CN102863487B - Process for preparing 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone - Google Patents
Process for preparing 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone Download PDFInfo
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Abstract
The invention relates to a process for preparing 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone. Tylosin tartrate serves as a raw material, an intermediate product of 23-oxhydryl-5-O-carbon mould amine glycosyl-tylosin lactone is obtained through hydrolyzation, an organic phase is extracted through phase inversion, and an intermediate product of 20-piperidyl-23-oxhydryl-5-O-carbon mould amine glycosyl-tylosin lactone is produced through combination with piperidine under the effect of methanoic acid. A final product of the 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone is formed by ammonization with the piperidine through iodination. By the aid of the process, the production technology is simplified, the dosage of auxiliary raw materials such as the piperidine, iodine and an organic solvent is greatly reduced, the purity of the obtained product is higher than 98%, the yield of the final product of the 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone reaches 58.7%, and the process has good industrial application prospects.
Description
Technical field
The preparation method who the present invention relates to a kind of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone, belongs to microbiotic synthesis technical field for animals.
Background technology
20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone, has another name called safe ground Luo Xin, molecular formula: C
41h
71n
3o
8molecular weight: 734.02, be a kind of Macrolide broad-spectrum antibiotics, be mainly used in treating livestock respiratory system disease.This compou nd synthesis method, foreign patent bibliographical information has two kinds of synthetic methods.
A kind of patent US 6514946 delivering for Japanese chemistry of micro-organisms WARF, adopting the iodo-5-O-mycaminose Ji-Tai Le of 20,23-bis-lactone is raw material, acetonitrile is solvent, with under piperidines reflux temperature, react 1h, column chromatography obtains product, mass yield 86.4%.The raw material 20 that it adopts, the iodo-5-O-mycaminose Ji-Tai Le of 23-bis-lactone should not obtain, and product is purified by column chromatography, is not suitable for suitability for industrialized production.
Holland Intervet patent WO 2008012343 has introduced another kind of synthetic method, taking tylosin as raw material, and by piperidines in 20 ammonifications, twice hydrolysis, 23 activation, ammonification five step reactions finally obtain product.This synthetic method, reactions steps is loaded down with trivial details, and its acidic hydrolysis adopts Hydrogen bromide, and by product is more, and iodo step moisture requirement is less than 100ppm, and condition is too harsh, and the finished product are purified by recrystallization repeatedly, and product loss is serious, yield only 12.2%, cost is higher.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, provide that a kind of technique is simple, raw material is easy to get, with low cost 20, the preparation method of 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone.
The present invention is achieved through the following technical solutions:
A kind of preparation method of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone, step is as follows:
(1) by tylosin tartrate 1:(15～20 in mass ratio) soluble in water, then keeping temperature is to add acid under the condition of 50～100 DEG C, tylosin tartrate and sour mol ratio are 1:(5～10), hydrolysis reaction 6～8h, makes 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone (formula 1);
Described acid is one of sulfuric acid, hydrochloric acid, Hydrogen bromide, tosic acid, trifluoroacetic acid or the mixing more than both;
(2) in the 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone reaction liquid making to step (1), add solvent, the mass ratio of 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone and solvent is 1:(5～6), adjust pH to 8～12, layering, get organic layer, add piperidines, formic acid, 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone, formic acid, piperidines mol ratio are 1:(1～3): (1～3), be heated to 39～41 DEG C, back flow reaction 5～6h, makes 20-piperidyl-23 hydroxyl-5-O mycaminose Ji-Tai Le lactones (formula 2);
Described solvent is one of methylene dichloride, ethyl acetate, trichloromethane or toluene;
(3) 1:(5～6 in mass ratio in the 20-piperidyl-23-hydroxyl-5-O mycaminose Ji-Tai Le lactone reaction liquid making to step (2)) adding water stirs, adjust pH to 8～10, layering, get organic layer, add anhydrous magnesium sulfate to stir dehydration, filter, in filtrate, add triphenyl phosphorus and imidazoles, be cooled to-10～0 DEG C, then add iodine, reaction 2～3h, add sodium sulfite solution, static layering, take off a layer organic phase and add anhydrous magnesium sulfate dehydration, cross leaching filtrate, through vacuum concentration, obtain the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone (formula 3),
Above-mentioned 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone, triphenyl phosphorus, imidazoles, iodine mol ratio are: 1:(1～3): (1～3): (1～3);
(4) the iodo-5-O-mycaminose Ji-Tai Le lactone of 20-piperidyl-23-1:(5～6 in mass ratio that step (3) made) be dissolved in ethyl acetate, then add piperidines and sodium carbonate, be warming up to 77～79 DEG C, back flow reaction 5～6h, cross leaching filtrate, add and the isopyknic water of ethyl acetate, adjust pH to 3.5～5.0, layering, water intaking phase, sodium hydroxide solution adjust pH to 10～11, crystallization, after filtration, filter cake adds in 10 times of water, hydrochloric acid adjust pH to 3.5～5.0, after dissolving, sodium hydroxide adjust pH to 8～10, secondary crystallization, filtration makes 20, 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone compound (formula 4), the purity that makes product is greater than 98%, and product yield reaches 58.7%.
