JPH0361674B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides high-quality 7-amino-3-substituted thiomethylcephem-4-carboxylic acids or their salts useful as intermediates for cephalosporic acid antibiotics. The objective is to produce it safely with high yield and high purity through industrially easy operations.

[Conventional technology]

Conventionally, 7-aminocephalosporanic acids or salts thereof are thio-
There are various methods for converting the acetoxy group at the 3-position by reacting a compound with a metal compound, but the inventors conducted a detailed follow-up study of the conventional methods and found that each of the conventional methods has the following drawbacks. There was found.

(a) As seen in Japanese Patent Publication No. 49-45880, when the reaction is carried out in water or a water-containing organic solvent at a pH of 6 to 7, the yield is 40 to 50% and only a colored product of low purity is obtained.

(b) As in JP-A-53-98987, when the reaction is carried out in the presence of boron trifluoride or its complex compound in an organic solvent, the target product 7-amino-
3-substituted thiomethyl cefem carboxylic acids are 70
Although a product with relatively high purity can be obtained with a high yield of ~90%, industrial implementation is difficult due to the hazardous nature of vapors and flammability of the materials used.

(c) Reacting in the presence of a lower alkylsulfonic acid such as sulfuric acid or methanesulfonic acid, or in the presence of halosulfonic acid or halomethanesulfonic acid, as seen in JP-A-55-139387 and JP-A-55-153790. In this case, the yield of the desired product is relatively high, but the product is highly colored and has low purity, making purification difficult.

(d) JP-A-57-82392 and JP-A-57-209292
When the reaction is carried out in water and an organic solvent in the presence of a halogenated phosphorus compound such as diphosphoryl tetrachloride or dichlorophosphoric acid, it is difficult to treat the waste liquid and it is not practical.

(e) Furthermore, as seen in JP-A No. 55-49383, when the reaction is carried out in the presence of an arylsulfonic acid or an alkylsulfonic acid in an organic solvent, the yield and purity must be reduced unless a considerably large amount of sulfonic acid is used. However, when a considerably large amount of sulfonic acid is used, there are a number of disadvantages such as excessive time required for post-treatment steps after the reaction, and large amounts of chemicals and time required for waste liquid treatment.

[Problem that the invention seeks to solve]

The present inventors have completed the present invention as a result of intensive research in order to achieve the above-mentioned object of the present invention in view of the drawbacks of the above-mentioned conventional methods.
general formula (Here, R ₁ is a hydrogen atom or an alkoxy group, and the dotted line in the cefem ring indicates a double bond between the 3rd and 4th positions or between the 2nd and 3rd positions.) Reacting an acid or a salt thereof with a thiol compound represented by the general formula R ₂ -SH () (where R ₂ represents an organic group) or a salt thereof in the presence of methane polysulfonic acid in an organic solvent, The present invention provides a method for producing 7-amino-3-substituted thiomethylcephem-4-carboxylic acids or salts thereof.

(In this case, in the present invention, methane polysulfonic acid is a general term for methanedisulfonic acid or methane trisulfonic acid.) [Means for solving the problem] The compound () used in the present invention is 7-amino Cephalosporanic acid, 7-α-methoxycephalosporanic acid, and salts of compound () and () include salts of hydrochloric acid, sulfuric acid, citric acid, etc.
The hydrogen atom of the carboxyl group at position is substituted with an alkali metal such as Na or K.

R ₂ in compounds () and () is a phenyl group, thiazolyl group, oxazolyl group, isothiazolyl group, thiadiazolyl group, triazolyl group, or tetrazolyl group, and these groups are alkyl groups such as methyl group, ethyl group, or phenyl group. or aryl group, carboxyalkyl group such as carboxymethyl group, carboxyethyl group, amino group,
May be substituted with an alkylamino group such as a methylamino group or a dimethylamino group, an aminoalkyl group such as an aminomethyl group or an aminoethyl group, an alkylaminoalkyl group such as a dimethylaminomethyl group or a diethylaminoethyl group, etc. .

The amount of compound () used for compound () is
It is 1.0 to 2.0 times the mole, preferably 1.0 to 1.5 times the mole.

If the amount used is less than 1.0 times the mole, the compound () will be mixed into the product and the purity of the product will decrease, and if it exceeds 2.0 times the mole, the amount mixed in the waste liquid will increase, causing problems in its treatment, both of which are undesirable. .

Organic solvents used in the reaction include nitriles such as acetonitrile and malondinitrile, ethers such as tetrahydrofuran and dioxane, organic carboxylic acids such as acetic acid and propionic acid, nitroalkanes such as nitromethane and nitroethane, and methylene dichlorochloride. Halogenated hydrocarbons such as ethane are preferred.

The methane polysulfonic acid used in the present invention is methanedisulfonic acid (methionic acid) or methanetrisulfonic acid, and methanedisulfonic acid is described, for example, in the method described in US Pat. No. 2,842,589, and methanetrisulfonic acid is described in, for example, in US Pat. It can be manufactured by the following method.

Since all of them have high melting points and are solid in normal state, it is easier to handle them if they are used as a 30 to 70% solution in an organic solvent.

