JPS6210994B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a cephalosporin derivative of structural formula () useful as an antibiotic agent. In the above formula, R ₁ is hydrogen or a lower alkyl organic salt-forming group having 1 to 5 carbon atoms, A is hydrogen or a hydroxy group, and B is hydrogen, halogen, methyl, hydroxymethyl, acetoxymethyl, methoxy or ―
It is a CH ₂ SR ₃ group, R ₂ is hydrogen, sodium, potassium or an ester-forming group, and R ₃ is triazolyl, tetrazolyl, thiadiazolyl, pyrimidinyl or a partially substituted group thereof. Cephalosporin antibiotics have been attracting attention and interest as agents for treating infections with Gram-negative and -positive pathogens. is known in many documents. Considering these known production methods, it is generally found that phenylglycine or its derivatives and 7-
It is produced by subjecting the amino group of a cephalosporin derivative such as ADCA or 7-ACA to an acylation reaction, and it is roughly classified into the following several methods. The first is U.S. Patent No. 3843639, No. 3957773,
No. 3997532; Japanese Pat. These methods are not industrially easy to produce acid chlorides, and the products produced by these methods are of poor quality, so they generally have little industrial efficiency. The second method, as disclosed in US Pat. No. 3,252,973, is to carry out the acylation reaction using a dehydrating agent such as carbodiimide, but these dehydrating agents are also expensive and therefore have little industrial utility. The third is U.S. Patent No. 3422103, No. 3489752,
No. 3518260, No. 3560489, No. 3769181, No.
No. 3925372, No. 3985741 and Japan Special Public Service 1977-
As in No. 72185, mixed acid anhydrides are used for acylation reaction, and these methods are very useful industrially. The amine protecting groups used in this case include urethane-based groups such as benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, tert-butoxycarbonyl, diphenylmethoxycarbonyl, β,β,β-trichloroethoxycarbonyl, and allylmethyl-o- Sulfenine series such as nitrophenyl, sulfenyl, para-nitrophenyl sulfenyl, enamine series such as ethyl acetoacetate, methyl acetoacetate, acetylacetone, benzoylacetone, propionylacetone,
Allylmethylene-based compounds such as 5-chlorosalicyaldehyde, 2-hydroxy-1-naphthaldehyde, and 3-hydroxypyrazine are mainly introduced. However, these conventional methods have many disadvantages from an economical point of view, such as the fact that these protective groups are relatively expensive and have large molecular weights, and some of the protective groups are not easy to remove. The present inventors completed the present invention after repeated research in search of a new method to compensate for these drawbacks. To explain the present invention in more detail, formaldehyde is reacted with a phenylglycine derivative to create a compound with the bis structural formula () in which the amine group is protected, and then acid chloride, ethyl chloroformate, or methyl An invention in which a compound of structural formula () is obtained in an acid anhydride state by reacting with chloroformate, etc., and then the compound of structural formula () is reacted and then hydrolyzed to produce a compound of structural formula (). It is. In the above formula, R ₁ and A, B are as defined above, R ₂ is hydrogen, sodium, potassium, or an ester-forming group, and R ₄ is a tert-butyl group, methoxy, ethoxy, or a carbon number of 1 to 1. 5 lower alkyl or phenyl group, and R ₅ is a lower alkyl group having 5 to 5 carbon atoms, an alkylsilyl group, or an organic salt-forming group. The compound of structural formula () is produced by reacting a phenylglycine derivative with formaldehyde. At this time, an inorganic base such as sodium chloride, potassium hydroxide, or triethylamine is added in a polar solvent such as methanol, ethanol, or isopropanol. After dissolving the phenylglycine derivative using a tertiary base, an aromatic base such as pyridine, etc., it is reacted with formalin, and then treated with an inorganic salt dehydrating agent such as anhydrous magnesium sulfate or anhydrous sodium sulfate, or an azeotrope. The water is removed using a forming solvent. In this case, the most preferred azeotropic solvent is benzene, toluene, or n-hexane. At this time, when the same equivalent amount of phenylglycine derivative and formaldehyde are reacted, a Schiff base is produced, but by using 1/2 equivalent of formaldehyde, the present inventors created a new substance, a bis-form compound, The formation of the structural formula () was confirmed by melting point, UV, and elemental analysis. The table below shows the analysis results of Schiff base and bis form of phenylglycine derivatives.

