Cefmetazole sodium compound and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical chemistry, and concretely provides a new cefmetazole sodium crystal form compound. The crystal form compound is obviously different from other cefmetazole sodium crystal forms in X-ray powder diffraction pattern characteristics, the purity of the new cefmetazole sodium crystal form compound is above 99.5%, and the new cefmetazole sodium crystal form compound also has the advantages of low content of impurities, uniform particle size distribution and good stability. The invention also provides a preparation method of the crystal form compound, and an application of the crystal form compound in a medicinal composition. The preparation method comprises the following steps: dissolving cefmetazole sodium in an aprotic polar good solvent, sequentially adding an alcoholic anti-solvent and an ether and ketone mixture in a dropwise manner, carrying out room temperature stirring, cooling for crystallization, filtering, and drying to prepare cefmetazole sodium crystals. The preparation method has the advantages of simplicity, easily available device, and suitableness of industrial mass production.

Description

technical field

[0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a crystal form compound of cefmetazole sodium. Background technique

[0002] Cefmetazole sodium, its English name is Cefmetazole Sodium, its chemical name is: (6R,7S)-7-[2-[(cyanomethyl)thio]acetamido]-7-methoxy-3-[[ (1-methyl)-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 - formic acid sodium salt, molecular formula is C 15 h 16 N 7 NaO 5 S 3 , the molecular weight is: 493.52, and the structural formula is:

[0003]

[0004] Cefmetazole sodium is white to light yellow powder; very hygroscopic. It is very soluble in water, easily soluble in methanol, slightly soluble in acetone, slightly soluble in ethanol, almost insoluble in ether or dichloromethane.

[0005] Cefmetazole sodium is a second-generation cephalosporin, also known as cefmetazol, pioneer metabolite, cyanazol-methoxycephalosporin, etc. Cefmetazole sodium is a broad...

Examples

Embodiment 1

[0058] Step 1: join the cefmetazole sodium of 20kg in the NMP of 60L, heat up and stir and make it dissolve, press into the crystallization tank of aseptic zone through the filter of 0.22 μm;

[0059] Step 2: Warm up the solution obtained in step 1 to 40°C; add 150 L of isopropanol that has been filtered through a 0.22 μm filter membrane at a stirring speed of 200 r / min at a speed of 340 ml / min; dropwise addition is complete Then add 150 L of the remaining isopropanol that is also sterile-filtered at a rate of 100 ml / min;

[0060] Step 3: At a stirring speed of 125r / min, the mixed solution of methyl tert-butyl ether and acetone (wherein methyl tert-butyl ether: acetone = 2:1) filtered through a 0.22μm filter membrane was mixed with 200ml / Add 720L dropwise at a speed of min. After the dropwise addition is completed, cool down to 25°C at a rate of 5°C / h and keep it warm for 4 hours to grow crystals;

[0061] Step 4: Cool the solution to 3°C and keep it warm for 2 hours, then ...

Embodiment 2

[0067] Step 1: Add 16kg of cefmetazole sodium into 32L of NMP, heat up and stir to dissolve;

[0068] Step 2: After heating the solution obtained in step 1 to 45°C, start to drop 48L of isopropanol at a rate of 300ml / min at a stirring speed of 250r / min, and then add dropwise at a rate of 100ml / min after the addition is completed The remaining 48L of isopropanol;

[0069] Step 3: At a stirring speed of 150r / min, add 320L of a mixed solution of methyl tert-butyl ether and acetone (wherein methyl tert-butyl ether: acetone = 1:1) dropwise at a speed of 200ml / min. After the dropwise addition, the temperature was lowered to 27°C at a rate of 5°C / h, and then kept for 4 hours for crystal growth;

[0070] Step 4: Cool the solution to 5°C and keep it warm for 1 hour, then suction filter; the filter cake was dried under reduced pressure at 40°C to constant weight to obtain cefmetazole sodium crystals with a yield of 86.2% and a purity of 99.7% by HPLC.

[0071] The X-ray powder diffrac...

Embodiment 3

[0073] Step 1: Add 15kg of Cefmetazole Sodium into 60L of NMP, heat up and stir to dissolve it; Step 2: After the solution obtained in Step 1 is warmed up to 35°C, start stirring at 400ml / min at a stirring speed of 150r / min. Add 210L of isopropanol dropwise at a speed of 1 min, and then add the remaining 210L of isopropanol dropwise at a speed of 100ml / min;

[0074] Step 3: At a stirring speed of 100r / min, add 900L of a mixed solution of methyl tert-butyl ether and acetone (wherein methyl tert-butyl ether: acetone = 3:1) dropwise at a speed of 200ml / min. After the dropwise addition is completed, cool down to 25°C at a rate of 5°C / h and keep it warm for 5 hours to grow crystals;

[0075] Step 4: Cool the solution to 0°C and keep it warm for 2 hours, then suction filter; the filter cake was dried under reduced pressure at 45°C to constant weight to obtain cefmetazole sodium crystals with a yield of 88.4% and a purity of 99.5% by HPLC.

