CN117384229A - Purification method of tylosin - Google Patents
Purification method of tylosin Download PDFInfo
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- CN117384229A CN117384229A CN202311233154.0A CN202311233154A CN117384229A CN 117384229 A CN117384229 A CN 117384229A CN 202311233154 A CN202311233154 A CN 202311233154A CN 117384229 A CN117384229 A CN 117384229A
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- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 title claims abstract description 127
- 239000004182 Tylosin Substances 0.000 title claims abstract description 125
- 229930194936 Tylosin Natural products 0.000 title claims abstract description 125
- 229960004059 tylosin Drugs 0.000 title claims abstract description 125
- 235000019375 tylosin Nutrition 0.000 title claims abstract description 125
- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000000746 purification Methods 0.000 title claims abstract description 22
- 239000007787 solid Substances 0.000 claims abstract description 45
- 238000000967 suction filtration Methods 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000001035 drying Methods 0.000 claims abstract description 14
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 239000013078 crystal Substances 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 238000002425 crystallisation Methods 0.000 claims abstract description 7
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- 230000001376 precipitating effect Effects 0.000 claims abstract description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 81
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 44
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 abstract description 21
- 239000000047 product Substances 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 7
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 62
- 230000000052 comparative effect Effects 0.000 description 23
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- 238000010586 diagram Methods 0.000 description 7
- 238000007670 refining Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- 238000007405 data analysis Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000013557 residual solvent Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- HNDXPZPJZGTJLJ-UEJFNEDBSA-N (4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4s,5s,6r)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-5,9,13-trimethyl-7-(2-piperidin-1-ylethyl)-15-(piperidin-1-ylmethyl)-1-oxacyclohexadeca-11,13-diene-2,10-dione Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1CCCCC1)CN1CCCCC1)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O HNDXPZPJZGTJLJ-UEJFNEDBSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960002659 tildipirosin Drugs 0.000 description 1
- JTSDBFGMPLKDCD-XVFHVFLVSA-N tilmicosin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O JTSDBFGMPLKDCD-XVFHVFLVSA-N 0.000 description 1
- 229960000223 tilmicosin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a purification method of tylosin, which belongs to the technical field of medicine purification and comprises the following steps: dissolving, suction filtering and layering, namely dripping V1 water under the first preset temperature condition, precipitating a small amount of solid in the system, layering after suction filtering, and taking the lower layer; crystallization: under the condition of a second preset temperature, dropwise adding V2 water to separate out a tylosin solid, and carrying out crystal growing, suction filtration and drying to obtain the tylosin, wherein the mass ratio of the crude product of the tylosin to the amount of V1 and the amount of the V2 water is 1:6.0-10.0: 30-50. The beneficial effects of the invention are as follows: the method reduces the use of other solvents, has no harmful gas, is easy to control the reaction temperature, reduces the probability of danger, and has the advantages of low cost, environmental protection, high product yield and high purity.
Description
Technical field:
the invention belongs to the technical field of medicine purification, and particularly relates to a purification method of tylosin.
The background technology is as follows:
the tylosin (Tildipirosin) is a new macrolide semisynthetic antibiotic special for animals developed by Intellitewei company, is a derivative of tylosin, has very obvious treatment effect on respiratory diseases of cattle and pigs, has stronger drug effect than tylosin and tilmicosin, and has the advantages of special use for animals, small dosage, one-time administration whole course treatment, ultra-long elimination half-life, high bioavailability, low residue and the like, and has the chemical name of: 20 23-dipiperidinyl-5-oxo-mycaminosyl-tylonolide.
The structure is as follows
For the synthesis of this compound, the methods that have been reported at present mainly include the following:
patent CN110981926a discloses a purification method of tylosin. The method comprises dissolving crude tylosin in acetonitrile, filtering, and adding water for crystallization. And (5) carrying out crystal growth, centrifugation and drying to obtain the Taidi Luo Xinchun product. The method uses acetonitrile as a refining solvent, which is a second solvent prescribed by ICH, and the residual limit is not more than 0.041%. After the product is dried, the acetonitrile limit cannot reach the specified level.