[Table] When R ₁ is hydrogen, the compound represented by the structural formula () is used in the acylation reaction after being protected with an appropriate silylating agent. As a silylation agent, dichlorodimethylsilane,
Trimethylchlorosilane, hexamethyldisilazane, N,O-bistrimethylsilylacetamide, N,O-bistrimethylsilylurea, etc. are used, and the solvent is methylene chloride, benzene,
Inert organic solvents such as toluene, tetrahydrobutane, chloroform, etc. are used. After the acylation and hydrolysis reactions in the final stage, crystals may be produced as a solvated substance depending on the characteristics of the product compound, or they may directly become the desired substance. Selection acts as a very important factor. When producing a compound of structural formula (), the solvent may be chloroform, halogenated alkanes such as dichloromethane, aromatic hydrocarbons such as benzene, ketones such as acetone or methyl isobutyl ketone, or ethyl acetate. Uses esters, nitriles such as acetonitrile, aprotic solvents such as dimethylformamide, dimethyl sulfoxide, mixed solvents of these, and mixed solvents of these with polar solvents such as water, methanol, ethanol, etc. and these are appropriately selected depending on the substituents of A and B.
In addition, when producing mixed acid anhydrides, methyl chloroformate, ethyl chloroformate, pihaloyl chloride, trichloroacetyl chloride,
Acid halides such as trifluoroacetyl chloride, alkyl phosphoric acids, sulfurous acids, etc. are used. Example 1 Production of N,N'-methylene-bis-α-aminophenylglycine potassium salt After dissolving 6.6 gr. of potassium hydroxide (85%) in 50 ml of methyl alcohol, 15.1 gr. of phenylglycine was dissolved. (0.1 mol) and dissolve it, 35
% formalin aqueous solution (0.005 mol) was added, reacted at room temperature for 4 hours, added 200 ml of n-hexane and removed water and methyl alcohol under reflux, and then dispersed in 200 ml of ether and filtered. Then, 19.0gr. (97.3%) of yellowish white crystals were obtained. Melting point: 159-160℃ UV: 248nm (λmax) Elemental analysis: Calculated values C52.3%, H4.13%, N7.17% Actual values C52.2%, H4.10%, N7.10% Examples 2 Production of N,N'-methylene-bis-α-amino-para-hydroxyphenylglycine potassium After dissolving 6.6gr. of potassium hydroxide (85%) in 50ml of methyl alcohol, para-hydroxyphenylglycine Add and dissolve 16.7gr. (0.1mol), and 4.3gr. (0.05mol) of 35% formalin aqueous solution.
200 ml of n-hexane was added and refluxed to remove water and methyl alcohol, and then 200 ml of ethyl
ml of yellowish white crystals 20.5gr.
(97.0%). Melting point: 173℃ (decomposition) UV: 250nm (λmax) Elemental analysis: Calculated values C48.3%, H3.8%, N6.63% Actual values C48.2%, H3.7%, N6.6% Implemented Example 3 7-(D-α-amino-α-phenylacetamino)-3-methyl-8-oxo-5-thia-
1-Azabaicyclo [4,2,C] Octo-2
- Production of N-2-carboxylic acid After dispersing 19.5 gr. (0.05 mol) of the substance obtained in Example 1 in 200 ml of methylene chloride, 0.3 ml of n-N-methylmorpholine was prepared while keeping the temperature below 0°C.
and 11.9gr. (0.11mol) of ethyl chloroformate and stirred at the same temperature for 40 minutes, then
Aminodesacetoxycephalosporinic acid
21.4gr. (0.1mol) methylene chloride 100ml
After refluxing with 20 ml of hexamethyldisilazane for 6 hours, the cooled solution was added over 1 hour, stirred at 0°C for 1.5 hours, then 50 ml of water and 10 ml of concentrated hydrochloric acid were added for 30 minutes. Stir. The aqueous layer was then separated to remove impurities and ethyl acetate
After adding 130ml and 50ml of methanol, adjust the pH to 5.0 with aqueous ammonia, filter the generated crystals, wash with acetone, and dry to produce yellowish white crystals.
