CN104031069B - Preparation method of cefquinome sulfate - Google Patents

Abstract

The invention provides a preparation method of cefquinome sulfate. The method comprises the following steps: starting from 7-ACA and tetrahydroquinoline in dichloromethane, with hexamethyldisilazane as a protective agent, trimethylchlorosilane as a reaction catalyst, diethylaniline as a reaction system polarity regulator, and dimethylacetamide as a dispersion medium of tetrahydroquinoline, and performing a reaction; after the reaction is complete, 25% ammonia water is added dropwise to grow crystals; after acetone is filtered and washed, a light yellow intermediate 7-ACQ is obtained; the intermediate 7-ACQ and AE active ester are reacted in an inert organic solution with a small amount of ethanol as a dispersant and sodium pyrosulfite as an antioxidant; triethylamine is used as an acid-binding agent to neutralize the acid continuously generated by the reaction; after the reaction, a mixed solution of dichloromethane and ethanol is filtered and washed, and then extracted with pure water for multiple times; pH is adjusted with sulfuric acid to control the temperature and crystallize to obtain a crude product; and the crude product is filtered and recrystallized to obtain refined cefquinome sulfate; the product has the advantages of high conversion rate, good purity, good color, and the like.

Description

A kind of preparation method of cefquinome sulfate

(1) Technical field

The invention relates to a preparation method of cefquinome sulfate.

(2) Background technology

Cephalosporins are a class of important substances in the current antibiotic market because of their advantages such as high efficiency, broad spectrum, low toxicity, and enzyme resistance. Since Italian Broyzn discovered cephalosporins in 1948, their development has been quite rapid. Nearly 60 varieties (excluding ester derivatives and various preparations) have been developed, and the number of varieties ranks first among all antibiotics.

According to the characteristics of their antibacterial effects and clinical application, cephalosporins can generally be divided into four generations, and their pharmacological properties are shown in Table 1.

Table 1: Comparison of antibacterial activities of four generations of cephalosporins

Anti-G+ Anti-G- enzyme stability nephrotoxin Indications generation powerful weak Difference high Drug-resistant Staphylococcus aureus infection second generation stronger stronger slightly stable low toxicity Gram-negative bacteria three generations stronger powerful Stablize non-toxic Treatment of serious, life-threatening infections Four generations stronger powerful highly stable non-toxic Treatment of multi- and highly resistant bacteria

Cefquinoxime, also known as cefquinol and cefquinome, is traded as Cobactan. It is the first animal-specific cephalosporin antibiotic developed and listed by the German company HoechstRousselVet. It belongs to the fourth generation of cephalosporin antibiotics. Its sulfate It was first approved for marketing in Germany in 1993.

Cefquinome sulfate is a new aminothiazolone imine oxide cephalosporin with good broad-spectrum antibacterial activity against many Gram-positive and Gram-negative bacteria, and its unique bullet-shaped bipolar molecular structure It can quickly pass through the cell wall of G-bacteria to reach the site of action. At the same time, it has small side effects, low residue, and stable resistance to β-lactamases encoded by chromosomes and plasmids, so it is very popular among veterinary clinicians.

Cefquinome sulfate is suitable for injection administration, with fast absorption, short peak time, high bioavailability, and can reach a high tissue concentration in lung and breast tissue. It has been approved by the EU Veterinary Medicines Committee (CVMP) for use It is used in the clinical treatment of respiratory bacterial infection of pigs and cattle and mastitis of dairy cows.

(3) Contents of the invention

The purpose of the invention is to provide a high conversion rate, a preparation method of cefquinome sulfate with good product purity and color.

The technical scheme adopted in the present invention is:

A preparation method of cefquinome sulfate, said method comprising:

(1) With 7-aminocephalosporanic acid (7-ACA) and tetrahydroquinoline as the reaction substrate, in dichloromethane with hexamethyldisilazane as the protective agent, with trimethylchlorosilane as the reaction Catalyst, use diethylaniline as the polarity regulator of the reaction system, and use dimethylacetamide as the dispersion medium of tetrahydroquinoline to carry out the reaction. After the reaction is complete, add 25% ammonia water to grow the crystal, and wash and filter with acetone to obtain the intermediate Body 7-aminocefaquine (7-ACQ); the molar ratio of the 7-aminocephalosporanic acid: tetrahydroquinoline: iodotrimethylsilane is 1:2～3:1.5～2;

