CN113979872A - Comprehensive recovery method of effective components in potassium clavulanate kettle residual liquid - Google Patents
Comprehensive recovery method of effective components in potassium clavulanate kettle residual liquid Download PDFInfo
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- CN113979872A CN113979872A CN202111319471.5A CN202111319471A CN113979872A CN 113979872 A CN113979872 A CN 113979872A CN 202111319471 A CN202111319471 A CN 202111319471A CN 113979872 A CN113979872 A CN 113979872A
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- butylamine
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- 239000007788 liquid Substances 0.000 title claims abstract description 59
- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 title claims abstract description 53
- 238000011084 recovery Methods 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 27
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims abstract description 100
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims abstract description 60
- 239000011347 resin Substances 0.000 claims abstract description 32
- 229920005989 resin Polymers 0.000 claims abstract description 32
- BGMXQLNMDVZYRF-UHFFFAOYSA-N tert-butylazanium;hydrogen sulfate Chemical compound CC(C)(C)[NH3+].OS([O-])(=O)=O BGMXQLNMDVZYRF-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000001179 sorption measurement Methods 0.000 claims abstract description 22
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 20
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229960003324 clavulanic acid Drugs 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims abstract description 14
- 239000012535 impurity Substances 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 238000004821 distillation Methods 0.000 claims abstract description 9
- SXWZSWLBMCNOPC-UHFFFAOYSA-M potassium;6-methylheptanoate Chemical compound [K+].CC(C)CCCCC([O-])=O SXWZSWLBMCNOPC-UHFFFAOYSA-M 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 43
- 239000000741 silica gel Substances 0.000 claims description 43
- 229910002027 silica gel Inorganic materials 0.000 claims description 43
- 239000012071 phase Substances 0.000 claims description 28
- 239000003480 eluent Substances 0.000 claims description 23
- 238000011068 loading method Methods 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 230000020477 pH reduction Effects 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 239000008346 aqueous phase Substances 0.000 claims description 7
- 239000000049 pigment Substances 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 239000012452 mother liquor Substances 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 4
- 238000013375 chromatographic separation Methods 0.000 claims description 4
- -1 clavulanic acid tert-butylamine salt Chemical class 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000003463 adsorbent Substances 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000012156 elution solvent Substances 0.000 claims description 2
- 230000000274 adsorptive effect Effects 0.000 claims 1
- 238000004132 cross linking Methods 0.000 claims 1
- 230000007613 environmental effect Effects 0.000 abstract description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 3
- 238000010898 silica gel chromatography Methods 0.000 abstract description 3
- 229910052708 sodium Inorganic materials 0.000 abstract description 3
- 239000011734 sodium Substances 0.000 abstract description 3
- 238000004064 recycling Methods 0.000 abstract description 2
- 238000004042 decolorization Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000005191 phase separation Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000223924 Eimeria Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000187433 Streptomyces clavuligerus Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229960002793 amoxicillin sodium Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009412 basement excavation Methods 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 229940090805 clavulanate Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- ILVPFTMKCHREDJ-UHFFFAOYSA-N methyl 5-amino-2-fluorobenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1F ILVPFTMKCHREDJ-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- FUGVTYHNTOTQMG-UHFFFAOYSA-M sodium;6-methylheptanoate Chemical compound [Na+].CC(C)CCCCC([O-])=O FUGVTYHNTOTQMG-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of pharmacy, and relates to a comprehensive recovery method of effective components in potassium clavulanate kettle residual liquid, which comprises the following steps: adjusting the pH value of the potassium clavulanate kettle residual liquid to acidity by adding dilute sulfuric acid, standing and layering to obtain a water phase containing tertiary butylamine sulfate and an isooctanoic acid oil phase; adjusting the pH of the water phase containing the tert-butylamine sulfate to be alkaline by using alkali, and then distilling to obtain tert-butylamine; the isooctanoic acid oil phase is subjected to silica gel column chromatography and macroporous adsorption resin for decolorization and impurity removal, and the solvent is removed by distillation, so that high-quality isooctanoic acid can be obtained. The tert-butylamine recovered by the method can be used for preparing the clavulanic acid tert-butylamine, and the isooctanoic acid recovered by the method can be used for preparing sodium isooctanoate or potassium isooctanoate, so that the recycling of the kettle residual liquid is realized, a new economic growth point is created for enterprises, the pollution of organic matters to the environment is reduced and avoided, and the strategic goal of safety and environmental protection win-win of the enterprises is achieved.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and relates to a comprehensive recovery method of effective components in potassium clavulanate kettle residual liquid, in particular to a comprehensive recovery method of tert-butylamine and isooctanoic acid in potassium clavulanate kettle residual liquid.