28.2gr. (77.1%) is obtained. Optical rotation: [α] ²⁰ _D = 145.0 (C = 1%, H ₂ O) UV: λmax, 261 nm IR: ν ^KBr _Max cm ^-1 3400 (amine), 1760 (β-lactam), 1680 (amide carbonyl) Content: 97.8% (anhydride standard, iodometric titration method) Example 4 7-(D-α-amino-para-hydroxyphenylacetamide)-3-methyl-3-oxo-5-thia-1-azabicyclo[4 ,2,
O] Production of oct-2-N-2-carboxylic acid 21.1gr. (0.005mol) of the substance obtained in Example 2 was added to 100ml of dimethylformamide, and the mixture was mixed with 0.3ml of N-methylmorpholine while keeping the temperature below 0°C. After adding 11.9 gr. (0.11 mol) of ethyl chloroformate and stirring at the same temperature for 40 minutes, 21.4 gr. (0.1 mol) of 7-aminodesacetoxycephalosporanic acid was added to 100 ml of methylene chloride and 20 ml of hexamethyldisilazane. After refluxing for 6 hours,
After adding the cooled solution over 1 hour and stirring at 0°C for 1.5 hours, 100 ml of water and 10 ml of concentrated hydrochloric acid were added and stirred for 30 minutes, and the aqueous layer was separated to remove impurities.
Adjust the pH to 5.0 with triethylamine while heating at 50℃.
The resulting crystals were allowed to stand at room temperature for 1 hour, then filtered, recrystallized with a small amount of water, and dried to yield 24.0gr. (62.8%) of slightly yellowish white crystals. Optical rotation: [α] ²⁰ _D = +163.4° (1%, H ₂ O) UV: λmax, 264nm ν ^KBr _Max cm ¹ 3400 (amine), 1760 (β-lactam), 1680 (amide carbonyl) Content :97.6% (anhydride standard, iodometry method) 96.8% (anhydride standard, biological method) Example 5 7-(D-α-amino-α-phenylacetamino)-3-chloro-3- Production of cefem-4-carboxylic acid Substance obtained in Example 1 in 200 ml of methylene chloride
After suspending 19.5 gr. (0.05 mol) and cooling it to -10°C, 0.3 ml of N-methylmorpholine and 10.4 gr. (0.11 mol) of chloroformate were added and reacted at the same temperature for 1 hour. , 23.4 gr. (0.1 mol) of 7-amino-3-cephem-4-carboxylic acid was added to this solution in 100 ml of methylene chloride and acetonitrile.
After silification with 20 ml and N,O-bistrimethylsilylacetamide, it is added dropwise over the course of 1 hour at -10°C. After reacting at 0℃ for 2 hours, add 100ml of water.
After adjusting the pH to 1.5 with hydrochloric acid, stir for 30 minutes to separate only the aqueous layer and remove impurities, add 50 ml of acetonitrile, and adjust the pH to 5.0 with triethylamine.
A product of 20.0gr. (54.4%) is obtained. UV: λmax 265nm (PH7 buffer) IR: ν ^KBr _Max 3400 (amine), 1750 (β-lactam), 1680 (amide carbonyl), 1590 (carboxylic acid) NMR: δppm 6.5-6.7 (2H, multiple C ₂ - H ₂ ), 4.84 (1H, double C ₆ -H), 4.26 (1H, double C ₇ -H), 2.44 (5H single, aromatic H) Example 6 7-(D-α-amino- Production of para-hydroxyphenylacetamide)-3-[(1,2,3-triazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid 4.23 gr. (0.01 mole)
was suspended in 80 ml of acetonitrile, 0.1 ml of N,N-dimethylbenzylamine was added thereto, 2.4 gr. (0.022 mol) of ethyl chloroformate was added at -10°C, and the mixture was allowed to react at the same temperature for 40 minutes. Separately, add 5.44 gr. (0.22 mol) of 7-aminocephalosporanic acid to 50 ml of chloroform, dissolve by adding 3.2 ml of triethylamine, and stir this solution at -10°C.
at the same temperature for 1 hour with a mixed anhydride solution.