(2) 7-aminocefotaxime and AE active ester with a molar ratio of 1:1.2 to 1.5 react in dichloromethane with ethanol as a dispersant, sodium metabisulfite as an antioxidant, and triethylamine as an acid-binding agent and the acid constantly produced by the reaction, after the reaction, wash and filter with dichloromethane and ethanol mixture (washing+filtering), take the filtrate and extract it with pure water, adjust the pH of the combined aqueous phase to 3.9±0.1 with sulfuric acid, add Stir the activated carbon for decolorization, filter the filtrate and adjust the pH to 1.9±0.1 with sulfuric acid, control the temperature at 20±2°C to crystallize to obtain the sulfuric acid head

Crude cefquinoxime, the crude product is washed, filtered and recrystallized to obtain refined cefquinoxime sulfate.

The reaction that the present invention relates to is as follows:

Specifically, in step (1), dichloromethane is used as a dispersion medium for 7-aminocephalosporanic acid, and dimethylacetamide is used as a dispersion medium for tetrahydroquinoline.

Preferably, after adjusting the pH to 1.9±0.1 with sulfuric acid in step (2), first control the temperature at 5±2° C. and stir for 15-30 min, then raise the temperature to 20±2° C., and stir and crystallize.

Further, the molar ratio of 7-aminocephalosporanic acid/hexamethyldisilazane described in step (1) is 1:1.15～1.45; the molar ratio of described 7-aminocephalosporanic acid/diethylaniline The ratio is 1:1.5~2.

Specifically, the method can be as follows:

Reaction (1): Add dichloromethane (reaction medium) and hexamethyldisilazane (aminoamino group, hydroxyl protection) into the reaction kettle, and stir. Add 7-ACA and a small amount of trimethylchlorosilane (catalyst). Heat up to 58±2°C, stir, and reflux for 12 hours. Cool down to 5±2°C, add diethylaniline, and stir well. Add iodotrimethylsilane and stir for 30 minutes. The temperature was raised to 18±2°C, and the reaction was stirred for 2.5 hours. Cool down to 8±2°C, add tetrahydrofuran, and stir for 30 minutes. Add tetrahydroquinoline and dimethylacetamide mixed solution, react for 6 hours. The above reaction solution was transferred to a kettle. Add dichloromethane and stir well. Cool down to 5±2°C, add isopropanol and petroleum ether dropwise, and stir for 30 minutes. Filter petroleum ether and wash and filter 3 times to obtain light yellow solid. 20wt% H ₂ SO ₄ was stirred and dissolved at 18±2°C. Static layering, take the water phase. Add water at 20°C to the solvent phase, and stir and extract for 10 minutes. The layers were separated, and the solvent phase was discarded. Combine the water phases, cool down to 5±2°C, and add 25% ammonia water dropwise to grow the crystals. Continue to add acetone dropwise to control the temperature at 5±2°C, and stir to grow the crystal. Filter, wash with acetone aqueous solution, and then wash with acetone 3 times. Vacuum-dry at below 40°C to obtain the light yellow intermediate 7-ACQ (the yield relative to 7-ACA is about 1.18-1.4).

Reaction (2): Add dichloromethane and a small amount of ethanol (dispersant) into the reaction kettle. Add 7-ACQ+AE active ester+sodium metabisulfite (antioxidant), and stir. Cool down to 5±2°C, add triethylamine (to neutralize the acid produced by the reaction), and stir for 30 minutes. The temperature was raised to 10±2°C, and the stirring reaction was continued for 3 hours. Filter and wash with a mixture of dichloromethane and ethanol. Take the filtrate and adjust the temperature to 20±2°C, add water, stir and extract several times. Combine the aqueous phases. Ethyl acetate was added to wash with stirring for 15 minutes. Static layering, take the water phase. Cool down to 10±2°C, stir and add acetone. Add 40wt% H ₂ SO ₄ dropwise to adjust pH=3.9±0.1. Add activated carbon and stir to decolorize. Filter and wash with aqueous acetone. Cool the filtrate to 5±2°C and stir. Add 40wt% H ₂ SO ₄ , and then adjust the pH to 1.9±0.1. Control the temperature at 5±2°C and stir for 30 minutes. Raise the temperature to 20±2°C, add a little seed crystal, stir and crystallize for 1.5 hours. Add acetone dropwise to lower the temperature to 5±2°C, measure and adjust the pH=1.8±0.1, and continue to stir and grow the crystal. Filter and wash with acetone. The filter cake was vacuum-dried below 40°C to obtain the crude quinoxime (the yield relative to 7-ACQ was about 0.75-0.95).