Background
The potassium clavulanate is a beta-lactamase inhibitor, can obviously reduce the drug resistance of bacteria after being compounded with the amoxicillin sodium, and has stronger and wider inhibition effect compared with other beta-lactamase inhibitors, so the potassium clavulanate is widely applied clinically.
In industrial production, the preparation method of the potassium clavulanate generally comprises the following steps: preparing clavulanic acid fermentation liquor by utilizing streptomyces clavuligerus fermentation, removing mycelium, most of protein and other solid particles in the fermentation liquor by using methods such as ceramic filtration, ultrafiltration and the like, and obtaining a clavulanic acid aqueous solution after membrane concentration; extracting the clavulanic acid from the clavulanic acid aqueous solution by using ethyl acetate which is immiscible with water under an acidic condition, and reacting the extract with tert-butylamine to form stable clavulanic acid tert-butylamine salt after the extract is subjected to reduced pressure concentration; finally, the tert-butylamine salt of clavulanic acid is converted into the required potassium clavulanate, the potassium clavulanate is generally prepared by mixing the tert-butylamine salt of clavulanic acid with a salt forming agent potassium isooctanoate in an isopropanol system, carrying out salt forming reaction to obtain insoluble potassium clavulanate, and filtering and drying to obtain the potassium clavulanate.
The crystallization mother liquor remained after the separation of the potassium clavulanate crystals contains a large amount of tert-butylamine iso-octanoate and isopropanol, only the isopropanol which is an organic solvent is generally recovered due to the lack of a comprehensive recovery technology in industrial production, and the kettle residue which contains a large amount of tert-butylamine iso-octanoate after the organic solvent is removed by distillation is directly discharged, so that the kettle residue has high organic impurities and poor biodegradability, and great pressure is brought to environmental protection. In fact, the isooctanoic acid in the tert-butylamine iso-caprylate can be used for synthesizing potassium iso-caprylate or sodium iso-caprylate, and the tert-butylamine can be used for synthesizing the tert-butylamine clavulanate, so that if the tert-butylamine iso-caprylate in the residual liquid of the kettle can be recycled, the pollution to the environment can be reduced, the comprehensive reutilization of resources can be realized, and more benefits can be increased for enterprises. Therefore, how to effectively and comprehensively recover the effective components in the residual liquid in the kettle becomes an important research subject in the current potassium clavulanate production process. In the prior art, there is a need for more effectively and environmentally friendly recovery of residual tert-butylamine isooctoate in still bottoms and maximum excavation of the value of the still bottoms.
Disclosure of Invention
Therefore, the invention aims to provide the comprehensive recovery method of the tert-butylamine and the isooctanoic acid in the potassium clavulanate kettle residual liquid, which has the advantages of reasonable process design, simple and convenient operation, good recovery effect, excellent product quality and environmental friendliness.
In order to realize the purpose of the invention, the technical scheme adopted by the invention is as follows: firstly, adjusting the pH value of potassium clavulanate kettle residual liquid to acidity by adding dilute sulfuric acid, converting isooctanoic acid tert-butylamine salt in the potassium clavulanate kettle residual liquid into sulfuric acid tert-butylamine salt and isooctanoic acid, standing for layering, taking a water phase with the dissolved tert-butylamine sulfate in a lower layer, and recovering tert-butylamine after the steps of adjusting the pH value to alkalinity, distilling and the like; and the upper layer of isooctanoic acid oil phase is subjected to silica gel column chromatography and macroporous adsorption resin decoloration and impurity removal, and the solvent is removed by distillation, so that high-quality isooctanoic acid can be obtained.
