JPS6340795B2 - - Google Patents

Description

[Detailed description of the invention]

OBJECTS OF THE INVENTION The present invention relates to a method for converting a carbamoyloxymethyl group at the 3-position of a cefamycin C derivative into a heterocyclic thiomethyl group. Cefamycin C (4) is a cephalosporin derivative having a methoxy group at the 7-position produced by Streptomyces bacteria, and compound (5) is known as a cefamycin derivative that exhibits excellent antibacterial activity (Japanese Patent Application Laid-Open No. 1973-1999- 83383). In order to lead cefamycin C (4) to compound (5), it is necessary to convert the carbamoyloxymethyl group at the 3-position of the cefamycin C derivative to a heterocyclic thiomethyl group. On the other hand, there are many reports regarding the method of converting the acetoxymethyl group at the 3-position of derivatives of cephalosporin C(6) into a heterocyclic thiomethyl group (Japanese Patent Publication No. 39-1736;
46-13023; Publication No. 49-45880 and Japanese Unexamined Patent Publication No. 1973-
295; 49-5987; 49-24992). In these methods, a cephalosporin C derivative and a mercaptan derivative are mixed at a pH of 5.5 to 7 to 20 times the weight of the cephalosporin C derivative as a solvent.
6.0 and heated to 60-80℃ for 0.5-7 hours.
The desired product (7) is obtained with a yield of 93%. However, it has been reported that when this method is applied to cefamycin C derivative (8), the target product (9) can only be obtained in a low yield (31%) (Japanese Patent Application Laid-open No. 83383/1983; Chem.
Pharm. Bull., 24 , 2629 (1976)). It has recently been reported that compound (11) can be obtained in good yield when a cephalosporin derivative (10) and a mercaptan derivative are reacted in the presence of BF ₃ (Japanese Patent Laid-Open No. 53-98987). However, this report does not describe any examples in which this method was applied to compounds in which X is a carbamoyloxy group, and the inventors
In this method, a cefamycin C derivative and a mercaptan derivative were reacted, but the desired product was not obtained and only a decomposition product was obtained. Since there is no practical method for substituting the 3-carbamoyloxy group of the cefamycin derivative (1) with a heterocyclic thio group, the inventors conducted various reactions between the cefamycin derivative (1) and the mercaptan derivative (2). Add 2 times the weight of water or less to the cefamycin derivative (1), and then add the cefamycin derivative (1).
(1) and mercaptan derivative (2) at 70 to 90℃ for 5 to 10 minutes.
The present invention was completed by discovering that the desired product (3) could be obtained in a yield of 53 to 92% by stirring for a minute. Structure of the invention The present invention is based on the formula (wherein, R represents an acyl group and X represents an alkoxy group) or a salt thereof, and a compound having the formula R″SH (2) (wherein, R″ represents a substituted or unsubstituted heterocyclic group) ) is added to a mercaptan derivative having a compound (1) or its salt in an amount of water that is not more than twice the weight of the compound (1) or its salt, and then heated. (In the formula, R, Any acyl group from
Examples include a substituted acetyl group, a substituted valeryl group, and a substituted benzoyl group. Examples of the substituents of the substituted acetyl group include an amino group, a substituted amino group, a carboxy group, a halogen atom, a sulfonyl group, a hydroxyl group, a heterocyclic group, a heterocyclic thio group, a heterocyclic oxy group, a substituted alkylthio group, and an alkynylthio group. It will be done. Examples of the substituent of the substituted valeryl group include an amino group, an acylamino group, and a carboxy group. Examples of the substituent of the substituted benzoyl group include an amino group, a hydroxyl group, and a sulfo group. Examples of the alkoxy group represented by X include methoxy, ethoxy, and propoxy. The heterocyclic group represented by R'' is a heterocyclic thiomethyl group substituted at the 3-position of the cephalosporin derivative, for example, 1 to 4 nitrogen atoms.
5- or 6-membered heterocyclic group having 1 oxygen atom
and a 5- or 6-membered heterocyclic group having 1 to 2 nitrogen atoms; a 5- or 6-membered heterocyclic group having 1 sulfur atom and 1 to 2 nitrogen atoms. Examples of the substituent of the heterocyclic group represented by R'' include an alkyl group. Suitable examples of R'' include 5-mercapto-1-methyltetrazole, 2-mercapto-5
-Methyl-1,3,4-thiadiazole and 3-mercapto-1,2,4-triazole. Suitable compounds (1) include, for example, cefamycin C 7β-(D-5-isobutoxycarbonylamino-5-carboxyvaleramide)-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid; 7β-(D-5-p-nitrobenzoylamino-
5-carboxyvaleramide)-7α-methoxy-
3-carbamoyloxymethyl-3-cephem-
4-carboxylic acid, 7β-(imidazol-2-yl)thioacetamido-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β-(1,3,4-thiadiazol-2-yl ) Thioacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β-(3-isoxazolyloxy)acetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem- 4-carboxylic acid, 7β-propargylthioacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β-cyanomethylthioacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem- 4-carboxylic acid, 7β-(5-methyl-1,3,4-thiadiazol-2-yl)thioacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β-(1 , 2,4-triazol-4H-3-yl)thioacetamido-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. The method for producing compound (3) will be explained below. Cefamycin derivatives (1) and mercaptan derivatives
When a small amount of water is added to the mixture of (2) and the mixture is heated, the desired product (3) is obtained. The amount of water used in this reaction is not more than twice the weight of compound (1), preferably 0.03 to 1.0 times the weight.