Product refining: add purified water and ethyl acetate to the reaction kettle. Add crude quinoxime and sodium metabisulfite, and stir. Cool down to 8±2°C, add triethylamine, stir to dissolve. Static layering, take the water phase. Extract with ethyl acetate and water at 20°C for 15 minutes. The layers were separated at rest, and the ethyl acetate phase was discarded. Combine the aqueous phases, lower the temperature to 8±2°C, add acetone and adjust the pH to 3.9±0.1 with 40wt% H ₂ SO ₄ . Add activated carbon and stir to decolorize. Filter and wash with aqueous acetone. The filtrate was cooled to 5±2°C and stirred. Add 40wt% H ₂ SO ₄ to adjust pH=1.8±0.1. Control the temperature at 5±2°C, stir for 30 minutes, raise the temperature to 20±2°C, add a little seed crystal, stir and crystallize for 1.5 hours. Add acetone dropwise, cool down to 5±2°C, measure and adjust pH=1.65±0.1. Continue to stir and grow the crystal for 1 hour. Filter and wash with acetone 3 times. The filter cake was vacuum-dried below 40°C to obtain refined quinoxime (the yield relative to the crude product was about 0.95).

The beneficial effects of the present invention are mainly reflected in that the method of the present invention has high conversion rate, good product purity and color (white or off-white), and is suitable for industrial production.

(4) Specific implementation methods

The present invention is further described below in conjunction with specific embodiment, but protection scope of the present invention is not limited thereto:

Embodiment 1: the synthesis of 7-ACQ

Add 90KG (68L) of dichloromethane + 19.5KG (25L) of hexamethyldisilazane into a 300L reactor, and stir. Add 7-ACA25KG+ trimethylchlorosilane 0.22KG (0.25L). Heat up to 58±2°C, stir, and reflux for 12 hours. Cool down to 5±2°C, add 25KG (27L) of diethylaniline, and stir evenly. Add 30KG (21.5L) of iodotrimethylsilane, and stir for 30 minutes. The temperature was raised to 18±2°C, and the reaction was stirred for 2.5 hours. Cool down to 8±2°C, add 4.5KG (5L) of tetrahydrofuran, and stir for 30 minutes. Add tetrahydroquinoline 26KG (23L) + dimethylacetamide 47KG (50L), and react for 6 hours. The above reaction solution was transferred to a 500L reactor. Add 150KG (113L) of dichloromethane and stir well. The temperature was lowered to 5±2°C, and 25KG (32L) of isopropanol was added dropwise. Add petroleum ether 100KG (154 L) dropwise, and stir for 30 minutes. Filter, wash and filter 3 times with petroleum ether 20KG (30.5L) to obtain light yellow solid. Add 20wt% H ₂ SO ₄ 60KG (55L) into the 300L reactor. Add the above light yellow solid, stir and dissolve at 18±2°C. Static layering, take the water phase. Add 5KG of water at 20°C to the solvent phase, stir and extract for 10 minutes. The layers were separated, and the solvent phase was discarded. Combine the water phases into a 300L reactor, cool down to 5±2°C, and add 25% ammonia water dropwise:

Add 9KG (8L) dropwise for the first time, add a little seed crystal, stir and crystallize for 20 minutes;

Add 7KG (6.2L) dropwise for the second time, stir and crystallize for 15 minutes;

Add 5KG (4.5L) dropwise for the third time, stir and crystallize for 15 minutes;

Add dropwise (about 3KG) for the fourth time, adjust pH=2.9±0.1, continue to stir and crystallize for 30 minutes;

Acetone 25KG (32L) was added dropwise. Control the temperature at 5±2°C, stir and grow the crystal for 1 hour. Filter, wash and filter with a mixture of acetone 56KG (71L) + water 20KG. Wash and filter with acetone 20KG (25L) for 3 times, and vacuum-dry the filter cake below 40°C to obtain light yellow intermediate 7-ACQ35KG (the relative yield of 7-ACA is about 1.4).