According to the invention, the comprehensive recovery method of tert-butylamine and isooctanoic acid in potassium clavulanate kettle residual liquid provided by the invention comprises the following steps:
(1) recovery of tert-butylamine
After distilling the potassium clavulanate crystallization mother liquor to remove the organic solvent, carrying out sulfuric acid acidification treatment on residual kettle residual liquid, converting tert-butylamine iso-octanoate in the kettle residual liquid into tert-butylamine sulfate salt and iso-octanoic acid, and then standing for layering to obtain a water phase containing the tert-butylamine sulfate salt and an oil phase of iso-octanoic acid;
adjusting the pH value of the water phase containing the tert-butylamine sulfate to be alkaline by using alkali, and then distilling to obtain tert-butylamine;
(2) recovery of isooctanoic acid
Carrying out silica gel chromatographic separation on the isooctanoic acid oil phase obtained in the step (1) to remove pigments and impurities, eluting by using dichloromethane, and collecting an eluent containing the isooctanoic acid; the eluent is decolorized and impurity-removed by macroporous adsorption resin, and then the organic solvent is distilled off to obtain the isooctanoic acid.
Advantageous effects
The invention has the advantages that:
the comprehensive recovery method of tert-butylamine and isooctanoic acid in potassium clavulanate kettle residual liquid provided by the invention realizes the maximization of digging residual value in potassium clavulanate kettle residual liquid, wherein, through the acidification treatment of the potassium clavulanate kettle residual liquid, the isooctanoic acid tert-butylamine salt in the kettle residual liquid is converted into tert-butylamine sulfate salt and isooctanoic acid, and the separation of tert-butylamine and isooctanoic acid is realized; the recycled tert-butylamine can be used for preparing clavulanic acid tert-butylamine, the recycled isooctanoic acid can be used for preparing sodium isooctanoate or potassium isooctanoate, the recycling of kettle residual liquid is realized, a new economic growth point is created for enterprises, the pollution of organic matters to the environment is reduced and avoided, and the strategic goals of safety and environmental protection win-win of the enterprises are achieved.
Detailed Description
The process for the comprehensive recovery of the active ingredients from the potassium clavulanate still residue of the present invention will be described in more detail below.
In the recovery of the tert-butylamine in the step (1), after distilling the potassium clavulanate crystallization mother liquor to remove the organic solvent, carrying out sulfuric acid acidification treatment on residual kettle residual liquid, converting tert-butylamine iso-octanoate in the kettle residual liquid into tert-butylamine sulfate and iso-octanoic acid, and then standing for layering to obtain a water phase containing the tert-butylamine sulfate and an oil phase of the iso-octanoic acid; the aqueous phase containing the tert-butylamine sulfate salt is adjusted to basic pH using a base and then subjected to distillation to give tert-butylamine.
In the field, in the production process of potassium clavulanate, tert-butylamine salt of clavulanic acid is usually selected as an intermediate, potassium isooctanoate is selected as a salt forming agent, the tert-butylamine salt of clavulanic acid is mixed in an organic solvent such as isopropanol and then reacts to form salt, a mother solution remained after crystallization and separation of potassium clavulanate salt is distilled to remove the organic solvent isopropanol to obtain potassium clavulanate kettle residual liquid, the appearance of the part of kettle residual liquid is dark brown, and the potassium clavulanate kettle residual liquid contains a large amount of pigments and impurities, wherein the concentration of the tert-butylamine salt of isooctanoate is 1000-1600 mg/ml, the pH is about 8.0-8.5, and the potassium clavulanate kettle residual liquid contains a small amount of water. The clavulanic acid kettle residual liquid can be subjected to acidification treatment by adopting sulfuric acid with the concentration of 15-30 wt% (w/w), the pH of the kettle residual liquid after the acidification treatment can be 5.0-6.0, tert-butylamine isooctanoate in the kettle residual liquid after the acidification treatment is converted into tert-butylamine sulfate and isooctanoic acid, phase separation is carried out, then standing and layering are carried out, and a water phase containing tert-butylamine sulfate and an oil phase of isooctanoic acid are respectively collected.
Then, a sodium hydroxide solution, for example, a 32 wt% sodium hydroxide solution, is added to the aqueous phase containing the tert-butylamine sulfate to adjust the pH to 11.0 to 12.0, and under an alkaline condition, tert-butylamine is liberated. Then, distilling the alkalized water phase at 65-70 ℃ by adopting a distilling device, and collecting tert-butylamine fractions to obtain the tert-butylamine with the content of more than or equal to 98.0 percent.
The recovered tert-butylamine has high purity and can be used for preparing the clavulanic acid tert-butylamine.
In the step (2), during the recovery of the isooctanoic acid, the isooctanoic acid oil phase obtained in the step (1) is subjected to silica gel chromatographic separation to remove pigments and impurities, and is eluted by using dichloromethane, and an eluent containing the isooctanoic acid is collected; the eluent is decolorized and impurity-removed by macroporous adsorption resin, and then the organic solvent is distilled off to obtain the isooctanoic acid.