Patent CN108033988A: the tylosin converts 20-site aldehyde group of tylosin into piperidyl through amination reaction, removes 4-site glycosyl and 15-site glycosyl through hydrolysis reaction, and converts 23-site hydroxyl into piperidyl through oxidation reaction and amination reaction in sequence to finally obtain tylosin. The method has the advantages of complicated operation, more steps, low product yield, and low purity of the tylosin (97%).
Patent CN104672287a discloses a purification method of tylosin. The method comprises the steps of acidifying a crude product of the tylosin by sulfuric acid, removing impurities by using silica gel or alumina, and alkalizing and crystallizing at 75 ℃. The method is easy to generate alkali damage impurities by adding alkali liquor at high temperature, and generates solid wastes such as silica gel, alumina and the like, thereby increasing the production cost.
Patent CN113201033A discloses a new purifying method, which comprises the steps of mixing a crude product of tylosin with ethanol and aqueous solution for dissolving, decoloring by active carbon, filtering and crystallizing to obtain a solid of tylosin. The method not only has high content of the obtained tylosin isomer, but also leads partial materials to be adsorbed easily due to the decoloration of the activated carbon at high temperature, so that the yield is low.
To sum up: the above methods all have more or less problems: some products have low yield; some residual solvent limits do not meet the standard and cannot meet the industrial production; some of the products have high impurity and by-products, resulting in low purity of the products. Therefore, the development of an environment-friendly, economically feasible purification method of the tylosin has important significance.
The invention comprises the following steps:
in order to solve the problems and overcome the defects of the prior art, the invention provides a purification method of tylosin, which can effectively solve the problems that the limit of residual solvent does not meet the standard and cannot meet the industrial production; high impurity content and high byproduct content.
The specific technical scheme for solving the technical problems is as follows: the purification method of the tylosin is characterized by comprising the following process steps:
(1) Dissolving: adding the crude product of the tylosin into a mixed solvent, heating to 71-81 ℃ for dissolving,
(2) Suction filtration and layering:
dropwise adding V1 water into the step (1) under the condition of a first preset temperature, precipitating a small amount of solid in the system, filtering, layering, and taking the lower layer;
(3) Crystallization:
and (3) under the second preset temperature condition, dropwise adding V2 water in the step (2), precipitating the tylosin solid, and carrying out crystal growing, suction filtration and drying to obtain the tylosin.
Further, the mixed solvent is a mixture of isopropyl alcohol and n-heptane.
Further, the mass volume ratio of the crude product of the tylosin to the isopropyl alcohol and the n-heptane is 1g (5-8) mL (15-25) mL.
Further, the first preset temperature is 71-81 ℃.
Further, the second preset temperature is 75-85 ℃.
Further, the crystal growing time in the step (3) is 10-20 hours; drying and controlling the temperature at 35-55 ℃; the drying time is 10-20 h.
Further, the mass ratio of the crude tylosin to the amount of V1 and the amount of V2 water is 1:6.0-10.0: 30-50.
The beneficial effects of the invention are as follows:
(1) The purification method of the tylosin provided by the invention reduces the use of other solvents of the second class, has no harmful gas, is easy to control the reaction temperature, reduces the probability of danger, and is low in cost, environment-friendly, high in product yield and high in purity;
(2) The method creatively refers to a step-by-step water adding mode to separate the impurity from the tylosin, and then the tylosin separated with the impurity is subjected to crystallization to obtain the tylosin with higher purity, so that the problem that the limit of the residual solvent does not meet the standard and cannot meet the industrial production is solved; the problem of high impurity and byproduct of the product;
(3) The invention creatively discovers that isopropyl alcohol and n-heptane are used as solvents, and in the addition amount of the embodiment of the invention, V1 amount=60-100 ml exists in a section, so that the impurities and the tylosin with similar physicochemical properties can be preferentially separated out, the preferentially separated out impurities can be separated from the tylosin, the waste of the tylosin is avoided, and the total yield is improved.