The mol ratio of the iodo-5-O-mycaminose Ji-Tai Le of above-mentioned 20-piperidyl-23-lactone, piperidines, sodium carbonate is 1:(1～2): (3～6).
Preferred according to the present invention, in described step (1), tylosin tartrate is 1:18 with quality ratio; Tylosin tartrate, sulfuric acid mol ratio are: 1:6.
Preferred according to the present invention, the acid in described step (1) is sulfuric acid, and the mass concentration of sulfuric acid is 40%.
Preferred according to the present invention, in described step (2), (3) and (4), with the sodium hydroxide solution of 5mol/L or 2mol/L and the hydrochloric acid adjust pH of 4mol/L.
Preferred according to the present invention, in described step (2), 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone, formic acid, piperidines mol ratio are 1:2:2.
Preferred according to the present invention, the solvent in described step (2) is methylene dichloride.
Preferred according to the present invention, in described step (3), 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone, triphenyl phosphorus, imidazoles, iodine mol ratio are: 1:2:2.5:2.
Preferred according to the present invention, in described step (3), the mass concentration of sodium sulfite solution is 10%.
Preferred according to the present invention, in described step (3), the temperature of vacuum concentration is 18～22 DEG C.
Preferred according to the present invention, in described step (4), the mol ratio of the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone, piperidines, sodium carbonate is 1:1.2:4.
Preferred according to the present invention, above-mentioned preparation method's step is as follows:
(1) tylosin tartrate 300kg is dissolved in 4500～6000kg purified water, then keeping temperature is that under the condition of 90 DEG C, to add mass percent be 20～98% sulfuric acid 742kg～302kg, hydrolysis reaction 6～8h; 23 hydroxyls-5-O-mycaminose Ji-Tai Le the lactone making;
(2) that gets that step (1) makes adds methylene dichloride 755kg containing in 23-hydroxyl-5-O mycaminose Ji-Tai Le lactone 130～150kg reaction solution, the sodium hydroxide solution of 5mol/L regulates pH value to 10～12, layering, get organic layer, add piperidines 21.5～43kg, anhydrous formic acid 11.5～26kg, be heated to 40 DEG C, back flow reaction 5～6h, HPLC detects 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone content and is less than 2g/L, makes 20-piperidyl-23 hydroxyl-5-O mycaminose Ji-Tai Le lactone;
(3) what make to step (2) adds purified water 800kg to stir containing in 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 138～149kg reaction solution, 5mol/L sodium hydroxide solution adjust pH to 8～10, layering, water layer is taken away impurity, get organic layer, add anhydrous magnesium sulfate 90kg to stir dehydration, filter, in filtrate, add triphenyl phosphorus 61～182.8kg and imidazoles 16～48kg, be cooled to-10～0 DEG C, then add solid iodine 30～90kg in 1h, to add in three batches, reaction 2～3h, HPLC detects 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone and is less than 3g/L, add 10～15wt% sodium sulfite solution 700kg, static layering, take off a layer organic phase and add anhydrous magnesium sulfate 90kg dehydration, cross leaching filtrate, through 20 DEG C of vacuum concentration, obtain the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone,
(4) the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone 141.5～153.5kg step (3) being made is dissolved in 780kg ethyl acetate, then add piperidines 20.2～60kg and sodium carbonate 40～120kg, be warming up to 78 DEG C, back flow reaction 5～6h, cross leaching filtrate, add 800kg purified water, hydrochloric acid adjust pH to 4.0, layering, water intaking phase, 2mol/L sodium hydroxide adjust pH to 10～11, crystallization filters, filter cake adds 800kg purified water, 4mol/L hydrochloric acid adjust pH to 4.0, stirring and dissolving, 2mol/L sodium hydroxide adjust pH to 10～11, secondary crystallization, filtration makes 20, 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone compound.
