JPS63115886A - Crystalline cephalosporin compound - Google Patents

Abstract

NEW MATERIAL:Crystalline (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 7beta- amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate monohydrochlo ride methanol solvate. USE:A high-purity intermediate for cephalosporin based compounds. PREPARATION:A crude product of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 7beta-amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate is treated with hydrochloric acid in a mixed solvent of THF and methanol and then preferably with active carbon.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to crystalline cephalosporin compounds, more particularly crystalline 7β-amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4. −
The present invention relates to carvone 1(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester monohydrochloride methanol solvate and its production method.

7β-amino-3-(1,2,4-thiadiazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid (
5-Methyl-2-oxo-1,3-dioxolene-4-
yl) methyl ester is a compound useful as an intermediate for cephalosporin compounds;
It is described in No. 106582.

The publication states that 7β-amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-
A method for preparing 2-oxo-1,3-dioxolen-4-yl) methyl ester is described. That is, 7β-formamido-3-(1,2,4-thiadiazol-5-yl) was prepared in a tetrahydrofuran-methanol mixed solvent.
Thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester and hydrochloric acid were reacted, and after the reaction was completed, one reaction solution was concentrated and diluted with aqueous ammonia. By adjusting the pH to 4.0, 7β-amino-3-(1,2,4-thiadiazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid (
5-Methyl-2-oxo-1,3-dioxolene-4-
It is described that the methyl ester can be obtained as a free monolith containing no hydrochloric acid.

However, the free solids obtained by such methods often have poor crystallinity and therefore have problems in production, such as poor filterability. In addition, impurity 7β-amino-3-(1
,2,4-thiadiazol-5-yl)-2-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-
There were also quality problems such as contamination of dioxolen-4-yl) methyl ester (hereinafter abbreviated as 2-cephem). The present inventors conducted research to solve these production problems and quality problems, and as a result, 7β-amino-3-(1,2゜4-thiadiazol-5-yl)thiomethyl -3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolene-
It has been found that a 4-yl)methiester/1-hydrochloride/methanol solvate can be obtained as crystals with extremely good filterability and high purity from the reaction solution.

The object of the present invention is to obtain such useful 7β-amino-3-(1
,2,4-thiadiazol-5-yl)thiomethyl-3
-cephem-4-carvone M (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester.
l hydrochloride/methanol solvate,
Furthermore, the purpose of f production in the present invention is 7β-amino-3-(1,
2,4-thiadiazol-5-yl)thiomethyl-3-
Cephem-4-carvone M (5-methyl-2-oxo-
1,3-dioxolen-4-yl)methyl ester 1
An object of the present invention is to provide a useful method for producing a hydrochloride/methanol solvate.

7β-amino-3-(1,2,4-thiadiazole-5
-yl) thiomethyl-3-cephem-4 rubonic acid (5-
The structure of methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, monohydrochloride, methanol solvate is 0.5 to 1.0% per mole of hydrochloride.
It is observed from the proton nuclear magnetic resonance spectrum that 0 mol of methanol is added.

7β-amino-3-(1,2,4-thiadiazole-5
-yl) thiomethyl-3-cephem-4 rubonic acid (5-
The method for producing methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester/l hydrochloride/methanol solvate will be described in detail below.

7β-amino-3-(1,2,4-thiadiazole-5
-yl)thiomethyl-3-cephem-4 Rubone M(5-
The crude product of methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester is treated with hydrochloric acid in a tetrahydrofuran-methanol mixed solvent, and then the crude product is treated with hydrochloric acid at around room temperature, e.g.
7β-Amino-3-(1,2,4-thiadiazol-5-yl) is obtained by stirring while maintaining the temperature at 8 to 23°C, preferably for at least 1 hour, and then cooling to 0°C or lower, preferably around -10°C. Thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester is suitable. Optionally 7β-amino-3-(1,2,4-thiadiazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolene-4
-yl) methyl ester/l hydrochloride/methanol solvate seed crystals can be added to promote crystal precipitation.

7β-formamido-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester 7β-amino-3-(
1,2,4-thiadiazol-5-yl)thiomethyl-
Detailed description of the production method for directly obtaining 3-cephem-4-carvone w1 (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester/l hydrochloride/methanol solvate from the reaction solution. Then, the elimination reaction of the formyl group with hydrochloric acid can be carried out in a tetrahydrofuran-methanol mixed solvent, preferably around room temperature, for example at 18 to 23°C. After the reaction is completed, the reaction solution is immediately cooled to 0°C or lower, preferably around -10°C, or stirred for a while at room temperature, e.g. 18 to 23°C, preferably for 1 hour, and then cooled to 0°C or lower, preferably around -10°C. Upon cooling, 7β-amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 5-methyl-2-oxo-1,3-dioxolene-4- Crystals of methyl ester monohydrochloride methanol solvate can be obtained. The appropriate cooling time is preferably 2 hours or more.