Description of the drawings:
FIG. 1 is a diagram showing the comparison of the content of tylosin and impurities in the first filtration solid content in example 1 of the present invention;
FIG. 2 is a diagram showing the comparison of the content of tylosin and impurities in the first filtration solid content in example 2 of the present invention;
FIG. 3 is a diagram showing the comparison of the content of tylosin and impurities in the first filtration solid content in example 3 of the present invention;
FIG. 4 is a schematic diagram showing the comparison of the content of tylosin and the content of impurities in the first suction filtration solid content in comparative example 9 of the present invention;
FIG. 5 is a schematic diagram showing the comparison of the content of tylosin and the content of impurities in the first suction filtration solid content in comparative example 15 of the present invention;
FIG. 6 is a schematic diagram showing the comparison of the content of tylosin and the content of impurities in the first suction filtration solid content in comparative example 17 of the present invention;
FIG. 7 is a schematic diagram showing the comparison of the content of tylosin and the content of impurities in the first suction filtration solid content in comparative example 18 of the present invention; in the accompanying drawings:
the specific embodiment is as follows:
specific details are set forth in the description of the invention in order to provide a thorough understanding of embodiments of the invention, it will be apparent to those skilled in the art that the invention is not limited to these details. In other instances, well-known structures and functions have not been shown or described in detail to avoid obscuring aspects of embodiments of the invention. The specific meaning of the above terms in the present invention will be understood in specific cases by those of ordinary skill in the art.
Specific embodiments of the invention:
for better understanding of the present invention, specific examples are given, and it should be emphasized that the effects of the examples are not substantially different from those of the various examples within the scope of the present invention, including the respective reagents and the content ratios of the reagents, and that other combinations are not described here;
(1) Mixing the crude product of the tylosin, isopropyl alcohol and n-heptane, and heating to dissolve; the dissolving temperature is 71-81 ℃; the mass volume ratio of the crude product of the tylosin to the isopropyl alcohol to the n-heptane is 1:5-8:15-25;
(2) Dripping water into the step (1) for the first time at the temperature of 71-81 ℃, precipitating a small amount of solid from the system, filtering, layering, and taking the lower layer; the mass volume ratio of the crude product of the tylosin to the water is 1:6.0-10.0; the mass volume ratio of the crude product of the tylosin to the water is 1:6.0-10.0;
(3) And (3) dripping water into the step (2) for the second time at the temperature of 75-85 ℃ to precipitate the tylosin solid. The tylosin with higher purity is obtained through crystal growing, suction filtration and drying. The dosage mass ratio of the crude product of the tylosin to the water is 1:30-50;
the crystal growing time in the step (3) is 10-20 h; drying and controlling the temperature at 35-55 ℃; the drying time is 10-20 h.
As specific examples of the present invention:
example 1:
sequentially placing 10.0g of crude tylosin (purity 95.8%), 70ml of isopropanol and 180ml of n-heptane into a 500ml three-port bottle, heating to 71-81 ℃ and stirring to dissolve; 100ml of water was added dropwise at 73℃and a small amount of solid was precipitated from the system, which was stirred for about 0.5h and then suction filtered. Layering the suction filtration mother liquor, discarding the upper n-heptane phase, taking the lower layer, placing into a 1000ml three-mouth bottle, and dripping 300ml water at 75 ℃ to separate out the tylosin solid, and ending the dripping about 1.0 h. Slowly cooling to 0-5 ℃ to grow crystals for 12h, carrying out suction filtration, washing a filter cake with water, and drying at 45 ℃ for about 15h to obtain the tylosin with the product yield of 94.4% and the purity of 99.68%.
Example 2:
sequentially placing 10.0g of crude tylosin (purity 95.1%), 50ml of isopropanol and 150ml of n-heptane into a 500ml three-port bottle, heating to 71-81 ℃ and stirring to dissolve; 60ml of water was added dropwise at 78℃and a small amount of solid was precipitated from the system, which was stirred for about 0.5h and then suction filtered. Layering the suction filtration mother liquor, discarding the upper n-heptane phase, taking the lower layer, placing into a 500ml three-mouth bottle, dripping 500ml water at 80deg.C, and precipitating tylosin solid, and ending dripping about 1.0 h. Slowly cooling to 0-5 ℃ to grow crystal for 15h, filtering, washing filter cakes with water, and drying at 45 ℃ for about 12h to obtain the tylosin with the product yield of 93.6% and the purity of 99.64%.
