JPS6113478B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an improved method for producing cephalosporin compounds. More specifically, the present invention provides an improved method for producing cephalosporins having an alpha-aminoacetamide substituent at position 7 of the cephalosporin nucleus. A number of cephalosporin antibiotics with α-aminoacetamide substituents are known (e.g. British Patent Nos. 985747, 1174335, 1265315,
1276314, 1283811, 1284227 and 1288282). The known compounds disclosed in these and many other patent specifications have the general formula: [wherein R ¹ is hydrogen, hydroxy, acyloxy or a thio substituent such as a heterocyclic thio group; R ² is hydrogen or a carboxylic acid protecting group; R is

[Formula] (wherein R ³ is a partially or completely unsaturated cyclic hydrocarbyl group or a heterocyclic group). The above compound is produced as follows. That is, in the general formula (), R
is hydrogen and R ² is a carboxylic acid protecting group in activated acid form. (wherein R ³ is as defined above and R ⁴ is an amine protecting group), then the amine protecting group is removed and the resulting product is optionally deesterified. The above compound can be prepared by preparing a compound of general formula () in which R ² is hydrogen. One suitable amine protecting group ^R4 is enamine (enamlne), which is formed by reaction with an appropriate β-dicarbonyl compound, but the utility of this protecting group is sometimes limited by the cleavage of the enamine. Its value can be diminished by problems associated with subsequent isolation of the desired product. In other words, β produced by the cleavage reaction
-Due to the reactivity of the -dicarbonyl compound, it may react again with the α-aminoacetamide compound, resulting in a decrease in yield during the next step of purification and isolation.
This problem can be overcome by carrying out the enamine cleavage as follows. That is, the free aminocephalosporin ester of general formula () is precipitated from the reaction solvent, the resulting β-dicarbonyl compound remains in the mother liquor, and is then deesterified, purified, and isolated. Although this method solves the first problem mentioned above, it requires the introduction of an additional replenishment step for the isolation of the free amino ester of general formula (), which reduces the yield, even if Even if the yield does not decrease, the yield will be reduced to the same degree as in the past, so this does not solve the problem of yield decrease. Therefore, the object of the present invention is to reduce α during the acylation reaction.
An improved process for producing a 7-α-aminoacetamidocephalosporin compound in which the -amino substituent is protected by enamine formation is provided. According to the broadest aspect of the invention, therefore, the following steps are carried out, namely: (a) preparing an α-aminoacetic acid whose amino group is protected by reaction with a β-dicarbonyl compound to form an enamine; (b) removing the amino protecting group from the obtained 7-α-aminoacetamidocephalosporin compound; (c) in step (b) (d) adding hydrazine or a derivative thereof to the reaction mixture in an amount sufficient to prevent the re-reaction of the produced 7-α-aminoacetamidocephalosporin compound with the β-dicarbonyl compound; If so, the resulting cephalosporin ester is deesterified to produce the desired 7-α-aminoacetamidocephalosporin-4-carboxylic acid. A method for producing 7-α-aminoacetamidocephalosporin-4-carboxylic acid is provided. In step (a) the acylation is preferably carried out in an aprotic solvent such as dimethylformamide or acetonitrile. Acylation is usually carried out at or below about 0°C, most preferably at -
It is carried out at a temperature within the range of 15 to -50°C. Suitable 7-aminocephalosporin-4-carboxylic acid esters that can be acylated according to the present invention have the formula: (wherein R ² is as defined above and R ⁵ is hydrogen, acetoxy or a heterocyclic thio group, in particular a thiadiazolylthio or tetrazolylthio group), and salts thereof such as hydrochloride and tosylate. ) is salt. R ² can be any group commonly used to protect the carboxylic acid function of a cephalosporin molecule. Examples of this group are benzyl, p-nitrobenzyl, p-methoxybenzyl, 3,5-
dimethoxybenzyl, diphenylmethyl, 2.