Embodiment 2: the synthesis of 7-ACQ

Add 90KG (68L) of dichloromethane + 17KG (21.8L) of hexamethyldisilazane into a 300L reactor, and stir. Add 7-ACA25KG+ trimethylchlorosilane 0.22KG (0.25L). Heat up to 58±2°C, stir, and reflux for 12 hours. Cool down to 5±2°C, add 20.4KG (22L) of diethylaniline, and stir evenly. Add 27.3 KG (19.5 L) of iodotrimethylsilane, and stir for 30 minutes. The temperature was raised to 18±2°C, and the reaction was stirred for 2.5 hours. Cool down to 8±2°C, add 4.5KG (5L) of tetrahydrofuran, and stir for 30 minutes. Add 24.2KG (17.4L) of tetrahydroquinoline + 43.8KG (46.6L) of dimethylacetamide, and react for 6 hours. The above reaction solution was transferred to a 500L reactor. Add 150KG (113L) of dichloromethane and stir well. The temperature was lowered to 5±2°C, and 25KG (32L) of isopropanol was added dropwise. Add petroleum ether 100KG (154 L) dropwise, and stir for 30 minutes. Filter, wash and filter 3 times with petroleum ether 20KG (30.5L) to obtain light yellow solid. Add 20wt% H ₂ SO ₄ 60KG (55L) into the 300L reactor. Add the above light yellow solid, stir and dissolve at 18±2°C. Static layering, take the water phase. Add 5KG of water at 20°C to the solvent phase, stir and extract for 10 minutes. The layers were separated, and the solvent phase was discarded. Combine the water phases into a 300L reactor, cool down to 5±2°C, and add 25% ammonia water dropwise:

Add 9KG (8L) dropwise for the first time, add a little seed crystal, stir and crystallize for 20 minutes;

Add 7KG (6.2L) dropwise for the second time, stir and crystallize for 15 minutes;

Add 5KG (4.5L) dropwise for the third time, stir and crystallize for 15 minutes;

Add dropwise (about 3KG) for the fourth time, adjust pH=2.9±0.1, continue to stir and crystallize for 30 minutes;

Acetone 25KG (32L) was added dropwise. Control the temperature at 5±2°C, stir and grow the crystal for 1 hour. Filter, wash and filter with a mixture of acetone 56KG (71L) + water 20KG. Then wash and filter with acetone 20KG (25L) for 3 times, and vacuum-dry the filter cake below 40°C to obtain 29.6KG of light yellow intermediate 7-ACQ (the yield relative to 7-ACA is about 1.18).

Embodiment 3: the synthesis of 7-ACQ

Add 90KG (68L) of dichloromethane + 21.5KG (27.5L) of hexamethyldisilazane into a 300L reactor, and stir. Add 7-ACA25KG+ trimethylchlorosilane 0.22KG (0.25L). Heat up to 58±2°C, stir, and reflux for 12 hours. Cool down to 5±2°C, add 27.2KG (29.5L) of diethylaniline, and stir well. Add 36.4KG (26 L) of iodotrimethylsilane, and stir for 30 minutes. The temperature was raised to 18±2°C, and the reaction was stirred for 2.5 hours. Cool down to 8±2°C, add 4.5KG (5L) of tetrahydrofuran, and stir for 30 minutes. Add 36.4KG (32L) of tetrahydroquinoline + 56.4KG (60L) of dimethylacetamide, and react for 6 hours. The above reaction solution was transferred to a 500L reactor. Add 150KG (113L) of dichloromethane and stir well. The temperature was lowered to 5±2°C, and 25KG (32L) of isopropanol was added dropwise. Add petroleum ether 100KG (154 L) dropwise, and stir for 30 minutes. Filter, wash and filter 3 times with petroleum ether 20KG (30.5L) to obtain light yellow solid. Add 20wt% H ₂ SO ₄ 60KG (55L) into the 300L reactor. Add the above light yellow solid, stir and dissolve at 18±2°C. Static layering, take the water phase. Add 5KG of water at 20°C to the solvent phase, stir and extract for 10 minutes. The layers were separated, and the solvent phase was discarded. Combine the water phases into a 300L reactor, cool down to 5±2°C, and add 25% ammonia water dropwise:

Add 9KG (8L) dropwise for the first time, add a little seed crystal, stir and crystallize for 20 minutes;

Add 7KG (6.2L) dropwise for the second time, stir and crystallize for 15 minutes;

Add 5KG (4.5L) dropwise for the third time, stir and crystallize for 15 minutes;

Add dropwise (about 3KG) for the fourth time, adjust pH=2.9±0.1, continue to stir and crystallize for 30 minutes;

Acetone 25KG (32L) was added dropwise. Control the temperature at 5±2°C, stir and grow the crystal for 1 hour. Filter, wash and filter with a mixture of acetone 56KG (71L) + water 20KG. Then wash and filter with acetone 20KG (25L) for 3 times, and vacuum-dry the filter cake below 40°C to obtain 3.5KG of light yellow intermediate 7-ACQ (the yield relative to 7-ACA is about 1.34).

Embodiment 4: Cefquinome sulfate crude product synthesis

1) Add 240KG (180L) of dichloromethane and 32KG (40L) of ethanol into a 500L reactor. 2) Add 7-ACQ30KG+AE active ester 30KG+sodium metabisulfite 0.2KG, stir. 3) Cool down to 5±2°C, add 15KG (20.5L) of triethylamine, and stir for 30 minutes. 4) The temperature was raised to 10±2°C, and the reaction was stirred for 3 hours. 5) Filter, wash and filter with a mixture of dichloromethane 70KG (53L) + ethanol 6.4KG (8L). 6) Pour the filtrate into a 500L reactor, adjust the temperature to 20±2°C, add 50KG of water, stir and extract for 20 minutes. 7) static layering, take the water phase. 8) Add 25KG of water to the dichloromethane phase, stir and extract for 20 minutes. 9) Static stratification, take the water phase. 10) Add 15KG of water to the dichloromethane phase, stir and extract for 15 minutes. 11) static layering, take the water phase. 12) Combine the aqueous phases of the above steps 7) and 9), add ethyl acetate 55KG (61L) and stir for washing for 15 minutes. 13) Static layering, take the water phase. 14) The ethyl acetate phase was added to the water phase of the above step 11), extracted and stirred for 15 minutes. 15) Static layering, take the water phase. 16) Combine the aqueous phases of step 13) and step 15), lower the temperature to 10±2°C, add acetone 95KG (120L) with stirring. 17) Add 40wt% H ₂ SO ₄ dropwise to adjust pH=3.9±0.1 (about 2L=2.5KG). 18) Add 3KG of activated carbon and stir for 40 minutes to decolorize. 19) Filter, wash and filter with acetone 24KG (30L) + water 10L mixture. 20) Pour the filtrate into a 500L reactor, cool down to 5±2°C, and stir. 21) Add 40wt% H ₂ SO ₄ 20KG (16.2L), and adjust the pH to 1.9±0.1 (another 5KG). 22) Control the temperature at 5±2°C and stir for 30 minutes. 23) Raise the temperature to 20±2°C, add a little seed crystal, stir and crystallize for 1.5 hours. 24) Add acetone 160KG (203L) dropwise. 25) Cool down to 5±2°C, measure and adjust pH=1.8±0.1. 26) Continue to stir and grow the crystal for 1 hour. 27) Filter and wash with acetone 79KG (100L). 28) The filter cake was vacuum-dried below 40°C to obtain 28.5KG of crude cefquinome sulfate (the yield relative to 7-ACQ was about 0.95).

