JPS6153357B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a new method for producing cefem-carboxylic acid. More specifically, the present invention provides a new method for deesterifying 7-acylamido-3-substituted methyl-cephem-4-carboxylic acid using a new ester. Conventionally, 7-acylamide-cephem-4-carboxylic acids are produced by heating the s-oxide of a penicillin ester in the presence of an acid to cause a ring expansion reaction, and then deesterifying the resulting ester of 7-acylamide-cephem-4-carboxylic acid. It is obtained by subjecting it to a chemical reaction. The type of ester group used here is the generated 7-acylamide-cephem-4-
When deesterifying the ester group of a carboxylic acid, the double bond of the cefem ring tends to move, so it has been limited to those that are easily deesterified under weakly alkaline or neutral, especially acidic conditions. As such esters, trialkylsilyl esters, β-β-β-trichloroethyl esters, p-nitrobenzyl esters, etc. have been used, particularly in industrial applications. As a result of various studies on ester groups that can be easily removed under weakly alkaline or acidic conditions without movement of the double bond of the cefem ring, the present inventors have developed a novel method unprecedented in the literature for the purpose of achieving this goal. We have discovered an ester group that achieves this, and have completed the present invention. According to the invention, the general formula [In the formula, A is an acylamido group, Y is a sulfur atom or its oxide, X is a hydrogen atom, and R is a formula

[Formula] (where R ¹ is a lower alkyl group, aryl group, aralkyl group or lower alkoxy group, R ² is a lower alkoxycarbonyl group, lower alkylcarbonyl group or

A group represented by [Formula] (where R ³ and R ⁴ are the same or different, and may be a hydrogen atom, an aryl group or a lower alkyl group, or R ³ and R ⁴ may be ring-closed together with an oxygen atom to form a morpholino group) 7-acylamido-3-methyl-3-
Cefem-4-carboxylic acid ester or 1
-By reacting the oxide with a nitrosating agent, the general formula (Each symbol in the formula has the same meaning as above) 7-acylamido-3-methyl-3-
A method for producing a heterocyclic carboxylic acid is provided which comprises obtaining cefem-4-carboxylic acid or its 1-oxide or a salt thereof. One of the features of the present invention is the use of a novel ester represented by the above general formula (). Another feature is that deesterification can be carried out using inexpensive reagents in a method unprecedented in the literature. Yet another feature is to provide a method that does not substantially involve movement of the double bond of the cefem ring during deesterification. Moreover, the present invention provides a method that has a high yield, is simple to operate, and has high industrial utility value. Other features and advantages will become apparent from the description below. The raw materials represented by the general formula () used in the present invention are new compounds, and they can be used to synthesize natural penicillins such as penicillin V and penicillin G by the formula