Wherein, in the silica gel chromatography purification of the isooctanoic acid oil phase, amorphous or spherical silica gel with the particle size of 300-400 meshes can be selected and filled into a round silica gel column bed, and the ratio of the column height to the diameter (namely the height-diameter ratio) is 8 or more.
Loading the isooctanoic acid oil phase on the top of a silica gel column bed, wherein the loading amount is 0.2-0.4 times of the volume of the silica gel column bed, and the flow rate in the loading process is 0.5-1.0 times of the volume of the silica gel column bed per hour; and after the sample loading is finished, eluting at a flow rate of 0.25-0.5 time of the volume of the silica gel bed per hour by using dichloromethane, separating the isooctanoic acid from other pigment impurities in the elution process, and collecting the eluent containing the isooctanoic acid.
In addition, before loading the silica gel, an elution solvent dichloromethane is used for fully balancing the silica gel column bed, and the using amount of the equilibrium solvent is not less than 2 times of the volume of the silica gel column bed; eluting with dichloromethane as eluting solvent to elute isooctanoic acid adsorbed on silica gel, wherein the amount of eluting solvent is not less than 3 times of the volume of silica gel column bed; after the elution is finished, regenerating the silica gel column bed by using a regeneration solvent methanol so as to elute the pigment and impurities adsorbed on the silica gel, wherein the dosage of the regeneration solvent is not less than 2 times of the volume of the silica gel column bed; the regenerated silica gel column bed can be continuously reused.
And then, carrying out macroporous adsorption resin decoloration and impurity removal on the isooctanoic acid-containing eluent, adsorbing pigment impurities in the isooctanoic acid eluent on the resin by utilizing the specific adsorption effect of the macroporous adsorption resin, and enabling the non-adsorbed isooctanoic acid to flow through the resin and be collected as adsorption residual liquid so as to further purify the isooctanoic acid.
The macroporous adsorption resin can be a non-polar material macroporous adsorption resin with the particle size of 400-1250 micrometers and a styrene and divinylbenzene crosslinked framework structure. Specifically, the macroporous adsorbent resin is preferably any one macroporous adsorbent resin selected from LXT053 (new materials science and technology ltd. in the blue of the high tom), DM700 (eimeria key (chinese) bio-medicine ltd.), HZ17SS (shanghai huasha science and technology ltd.).
The macroporous adsorption resin is used in a column bed form, the height-to-diameter ratio (namely the height-to-diameter ratio) of the column bed is 4 or more, the obtained eluent containing the isooctanoic acid passes through the resin column bed at the flow rate of 0.5-1.5 times of the volume of the resin column bed per hour, when the light transmittance of the absorption raffinate at 430nm at the lower end of the resin column bed is less than 95%, the eluent stops being fed into the column, flows through the resin and is collected to enable the concentration of the isooctanoic acid in the absorption raffinate to be 150-300 g/L.
Then, under the condition of 50-70 ℃, removing dichloromethane in the adsorption residual liquid by adopting a distillation mode to obtain the isooctanoic acid liquid with quality meeting the standard.
The recovered isooctanoic acid is clear and colorless, has purity of more than or equal to 98%, and can be used for preparing sodium isooctanoate or potassium isooctanoate.
The present invention will be described more specifically with reference to the following examples, but the scope of the present invention is not limited to these examples.
Example 1
(1) Recovery of tert-butylamine
Taking 5L potassium clavulanate kettle residual liquid, wherein the concentration of the tert-butylamine isocaprylate in the potassium clavulanate kettle residual liquid is 1150mg/ml, the pH value is about 8.2, using 20 wt% (w/w) sulfuric acid to carry out acidification treatment, adjusting the pH value to 5.2, converting the tert-butylamine isocaprylate in the potassium clavulanate kettle residual liquid after the acidification treatment into tert-butylamine sulfate salt and isocaprylic acid, carrying out phase separation, then standing for layering, and respectively collecting 3.8L of water phase containing the tert-butylamine sulfate salt and 4.7L of oil phase of the isocaprylic acid, wherein the concentration of the isocaprylic acid is 785 mg/ml.