There are 2,2-trichloroethyl, tert-butyl, phenacyl, benzyloxymethyl and tetrahydropyranyl groups. Most effective is the case where the compound of general formula () is p-nitrobenzyl 7-aminodesacetoxycephalosporanate. The protected α-aminoacetic acid used in step (a) preferably has the formula: (wherein R ⁷ is C _1-4 alkyl, or C _1-4 alkoxy, preferably methyl, ethyl, methoxy or ethoxy, and R ⁶ is thienyl or optionally C _1-4 alkyl, C phenyl or cyclohex _- 1,4-dienyl group substituted with 1-4 alkoxy, halogen, hydroxy, amino, substituted amino, nitro or trifluoromethyl group). A compound with this formula () has the formula

An acid or its salt having the formula and β having the formula CH ₃ −CO−CH ₂ −CO−R ⁷
-Easily produced by reaction with dicarbonyl compounds. Since the α-carbon atom of the acid with formula () is an asymmetric carbon atom, this acid can exist in two optically active isomeric forms, namely the D-form and the L-form, as well as in the form of a racemic mixture. . D
It is also suitable to use acids of formula () having the form -. Most preferred are D-type acids of formula () in which R ⁶ is unsubstituted phenyl, cyclohex-1,4-dienyl or thienyl;
This is the case when R ⁷ is methoxy. As mentioned above, the activated form of the acid of formula () is used as the acylating agent in step (a). This active form may be an acid chloride or an anhydride, but is preferably a mixed anhydride, such as those formed by the reaction of C _1-4 alkyl chloroformates, especially methyl chloroformates, with salts of the individual acids. It is. In step (b) above, the amino protecting group is removed by methods known in the art, such as acid hydrolysis using dilute acetic acid or hydrochloric acid. Following hydrolysis, free 7-α-aminoacetamidocephalosporin is obtained, along with the product of the β-dicarbonyl compound initially used to protect the α-aminoacetate acylating agent. can get. In this step, as step (c), a sufficient amount of hydrazine or a derivative thereof (e.g. hydrazine hydrate or preferably semicarbazide or its hydrochloride salt) is added to the reaction mixture. The hydrazine is usually used in an equimolar ratio with the β-dicarbonyl compound, but if desired, an excess of hydrazine can be used. Following this step, if necessary, the resulting cephalosporin ester is treated in a conventional manner, for example with aqueous acetic acid and zinc dust, with trifluoroacetic anhydride, with zinc and an aqueous mineral acid (e.g. hydrochloric acid) solution, or Deesterification is carried out by other convenient mild hydrolysis or hydrogenolysis depending on the ester group to be removed. It will therefore be appreciated that in many cases the acid hydrolysis or hydrogenolysis used to cleave the enamine protecting group in step (b) also achieves the desired deesterification. And it is a preferred embodiment of the invention that the ester and enamine groups used to protect the reactants of formulas () and (), respectively, must be chosen to allow simultaneous removal. For example, when R ² is p-nitrobenzyl and R ⁷ is methoxy, the use of zinc and hydrochloric acid in step (b) simultaneously deblocks the amino and carboxyl groups and directly forms the desired 7-α-aminoacetamide. Cephalosporin-4-carboxylic acid is produced and the produced acid can be purified and isolated by the application of conventional techniques following addition of the hydrazine compound to the reaction mixture. The method of the present invention preferably uses cephalexin (cephalexin).
Cephalosporin antibiotic known as -lexin) i.e. formula: used in the production of compounds with In the production of cephalexin by the method of the present invention, p-nitrobenzyl ester of 7-aminodesacetoxycephalosporanic acid is converted into N-(2-methoxycarbonyl-1-methylvinyl)-D-α
- mixed anhydride of phenylglycine in dimethylformamide to obtain 7-[N-(2-
methoxycarbonyl-1-methylvinyl)-D-
[α-Aminophenyl acetamide] p-nitrobenzyl ester of desacetoxycephalosporanic acid is reduced in an acidic medium to remove the protecting groups of the amino and carboxyl groups, and the resulting cephalexin is re-reacted with methyl acetoacetate. A sufficient amount of the hydrazine compound is added to prevent the cephalexin from being removed, and the cephalexin is then isolated in a conventional manner to obtain highly purified cephalexin. In particular, the cephalexin obtained here is substantially free of aromatic amine impurities, but this impurity is caused by the acylation of p-nitrobenzyl ester of 7-aminodesacetoxycephalosporanic acid with enamine-protecting phenylglycine. may be present in cephalexin manufactured by the prior art including. Although these prior art processes can produce cephalexin in high yields, the presence of the aromatic amine impurities mentioned above precludes the use of cephalexin (containing impurities) without expensive extra purification steps. . And as a result of this extra step, the overall yield decreases rapidly and adds significant cost. While the foregoing description alone will teach one skilled in the art how to carry out the method of the present invention, the following is intended to illustrate implementation details in connection with the actual operation of the improved method of the present invention. Here are some examples. Example 1 In one flask containing dimethylformamide
24.8 g of N-(2-methoxycarbonyl-1-methylvinyl)-D-α-phenylglycine sodium salt (prepared from D-α-phenylglycine sodium salt and methyl acetoacetate) was The mixture was added at a temperature of ℃. The mixture was cooled to -40°C and methyl chloroformate (7.5ml) and dimethylbenzylamine (0.26ml) were added. twenty five
After stirring for minutes p-nitrobenzyl 7-aminodesacetoxycephalosporanate (32.8 g)
was added as its hydrochloride salt followed by triethylamine (12.1 ml) and dimethylformamide (140 ml) over 20 minutes. The reaction mixture is −25 to −35
Stir at ℃ for 2 hours, warm to 0℃, and add water (32
ml) was added. Add hydrochloric acid (54 ml) to the resulting solution.