To further improve the yield, 7β-amino-3-(1,
2,4-thiadiazol-5-yl)thiomethyl-3-
Cephem-4-carboxylic acid (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyl ester
Organic solvents with lower solubility of hydrochloride/methanol solvates, such as esters such as methyl acetate and ethyl acetate, ethers such as diethyl ether and diisoproether,
It is desirable to add hydrocarbons such as toluene and n-hexane, halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane, acetonitrile, and the like to the reaction system. Among the organic solvents mentioned, diisoproether and ethyl acetate are particularly preferably used.

The present inventors further discovered that 7β-amino-3-(1
,2,4-thiadiazol-5-yl)thiomethyl-3
-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester.
It was found that monohydrochloride/methanol solvate could be obtained. That is, during or after the reaction, an appropriate amount of activated carbon (preferably 10% of the reaction raw material) is added to the reaction solution.
In addition, the mixture is stirred for a while, preferably at least 30 minutes, at around room temperature, preferably from 18 to 23°C, and the activated carbon is filtered off. The filtrate is cooled to below 0°C, preferably around -10°C, and the precipitated crystals are collected by filtration with or without the addition of the above-mentioned organic solvent, such as diisopropyl ether. Alternatively, while maintaining the filtrate at around room temperature, preferably 18 to 23°C, add the aforementioned Im-containing solvent, such as diisopropyl ether, and stir for a while, preferably at least 1 hour, at around room temperature, preferably at 18 to 23°C, and then stir at 0°C or lower. Preferably -
Cool to around 10°C, stir preferably for 2 hours or more,
By filtering the precipitated crystals, 7β-amino-3-
(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, monohydrochloride, methanol Solvates can be obtained.

In the present invention, the tetrahydrofuran-methanol mixed solvent is used, for example, in a volume ratio of about 1:3 to about 3=1, and usually good results are obtained by using a mixed solvent with a volume ratio of about 1:1. The quantitative ratio is not necessarily limited to this, and the mixed solvent can be suitably set in any ratio as long as the purpose can be achieved. Such an arbitrary ratio may be, for example, about 1:10 to about 1:10. You can choose from a range of 10:1.

In addition, low solubility solvents used for the purpose of improving yield are
If too much is added, the layer containing hydrochloric acid in the reaction system will separate and form two layers, which is unfavorable for operation.
The amount of the low-solubility solvent to be added should be appropriately set according to the amount and mixing ratio of the tetrahydrofuran-methanol mixed solvent, the type of the low-solubility solvent, etc., within a range that does not separate the layer containing hydrochloric acid in the reaction system. For example, if the volume ratio of tetrahydrofuran-methanol mixed solvent is approximately 1=1
In this case, good results can be obtained by adding about half the amount of diisopropyl ether to the amount of the solvent.

In either case, if desired, 7β-amino-3-cephem-4-carboxylic acid (1,2,4-thiadiazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (5
-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester monohydrochloride methanol solvate seed crystals can be added to promote crystal precipitation.

Examples are given below, and 7β-amino-3-
(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, monohydrochloride, methanol The production of solvates will be explained.

Proton nuclear magnetic resonance spectra were measured at 270 MHz.

7β-formamido-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolene-4 -yl) methyl ester (7β-formamide-3-(1,2,4
-thiadiazol-5-yl)thiomethyl-2-cephem-4-carvone vi(5-methyl-2-oxo-1,
3-dioxolen-4-yl) methyl ester to 1.1
%contains. ) 9.50g (20.2mM) was dissolved in 76ml of tetrahydrofuran, and 76ml of methanol was dissolved.
Add ml. 19 ml of concentrated hydrochloric acid was added dropwise to this solution while stirring at 0 to 10°C, and after the dropwise addition was completed, it was kept at 20°C for 3 hours.
It was allowed to react for 0 minutes. This reaction solution was cooled to 0 to -10°C,
The mixture was stirred at the same temperature for about 2 hours. Filter the precipitated crystals,
After washing with 30 ml of cooled tetrahydrofuran, vacuum drying was carried out overnight at room temperature to obtain 7β-amino-3-(1,2
,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1
, 3-dioxolen-4-yl) methyl ester monohydrochloride methanol solvate was obtained. The purity measured by high performance liquid chromatography was 99.63%.

NMR (d6-DMSO): δ2. 19 (31-I
OH), 3.78, 3.87 (2) I, ABq, J=
17.8Hz, C2-H2), 4. ．． 32.4°69
(2H, ABq, J=13.5Hz, C3-CH2)
, 5.19, 5.32 (2H, ABq.