Then, 32 wt% sodium hydroxide solution was added to the aqueous phase containing t-butylamine sulfate to adjust the pH to 11.5, followed by distillation at 65 ℃ to 70 ℃ to collect t-butylamine fraction, yielding 98.0% t-butylamine 1722 g with a yield of 81.6%.
(2) Recovery of isooctanoic acid
Taking 16L of silica gel, loading the silica gel into a column, wherein the height-diameter ratio is 8:1, using 32L of dichloromethane to balance a silica gel column bed, loading 4.7L of isooctanoic acid oil phase at the flow rate of 8L per hour, using 48L of dichloromethane to elute the adsorbed isooctanoic acid on the silica gel at the flow rate of 4L per hour after loading, and collecting 18.5L of eluent containing the isooctanoic acid in total, wherein the concentration of the isooctanoic acid is 186 mg/ml.
Then, the eluent containing the isooctanoic acid was decolorized and purified using LXT053 resin, the eluent containing the isooctanoic acid was passed through a resin bed (height to diameter ratio of 4:1) at a flow rate of 1.0 times the volume of the resin bed per hour, and the adsorption residual liquid was collected.
The collected adsorption raffinate was distilled to remove methylene chloride, to obtain 3269 g of isooctanoic acid liquid with 98.5% purity and 78.6% yield.
Example 2
(1) Recovery of tert-butylamine
Taking 5L potassium clavulanate crystallization kettle residual liquid, wherein the concentration of the tert-butylamine isocaprylate contained in the potassium clavulanate crystallization kettle residual liquid is 1520mg/ml, the pH value is about 8.2, using 15 wt% (w/w) sulfuric acid to carry out acidification treatment, adjusting the pH value to 5.5, converting the tert-butylamine isocaprylate in the potassium clavulanate crystallization kettle residual liquid after the acidification treatment into tert-butylamine sulfate salt and isocaprylic acid, carrying out phase separation, then standing for layering, and respectively collecting 4.7L of water phase containing the tert-butylamine sulfate salt and 6.1L of oil phase of the isocaprylic acid, wherein the concentration of the isocaprylic acid is 820 mg/ml.
Then, 32 wt% sodium hydroxide solution was added to the aqueous phase containing t-butylamine sulfate to adjust the pH to 11.5, followed by distillation at 65 ℃ to 70 ℃ to collect t-butylamine fraction, yielding 98.5% t-butylamine 2248 g with a yield of 80.6%.
(2) Recovery of isooctanoic acid
Taking 16L of silica gel, loading the silica gel into a column with the height-diameter ratio of 8:1, balancing a silica gel column bed by using 32L of dichloromethane, loading 6.1L of isooctanoic acid oil phase at the flow rate of 8L per hour, eluting the adsorbed isooctanoic acid on the silica gel by using 48L of dichloromethane at the flow rate of 4L per hour after loading, and collecting 18.0L of eluent containing the isooctanoic acid in total, wherein the concentration of the isooctanoic acid is 266 mg/ml.
Then, the eluent containing the isooctanoic acid was decolorized and purified using LXT053 resin, the eluent containing the isooctanoic acid was passed through a resin bed (height to diameter ratio of 4:1) at a flow rate of 1.0 times the volume of the resin bed per hour, and the adsorption residual liquid was collected.
The collected adsorption raffinate was distilled to remove methylene chloride, to obtain 4596 g of isooctanoic acid liquid with a purity of 98.2% and a yield of 83.6%.
Example 3
(1) Recovery of tert-butylamine
Taking 5L potassium clavulanate crystallization kettle residual liquid, wherein the concentration of the tert-butylamine isocaprylate contained in the potassium clavulanate crystallization kettle residual liquid is 1290mg/ml, the pH value is about 8.3, using 20 wt% (w/w) sulfuric acid to carry out acidification treatment, adjusting the pH value to 6.0, converting the tert-butylamine isocaprylate in the potassium clavulanate crystallization kettle residual liquid after the acidification treatment into tert-butylamine sulfate salt and isocaprylic acid, carrying out phase separation, then standing for layering, and respectively collecting 4.6L of water phase containing the tert-butylamine sulfate salt and 6.0L of oil phase of the isocaprylic acid, wherein the concentration of the isocaprylic acid is 725 mg/ml.
Then, 32 wt% sodium hydroxide solution was added to the aqueous phase containing t-butylamine sulfate to adjust the pH to 11.5, followed by distillation at 65 ℃ to 70 ℃ to collect t-butylamine fraction, yielding 1905 g of 98.2% t-butylamine with a yield of 80.5%.