The amount of methane polysulfonic acid used is 1 to 5 times the mole of compound (), preferably 2.0 to 4.5 times the mole of methanedisulfonic acid, and 1.3 to 3.0 times the mole of methanesulfonic acid.

If it is less than 1 times the mole, the reaction will not proceed smoothly and the compound () will be mixed into the product, reducing the purity of the product.If it exceeds 5 times the mole, the product will decompose, the color tone of the product will deteriorate, and the purity will decrease. decreases.

The reaction temperature is usually 20 to 70°C, preferably 35 to 50°C. If the temperature is too low, below 20°C, the reaction will not proceed smoothly. On the other hand, if the temperature is too high, exceeding 70°C, the decomposition reaction will proceed, which is both undesirable.

Furthermore, the reaction time varies depending on the type and amount of solvent, the type and amount of acid, reaction temperature, etc., and is usually 0.5 to 20 hours, but from the viewpoint of industrial ease of operation, the reaction time is about 1 to 10 hours. It is preferable to choose conditions that complete the following.

After completion of the reaction, the target compound () is separated from the reaction mixture by a conventional method. For example, water is added to the reaction mixture, the pH is adjusted with concentrated ammonia water, etc., the target compound () is precipitated and separated, further washed with water and an organic solvent, and dried.

The target compound () obtained in this way already has a fairly high purity and does not require purification and can be used as it is in the next reaction, but if necessary, it can be further purified by conventional methods such as reprecipitation. can do.

〔effect〕

By using methanesulfonic acid in the present invention, (i) Compound () can be obtained in high yield and purity through industrially easy operations with a relatively small amount of acid used.

(ii) It uses less energy, has relatively mild reaction conditions, and has no problems in post-reaction treatment steps, making it easy to implement industrially.

(iii) It is simple and easy to perform waste liquid treatment.

[Effect]

The reason why the present invention exhibits the above-mentioned excellent effects is that the present invention conducts the reaction in the presence of methane polysulfonic acid, which, according to the research results of the present inventor, has not yet been fully elucidated. but,
The fact that methane polysulfuric acid has an organic group, the acid content per unit weight is high, the (inorganic/organic) ratio is extremely effective for the reaction, and oxidation is required during waste liquid treatment. This is thought to be due to the overall effect of easy decomposition by agents, etc.

Next, the present invention will be explained with reference to Examples.

Example 1 27.2 g of 7-aminocephalosporanic acid and 5
-Mercapto-1-methyl-1H-tetrazole
12.7 g was suspended in 140 ml of acetic acid, and 116 g of 50% methanedisulfonic acid acetic acid solution was added thereto to dissolve it.

After heating and reacting this solution at 40°C for 3 hours,
Cool, add 210 ml of water, and adjust the pH to 4.0 using 28% ammonia water while cooling with water. The precipitated crystals were collected, washed successively with 200 ml of water and 200 ml of methyl alcohol, and dried to a melting point of 218-220°C.
7-Amino-3- as a white crystalline solid showing (decomposition)
[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]cephem-4-carboxylic acid 27.9
g (yield 85.1%) was obtained.

Area purity by high performance liquid chromatography: 98.1
It was %.

IR (KBr) νc=O, cm ^-1 : 1802, 1620, 1540 NMR (D ₂ O + CF ₃ CO ₂ D) δ, ppm value: 3.57 (2H:S:2-CH ₂ ) 4.12 (3H:S:N _-CH3 ) 4.38 (2H:S:3- _CH2 ) 5.24 (1H:d, J=5cps:6-H) 5.36 (1H:d, J=5cps:7-H) Example 2 7-Aminocef Allosporanic acid 27.2g and 5
-Mercapto-1-methyl-1H-tetrazole
13.9 g was suspended in 140 ml of acetic acid, and 101 g of a 50% methanesulfonic acid acetic acid solution was added thereto to dissolve it.

After heating and reacting this solution at 45°C for 3 hours,
Cool, add 210 ml of water, and adjust the pH to 4.0 using 28% ammonia water while cooling with water. The precipitated crystals were collected, washed successively with 200 ml of water and 200 ml of acetonitrile, and then dried to yield 7-amino-3-[5-(1-methyl-1,2,
3,4-tetrazolyl)thiomethyl]cephem-
26.9 g (yield 82.0%) of 4-carboxylic acid was obtained. The melting point, IR and NMR values of this product matched those of the standard product.

Area purity by high performance liquid chromatography: 98.3
It was %.

Example 3 27.2 g of 7-aminocephalosporanic acid and 5
- Suspend 19.6 g of mercapto-1-phenyl-1H-tetrazole in 140 ml of acetonitrile, and add 50% methanedisulfonic acid acetonitrile solution.
Add 116g and dissolve. This solution was heated to 40°C for 3
After reacting by heating for an hour, the mixture was cooled, 210 ml of water was added, and the pH was adjusted to 3.7 using 28% aqueous ammonia under water cooling. The precipitated crystals were collected, washed successively with 200 ml of water and 200 ml of acetonitrile, and dried to give 7-amino-3-[5-(1-phenyl-1,
34.8 g (yield: 89.2%) of 2,3,4-tetrazolyl)thiomethyl]cephem-4-carboxylic acid was obtained.