Example 3:
sequentially placing 10.0g of crude tylosin (purity 94.2%), 80ml of isopropanol and 200ml of n-heptane into a 500ml three-port bottle, heating to 71-81 ℃ and stirring to dissolve; 80ml of water was added dropwise at 81℃and a small amount of solid was precipitated in the system, which was stirred for about 0.5h and then suction filtered. Layering the suction filtration mother liquor, discarding the upper n-heptane phase, taking the lower layer, placing into a 1000ml three-mouth bottle, and dripping 400ml water at 85 ℃ to separate out the tylosin solid, and ending dripping about 1.0 h. Slowly cooling to 0-5 ℃ to grow crystals for 17h, carrying out suction filtration, washing a filter cake with water, and drying at 45 ℃ for about 18h to obtain the tylosin, wherein the product yield is 92.8%, and the purity is 99.73%.
In order to more intuitively show the technological advantages of the invention, the purification method of the tylosin described by the invention is compared with the equivalent replacement method of the same technology,
comparative example 1:
the preparation method is the same as in example 3, except that: in the preparation process of the comparative example, water is added at one time, and the water amount v=v1+v2 is added;
comparative example 2:
the preparation method is the same as in example 3, except that: in the preparation process of the comparative example, the water drop adding mode is replaced by rapid adding;
comparative example 3:
the preparation method is the same as in example 3, except that: in the preparation process of the comparative example, a single solvent was added: isopropyl alcohol;
comparative example 4:
the preparation method is the same as in example 3, except that: in the preparation process of the comparative example, the mixed solvent is a mixture of n-propanol and n-heptane;
comparative example 5:
the preparation method is the same as in example 3, except that: in the preparation process of the comparative example, the mixed solvent is a mixture of ethanol and n-heptane;
table 1: comparison of the content of thetylosin and the impurity content in different suction filtration solids in different processes
From the data analysis in table 1, it can be seen that:
(1) Examples 1-3 compare with comparative examples 1-2:
the impurity content in the first suction filtration solid is higher and the tylosin content is extremely low in the embodiment of the invention, while the impurity content in the first suction filtration solid in comparative examples 1-2 is lower than 2.0% and 2.6%, and the tylosin content is as high as 97.4% and 98%;
therefore, the invention creatively introduces a mode of twice water addition, wherein the first water addition is less, impurities with similar physical and chemical properties and tylosin are preferentially separated out, and a large amount of water solvent is added after separation to carry out crystallization on the tylosin, so that the purpose of removing the impurities is realized;
according to the comparison example, water is added at one time, although impurities are precipitated, a large amount of tylosin is precipitated, so that the impurities are completely introduced into the tylosin, and finally the impurities in the product are higher, and the requirements of national formulary on the tylosin medicine are not met on the premise of not refining;
(2) Examples 1-3 compare with comparative example 3:
the impurity content in the first suction filtration solid in comparative example 3 is higher and the content of the tylosin is extremely low, but the impurity content in the second suction filtration solid is as high as 2.64%, so that the impurity in the product is higher, and the requirements of the national formulary on the tylosin drug are not met on the premise of not refining;
the method is probably because a single solvent, namely isopropanol, cannot separate impurities from the tylosin in a stepwise water adding manner, wherein the single solvent, namely isopropanol, can enable the impurities not to be more similar to physical and chemical properties and the tylosin to be preferentially separated out through adding a small amount of water for the first time, so that a large amount of impurities enter a system, and finally the impurities in the product are higher, and the requirements of national formulary on the tylosin drug are not met on the premise of not refining;
(3) Examples 1-3 compare with comparative example 4:
in the comparative example 4, no first suction filtration solid is generated, impurities with similar physical and chemical properties and tylosin are preferentially separated out, and finally the impurities in the product are higher, so that the requirements of national formulary on the tylosin medicine are not met on the premise of not refining;
this is probably due to the fact that the mixed solvent, n-propanol and n-heptane, cannot separate impurities from tylosin by means of stepwise water addition;
(4) Examples 1-3 compare with comparative example 5:
in comparative example 5, the first suction filtration solid can be generated, but the suction filtration solid tylosin is greatly separated out, so that most of impurities enter the tylosin, and finally, the impurities in the product are higher, and the requirements of national formulary on the tylosin medicine are not met on the premise of not refining.