Synthesis route of the present invention is as follows:
Beneficial effect
1, the present invention adopts the tylosin tartrate of wide material sources as synthesis material, has overcome the rare expensive deficiency of prior art raw material, greatly reduces the production cost of 20,23-dipiperidino-5-O mycaminose Ji-Tai Le lactone;
2, the present invention, by adjusting reactions steps and condition, has simplified production technique, has significantly reduced the consumption of auxiliary material piperidines, iodine and organic solvent;
3, the purity of the inventive method products obtained therefrom is high, and HPLC purity is greater than 98%, and molar product yield can be up to 58.7%.Method of the present invention is easy to industrial applications.
Brief description of the drawings
Fig. 1 be embodiment 3 make 20, the mass spectrum of 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone.
Embodiment
Below in conjunction with embodiment, technical scheme of the present invention is further elaborated, described embodiment is just used for illustrating the present invention, and should not be considered to be limitation of the present invention.
Raw material sources
Tylosin tartrate is purchased from the pharmacy Inner Mongol, Shandong company limited;
Piperidines is purchased from Chemical Reagent Co., Ltd., Sinopharm Group;
Triphenyl phosphorus is purchased from Jinan Run De Chemical Co., Ltd.;
Imidazoles is purchased from Tianjin great Mao chemical reagent factory;
Iodine is purchased from Xi Long Chemical Co., Ltd.
In embodiment, other reagent are common commercially available prod.
Embodiment 1
A kind of preparation method of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone, step is as follows:
(1) tylosin tartrate 300kg is dissolved in 4500kg purified water, then keeping temperature is that under the condition of 50 DEG C, to add mass percent be 20% sulfuric acid 741.6kg, hydrolysis reaction 8h, HPLC detects the completely dissolve of tylosin peak, detect through HPLC, make 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 150kg, molar yield 82.8%;
(2) what make to step (1) adds methylene dichloride 755kg containing in 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 150kg reaction solution, the sodium hydroxide solution of 5mol/L regulates pH value to 8, layering, get organic layer, add piperidines 21.5kg, anhydrous formic acid 11.5kg, be heated to 40 DEG C, back flow reaction 5h, HPLC detects 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone content and is less than 2g/L, makes 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 149kg; Molar yield 89.1%;
(3) what make to step (2) adds purified water 800kg to stir containing in 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 149kg reaction solution, the molten adjust pH to 8 of 5mol/L sodium hydroxide, layering, water layer is taken away impurity, get organic layer, add anhydrous magnesium sulfate 90kg to stir dehydration, filter, in filtrate, add triphenyl phosphorus 61kg and imidazoles 16kg, be cooled to-10 DEG C, then add solid iodine 30kg in 1h, to add in three batches, reaction 2h, HPLC detects 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone and is less than 3g/L, add 15wt% sodium sulfite solution 700kg, static layering, take off a layer organic phase and add anhydrous magnesium sulfate 90kg dehydration, cross leaching filtrate, through 20 DEG C of vacuum concentration, obtain the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone 147.5kg, molar yield 85.0%,
(4) the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone 147.5kg step (3) being made is dissolved in 780kg ethyl acetate, then add piperidines 20.2kg and sodium carbonate 40kg, be warming up to 78 DEG C, back flow reaction 5h, cross leaching filtrate, add 800kg purified water, hydrochloric acid adjust pH to 4.0, layering, water intaking phase, 2mol/L sodium hydroxide adjust pH to 10, crystallization, filter, filter cake adds 800kg purified water, 4mol/L hydrochloric acid adjust pH to 4.0, stirring and dissolving, 2mol/L sodium hydroxide adjust pH to 10, secondary crystallization, filtration makes 20, 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone compound 124kg, the purity that HPLC detection makes product is greater than 98%, molar product yield: 88.9%,
After testing, the mass spectrum result of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone is MS m/z734[M+1]
+, the molar yield of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone is 55.7%.