The reaction temperature is 50-150°C, preferably 65-90°C. The reaction time is several seconds to several tens of minutes, preferably 5 to 15 minutes. After the reaction has ended, the reaction product is isolated from the reaction mixture in a conventional manner. For example, compound (3) can be obtained by adding water and an organic solvent (separable from water) to the reaction mixture, making the aqueous layer acidic and extracting with the organic solvent, and distilling off the solvent from the extract under reduced pressure. It will be done. For further purification, use chromatography or the like. Compound (3) can be converted into a salt thereof according to a conventional method. Such salts include inorganic metal salts such as lithium, sodium, potassium, calcium, magnesium; ammonium, cyclohexylammonium, diisopropylammonium,
Examples include ammonium salts such as triethylammonium, preferably sodium and potassium salts. 7β-(imidazol-2-yl)thioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-obtained according to the present invention -(1,3,4-thiadiazol-2-yl)thioacetamide-7α-methoxy-3-(1
-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-(5-isoxazolyloxy)acetamide-7α-methoxy-3-(1-methyl-1H-tetrazole- 5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-propargylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-(5-methyl-1,3,4-thiadiazol-2-yl)thioacetamide-7α-methoxy-3-(1-methyl-1H- Tetrazole-5-
7β-(D-5-amino-5-carboxyvaleramide)-7α-methoxy-3-(1-methyl-1H) has excellent antibacterial activity.
-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-(D-5-isobutoxycarbonylamino-5-carboxyvaleramide)-7α-methoxy-3-(1-methyl-1H- Tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-(D-5-p-nitrobenzoylamino-
5-carboxyvaleramide)-7α-methoxy-
3-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and the like are useful as intermediates for the synthesis of cefamycin derivatives (5). Effects of the Invention This method replaces the carbamoyloxy group at the 3-position of the cefamycin derivative (1) with a heterocyclic thio group.
This is a practical method to obtain (3). That is, with the known methods, compound (3) is not obtained at all (Japanese Patent Application Laid-open No. 53-98987), or the yield is 31% (Japanese Patent Application Laid-Open No. 50-83383; Chem.Pharm.
Bull., 24, 2629 (1976), the object (3) can only be obtained. However, in this method, compound (3) is obtained with a yield of 53 to 92%, and especially when the amount of water used in the reaction is 0.1 to 0.8 times the weight of compound (1), compound (3) can be obtained with a yield of 53 to 92%.
is obtained in a yield of 83-92%. The results of comparing the yield of compound (13) obtained by reacting compound (12) with a mercaptan derivative by varying the amount of water used for the reaction from 0.5 to 30 g per 1 g of compound (12). is shown in the test example. The following is clear from this test example. Yield 18.8% when water used for reaction is 30g
(13) is obtained, and as the amount of water decreases, the yield of compound (13) increases, and when the amount of water decreases to 5.0 g (compound (12)
(5 times the amount), compound (13) is obtained with a yield of 35%. This yield was determined by a known method (Japanese Patent Application Laid-Open No.
−83383; Chem.Pharm.Bull., 24 , 2629
(1976)), the target compound (9) was obtained in a yield of 31%. When the amount of water is decreased after 5 times this amount of water, the compound (13) rapidly (not linearly increased).
The yield increases and when the amount of water is doubled, compound (13) is obtained with a yield of 53%, and when the amount of water is increased by 0.5 times, compound (13) is obtained with a yield of 68%. Next, Examples and Test Examples of the present invention will be shown. Example 1 1-Methyl-5 to 3.0 g of 7β-(D-5'-isobutoxycarbonylamino-5'-carboxyvaleramide)-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid - Add 3.0 g of mercaptotetrazole and 1 ml of water and stir for 5 minutes at internal temperature (70-90°C) on an oil bath. Cool immediately, add 20 ml of water and 30 ml of ethyl acetate, and remove the aqueous layer.
Adjust the pH to 2.0 with dilute hydrochloric acid. The ethyl acetate layer is separated, the aqueous layer is further extracted twice with 30 ml of ethyl acetate, and the extract is concentrated under reduced pressure. Add 30ml of isopropyl ether to the remaining oil and stir well to turn the oil into a powder. When this is collected and dried, 7β
-(D-5'-isobutoxycarbonylamino-
5′-carboxyvaleramide)-7α-methoxy-
2.9 g of 3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid are obtained. nmr spectrum, heavy acetone (ppm value): 0.83, 0.93 (doublet, 6H), 1.52-2.77 (multiplet, 7H), 3.51 (singlet, 3H), 4.03 (singlet,
3H), 5.15 (singlet, 1H) Example 2 1.8 g of 7β-cyanomethylthioacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and 1-methyl-5
- Add 1.4 g of mercaptotetrazole and 0.9 ml of water, and heat and stir on an oil bath at 85-90°C (internal temperature) for 5 minutes. The reactant dissolves and becomes an oil. Cool it, add 20 ml of water, adjust the pH to 2.0, and extract three times with 30 ml of ethyl acetate. Ethyl acetate was distilled off under reduced pressure, the residue was dissolved in 20 ml of acetone, and a solution of sodium 2-ethylhexanoate in ethyl acetate (1mM/1
ml) Add 4.5ml and concentrate under reduced pressure. Add ethyl acetate to this and stir well with a glass rod to turn the oil into a powder. This was collected, washed with ethyl acetate, and dried, yielding 1.7 g of 7β-cyanomethylthioacetamide-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-3-cepheme-4.
- A carboxylic acid sodium salt is obtained. nmr spectrum, _D2O (ppm value): 3.25-3.90 (2H, quadruplet), 3.60 (3H, singlet), 3.68 (2H, singlet), 3.73 (2H, singlet), 4.08 (3H, Singlet), 5.2 (1H, singlet) The reaction was carried out in the same manner as in Example 1, and the results shown in the following table were obtained.