Embodiment 5: the crude product of cefquinome sulfate is synthesized

1) Add 240KG (180L) of dichloromethane and 32KG (40L) of ethanol into a 500L reactor. 2) Add 7-ACQ30KG+AE active ester 26KG+sodium metabisulfite 0.2KG, stir. 3) Cool down to 5±2°C, add 15KG (20.5L) of triethylamine, and stir for 30 minutes. 4) The temperature was raised to 10±2°C, and the reaction was stirred for 3 hours. 5) Filter, wash and filter with a mixture of dichloromethane 70KG (53L) + ethanol 6.4KG (8L). 6) Pour the filtrate into a 500L reactor, adjust the temperature to 20±2°C, add 50KG of water, stir and extract for 20 minutes. 7) static layering, take the water phase. 8) Add 25KG of water to the dichloromethane phase, stir and extract for 20 minutes. 9) Static stratification, take the water phase. 10) Add 15KG of water to the dichloromethane phase, stir and extract for 15 minutes. 11) static layering, take the water phase. 12) Combine the aqueous phases of the above step 7) and step 9), add ethyl acetate 55KG (61L) and stir for washing for 15 minutes. 13) Static layering, take the water phase. 14) The ethyl acetate phase was added to the water phase of the above step 11), extracted and stirred for 15 minutes. 15) Static layering, take the water phase. 16) Combine the aqueous phases of step 13) and step 15), lower the temperature to 10±2°C, add acetone 95KG (120L) with stirring. 17) Add 40wt% H ₂ SO ₄ dropwise to adjust pH=3.9±0.1 (about 2L=2.5KG). 18) Add 3KG of activated carbon and stir for 40 minutes to decolorize. 19) Filter, wash and filter with acetone 24KG (30L) + water 10L mixture. 20) Pour the filtrate into a 500L reactor, cool down to 5±2°C, and stir. 21) Add 40wt% H ₂ SO ₄ 20KG (16.2L), and adjust the pH to 1.9±0.1 (another 5KG). 22) Control the temperature at 5±2°C and stir for 30 minutes. 23) Raise the temperature to 20±2°C, add a little seed crystal, stir and crystallize for 1.5 hours. 24) Add acetone 160KG (203L) dropwise. 25) Cool down to 5±2°C, measure and adjust pH=1.8±0.1. 26) Continue to stir and grow the crystal for 1 hour. 27) Filter and wash with acetone 79KG (100L). 28) The filter cake was vacuum-dried below 40° C. to obtain 22.5 kg of crude cefquinome sulfate (the yield relative to 7-ACQ was about 0.95).

Embodiment 6: the synthesis of cefquinome sulfate crude product

1) Add 240KG (180L) of dichloromethane and 32KG (40L) of ethanol into a 500L reactor. 2) Add 7-ACQ30KG+AE active ester 32.6KG+sodium metabisulfite 0.2KG, stir. 3) Cool down to 5±2°C, add 15KG (20.5L) of triethylamine, and stir for 30 minutes. 4) The temperature was raised to 10±2°C, and the reaction was stirred for 3 hours. 5) Filter, wash and filter with a mixture of dichloromethane 70KG (53L) + ethanol 6.4KG (8L). 6) Pour the filtrate into a 500L reactor, adjust the temperature to 20±2°C, add 50KG of water, stir and extract for 20 minutes. 7) static layering, take the water phase. 8) Add 25KG of water to the dichloromethane phase, stir and extract for 20 minutes. 9) Static stratification, take the water phase. 10) Add 15KG of water to the dichloromethane phase, stir and extract for 15 minutes. 11) static layering, take the water phase. 12) Combine the aqueous phases of the above step 7) and step 9), add ethyl acetate 55KG (61L) and stir for washing for 15 minutes. 13) Static layering, take the water phase. 14) The ethyl acetate phase was added to the water phase of the above step 11), extracted and stirred for 15 minutes. 15) Static layering, take the water phase. 16) Combine the aqueous phases of step 13) and step 15), lower the temperature to 10±2°C, add acetone 95KG (120L) with stirring. 17) Add 40wt% H ₂ SO ₄ dropwise to adjust pH=3.9±0.1 (about 2L=2.5KG). 18) Add 3KG of activated carbon and stir for 40 minutes to decolorize. 19) Filter, wash and filter with acetone 24KG (30L) + water 10L mixture. 20) Pour the filtrate into a 500L reactor, cool down to 5±2°C, and stir. 21) Add 40wt% H ₂ SO ₄ 20KG (16.2L), and adjust the pH to 1.9±0.1 (another 5KG). 22) Control the temperature at 5±2°C and stir for 30 minutes. 23) Raise the temperature to 20±2°C, add a little seed crystal, stir and crystallize for 1.5 hours. 24) Add acetone 160KG (203L) dropwise. 25) Cool down to 5±2°C, measure and adjust pH=1.8±0.1. Continue to stir and grow the crystal for 1 hour. 26) Filter and wash with acetone 79KG (100L). 27) Vacuum-dry at below 40°C to obtain 27.3KG of crude cefquinome sulfate (the yield relative to 7-ACQ is about 0.91). Embodiment 7: product refining