React for 1 hour at room temperature. The solution was evaporated under reduced pressure, suspended in 40 ml of acetone and 15 ml of N,N'-dimethylformamide, and dissolved in potassium 2-ethyl hexaate (43%) at 0°C.
8.8 gr. (0.02 mol) and 2 drops of triethylamine are added dropwise and allowed to react for 1 hour. After adding 2.0gr. (0.02mol) of 5-mercapto-1,2,3-triazole, the mixture was allowed to react at 70°C for 2 hours, cooled to 5°C, and then 30ml of water was added. PH with hydrochloric acid
After adjusting the temperature to 2, let it react for 20 minutes. After removing the solvent by distillation under reduced pressure and removing insoluble substances, extract with ethyl acetate three times, distill under reduced pressure, dissolve again in 30 ml of water, adjust the pH to 5.0, and leave to stand to precipitate crystals. When this crystal is filtered, washed with methyl alcohol, and dried, it yields 4.3gr. (46.5gr.
%) of the target product is obtained. Specific optical rotation: [α] ²⁰ _D = +54 IR: ν ^KBr _Max cm ^-1 3400 (hydroxyl, amine group), 1760 (β-lactam), 1675 (amide carbonyl) 1595 (carboxylic acid) NMR: δppm 3.4 ( 2H single SCH ₂ ), 4.40 (2H single CH ₂ S), 4.85 (1H single α-hydrogen), 5.10 (2H multiple, lactam), 6.85 (2H double, aromatic), 7.20 (2H double , aromatic), 7.45 (1H single, triazole=CH—N
=) Example 7 Production of 7-(D-α-amino-α-phenylacetamide)-cephalosporanic acid 3.90 gr. (0.01 mol) of the compound obtained in Example 1 was suspended in 70 ml of acetonitrile, and N, Add 0.1 ml of N-dimethylbenzylamine and cool to -10°C, then add 2.4 gr. of ethyl chloroformate and mix for 40 minutes.
Incubate at the same temperature for minutes. Separately, 5.44 gr. (0.02 mol) of 7-aminocephalosporanic acid was added to 50 ml of chloroform, and 3.2 ml of triethylamine was added to dissolve the solution, which was added dropwise to the above mixed anhydride solution at -10°C over 1 hour. , react at this temperature for 2 hours and at room temperature for 1 hour. The solvent was distilled off under reduced pressure, washed with ethyl acetate, adjusted to acidic pH with 30 ml of water and 42% phosphoric acid solution, and extracted three times with ethyl acetate.
Add 30 ml of water and hydrochloric acid to the residue obtained by distilling the solvent under reduced pressure, dissolve it, adjust the pH to 4.8 with triethylamine while keeping it at 5°C, filter the obtained substance, wash with methyl alcohol, and dry it to form a milky white crystalline powder. 7-D-(α-aminophenylacetamide)-cephalosporanic acid dihydrate 5.4gr.
(61.4%) is obtained. Melting point: 222℃ (decomposition) UV: λmax, 260nm Specific rotation: [α] ²⁰ _D = +83 (C = 0.5%, H ₂ O: CH ₃ CN mixed solution)

Claims (1)

[Scope of Claims] 1. Reacting a compound of the following structural formula () with a compound of the following structural formula (), then reacting it with a compound of the following structural formula (), and further hydrolyzing this reaction product. According to (In the formula, R ₁ is hydrogen or a lower alkyl group having 1 to 5 carbon atoms, A is hydrogen or a hydroxy group, and B is hydrogen, halogen, methyl, hydroxymethyl, acetoxymethyl, methoxy or -
CH ₂ SR ₃ group, R ₂ is hydrogen, sodium, potassium or an ester-forming group, R ₃ is triazolyl, tetrazolyl, thiadiazolyl, pyrimidinyl or a partially substituted group thereof, R ₄ is Tert- It represents a butyl, methoxy, ethoxy group, a lower alkyl group having 1 to 5 carbon atoms, or a phenyl group, and R ₅ represents a lower alkyl group having 1 to 5 carbon atoms, an alkylsilyl group, or an organic salt-forming group. ) A method for producing a cephalosporin derivative, which comprises producing a compound of the above structural formula ().