[Formula] (wherein X is a halogen atom, R ¹ and R ² have the same meanings as the symbols above) is esterified with a halogen compound, oxidized with peroxide to form s-oxide, and then dichloro Methylphosphonic acid pyridine salt, trichloromethylsulfonic acid picoline salt, 2,2,2-trichloroethyl phosphate pyridine salt, piperidine hydrobromide and a small amount of acid, toluenesulfonic acid and pyridine, pyridine hydrobromide and pyridine , 7-acylamide-
It can be obtained by preparing a 3-methyl-cephem-4-carboxylic acid ester and, if necessary, oxidizing it again with a peroxide to obtain the corresponding 1-oxide. Here, the compound of general formula () having an acyl group different from the acyl group in the side chain of penicillin V or penicillin G can be obtained by acylating, for example, 6-aminopenicillanic acid according to a conventional method, and using it as a raw material for the above reaction. Just go. Furthermore, in the above-mentioned 7-acylamido-3-methyl-cephem-4-carboxylic acid ester, compounds in which the methyl group at the 3-position is substituted with a lower acyloxy group or an azido group may be substituted with N-bromosuccinimide or N-bromosuccinimide in the 3-methyl form. - By reacting bromophthalimide, N-bromoacetamide, etc., 3-
It can be obtained by reacting the bromomethyl compound with sodium azide or a lower fatty acid salt. Preferred examples of the symbol A (acylamide group) in the compound of the general formula () which is the raw material of the present invention are a phenyl acetamide group, a phenoxyacetamide group, a formylamino group, a phthalylamide group, a 2-2- dimethyl-3-nitroso-4-phenyl-5-oxoimidazolin-1-yl group,
2-Methyl-3-nitroso-4-phenyl-5-
An example is an oxo-imidazolin-1-yl group. However, groups other than these may also be used. Furthermore, the most preferred example of X in the compound of general formula () is a hydrogen atom. Other examples include azide groups or lower acyloxy groups such as acetyloxy groups. Further, as the substituent R of the compound of general formula (), that is, the ester moiety, diacetylmethyl group, acetyl-benzoylmethyl group, acetyl-phenylacetylmethyl group, dibenzoylmethyl group, acetyl-methoxycarbonylmethyl group, acetyl-
Ethoxycarbonylmethyl group, benzoyl-methoxycarbonylmethyl group, benzoyl-ethoxycarbonylmethyl group, dimethoxycarbonylmethyl group, diethoxycarbonylmethyl group, acetyl-N/N-dimethylaminocarbonylmethyl group,
Examples include acetyl-morpholino-4-ylcarbonylmethyl group and acetyl-aminocarbonylmethyl group. Among these, industrially preferred examples include diacetylmethyl group, acetyl-methoxycarbonylmethyl group, and acetyl-ethoxycarbonylmethyl group. According to the present invention, the ester of 7-acylamido-3-substituted methyl-cephem-4-carboxylic acid of general formula () or its 1-oxide is reacted with a nitrosating agent in an inert solvent. Examples of the inert solvent used here include water, acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, methyl cellosolve, ethyl cellosolve,
Propyl cellosolve, butyl cellosolve, formic acid,
Examples include acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, 2-ethylhexonic acid, diethyl acetic acid, acetonitrile, propionitrile, butyronitrile, dimethylformamide, dimethylacetamide, formamide, tetrahydrofuran, dioxane, and the like. However, in particular, aqueous acetone, aqueous methyl ethyl ketone, aqueous methyl propyl ketone, aqueous methyl isobutyl ketone, aqueous methanol, aqueous ethanol, aqueous propanol, aqueous butanol, aqueous acetonitrile, aqueous propionitrile, aqueous tetrahydrofuran, aqueous acetic acid, or a mixture of two or more. It is desirable to use it as such. As the nitrosating agent, nitrous acid or a salt thereof, nitrite ester, nitrosyl halide, nitrogen oxide, etc. can be used. Examples of nitrites include lithium salts, potassium salts, sodium salts, calcium salts, magnesium salts, and zinc salts of nitrous acid. Among these, sodium nitrite is preferably used industrially. Nitrite esters include nitrite methyl ester, ethyl ester, propyl ester,