Embodiment 2
A kind of preparation method of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone, step is as follows:
(1) tylosin tartrate 300kg is dissolved in 5400kg purified water, then keeping temperature is that under the condition of 80 DEG C, to add mass percent be 40% sulfuric acid 370.8kg, hydrolysis reaction 6h, HPLC detects the completely dissolve of tylosin peak, detect through HPLC, make 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 151kg, molar yield 83.4%;
(2) what make to step (1) adds methylene dichloride 755kg containing in 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 151kg reaction solution, the sodium hydroxide solution of 5mol/L regulates pH value to 10, layering, get organic layer, add piperidines 25.8kg, anhydrous formic acid 13.8kg, be heated to 40 DEG C, back flow reaction 5.5h, HPLC detects 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone content and is less than 2g/L, makes 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 155kg; Molar yield 92.0%;
(3) what make to step (2) adds purified water 800kg to stir containing in 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 155kg reaction solution, the molten adjust pH to 9 of 5mol/L sodium hydroxide, layering, water layer is taken away impurity, get organic layer, add anhydrous magnesium sulfate 90kg to stir dehydration, filter, in filtrate, add triphenyl phosphorus 121.9kg and imidazoles 31.65kg, be cooled to 0 DEG C, then add solid iodine 59kg in 1h, to add in three batches, reaction 2.5h, HPLC detects 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone and is less than 3g/L, add 10wt% sodium sulfite solution 700kg, static layering, take off a layer organic phase and add anhydrous magnesium sulfate 90kg dehydration, cross leaching filtrate, through 20 DEG C of vacuum concentration, obtain the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone 153.5kg, molar yield 85.0%,
(4) the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone 153.5kg step (3) being made is dissolved in 780kg ethyl acetate, then add piperidines 40kg and sodium carbonate 80kg, be warming up to 78 DEG C, back flow reaction 5.5h, cross leaching filtrate, add 800kg purified water, hydrochloric acid adjust pH to 4.0, layering, water intaking phase, 2mol/L sodium hydroxide adjust pH to 10.5, crystallization, filter, filter cake adds 800kg purified water, 4mol/L hydrochloric acid adjust pH to 4.0, stirring and dissolving, 2mol/L sodium hydroxide adjust pH to 10.5, secondary crystallization, filtration makes 20, 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone compound 130.5kg, the purity that HPLC detection makes product is greater than 98%, molar product yield: 89.97%,
After testing, the mass spectrum result of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone is MS m/z734[M+1]
+, the molar yield of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone is 58.7%.