[Table] Example 7 7β-(D-5′-p-nitrobenzoylamino-5′-carboxyvaleramide)-7α with a purity of 84.5%
-methoxy-3-carbamoyloxymethyl-3
-1-methyl to 10g of cefem-4-carboxylic acid-
Mix 30 g of 5-mercaptotetrazole and 1 ml of water, and react on an oil bath heated to 100°C with vigorous stirring at an internal temperature of 75 to 80°C for 10 minutes. At this time, the internal temperature
When the temperature exceeds 75°C, water is distilled off under reduced pressure. As the reaction approaches its end, it begins to solidify and is almost solidified in about 10 minutes. After the reaction, add 100 ml of water, 100 ml of ethyl acetate, and 45 g of common salt, and adjust the pH of the aqueous layer to 1.8 with 6N hydrochloric acid. The ethyl acetate layer is separated and the aqueous layer is further extracted with ethyl acetate. (80ml x 3) Concentrate the ethyl acetate layer under reduced pressure, and add isopropyl ether to the remaining oil.
Add 500ml and stir to solidify. Collect this,
Wash this solid with isopropyl ether at 50%
ml of acetone to remove insoluble matter, concentrate the acetone under reduced pressure, and further dry the oil to obtain 7β-(D-
13.8 g of 5'-p-nitrobenzoylamino-5'-carboxyvaleramide)-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained. It will be done. Purity 62.3% Yield 93.1% Take 2.0g of the above powder and dissolve it in 4ml of acetone.
Add 100 ml of ethyl acetate to remove a small amount of insoluble matter, concentrate under reduced pressure until the solution starts to become cloudy, and leave it overnight at room temperature to precipitate white columnar crystals. This is collected, washed with ethyl acetate, and dried to obtain a pure product.
Melting point: 160°C (decomposed), contains one molecule of crystalline ethyl acetate. Analysis value C ₂₄ H ₂₆ N ₈ O ₁₀ S ₂ −C ₄ H ₈ O ₂ Calculation value C45.52, H4.64, N15.17, S8.68 Analysis value C45.65, H4.76, N15.03, S8.46 nmr spectrum, heavy acetone (ppm value): 1.12-1.35 triplet (3H), 1.83-2.8 multiplet (7H), 2.0 singlet (3H), 3.57 singlet (3H),
4.06 singlet (3H), 3.42~4.06 quartet (2H)
(J=18Hz), 4.23-4.77 quartet (2H) (J=
14Hz), 5.18 singlet (1H), 8.2-8.63 multiplet (4H) Test example 3-carbamoyloxy-7α-methoxy-7β
-[D-5-isopropoxycarbonylamino-
5-carboxyvaleramide]-3-cephem-
1.0 g of 4-carboxylic acid (12) and 1.0 g of 1-methyl-1H-tetrazol-5-ylmercaptan are reacted with varying amounts of water at an internal temperature of 70 to 88°C for 15 to 20 minutes to obtain 3. -(1-Methyl-1H-tetrazol-5-ylthio)methyl-7α-methoxy-7β
-[D-5-isopropoxycarbonylamino-
5-carboxyvaleramide]-3-cephem-
The yields of 4-carboxylic acid (13) were compared and the following results were obtained.

【table】

【table】

Claims (1)

[Claims] 1 formula (wherein, R represents an acyl group and X represents an alkoxy group) or a salt thereof, and a compound having the formula R″SH (2) (wherein, R″ represents a substituted or unsubstituted heterocyclic group) ) is added to a mercaptan derivative having the formula (1) or its salt in an amount of not more than twice the weight of water, and then heated. (wherein R, X and R'' have the same meanings as defined above) or a method for producing a salt thereof.