Area purity by high performance liquid chromatography: 97.9
% IR (KBr) νc=o, cm ^-1 : 1805, 1619, 1543 NMR (D ₂ O + CF ₃ CO ₂ D) δppm value: 3.80 (2H:S:2-CH ₂ ) 4.39, 4.69 (2H:ABg, J=14cps, 3- _CH2 ) 5.28 (2H:m:6-H,7-H) 7.626 2(5H:S:phenyl) Example 4 7-Aminocephalosporanic acid 27.2g and 5
19.6 g of -mercapto-1-phenyl-1H-tetrazole is suspended in 140 ml of acetic acid, and 105 ml of 50% methane trisulfonic acid acetic acid solution is added thereto to dissolve it.

After heating and reacting this solution at 40°C for 3 hours,
After cooling, 210 ml of water was added, and the pH was adjusted to 3.7 using 28% aqueous ammonia while cooling with water. The precipitated results were collected, washed sequentially with 200 ml of water and 200 ml of methyl alcohol, and dried to give a pale yellow solid of 7-
Amino-3-[5-(1-phenyl-1,2,3,
4-tetrazolyl)thiomethyl]cephem-4-
33.2 g (yield 82.6%) of carboxylic acid was obtained. The melting point, IR and NMR values of this product matched those of the standard product.

Area purity by high performance liquid chromatography: 98.2
It was %.

Example 5 27.2 g of 7-aminocephalosporanic acid and 2
- Suspend 14.5 g of methyl-5-mercapto-1,3,4-thiadiazole in 140 ml of acetic acid, add 50 ml of
% methanedisulfonic acid acetic acid solution was added and dissolved.

After heating and reacting this solution at 40°C for 3 hours,
After cooling, 210 ml of water was added, and the pH was adjusted to 4.0 using 28% aqueous ammonia while cooling with water. The precipitated crystals were collected, washed successively with 200 ml of water, and dried to give 7-amino-3-[5-(2-methyl-1,3,
25.8 g (yield 75.0%) of 4-thiazolyl)thiomethyl]cephem-4-carboxylic acid was obtained.

by high performance liquid chromatography Area purity: 96.7%.

IR (KNr) νc=o, cm ^-1 : 1801, 1621, 1542, NMR (D ₂ O + CF ₃ CO ₂ D) δppm value 2.98 (3H:S:2-CH ₃ ) 3.80 (2H:S:2-CH ₂ ) 4.43, 4.70 (2H: ABg, J=14cps: 3-
CH ₂ ) 5.29 (2H: m: 6-H, 7-H) Example 6 27.2 g of 7-aminocefrosporanic acid and 12.1 g of thiophenol were suspended in 140 ml of acetonitrile, and 97 g of 50% methanedisulfonic acid acetonitrile solution was added to this. Add and dissolve. This solution was heated at 45°C.
After heating and reacting for 3 hours, cool and add 210ml of water.
and PH using 28% ammonia water under water cooling.
Adjusted to 3.5.

The precipitated crystals were collected, washed sequentially with 200 ml of water and 200 ml of methyl alcohol, and dried to give a white crystalline solid with a melting point of 225°C (decomposition).
-amino-3-phenylthiomethylcephem-4
-27.4 g (yield 85.1%) of carboxylic acid was obtained.

Area purity by high performance liquid chromatography: 98.1
It was %.

IR (KBr) νc=o, cm ^-1 : 1800, 1619, 1540 NMR (D ₂ O + CF ₃ CD ₂ D) δppm value 3.50 (2H:S:2-CH ₂ ) 3.75, 4.30 (2H:ABg, J= 14cps: 3-
_CH2 ) 5.05 (2H:m:6-H, 7-H) 7.35 (5H:m:phenyl)

Claims (1)

[Claims] 1. General formula (Here, R ₁ is a hydrogen atom or an alkoxy group, and the dotted line in the cefem ring indicates a double bond between the 3rd and 4th positions or between the 2nd and 3rd positions.) It is characterized by reacting acids or their salts with a thiol compound represented by the general formula R ₂ −SH () (where R ₂ represents an organic group) or its salts in an organic solvent in the presence of methane polysulfonic acid. General formula for A method for producing 7-amino-3-substituted thiomethylcephem-4-carboxylic acids or salts thereof. (In the present invention, methane polysulfonic acid is a general term for methanedisulfonic acid or methane trisulfonic acid.) 2. Compound () is 1.0 to 1.0 to
7-Amino-3-substituted thiomethylcephem-4- according to claim 1, which is used in 2.0 times the molar amount.
Method for producing carboxylic acids or their salts. 3. 7-amino-3-substituted thiomethylcephem-4-carboxylic acids or salts thereof according to claim 1 or 2, in which 1.0 to 5.0 times the molar amount of methane polysulfonic acid is used relative to compound (). manufacturing method. 4. A method for producing 7-amino-3-substituted thiomethylcephem-4-carboxylic acids or salts thereof according to claim 1, 2, or 3, wherein the reaction temperature is 20 to 70°C.