(2) Recovery of isooctanoic acid
Taking 16L of silica gel, loading the silica gel into a column with the height-diameter ratio of 8:1, balancing a silica gel column bed by using 32L of dichloromethane, then loading 6.0L of isooctanoic acid oil phase at the flow rate of 8L per hour, eluting the adsorbed isooctanoic acid on the silica gel by using 48L of dichloromethane at the flow rate of 4L per hour after loading, and collecting 17.9L of eluent containing the isooctanoic acid in total, wherein the concentration of the isooctanoic acid is 227 mg/ml.
Then, the eluent containing the isooctanoic acid was decolorized and purified using LXT053 resin, the eluent containing the isooctanoic acid was passed through a resin bed (height to diameter ratio of 4:1) at a flow rate of 1.0 times the volume of the resin bed per hour, and the adsorption residual liquid was collected.
The collected adsorption raffinate was distilled to remove methylene chloride, yielding 3817 g of isooctanoic acid liquid with 98.3% purity and 81.8% yield.
Claims (10)
1. A comprehensive recovery method of effective components in potassium clavulanate kettle residual liquid comprises the following steps:
(1) recovery of tert-butylamine
After distilling the potassium clavulanate crystallization mother liquor to remove the organic solvent, carrying out sulfuric acid acidification treatment on residual kettle residual liquid, converting tert-butylamine iso-octanoate in the kettle residual liquid into tert-butylamine sulfate salt and iso-octanoic acid, and then standing for layering to obtain a water phase containing the tert-butylamine sulfate salt and an oil phase of iso-octanoic acid;
adjusting the pH value of the water phase containing the tert-butylamine sulfate to be alkaline by using alkali, and then distilling to obtain tert-butylamine;
(2) recovery of isooctanoic acid
Carrying out silica gel chromatographic separation on the isooctanoic acid oil phase obtained in the step (1) to remove pigments and impurities, eluting by using dichloromethane, and collecting an eluent containing the isooctanoic acid; the eluent is decolorized and impurity-removed by macroporous adsorption resin, and then the organic solvent is distilled off to obtain the isooctanoic acid.
2. The method for comprehensively recovering the active ingredients from the potassium clavulanate kettle residue according to claim 1, wherein the potassium clavulanate kettle residue is obtained as follows: carrying out salt forming reaction on the clavulanic acid tert-butylamine salt and potassium isooctanoate in isopropanol to generate potassium clavulanate salt crystals; and distilling the residual mother liquor after the separation of the potassium clavulanate salt crystals to remove the organic solvent isopropanol to obtain the potassium clavulanate kettle residual liquid.
3. The comprehensive recovery method of active ingredients in potassium clavulanate kettle residual liquid according to claim 2, characterized in that the concentration of the tert-butylamine iso-octanoate in the potassium clavulanate kettle residual liquid is 1000-1600 mg/ml, and the pH is 8.0-8.5.
4. The method for comprehensively recovering the active ingredients from the clavulanic acid potassium kettle residual liquid according to claim 1, wherein in the step (1) of recovering the tert-butylamine, the clavulanic acid kettle residual liquid is acidified by using sulfuric acid with the concentration of 15-30 wt%, and the pH value of the kettle residual liquid after the acidification treatment is 5.0-6.0.
5. The comprehensive recovery method of effective components in potassium clavulanate kettle residual liquid according to claim 1, characterized in that in the recovery of tert-butylamine in the step (1), the pH of the aqueous phase containing tert-butylamine sulfate is adjusted to 11.0-12.0 by using a sodium hydroxide solution, then the alkalized aqueous phase is distilled at 65-70 ℃ by adopting a distillation device, and tert-butylamine fractions are collected, so that tert-butylamine with the content of more than or equal to 98.0% can be obtained.
6. The comprehensive recovery method of effective components in potassium clavulanate kettle residue according to claim 1, wherein in the recovery of isooctanoic acid in the step (2), amorphous or spherical silica gel with a particle size of 300-400 meshes is selected and filled into a round silica gel column bed in the chromatographic separation of silica gel, and the ratio of column height to diameter is 8 or more; loading the isooctanoic acid oil phase on the top of a silica gel column bed, wherein the loading amount is 0.2-0.4 times of the volume of the silica gel column bed, and the flow rate in the loading process is 0.5-1.0 times of the volume of the silica gel column bed per hour; and after the sample loading is finished, eluting with dichloromethane at a flow rate of 0.25-0.5 time of the volume of the silica gel bed per hour, and collecting the eluent containing the isooctanoic acid.
