JPS6139953B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel cefem-carboxylic acid esters and a method for deesterifying the same. According to this invention, the general formula (): [Wherein, W is a phenyl group, or a cyclohexadienyl group, which may be substituted with a hydroxyl group and/or a halogen atom; Q is a protected amino group or an azido group; R ¹ is an alkyl group or an aryl group;
R ² means an alkyl group or an alkoxy group, respectively. ] A compound represented by these is provided. The inventors of this invention first esterified penicillin G or penicillin V with a specific compound, and then processed this through a series of steps including a ring expansion reaction to form 7-acylamino-3-methyl-3-cephem-4-carboxylate. We have found a method for producing acid esters or their S-oxides (German Published Application No. 2538387).
issue). However, the 7-position acylamino group specifically disclosed herein was suitable for the ring expansion reaction from a penam ring to a cefem ring, such as a phenylacetamide group or a phenoxyacetamide group. Further, the inventors conducted research to obtain useful derivatives of 7-acylamino-3-methyl-3-cephem-4-carboxylic acid ester obtained from penicillin, and as a result, the present invention was achieved. One of the main features of the compounds of this invention is that the carboxyl group at the 4-position of the cefem ring is esterified with a specific compound. This ester group allows the desired reaction to be carried out in a non-aqueous solvent system and is extremely easy to carry out under mild conditions after the desired reaction is completed without substantially affecting the cefem ring or side chain groups. It is a group that can be removed. Therefore,
This ester group provides good results in obtaining useful cephalosporin antibiotics in high yield and purity. Another feature is that the substituent at position 7 of the cefem ring is a specific acylamino group having a precursor of an amino group at the α position. The compound of the general formula () of this invention can be produced, for example, by the following method. That is, formulas for penicillins such as penicillin G and penicillin V

[Formula] (In the formula, X is a halogen atom such as a chlorine atom, R ¹ and R ² are general formulas ()
) is reacted to give a penicillin ester, which is oxidized with a peroxide to form an S-oxide and then subjected to a ring expansion reaction (see the above-mentioned German publication). The 7-phenylacetamide (or phenoxyacetamide)-3-methyl-3-cephem-4-carboxylic acid ester (or its S-oxide form) produced here can be subjected to, for example, an iminohalide method. , the resulting iminoether or its hydrolyzate (7-position is a free amino group) has the formula

By reacting a reactive derivative of carboxylic acid of [formula] (in which W and Q have the same meanings as defined in general formula ()), it is possible to lead to the compound of general formula () in high yield. Formula used to construct the ester moiety of the invention

Preferred compounds of the formula are α-bromoacetoacetic acid or α-bromo-α-
α-halogenoketo acid esters such as the methyl, ethyl or isobutyl esters of benzoylacetic acid and their corresponding chloro compounds; 3-
Mention may be made of halogenodiketones such as bromo-2,4-pentanedione, 1-phenyl-2-bromo-1,3-butanedione and their corresponding chloro compounds. Among these, preferred examples are 3
-chloro-2,4-pentanedione, methyl α-chloroacetoacetate and ethyl α-chloroacetoacetate. Next, the above acyl group exchange reaction carried out to obtain the compound () of this invention will be explained. 7-Phenylacetamide (or phenoxyacetamide)-3-methyl-3-cephem-4-carboxylic acid ester (or its S-oxide form) is an organic compound such as methylene chloride, chloroform, ethylene chloride, tetrahydrofuran, etc. Can be dissolved in a solvent. Therefore, the ester is dissolved in these organic solvents, a base such as dimethylaniline, pyridine, quinoline or their homologs is added thereto, and phosphorus pentachloride is reacted to form the iminohalide. (When using S-oxide, it is better to use slightly more phosphorus pentachloride, usually 2 to 2.5 times the mole amount.) Add to this, methanol, ethanol, isopropyl alcohol, isobutanol, butanol,
Reacts with a lower alcohol such as pentanol to form an imino ether. This iminoether form can be used as is or after hydrolysis, the formula