was added followed by the addition of zinc (21.8 g) in small portions over a 5 minute period while maintaining the temperature at 5-10°C. Furthermore, add hydrochloric acid (35ml) and make the solution 15~
The mixture was stirred at 20°C for 7 hours. The pH of this solution was adjusted to 3.3 with triethylamine, and semicarbazide hydrochloride (9.5 g) was added. Add triethylamine to this mixture and pH = 3
The mixture was returned to its original state and stirred for 30 minutes at pH=3. The resulting mixture was adjusted to pH=6.8 by addition of triethylamine over a period of 4 hours. Seeding was done when pH = 4.5. The precipitated cephalexin was separated and washed with dimethylformamide (200 ml) to recover the cephalexin. Yield 75%. Example 2 The above procedure was repeated, but the semicarbazide hydrochloride addition step was omitted. The yield of cephalexin corresponded to 48-52%, demonstrating the value of the process of the invention. Example 3 The procedure of Example 1 was repeated, but hydrazine hydrate (4.26 g) was added instead of semicarbazide hydrochloride. After addition, its PH increased to 4.5-5.0. Seed material was added to the reaction mixture and stirred for 30 minutes. The pH was then slowly raised to 6.8 as described in Example 1, and the precipitated cephalexin was separated and recovered by washing with dimethylformamide. Yield 70-75%. Example 4 The procedure of Example 1 was repeated, but the sodium salt of N-(2-methoxycarbonyl-1-methylvinyl)-D-α-phenylglycine was -Sodium salt of α-cyclohexa-1,4-dienylglycine was substituted. The yield of cephradine was improved over that achievable with the process without semicarbazide. Matters related to the present invention will be described below. (1) 7-aminocephalosporin-4-carboxylic acid ester has the general formula: (However, in the formula, R ² is a carboxylic acid protecting group, and R ⁵
is hydrogen, acetoxy or a heterocyclic thio group) and an acid addition salt thereof. (2) α-Aminoacetic acid has the general formula: (However, in the formula, R ⁷ is C _1-4 alkyl or C _1-4
and R ⁶ is a thienyl group or phenyl or cyclohexane optionally substituted with C _1-4 alkyl, C _1-4 alkoxy, halogen, hydroxy, amino, substituted amino, nitro or trifluoromethyl 1,4-dienyl group). (3) R ⁶ is unsubstituted phenyl, cyclohex-1.
4-dienyl or thienyl, and ^R7 is methoxy. (4) The 4-carboxylic acid ester is p-nitrobenzyl ester of 7-aminodesacetoxycephalosporanic acid, and the active form of α-aminoacetic acid is N-(2-methoxycarbonyl-1-methylvinyl)-D -A method for producing cephalexin as claimed in the claims, which is α-phenylglycine. (5) A cephalosporin antibiotic obtained by the manufacturing method described in the claims.

Claims (1)

[Scope of Claims] 1. In producing 7-α-aminoacetamidocephalosporin-4-carboxylic acid, (a) 7-aminocephalosporin-4-carboxylic acid ester is converted into activated α-aminoacetic acid. At this time, the amino group of the α-aminoacetic acid is converted to β
- react with a dicarbonyl compound to protect it as an enamine, (b) remove the protecting group for the amino group from the resulting 7-α-aminoacetamidocephalosporin compound, and (c) remove the protecting group from the amino group in the previous step (b). (d) adding a sufficient amount of hydrazine or a derivative thereof to the reaction mixture to prevent the generated 7-α-aminoacetamidocephalosporin compound from reacting with the β-dicarbonyl compound; The method for producing a cephalosporin compound as described above, which comprises deesterifying the cephalosporin ester, if necessary, to produce the desired 7-α-aminoacetamidocephalosporin-4-carboxylic acid.