7. The method for comprehensively recovering the active ingredients from the potassium clavulanate kettle residual liquid according to claim 6, wherein before loading the silica gel, the silica gel column bed is fully balanced by using an elution solvent dichloromethane, and the amount of the equilibrium solvent is not less than 2 times of the volume of the silica gel column bed; and in the process of eluting the silica gel column bed, eluting with an eluting solvent dichloromethane to elute the isooctanoic acid adsorbed on the silica gel, wherein the dosage of the eluting solvent is not less than 3 times of the volume of the silica gel column bed.
8. The comprehensive recovery method of active ingredients in potassium clavulanate kettle residual liquid according to claim 1, characterized in that in the recovery of isooctanoic acid in the step (2), macroporous adsorption resin is used for decoloring and impurity removal of eluent, wherein the macroporous adsorption resin is selected from non-polar material macroporous adsorption resin with the particle size of 400-1250 micrometers and a framework structure of styrene and divinylbenzene crosslinking.
9. The process of claim 8, wherein the macroporous adsorbent resin is used in the form of a bed having a height to diameter ratio of 4 or more, the eluent containing isooctanoic acid is passed through the bed at a flow rate of 0.5 to 1.5 bed volumes per hour, and the unadsorbed isooctanoic acid is passed through the resin and collected as a raffinate.
10. The process of claim 9, wherein the adsorptive raffinate is distilled at 50-70 ℃ to remove dichloromethane and obtain isooctanoic acid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115894202A (en) * | 2022-12-06 | 2023-04-04 | 常州久日化学有限公司 | Method for treating distillation still residue of photoinitiator 1173 |
| CN116283498A (en) * | 2023-03-07 | 2023-06-23 | 国药集团威奇达药业有限公司 | Method for recovering organic solvent from potassium clavulanate production waste liquid |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010029038A1 (en) * | 1996-11-27 | 2001-10-11 | Harald Summer | Purification of fermented clavulanic acid |
| CN108558909A (en) * | 2018-05-17 | 2018-09-21 | 国药集团威奇达药业有限公司 | The method of active ingredient in synthetical recovery clavulanic acid tert-butylamine salt crystalline mother solution |
| CN108773924A (en) * | 2018-05-03 | 2018-11-09 | 国药集团威奇达药业有限公司 | The comprehensive recovering process of active ingredient in clavulanic acid extraction raffinate |
| CN109305978A (en) * | 2017-07-26 | 2019-02-05 | 山东睿鹰先锋制药有限公司 | A kind of new method preparing Clavulanate |
| CN111087297A (en) * | 2019-12-27 | 2020-05-01 | 四川仁安药业有限责任公司 | Method for treating pharmaceutical waste liquid of antibiotics |
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010029038A1 (en) * | 1996-11-27 | 2001-10-11 | Harald Summer | Purification of fermented clavulanic acid |
| CN109305978A (en) * | 2017-07-26 | 2019-02-05 | 山东睿鹰先锋制药有限公司 | A kind of new method preparing Clavulanate |
| CN108773924A (en) * | 2018-05-03 | 2018-11-09 | 国药集团威奇达药业有限公司 | The comprehensive recovering process of active ingredient in clavulanic acid extraction raffinate |
| CN108558909A (en) * | 2018-05-17 | 2018-09-21 | 国药集团威奇达药业有限公司 | The method of active ingredient in synthetical recovery clavulanic acid tert-butylamine salt crystalline mother solution |
| CN111087297A (en) * | 2019-12-27 | 2020-05-01 | 四川仁安药业有限责任公司 | Method for treating pharmaceutical waste liquid of antibiotics |
Non-Patent Citations (1)
| Title |
|---|
| 曹广祥 等: "制药工业结晶母液中异辛酸的回收研究", 当代化工, vol. 37, no. 6, pages 583 - 585 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115894202A (en) * | 2022-12-06 | 2023-04-04 | 常州久日化学有限公司 | Method for treating distillation still residue of photoinitiator 1173 |
| CN116283498A (en) * | 2023-03-07 | 2023-06-23 | 国药集团威奇达药业有限公司 | Method for recovering organic solvent from potassium clavulanate production waste liquid |
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