point in the method of the present invention is that the reaction is carried out in the presence of acids. In the absence of acids, the reaction yield is extremely poor as is clear from the above-mentioned Japanese Patent Publication No. 50-10873. On the other hand, we have found that when the reaction is carried out in the presence of acids, the reaction proceeds smoothly and the reaction yield increases.

Acids used as condensation reagents in the method of the present invention include all acids that do not adversely affect the reaction, but in order to speed up the reaction, it is preferable to use acids with strong acidity; Such an acid is an acid represented by the general formula R ¹ -SO ₃ H (in the formula, R ¹ represents an organic group, a halogen atom, or a hydroxyl group). Examples of compounds in which R ¹ is an organic group include alkyl sulfonic acids such as methanesulfonic acid and ethanesulfonic acid; methyl sulfuric acid (R ¹ :OCH ₃ ), and ethyl sulfuric acid (R ¹ :C ₂ H ₅ O). halogen-substituted alkyl sulfonic acids such as trifluoromethanesulfonic acid; and compounds in which R ¹ is a hydroxyl group include sulfuric acid and fuming sulfuric acid. Furthermore, compounds in which the above compounds are supported on various carriers are also included.

The amount of acids used in the reaction varies depending on the type of acid used, reaction conditions, etc., but is generally used in an amount equivalent to 20 times the mole of the starting material, usually in excess. Further, as the condensation reagent, two or more types of acids may be used in combination.

The lower alcohol used in the method of the present invention includes 1 to 3 carbon atoms having 1 to 5 carbon atoms, such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, etc.
Grade alcohol can be given.

The reaction is usually carried out in a suitable solvent. Such a solvent is not particularly limited as long as it does not adversely affect the reaction; for example, the lower alcohol used in the reaction can be used as is, as well as nitriles such as acetonitrile and propionitrile;
Organic carboxylic acids and their esters such as formic acid, acetic acid, propionic acid, and trifluoroacetic acid; Ethers such as dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, and ethylene glycol dimethyl ether; Nitroalkanes such as nitromethane, nitroethane, and nitropropane; Acetone , methyl ethyl ketone,
Alkyl ketones such as methyl isobutyl ketone; halogenated alkanes such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride;
Halogenated alkenes such as dichloroethylene and trichlorethylene; Acid amides such as formamide, dimethylformamide, and acetamide; Aromatic alkanes such as benzene, toluene, chlorobenzene, and nitrobenzene; Alkanes such as n-hexane and heptane; Examples include alicyclic alkanes such as cyclohexane; sulfolane; and dimethyl sulfoxide. These solvents are 2
It is also possible to use a mixture of two or more species. Furthermore, when the sulfonic acid used as a reagent is liquid at the reaction temperature, it can also be used itself as a solvent. These solvents are preferably used in a substantially anhydrous state.

There is no particular limitation on the reaction temperature, and the reaction is usually carried out preferably at -30°C to 80°C, especially at a low temperature, but the reaction will proceed at higher or lower temperatures.

The time required for the reaction mainly depends on the starting materials, reagents,
The time required varies depending on the type of solvent, amount of reagent, reaction temperature, etc., and ranges from several minutes to several tens of hours.

After the reaction is completed, the target compound is collected from the reaction mixture by a conventional method. For example, after adding ice water to the reaction mixture, adjust the liquid nature of the reaction mixture to PH3-4 or 6.
Adjust to ~7. The precipitated crystals can be collected, or the desired base-forming substance can be added to neutralize the crystals before precipitation and the desired salt can be collected. The target compound is obtained by washing the crystals with water and drying them under reduced pressure. If necessary, this product can be further purified by conventional methods such as reprecipitation.

In addition, 7- having the above formula () of the raw material compound
When ACA is a salt, the salt of the target compound having the general formula () may be collected in a salt form different from the salt of the starting compound depending on the reaction conditions and the like.

Furthermore, when the compound having the general formula () is collected in a free form, it can be converted into a salt form by a conventional method if necessary. Furthermore, when the compound having the general formula () is collected in the form of a salt, it can be converted into a free form by a conventional method if necessary, and the obtained free form can be converted into another desired form. It can also be converted into salt. These transformations can also be carried out sequentially without isolation of the respective products.

Next, the method of the present invention will be specifically explained with reference to Examples, but the method of the present invention is not limited thereto.

Example 1 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid (1) 5.4 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) and 0.85 g of methanol ml and dichloromethane 30ml and after cooling, methanesulfonic acid 7.8ml
added. The reaction mixture was stirred at 14-17°C for 2 hours. After the reaction was completed, the reaction mixture was poured into ice water, and then a 10% aqueous sodium hydroxide solution was added to adjust the pH to 3.5. Take the generated crystals,
After washing with cold water and drying, the crude 7-amino-3-
2.6 g of methoxymethyl-3-cephem-4-carboxylic acid methanesulfonate was obtained.