Add 75KG of purified water + 55KG of ethyl acetate (61L) into the 500L reactor. Add 25KG of cefquinome sulfate crude product + 0.2KG of sodium metabisulfite, and stir. Cool down to 8±2°C, add 10KG (14L) of triethylamine, stir to dissolve. Static layering, take the water phase. Ethyl acetate was added to 20°C water 10KG for extraction for 15 minutes. The layers were separated at rest, and the ethyl acetate phase was discarded. Combine the aqueous phases, lower the temperature to 8±2°C, and add 95KG (120L) of acetone. Use 40wt% H ₂ SO ₄ to adjust pH=3.9±0.1 (about 2KG). Add activated carbon 3KG, stir and decolorize for 40 minutes. Filter, wash and filter with acetone 24KG (30L) + water 10KG mixture. The filtrate was poured into a 500L reactor, cooled to 5±2°C, and stirred. Add 40wt% H ₂ SO ₄ 20KG (16.2L) to adjust pH=1.8±0.1. Control the temperature at 5±2°C, stir for 30 minutes, raise the temperature to 20±2°C, add a little seed crystal, stir and crystallize for 1.5 hours. Add acetone 160KG (203L) dropwise to cool down to 5±2°C, measure and adjust pH=1.65±0.1, and continue to stir and grow the crystal for 1 hour. Filter, wash and filter 3 times (25L) with acetone 20KG, and vacuum-dry the filter cake below 40°C to obtain refined (white or off-white) cefquinome sulfate 23.75KG (purity detected by HPLC is above 99%) (relative crude product yield about 0.95).

Claims (5)

1. a preparation method for Cefquinome sulfate, is characterized in that described method comprises:

(1) taking 7-amino-cephalosporanic acid and tetrahydroquinoline as reaction substrate, in carrene with pregnancyBase disilazane is protective agent, taking trim,ethylchlorosilane as reaction catalyst, with diethylbenzeneAmine is as reaction system polar modifier, the dispersion taking dimethylacetylamide as tetrahydroquinolineMedium reacts under Iodotrimethylsilane exists, and drips 25% ammonia after reacting completelyWater growing the grain, obtains the amino Cefquinome of intermediate 7-after acetone filter wash; The amino cephalo of described 7-Alkanoic acid: tetrahydroquinoline: the consumption mol ratio of Iodotrimethylsilane is 1:2～3:1.5～2;

(2) the amino Cefquinome of 7-that mol ratio is 1:1.2～1.5 and MEAM are at carreneIn taking ethanol as dispersant, sodium pyrosulfite is that antioxidant reacts, with triethylamineThe acid constantly producing as acid binding agent neutralization reaction, after reaction finishes, with carrene andAfter alcohol mixeding liquid filter wash, get filtrate and extract with pure water, the water of merging is first adjusted with sulfuric acidPH3.9 ± 0.1, adds active carbon and stirs decolouring, crosses leaching filtrate and adjusts pH with sulfuric acid again1.9 ± 0.1, to control temperature and obtain Cefquinome sulfate crude product at 20 ± 2 DEG C of crystallizatioies, crude product is againCefquinome sulfate after must refining after filter wash recrystallization.

2. the method for claim 1, is characterized in that the amino cephalo alkane of 7-in step (1)Acid is taking carrene as decentralized medium, and tetrahydroquinoline is taking dimethylacetylamide as decentralized medium.

3. the method for claim 1, is characterized in that in step (2), sulfuric acid is adjusted pH1.9 ± 0.1After, first control temperature and stir 15-30min at 5 ± 2 DEG C, be then warming up to 20 ± 2 DEG C, stirMix crystallization.

4. the method for claim 1, is characterized in that the 7-amino described in step (1)The molar ratio of cephalosporanic acid/HMDS is 1:1.15～1.45.

5. the method for claim 1, is characterized in that the 7-amino described in step (1)The molar ratio of cephalosporanic acid/diethylaniline is 1:1.5～2.