In order to further demonstrate the technical advantages of the invention, the purification method of the tylosin described by the invention is compared with the same technology by adopting an equivalent replacement method,
on the basis of comparative example 4, the amount of water V1 added dropwise to step (1) was adjusted in gradient: detailed in the following table
Table 2: gradient addition of different V1 of isopropanol and n-heptane solvents for comparison of tylosin and impurity content in first suction filtration solid content
From the data analysis in table 2, it can be seen that:
isopropyl alcohol and n-heptane are used as solvents, the gradient addition amounts of different V1 are adopted, the content of the tylosin and the impurity content in the solid content of the first suction filtration are different,
specifically:
(1) In the addition amount of the embodiment of the invention, namely, v1 amount=60-100 ml, there is a section in which a large amount of impurities are precipitated, but the amount of the precipitated tylosin is not too large, the amount of the first suction filtration solid matter is small, the loss of the tylosin with the 0.2 percent ratio is not large, and the final comprehensive yield can reach more than 93 percent.
(2) When the gradient addition amount of V1 is smaller than the protection range of the invention, the first suction filtration solid is found not to be separated out, which means that the addition amount does not influence the polarity of the system, so that impurities cannot be more similar to physical and chemical properties and tylosin is preferentially separated out, and thus, all the impurities enter a final product;
(3) When the gradient addition amount of V1 is larger than the protection range of the invention, more solid matters are precipitated after the first suction filtration, and the detection shows that the content of the tylosin is up to 5.21%, so that the final yield is lower, and the recovery difficulty of the tylosin is higher.
Table 3: gradient addition of different V1 in n-propanol and n-heptane solvents for comparison of tylosin and impurity content in first suction filtration solid content
From the data analysis in table 3, it can be seen that:
n-propanol and n-heptane are used as solvents, the gradient addition amounts of different V1 are adopted, the content of tylosin and the impurity content in the solid content of the first suction filtration are different,
specifically:
(1) In the addition amount of the embodiment of the invention, namely, v1 amount=60-100 ml, unlike the invention, the solid matters are not precipitated in the first suction filtration, which means that the addition amount cannot influence the polarity of the system, so that the impurities cannot be more similar to the physicochemical properties and the tylosin is preferentially precipitated, and thus, all the impurities enter the final product;
(2) When the gradient addition amount of V1 is smaller than the protection range of the invention, the first suction filtration solid is found to be less separated out;
(3) When the gradient addition amount of V1 is larger than the protection range of the invention, more solid matters are precipitated after the first suction filtration, and the detection shows that the content of the tylosin is up to 93.2 percent and the impurity content is only 6.8 percent, which indicates that when the gradient addition amount of V1 is larger than the V1 of the embodiment of the invention, the tylosin is precipitated in a large amount along with the impurity, so that the final yield is lower, and the recovery difficulty of the tylosin is higher; more importantly, n-propanol and n-heptane are used as solvents, and a section does not exist, namely, in the section, impurities can be more similar to physical and chemical properties and tylosin is preferentially separated out, so that the effect of separating the tylosin is met.
Table 4: gradient addition of ethanol and n-heptane solvents with different V1 for comparison of Taderosin and impurity content in the first suction filtration solids content
From the data analysis in table 4, it can be seen that:
ethanol and n-heptane are used as solvents, the gradient addition amounts of different V1 are adopted, the content of the tylosin and the impurity content in the solid content of the first suction filtration are different,
specifically:
(1) In the addition amount of the embodiment of the invention, namely, the V1 amount=60-100 ml, unlike the invention, in the interval, more solid matters are precipitated in the first suction filtration, the detection shows that the content of the tylosin is up to 93.2 percent, the impurity content is only 6.8 percent, the tylosin is precipitated in a large amount along with the impurity, the final yield is lower, and the recovery difficulty of the tylosin is higher;
(2) When the gradient addition amount of V1 is smaller than the protection range of the invention, the first suction filtration solid is found to be not separated out, and a section which appears in the invention is not found, and impurities can be separated out preferentially with the tylosin in the section which has relatively similar physicochemical properties, so that the effect of separating the tylosin is met;
(3) When the gradient addition amount of V1 is larger than the protection range of the invention, more solid matters are precipitated after the first suction filtration, and the detection shows that the content of the tylosin is up to 98.4 percent, the impurity content is only 1.60 percent,
this shows that, when the amount of the tylosin is larger than the amount of the embodiment V1 of the invention, the tylosin is precipitated in a large amount along with impurities, so that the final yield is low, and the recovery difficulty of the part of the tylosin is high.