[0076] The X-ray powder diffraction patte...

technical field

[0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a crystal form compound of cefmetazole sodium. Background technique

[0002] Cefmetazole sodium, its English name is Cefmetazole Sodium, its chemical name is: (6R,7S)-7-[2-[(cyanomethyl)thio]acetamido]-7-methoxy-3-[[ (1-methyl)-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 - formic acid sodium salt, molecular formula is C 15 h 16 N 7 NaO 5 S 3 , the molecular weight is: 493.52, and the structural formula is:

[0003]

[0004] Cefmetazole sodium is white to light yellow powder; very hygroscopic. It is very soluble in water, easily soluble in methanol, slightly soluble in acetone, slightly soluble in ethanol, almost insoluble in ether or dichloromethane.

[0005] Cefmetazole sodium is a second-generation cephalosporin, also known as cefmetazol, pioneer metabolite, cyanazol-methoxycephalosporin, etc. Cefmetazole sodium is a broad...

Examples

Embodiment 1

[0058] Step 1: join the cefmetazole sodium of 20kg in the NMP of 60L, heat up and stir and make it dissolve, press into the crystallization tank of aseptic zone through the filter of 0.22 μm;

[0059] Step 2: Warm up the solution obtained in step 1 to 40°C; add 150 L of isopropanol that has been filtered through a 0.22 μm filter membrane at a stirring speed of 200 r / min at a speed of 340 ml / min; dropwise addition is complete Then add 150 L of the remaining isopropanol that is also sterile-filtered at a rate of 100 ml / min;

[0060] Step 3: At a stirring speed of 125r / min, the mixed solution of methyl tert-butyl ether and acetone (wherein methyl tert-butyl ether: acetone = 2:1) filtered through a 0.22μm filter membrane was mixed with 200ml / Add 720L dropwise at a speed of min. After the dropwise addition is completed, cool down to 25°C at a rate of 5°C / h and keep it warm for 4 hours to grow crystals;

[0061] Step 4: Cool the solution to 3°C and keep it warm for 2 hours, then ...

Embodiment 2

[0067] Step 1: Add 16kg of cefmetazole sodium into 32L of NMP, heat up and stir to dissolve;

[0068] Step 2: After heating the solution obtained in step 1 to 45°C, start to drop 48L of isopropanol at a rate of 300ml / min at a stirring speed of 250r / min, and then add dropwise at a rate of 100ml / min after the addition is completed The remaining 48L of isopropanol;

[0069] Step 3: At a stirring speed of 150r / min, add 320L of a mixed solution of methyl tert-butyl ether and acetone (wherein methyl tert-butyl ether: acetone = 1:1) dropwise at a speed of 200ml / min. After the dropwise addition, the temperature was lowered to 27°C at a rate of 5°C / h, and then kept for 4 hours for crystal growth;

[0070] Step 4: Cool the solution to 5°C and keep it warm for 1 hour, then suction filter; the filter cake was dried under reduced pressure at 40°C to constant weight to obtain cefmetazole sodium crystals with a yield of 86.2% and a purity of 99.7% by HPLC.

[0071] The X-ray powder diffrac...

Embodiment 3

[0073] Step 1: Add 15kg of Cefmetazole Sodium into 60L of NMP, heat up and stir to dissolve it; Step 2: After the solution obtained in Step 1 is warmed up to 35°C, start stirring at 400ml / min at a stirring speed of 150r / min. Add 210L of isopropanol dropwise at a speed of 1 min, and then add the remaining 210L of isopropanol dropwise at a speed of 100ml / min;

[0074] Step 3: At a stirring speed of 100r / min, add 900L of a mixed solution of methyl tert-butyl ether and acetone (wherein methyl tert-butyl ether: acetone = 3:1) dropwise at a speed of 200ml / min. After the dropwise addition is completed, cool down to 25°C at a rate of 5°C / h and keep it warm for 5 hours to grow crystals;

[0075] Step 4: Cool the solution to 0°C and keep it warm for 2 hours, then suction filter; the filter cake was dried under reduced pressure at 45°C to constant weight to obtain cefmetazole sodium crystals with a yield of 88.4% and a purity of 99.5% by HPLC.

[0076] The X-ray powder diffraction patte...

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