[Formula] (each symbol in the formula has the same meaning as above) is reacted with a reactive derivative of carboxylic acid. Here, Q may be a precursor of an amino group that can be induced into an amino group. However, those which are not affected by the process of removing the ester moiety from the compounds of this invention are preferred. In addition, when the final useful substance is an optically active substance, it is preferable that racemization does not occur in the step of induction or conversion into an amino group, or that the optically active form of the raw acid can be easily produced. From this viewpoint, specific examples of the protected amino group of the present invention include a formylamino group, a t-butoxycarbonylamino group, a chloroacetylamino group, a 2,2,2-trichloroethoxycarbonylamino group, and a benzyloxycarbonylamino group. Examples include acylamino groups such as acylamino groups. Of course, it may be an azide group. Furthermore, these groups should be understood as specific examples of Q in general formula ().
Further, as reactive derivatives of carboxylic acids, acid halides, mixed acid anhydrides, etc. are commonly used. This acylation reaction is preferably carried out in an organic solvent such as those mentioned above at a low temperature of, for example, 0 to -40°C. Preferred compounds of this invention include the following. In the above formula, Q is −N ₃ , −NHCOOC
( _CH3 ) ₃ , _-NHCOCH2Cl , -NHCHO, -
It was selected from NHCOOCH ₂ CCl ₃ and -NHCOOCH ₂ C ₆ H ₅ . The compounds of the present invention, including the compounds exemplified above, have an asymmetric carbon atom at the α-position of the side chain, and all optical isomers that exist based on this are included in the present invention. Next, the process of deesterifying the compound () of this invention will be explained. Deesterification can be effectively carried out using a nitrosating agent such as nitrous acid or its salt, nitrite ester, nitrosyl halide, nitrogen oxide, or the like. 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,
Alkyl esters such as butyl esters or pentyl esters; aralkyl esters such as benzyl esters; cyclohexyl esters,
Examples include cycloalkyl esters such as cyclopentyl ester. Preferred examples of these include propyl nitrite, butyl nitrite, and pentyl nitrite. Alternatively, nitrosyl halide or nitrogen oxide may be introduced into a solution of the compound () and reacted. 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, sodium acetate, potassium acetate, and triethylamine salts of acetic acid are particularly preferred. Examples of organic acids include formic acid, acetic acid, propionic acid, butyric acid, diethyl acetate, citric acid, succinic acid, and oxalic acid, and 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. This deesterification reaction is carried out by suspending or dissolving the compound of general formula () in an inert solvent (e.g., aqueous acetone, aqueous tetrahydrofuran, aqueous methyl ethyl ketone, etc.), and adding, for example, excess nitrite as a solid or as an aqueous solution. , or by adding excess nitrite along 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 croftography. 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 nitrite, nitrite ester, etc. to be used is about 1.2 to 5 times the mole, preferably about 1.5 to 3 times the mole of the compound of general formula (). The reaction mechanism of this deesterification reaction 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, but the current method is However, the details are unknown. 7-acylamide-3 produced by the present invention
-Methyl-cefem-4-carboxylic acid is the 4th
The acidity of the carboxyl group at position is quite strong, and it seems that an alkaline salt is formed in the system of alkali nitrite and acetic acid. Therefore, when using a water-containing organic solvent, the pH should be 7.5.
After adjusting to about 100%, the organic solvent is distilled off under reduced pressure, washed with a solvent that is poorly soluble in water to remove unreacted raw material esters and byproducts, and then mixed with a strong acid such as formic acid, citric acid, tartaric acid, organic sulfonic acid, and halogeno fatty acid. The desired product can be obtained by adjusting the pH to around 2.0 with hydrohalic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Next, the conversion of a protected amino group to an amino group and the induction of an azide group to an amino group can be carried out by methods known per se. For example, formylamino groups are reacted with phosphorus oxychloride in methanol solvent, 2,2,2-trichloroethoxycarbonylamino groups are reduced with zinc powder in the presence of acid, and chloroacetylamino groups are reduced in water at around pH 6.5. It can be converted to an amino group by reacting with thiourea. The azide group is converted to an amino group by reduction using conventional methods. Thus, the compound () of the present invention can be said to be a useful compound in the industrial production of known useful cephalosporin antibiotics, for example, using natural penicillin as a raw material. Next, the present invention will be explained with reference to examples. Example 1 (a) Preparation of 1'-methoxycarbonyl-2'-oxopropan-1'-yl ester of 7-(D-α-formylamino-phenylacetamide)-deacetoxycephalosporanic acid 7 -(phenylacetamide)-1'-methoxycarbonyl of deacetoxycephalosporanic acid-