Examples include alkyl esters such as butyl ester or pentyl ester; aralkyl esters such as benzyl ester; and cycloalkyl esters such as cyclohexyl ester and cyclopentyl ester. Preferred examples of these include propyl nitrite, butyl nitrite, and pentyl nitrite. Alternatively, nitrosyl halide or nitrogen oxide may be introduced into the reaction solution for reaction. When carrying out a reaction using a nitrite ester, it is desirable to add a small amount of an organic or inorganic acid and, if necessary, an organic acid salt. Examples of organic acid salts include sodium salts, potassium salts, and trialkylamine salts of organic acids such as formic acid, acetic acid, propionic acid, butyric acid, diethyl acetic acid, and 2-ethylhexonic acid. Among these, it is particularly desirable to use sodium acetate, potassium acetate, and triethylamine salt of acetic acid. Examples of organic acids include formic acid, acetic acid, propionic acid, butyric acid, diethyl acetate, citric acid, succinic acid, and oxalic acid; examples of inorganic acids include hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid. Although the use of an organic acid salt is not an essential condition, when the starting cefem-carboxylic acid ester is used at a high concentration, the produced cefem-carboxylic acid is solubilized as a salt. The deesterification reaction of the present invention is carried out by suspending or dissolving the compound of general formula () in an inert solvent as described above, adding, for example, an excess of nitrite as a solid or as an aqueous solution, and This can be done by adding the ester together with the acid. Organic acid salts may be added if necessary. This reaction usually takes place exothermically. When using a low boiling point solvent, external cooling is also required. The progress of the reaction can be followed by thin layer chromatography. Depending on the type of ester group in the raw material used, if the reaction rate is slow and difficult to complete, an acid may be added and heated. The amount of the nitrosating agent used in the deesterification of the present invention, such as nitrite or nitrite ester, is as follows:
The amount is about 1.2 to 5 times by mole, preferably about 1.5 to 3 times by mole, relative to the compound of general formula (). The reaction mechanism of the deesterification reaction of the present invention is variously speculated based on the use of equimolar or more of a nitrosating agent such as nitrite or nitrite ester and the extremely good reaction yield of deesterification. However, the details are unknown. 7-acylamide-3 produced by the present invention
Methyl-3-cephem-4-carboxylic acid or its 1-oxide has a carboxyl group at the 4-position that is quite acidic, and appears to form an alkali in the system of alkali nitrite and acetic acid. Therefore, when using a water-containing organic solvent as mentioned above, after adjusting the pH to around 7.5, distill off the organic solvent under reduced pressure, and wash with a solvent that is sparingly soluble in water to remove unreacted raw material esters and by-products. Then, adjust the pH to around 2.0 with a strong acid such as formic acid, citric acid, tartaric acid, organic sulfonic acid, halogeno fatty acid, hydrohalic acid, nitric acid, sulfuric acid, phosphoric acid, etc. to obtain the desired product ().
can be obtained as crystals. If necessary, by solvent extraction of the aqueous solution from which the crystals were taken,
Furthermore, the yield can be increased. Note that the solvents that are sparingly soluble in water include methylene chloride, chloroform, carbon tetrachloride, ethylene chloride,
Trichlorethylene, trichloroethane, propylene chloride, ethyl acetate, butyl acetate, butanol, isobutanol, methyl isobutyl ketone,
Examples include methyl ethyl ketone and methyl propyl ketone. Furthermore, even if the compound △ ² is mixed in the product of the ring expansion reaction from the 1-oxide of the penicillin ester, it is led to the 1-oxide of the 3-cephem-carboxylic acid ester through the oxidation reaction, and the deesterification method of the present invention is performed. It can be subjected to chemical reaction. The method of the present invention usually yields the desired product () in a yield of over 90%, making it an extremely valuable method industrially. Next, the present invention will be explained by reference examples and examples. Reference example 1 6-phenylacetamide-penam-3-carboxylic acid diacetyl methyl ester-1-oxide [melting point: 65-80°C (decomposition)] 4.5 g and 2.2.2-
84 mg of the pyridine salt of trichloroethyl phosphoric acid are stirred in 30 ml of anhydrous dioxane while heating to 98-101°C. Thin layer chromatography (benzene:
The reaction was monitored using ethyl acetate = 2:1 (sprayed with iodized azide solution and heated to develop color). Since the reaction will be completed in 4 to 8 hours, the mixture is cooled to room temperature and the solvent is distilled off under reduced pressure. Add methylene chloride and water to the residue, adjust the pH to 7.0 to 7.5, and separate the organic layer. The aqueous layer is extracted several times with methylene chloride. The organic layers are combined, washed with brine, dried, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography (benzene + ethyl acetate). 7-phenylacetamide-3-methyl-
3.5 g (82%) of 3-cephem-4-carboxylic acid diacetyl methyl ester was obtained. Recrystallized from ethyl acetate and ether. Melting point: 186-188℃ (decomposed).
Infrared absorption spectrum: 1765 cm ^-1 (β-lactam). Ultraviolet absorption spectrum λmax: 260nm. As C ₂₁ H ₂₂ N ₂ O ₆ S Calculated value C58.39, H5.15, N6.20 Analytical value C58.21, H5.19, N6.17 Dissolve the cefem-ester obtained here in methylene chloride, Oxidize with 40% peracetic acid. Follow up with thin layer chromatography. After the reaction is complete, ice water is added, the pH is adjusted to 7.3 with aqueous ammonia, the organic layer is separated, washed with brine, dried, and the solvent is distilled off under reduced pressure.
The residue can be solidified by treatment with isopropanol + petroleum ether. 7-phenylacetamide-3-
Methyl-3-cephem-4-carboxylic acid diacetyl methyl ester-1-oxide was obtained in a yield of 95%. Melting point: 115-143℃ (decomposed). Infrared absorption spectrum: 1775cm ^-1 . Ultraviolet absorption spectrum λ
max: 254nm Reference example 2 6-phenylacetamido-penam-3-carboxylic acid-1'-methoxycarbonyl-2'-oxo-
Propyl-(1')-ester-1-oxide 4.15g
and 73 mg of dichloromethylphosphonic acid pyridine salt are reacted in 30 ml of anhydrous dioxane at 98-101°C with stirring. Follow the reaction with thin layer chromatography. The reaction is completed in 4 to 7 hours, so the mixture is cooled and the solvent is distilled off under reduced pressure. Add methylene chloride and water to the residue, adjust the pH to 7.0 to 7.5, and separate the organic layer. The aqueous layer is extracted several times with methylene chloride, and the methylene chloride layer is washed with brine and dried. 2 methylene chloride solution
divide The solvent is distilled off under reduced pressure. Ethyl acetate +n
- Solidify with hexane. 7-Phenylacetamido-3-methyl-3-cephem-4-carboxylic acid (1'-methoxycarbonyl)-2'-oxopropyl-(1')-ester melting point 110-120°C, 1.81 g (81
%)Obtained. Purified by silica gel chromatography (benzene: ethyl acetate = 4:1), melting point 119 ~
122°C, infrared absorption spectrum 1765 cm ^-1 (β-lactam), ultraviolet absorption spectrum λmax 259 nm. C ₂₁ H ₂₂ N ₂ O ₇ S Calculated value C56.49, H4.96, N6.27 Analyzed value C56.57, H4.98, N6.23. While stirring the methylene chloride solution under ice-cooling, add several drops of an aqueous sodium tungstate solution or an aqueous vanadium pentoxide solution, and gradually add 0.76 g of 40% peracetic acid dropwise. Follow up with thin layer chromatography and add peracetic acid if necessary. After the reaction is complete, add ice water, adjust the pH to 7.5 with aqueous ammonia, and separate the organic layer. After extracting the aqueous layer several times, the organic solvent is combined, washed with brine, dried, and the solvent is distilled off. The residue is treated with isopropanol + n-hexane to solidify.
Melting point: 144-47℃ (decomposed) 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid-(1'-methoxycarbonyl)-2'-oxopropyl-(1')-ester 1.97 g (85
%)Obtained. Purified by silica gel chromatography (ethyl acetate), melting point 169-170°C (decomposition), infrared absorption spectrum 1775 cm ^-1 , ultraviolet absorption spectrum λmax 254 nm. C ₂₁ H ₂₂ N ₂ O ₈ S Calculated value C54.53, H4.79, N6.05 Analyzed value C54.38, H4.82, N6.03. Instead of performing the above oxidation reaction with peracetic acid, methylene chloride is distilled off, 0.5 ml of an aqueous sodium tungstate solution is added in acetonitrile, and the ester of 1-oxide is obtained with almost the same yield even if the reaction is carried out with 30% hydrogen peroxide solution. I got it. Reference Example 3 Using 6-phenylacetamido-penam-3-carboxylic acid-(1'-methoxycarbonyl)-2'-oxopropyl-(1')-ester-1-oxide, dichloro in Reference Example 2 The following various catalysts are used in place of the pyridine salt of methylphosphonic acid, and the reaction and treatment are carried out according to the reference examples. Obtained 7-
The yield of phenylacetamido-3-methyl-3-cephem-4-carboxylic acid ester and the yield of sulfoxide of the ester obtained by direct oxidation of the crude ester after ring conversion are shown in the table below.