Therefore, ethanol and n-heptane are used as solvents and n-propanol and n-heptane are used as solvents, and a section does not exist, namely, in the section, the impurity can be preferentially separated out from the tylosin, which is similar to the physical and chemical properties, so that the effect of separating the tylosin is met, and only isopropanol and n-heptane are used as solvents, and in the addition amount of the embodiment of the invention, V1 amount=60-100 ml, the impurity can be preferentially separated out from the tylosin, which is similar to the physical and chemical properties, the waste of the tylosin is avoided, and the total yield is improved.
To sum up: (1) The purification method of the tylosin provided by the invention reduces the use of other solvents of the second class, has no harmful gas, is easy to control the reaction temperature, reduces the probability of danger, and is low in cost, environment-friendly, high in product yield and high in purity;
(2) The method creatively refers to a step-by-step water adding mode to separate the impurity from the tylosin, and then the tylosin separated with the impurity is subjected to crystallization to obtain the tylosin with higher purity, so that the problem that the limit of the residual solvent does not meet the standard and cannot meet the industrial production is solved; the problem of high impurity and byproduct of the product;
(3) The invention creatively discovers that isopropyl alcohol and n-heptane are used as solvents, and in the addition amount of the embodiment of the invention, V1 amount=60-100 ml exists in a section, so that the impurities and the tylosin with similar physicochemical properties can be preferentially separated out, the preferentially separated out impurities can be separated from the tylosin, the waste of the tylosin is avoided, and the total yield is improved.
Claims (7)
1. The purification method of the tylosin is characterized by comprising the following process steps of:
(1) Dissolving: adding the crude product of the tylosin into a mixed solvent, heating to 71-81 ℃ for dissolving,
(2) Suction filtration and layering:
dropwise adding V1 water into the step (1) under the condition of a first preset temperature, precipitating a small amount of solid in the system, filtering, layering, and taking the lower layer;
(3) Crystallization:
and (3) under the second preset temperature condition, dropwise adding V2 water in the step (2), precipitating the tylosin solid, and carrying out crystal growing, suction filtration and drying to obtain the tylosin.
2. The purification method of tylosin according to claim 1, characterized in that the mixed solvent is a mixture of isopropyl alcohol and n-heptane.
3. The purification method of the tylosin according to claim 2, which is characterized in that the mass-volume ratio of the crude product of the tylosin to the isopropyl alcohol and the n-heptane is 1g (5-8) mL (15-25) mL.
4. The purification method of tylosin according to claim 1, characterized in that the first preset temperature is 71-81 ℃.
5. The purification method of tylosin according to claim 1, characterized in that the second preset temperature is 75-85 ℃.
6. The purification method of tylosin according to claim 1, characterized in that the crystal growing time in the step (3) is 10-20 hours; drying and controlling the temperature at 35-55 ℃; the drying time is 10-20 h.
7. The purification method of the tylosin according to claim 1, which is characterized in that the mass ratio of the crude tylosin to the amount of V1 and the amount of V2 water is 1:6.0-10.0: 30-50.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311233154.0A CN117384229A (en) | 2023-09-22 | 2023-09-22 | Purification method of tylosin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311233154.0A CN117384229A (en) | 2023-09-22 | 2023-09-22 | Purification method of tylosin |
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| CN117384229A true CN117384229A (en) | 2024-01-12 |
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| CN202311233154.0A Pending CN117384229A (en) | 2023-09-22 | 2023-09-22 | Purification method of tylosin |
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