2'-oxopropane-1'-yl ester (0.01
mol) and N-N-dimethylaniline (0.04 mol) were added to 30 ml of methylene chloride, cooled to -30°C, and phosphorus pentachloride (0.013 mol) was added to -30 to -
After stirring at 10°C for 2 hours, the mixture was cooled to -30°C and anhydrous methanol (0.15 mol) was added dropwise. Thereafter, the reaction was carried out at -30°C for 2 hours. The reaction solution was poured into 30 ml of ice water, and after stirring for 30 minutes while adjusting the pH to around 1 with an aqueous sodium hydrogen carbonate solution, the methylene chloride layer was separated and washed with water. Combine the aqueous layers and add methylene chloride
Add 30ml and adjust the pH with sodium bicarbonate aqueous solution.
Adjust to 7.0 and separate the organic layer. After washing the organic layer with water, it is immediately cooled to 0°C. Meanwhile, potassium salt of D-α-formylamino-phenylacetic acid (0.01 mol) and 4-methylmorpholine (2 drops) were added to 20 ml of methylene chloride at -30
Add ethyl chloroformate (0.011 mol) at -
The reaction was carried out at 30 to -20°C for 90 minutes, then cooled to -40°C, and the solution of the ester was added dropwise to -40 to -20°C.
React at 30°C for 2 hours. The reaction was monitored by thin layer chromatography (benzene:ethyl acetate=1:1, sprayed with azide iodide solution and heated to develop color). The temperature of the reaction solution was gradually raised, 20 ml of ice water was added, and 2
Adjust the pH to 2 with normal hydrochloric acid. Remove the aqueous layer, add 20 ml of ice water to the organic layer, and adjust the pH to 7.0 with an aqueous sodium hydrogen carbonate solution. The organic layer is washed with water, dried and the solvent is distilled off, and the residue is recrystallized from isopropyl alcohol and isopropyl ether. 7-(D-α-formylaminophenyl acetamide)-deacetoxycephalosporanic acid
1'-methoxycarbonyl-2'-oxopropan-1'-yl ester was obtained in a yield of 82%; mp.210-214°C (decomposition) (b) 7-(D-α-formylaminophenyl ester Production of cetamide)-deacetoxycephalosporanic acid. 1'-Methoxycarbonyl-2'-oxopropan-1'-yl ester of 7-(D-α-formylaminophenyl acetamide)-deacetoxycephalosporanic acid obtained in Example 1(a) 50
% acetone, 1 drop of acetic acid and 2 equivalents of an aqueous sodium nitrite solution are added dropwise, and the mixture is stirred at 40° C. or less for about 1 hour to react. Acetone was distilled off from the reaction solution under reduced pressure, the pH was adjusted to 7, and the solution was washed with ethyl acetate. Next, ethyl acetate is added to the aqueous layer, the pH is adjusted to 2 with 6N hydrochloric acid, and the organic layer is separated, washed three times with brine and dried. The solvent is removed under reduced pressure and treated with isopropyl alcohol and isopropyl ether. 7-(D-α-formylaminophenyl acetamide)-deacetoxycephalosporanic acid was obtained in a yield of 92%: mp.173-179°C (decomposition) Examples 2-4 D in Example 1 - Instead of α-formylaminophenyl acetic acid, another potassium salt of D-α-acylaminophenyl acetic acid was used, and the rest was as in Example 1(a).
and 1(b) to obtain the following, respectively. 2(a) 1'-Methoxycarbonyl- of 7-(D-α-t-butoxycarbonylamino)-phenylacetamide-deacetoxycephalosporanic acid
2'-Oxopropan-1'-yl ester; Yield: 78% mp.145-147℃ (b) 7-(D-α-t-butoxycarbonylamino)-phenylacetamide-deacetoxycephalo Sporanic acid; Yield: 91% mp.135℃ 3(a) 7-(D-α-chloromethylcarbonylamino)-phenylacetamide-deacetoxycephalosporanic acid 1'-methoxycarbonyl-
2'-Oxopropan-1'-yl ester; Yield: 83% mp.214-215℃ (decomposition) (b) 7-(D-α-chloromethylcarbonylamino)-phenylacetamide-deacetoxy Cephalosporanic acid; Yield: 93% mp.169-171℃ (decomposition) 4(a) 7-(D-α-2,2,2-trichloroethoxycarbonylamino)-phenylacetamide-deacetoxy 1′-methoxycarbonyl-2′-oxopropane-1′- of cephalosporanic acid
Yield: 85% mp.201-204℃ (decomposition) (b) 7-(D-α-2,2,2-trichloroethoxycarbonylamino)-phenylacetamide-deacetoxycephalosporan Acid; Yield: 93% mp.183-185°C (decomposition) Example 5 D-α-formylamino-1.
The following compounds were obtained by using 4-cyclohexadienyl acetic acid and otherwise reacting in accordance with Example 1(a) and 1(b). (a) 1'-methoxycarbonyl-2'-oxopropan-1'-yl ester of 7-(D-α-formylamino-1,4-cyclohexadienyl acetamide)-deacetoxycephalosporanic acid; Yield: 84% mp.214-217℃ (decomposition) (b) 7-(D-α-formylamino-1,4-cyclohexadienyl acetamide)-deacetoxycephalosporanic acid; Yield: 91 %mp.220~221℃

Claims (1)

[Claims] 1 General formula (): [In the formula, W is a phenyl group or a cyclohexadienyl group which may be substituted with a hydroxyl group and/or a halogen atom; Q is a protected amino group or an azido group; R ¹ is an alkyl group; R ² is an alkoxy group, respectively means. ] A compound represented by 2 In the general formula (), [formula] is 1-methoxycarbonyl-2-oxopropane-1
The compound according to claim 1, which is -yl.