[Table] Reference example 4 Various 6-phenylacetamide-penam-3-
The carboxylic acid ester-1-oxide is reacted and treated according to Reference Example 2. The results are shown in the table below.

[Table] Reference example 5 Various 6-phenoxyacetamide penum-3
-Carboxylic acid ester-1-oxide Reference example 2
React and process according to. The results are shown in the table below.

[Table] Example 1 4.3 g of 7-phenylacetamide-3-methyl-3-cephem-4-carboxylic acid-1',1'-diacetyl methyl ester was suspended in 20 ml of acetone and stirred while cooling with water. Drop 10 ml of an aqueous solution containing 1.0 g of sodium nitrite. A reaction will soon occur with slight heat generation. If the reaction is difficult to occur, add acetic acid 0.6
Add ml in several portions. The progress of the reaction is monitored by thin layer chromatography (benzene:ethyl acetate = 2:1; azide iodide solution is sprayed and heated. The carboxylic acid produced remains at the origin as a sodium salt). To complete the reaction, add 1 g of sodium nitrite and 1 ml of acetic acid in several portions for a short period of 50~
Warm to 55℃. After confirming the completion of the reaction, the pH was adjusted to 7.5, and the acetone was distilled off under reduced pressure. To remove impurities, the aqueous solution was washed twice with methylene chloride and then washed with hydrochloric acid.
Adjust the pH to 1.5 and cool on ice. Collect the precipitated crystals, wash with a small amount of cold water, and dry. The ice layer is saturated with sodium chloride and extracted with ethyl acetate, and the ethyl acetate solution is combined and washed twice with a small amount of brine, dried, and then the solvent is distilled off under reduced pressure. A total yield of 3.1 g (95%) of 7-phenylacetamido-3-cephem-4-carboxylic acid was obtained. Melting point 180-84℃ (decomposition). Recrystallized from methanol + n-hexane, melting point 191-192°C (decomposition). Infrared absorption spectrum 1770cm ^-1 (β-lactam),
Ultraviolet absorption spectrum λmax 260nm. Nuclear magnetic resonance, infrared absorption, and ultraviolet absorption spectra were consistent with the product. In the above experiment, 7-phenylacetamide-3-methyl-3-cephem-4-carboxylic acid-1'·1'-
A similar reaction is carried out using 1-oxide of diacetyl methyl ester. 3.27 g (94%) of 7-phenylacetamide-3-methyl-3-cephem-4-carboxylic acid-1-oxide was obtained. Dissolve in dilute ammonia water, treat with activated carbon, and acidify with hydrochloric acid for purification. The melting point was 182-83°C (decomposed), the infrared absorption spectrum was 1785 cm ^-1 (β-lactam), and the ultraviolet absorption spectrum was λmax 264 nm, which were consistent with the standard product. Example 2 4.5 g of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid-1'-methoxycarbonyl-2'-oxo-propyl-(1') ester
Add to a mixture of 30 ml of acetone and 20 ml of water and cool with water. 2.7 g of butyl nitrite is added dropwise while stirring. A reaction will occur soon. Add 1.7 g of sodium acetate and 1 g of acetic acid to this in several portions, and gradually warm the mixture to 40-50°C for 30 minutes. The reaction is
Track with TLC. Add butyl nitrite and acetic acid if necessary. After confirming the completion of the reaction, add 10 ml of water, adjust the pH to 7.5, and distill off the acetone under reduced pressure. The aqueous layer is washed several times with ethyl acetate, and the pH is adjusted to 2.0 with hydrochloric acid while stirring. The crystals are collected, washed with water, and dried. The mother liquor and washings are combined and extracted several times with ethyl acetate. The ethyl acetate layers were combined and washed several times with brine, dried, and then the solvent was distilled off under reduced pressure. 7-phenylacetamide-3-methyl-3-cephem-4
A total of 3.16 g (95%) of -carboxylic acid was obtained. Recrystallized from methanol + n-hexane, melting point 191-92℃
(Disassembly). It matched the standard. Infrared absorption spectrum
177cm ^-1 , ultraviolet absorption spectrum λmax 260nm. The above reaction was carried out with the sulfoxide of the same ester. 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid sulfoxide was obtained with a yield of 93%. Melting point 182-83°C (decomposed). Infrared absorption spectrum 1785cm ^-1 Ultraviolet absorption spectrum λ
max264nm. Furthermore, almost the same results were obtained when the above reaction was carried out using hydrous methyl ethyl ketone instead of the aqueous acetone solvent. Example 3 A reaction and treatment were carried out in accordance with Example 2 except that sodium acetate was not used and the amount of aqueous acetone was changed to 50 ml of acetone and 20 ml of water. 7-phenylacetamide-3-methyl-3-cephem-4
-carboxylic acid was obtained with a yield of 92%. Examples 4-8 7-phenylacetamide-3 in Example 1
-Methyl-3-cephem-4-carboxylic acid diacetyl methyl ester was replaced with the following esters and sulfoxides, and the reaction was carried out according to Example 1. The yields of the cefem-carboxylic acid and its sulfoxide are shown in the table below.

[Table] Examples 9 to 12 7-phenylacetamide-3 in Example 1
-Methyl-3-cephem-4-carboxylic acid-1'.
Various 7- in place of 1'-diacetyl methyl ester
Phenoxyacetamide-3-methyl-3-cephem-4-carboxylic acid ester and its sulfoxide are reacted and worked up according to Example 1. 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (melting point 173
~75℃ (decomposed), infrared absorption spectrum 1770cm ^-1
(β-lactam), ultraviolet absorption spectrum λ
max261nm) and its sulfoxide (melting point 199
~200℃ (decomposition), infrared absorption spectrum 1795cm
^-1 , ultraviolet absorption spectrum λmax 263 nm) was obtained as shown in the table below.

【table】

[Table] * For various ester-sulfoxide raw materials, amorphous solids were used as they were.

Claims (1)

[Claims] 1. General formula [In the formula, A is an acylamido group, Y is a sulfur atom or its oxide, ^X is a hydrogen atom, and R is a group represented by the formula , R ^{2 is} a lower alkoxycarbonyl group, ^a lower alkylcarbonyl group ^, or a group ^represented by the formula may be ring-closed with an oxygen atom to form a morpholino group)] 7-acylamido-3-methyl-3-
Cefem-4-carboxylic acid ester or 1
-By reacting the oxide with a nitrosating agent, the general formula (In the formula, A and X have the same meanings as above) 7-acylamido-3-methyl-3-
A method for producing a heterocyclic carboxylic acid, which comprises obtaining cefem-4-carboxylic acid, its 1-oxide, or a salt thereof.