NMR spectrum ( _CF3COOH , δ: _ppn ) 3.12 (3H, S, _CH3SO3H ) 3.63 (3H, S _{, -CH2OCH3} ) 3.77 (2H, S, _-CH2 at the _2nd position −) 4.86 (2H, S, −CH ₂ OCH ₃ ) 5.43 (2H, S, H at the 6th and 7th positions) IR spectrum (νNujol maxcm ⁻¹ ) 3160 (−NH ₂ ) 1800 (c=0, β -lactam) 1620 (-COOH) 1540-1520 (-NH ₂ ) 1190 (CH ₂ SO ₃ H) 1100 (-CH ₂ OCH ₃ ) (2) Crude 7-amino-3-methoxy obtained in (1) Methyl-3-cephem-4-carboxylic acid methanesulfonate was suspended in 15 ml of water, then hydrochloric acid was added to dissolve it, and 10% aqueous sodium hydroxide solution was added to adjust the pH to 3.5. When the precipitated crystals are collected, washed with water and dried, 1.48g of the listed compound is obtained.
was gotten.

NMR spectrum CF ₃ COH, δ: _ppn ) 3.63 (3H, S, -CH ₂ OCH ₃ ) 3.77 (2H, S, -CH ₂ - at the 2nd position) 4.86 (2H, S, -CH ₂ OCH ₃ ) 5.43 (2H, S, H at positions 6 and 7) IR spectrum (νNujol maxcm ^-1 ) 3160 (-NH ₂ ) 1800 (c=0, β-lactam) 1620 (-COOH) 1540 ~ 1520 (-NH ₂ ) 1100 (-CH ₂ OCH ₃ ) Elemental analysis value C ₉ H ₁₂ O ₄ N ₂ S Calculated value C, 44.26; H, 4.95; N, 11.47;
S, 13.12 Actual value C, 43.93; H, 4.82; N, 11.23;
S, 13.13 Example 2 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 0.27 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) and 0.4 g of methanol After cooling, 0.49 g of sulfuric acid was added. reaction mixture
Stir at 10°C. The progress of the reaction was checked by HPLC. After the reaction was completed, the reaction mixture was treated as described in Example 1 below.
When treated according to methods (1) and (2), the listed compound
0.05g was obtained.

The NMR and IR spectra were the same as those obtained in Example 1.

Example 3 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 0.54 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA), 0.49 ml of methanol and trichlor After adding 5 ml of ethylene and cooling, 1 ml of methanesulfonic acid was added. The reaction mixture was left in the refrigerator (-8°C) for 24 hours. After the reaction was completed, the reaction mixture was treated according to methods (1) and (2) of Example 1 to obtain 0.2 g of the title compound.

The NMR and IR spectra were the same as those obtained in Example 1.

Example 4 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 2.72 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) was dissolved in 13.6 ml of carbon tetrachloride. and 9.8 ml of ethanesulfonic acid after cooling to −20°C in addition to 2.05 ml of methanol.
added. Place the reaction mixture in the refrigerator (-8°C)
It was left for 41.5 hours. After the reaction was completed, the reaction mixture was poured into crushed ice, and then a 10% aqueous sodium hydroxide solution was added to adjust the pH to 3.5. The formed crystals are collected, washed with cold water, and dried to give crude 7-amino-
1.17 g of 3-methoxymethyl-3-cephem-4-carboxylic acid ethanesulfonate was obtained.

5 ml of ice water was added to 1.0 g of the crude 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid ethanesulfonate obtained above, and then 1 ml of hydrochloric acid was added and dissolved under stirring. 0.2 g of activated carbon was added to the reaction mixture to decolorize the mixture, and a 20% aqueous sodium hydroxide solution was added to the resulting liquid to adjust the pH to 3.5. The precipitated crystals were collected, washed with water, and then dried to obtain 0.57 g of the title compound.

The NMR and IR spectra were the same as those obtained in Example 1.

Example 5 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 2.05 ml of methanol was added to 21.6 g of trifluoromethanesulfonic acid under cooling with ice water and mixed. The above solution was converted into 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA).
2.72 g was suspended in 18 ml of carbon tetrachloride and added to the solution cooled to -15°C. Store the reaction mixture in the refrigerator (-8
℃). After 24 hours, the reaction mixture was
As a result of analysis using HPLC, the listed compound was 25%
It was confirmed that the product was produced with a yield of .

Example 6 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 0.27 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid in dichloromethane
Add 2.2 ml and 0.2 ml of methanol, then 10~
At 12°C, 0.63 g of ethyl sulfate was added. reaction mixture
As a result of analysis using HPLC after 250 minutes, it was confirmed that the title compound was produced at a yield of 13.6%.

Example 7 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid 10 g of 25% oleum was mixed with 13.6 ml of dichloroethylene, and then 2 ml of methanol was added under cooling. The above solution was mixed with 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-
ACA) was added to a solution of 2.72 g dissolved in 13.6 ml of dichloroethylene and 2.05 ml of methanol at -30°C.
Then, it was left in a refrigerator (-8°C). After 16 hours, the reaction mixture was analyzed using HPLC.
It was confirmed that the title compound was produced at a yield of 25.1%.

Claims (1)

[Claims] 1 formula 7-amino-3-acetoxymethyl-
A general formula characterized by reacting 3-cephem-4-carboxylic acid or a salt thereof with a lower alcohol in the presence of an alkylsulfonic acid, an alkylsulfuric acid, a halogen-substituted alkylsulfonic acid, or sulfuric acid. [In the formula, R represents a lower alkyl group. ] A method for producing 3-alkoxymethylcephalosporin or a salt thereof.