CH3 J=13.9H2,), 5.20 (IH, d, J=5
．． 1Hz, C6-H), 5.23 (IH, d, J=5.
1l-1z, C7-H), 8゜69 (IH, s, th
i az 1azo l e-H) CI5H14N4
The elemental analysis values for S306 ・HCl-CH30H are as follows.

Calculated value: 37.61 3.75 10.96 18
．． 83 6.94 Actual value: 37.45 3.66
10.92 19.0? . dioxolen-4-yl) methyl ester 6, OOg (12,8m
M) is dissolved in 48 ml of tetrahydrofuran, and 48 ml of methanol is added. 112 m 1 tt of concentrated hydrochloric acid was added dropwise to this solution while stirring at 0 to 10°C, and after the completion of the dropwise addition,
The reaction was carried out at 3°C for 4 hours. While keeping this reaction solution at 23°C, 48 ml of diisopropyl ether was added dropwise, and 7β
-Amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-
Seed crystals of methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester monohydrochloride methanol solvate were added. After further stirring at 23°C for 1 hour, 0
The mixture was cooled to -10°C and stirred at the same temperature for about 2 hours. The precipitated crystals were collected by filtration, washed with diisopropyl ether, and vacuum dried overnight at room temperature to obtain 4.65 g of the desired compound.

100% purity measured by high performance liquid chromatography
Met.

Sokakukei-1 7β-formamido-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolene-4 -yl) methyl ester was dissolved in 95.81 kg of tetrahydrofuran, and 11.98 kg of methanol was dissolved in 95.81 kg of methanol.
added. This solution was stirred at 2°C and then concentrated with 24% hydrochloric acid.
01 was added dropwise, and after the dropwise addition was completed, the reaction was carried out at 21° C. or lower for 4 hours. While keeping this reaction solution at about 20° C., 1.2 kg of activated carbon (purified Shirasagi) was added, and the mixture was stirred at the same temperature for about 45 minutes. The activated carbon was separated by filtration and washed with a mixed solvent consisting of 121 parts of tetrahydrofuran and 12 parts of methanol.

The filtrate and washing liquid were combined, and 95.81 g of diisopropyl ether was added dropwise while keeping the temperature at about 20°C. The aforementioned seed crystals were added, and the mixture was stirred at the same temperature for about 1 hour, and then stirred overnight while cooling to 0 to -10°C. The precipitated crystals were collected by filtration, washed four times with diisopro and ether 33.11, and dried under vacuum at room temperature to give 7β-amino-3-(1°2.4-thiadiazol-5-yl)thiomethyl-3-cephem. 9.30 kg of -4-carboxylic acid (5-methyl-2-oxo-13-dioxolen-4-yl) methyl ester monohydrochloride methanol solvate was obtained. The purity measured by high performance liquid chromatography was 99.37%. Example 3
7β-amino-3-(1,2,4
-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3
-dioxolen-4-yl) methyl ester monohydrochloride methanol solvate showed the following powder X-ray diffraction pattern. (As the X-ray, alpha rays of copper with a wavelength of 1.54 A were used. d represents the lattice spacing, and I/ImaX
represents relative intensity. ) Earthwork Ah Upper mLtX- 2,1573 2,2843 2,4052 2,5114 2,6967 2,7484 2,8633 2,9913 3,2467 3,4953 3,70518 3,8446 4,7504 4,9832 5, 376100 5,46122 6,2313 7,32920 10,67559 12,7343

Claims (7)

[Claims] (1) Crystalline 7β-amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, monohydrochloride, methanol solvate. (2) 7β-amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) ) Crystalline 7β-amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem- characterized by treating the crude product of methyl ester with hydrochloric acid in a tetrahydrofuran-methanol mixed solvent. 4
- Method for producing carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester monohydrochloride methanol solvate. (3) 7β-amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) ) The crystalline 7β-amino-3-(1,2, Production of 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, monohydrochloride, methanol solvate Law. (4) 7β-formamido-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-
Crystalline 7β-amino-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester is reacted with phosphorus oxychloride or hydrochloric acid in a tetrahydrofuran-methanol mixed solvent.
3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (5-methyl-2
-Oxo-1,3-dioxolen-4-yl) methyl ester monohydrochloride methanol solvate production method. (5) 7β-formamido-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester is reacted with phosphorus oxychloride or hydrochloric acid in a tetrahydrofuran-methanol mixed solvent, and after the reaction is completed, a less soluble solvent is added. Crystalline 7β-amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid according to claim 4, which is added and crystallized. A method for producing (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester monohydrochloride methanol solvate. (6) The production method according to claim 5, wherein the poorly soluble solvent is diisopropyl ether or ethyl acetate. (7) The production method according to claim 4 or 5, characterized in that activated carbon is added during or after the reaction with phosphorus oxychloride or hydrochloric acid.