Embodiment 3
A kind of preparation method of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone, step is as follows:
(1) tylosin tartrate 300kg is dissolved in 6000kg purified water, then keeping temperature is that under the condition of 90 DEG C, to add mass percent be 98% sulfuric acid 302kg, hydrolysis reaction 6h, HPLC detects the completely dissolve of tylosin peak, detect through HPLC, make 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 130kg, molar yield 71.8%;
(2) what make to step (1) adds methylene dichloride 755kg containing in 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 130kg reaction solution, the sodium hydroxide solution of 5mol/L regulates pH value to 12, layering, get organic layer, add piperidines 43kg, anhydrous formic acid 26kg, be heated to 40 DEG C, back flow reaction 6h, HPLC detects 23 hydroxyls-5-O-mycaminose Ji-Tai Le lactone content and is less than 2g/L, makes 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 138kg; Molar yield 95.0%;
(3) what make to step (2) adds purified water 800kg to stir containing in 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 138kg reaction solution, the molten adjust pH to 10 of 5mol/L sodium hydroxide, layering, water layer is taken away impurity, get organic layer, add anhydrous magnesium sulfate 90kg to stir dehydration, filter, in filtrate, add triphenyl phosphorus 182.8kg and imidazoles 48kg, be cooled to-5 DEG C, then add solid iodine 90kg in 1h, to add in three batches, reaction 3h, HPLC detects 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone and is less than 3g/L, add 10wt% sodium sulfite solution 700kg, static layering, take off a layer organic phase and add anhydrous magnesium sulfate 90kg dehydration, cross leaching filtrate, through 20 DEG C of vacuum concentration, obtain the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone 141.5kg, molar yield 88.0%,
(4) the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone 141.5kg step (3) being made is dissolved in 780kg ethyl acetate, then add piperidines 60kg and sodium carbonate 120kg, be warming up to 78 DEG C, back flow reaction 6h, cross leaching filtrate, add 800kg purified water, hydrochloric acid adjust pH to 4.0, layering, water intaking phase, 2mol/L sodium hydroxide adjust pH to 11, crystallization filters, filter cake adds 800kg purified water, 4mol/L hydrochloric acid adjust pH to 4.0, stirring and dissolving, 2mol/L sodium hydroxide adjust pH to 11, secondary crystallization, filtration makes 20, 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone compound 126kg, the purity that HPLC detection makes product is greater than 98%, molar product yield: 94.2%.
After testing, the mass spectrum of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone as shown in Figure 1, result is MS m/z734[M+1]
+, the molar yield of 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone is 56.5%.
Embodiment 4
As described in Example 3 20, the preparation method of 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone, difference is:
(1) tylosin tartrate 300kg is dissolved in 6000kg purified water, then keeping temperature is that under the condition of 90 DEG C, to add mass percent be 50% trifluoroacetic acid 343kg, hydrolysis reaction 6h, HPLC detects the completely dissolve of tylosin peak, detect through HPLC, make 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 102kg, molar yield 56.3%;
All the other steps are identical with embodiment 3, finally make 20, the molar yield of 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone is 44.3%.
Embodiment 5
As described in Example 3 20, the preparation method of 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone, difference is:
(1) tylosin tartrate 300kg is dissolved in 6000kg purified water, then keeping temperature is that under the condition of 90 DEG C, to add mass percent be that 30% Hydrogen bromide and the mass percent tosic acid that is 99% is in the mixing 235kg of 1:1 ratio, hydrolysis reaction 6h, HPLC detects the completely dissolve of tylosin peak, detect through HPLC, make 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 113kg, molar yield 62.4%;
All the other steps are identical with embodiment 3, finally make 20, the molar yield of 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone is 49.1%.
Embodiment 6
As described in Example 3 20, the preparation method of 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone, difference is:
(2) in the 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 130kg making to step (1), add ethyl acetate 755kg, the sodium hydroxide solution of 5mol/L regulates pH value to 12, layering, get organic layer, add piperidines 43kg, anhydrous formic acid 26kg, be heated to 78 DEG C, back flow reaction 6h, HPLC detects 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone content and is less than 2g/L, makes 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 130kg; Molar yield 89.5%;
All the other steps are identical with embodiment 3, finally make 20, the molar yield of 23-dipiperidino-5-O mycaminose Ji-Tai Le lactone is 53.3%.
Comparative example 1
Prepare 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone by background technology patent US 6514946, concrete steps are as follows:
20,23-bis-iodos-5-O-mycaminose Ji-Tai Le lactone 151.2mg, add 3ml acetonitrile stirring and dissolving, 80 DEG C of reaction 1h, TCL detects raw material point and disappears, reaction completes, 40 DEG C of vacuum concentration of reaction solution, column chromatography purification, obtains 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone 130mg, purity 97%.
Comparative example 2
Prepare 20,23-dipiperidino-5-O mycaminose Ji-Tai Le lactone by background technology patent by background technology patent WO 2008012343, concrete steps are as follows:
(1) 23-O-(6-deoxidation-2,3-bis--D-allose base) preparation of-20-piperidyl-5-O-mycaminose base-4 ＇-mycaminose Ji-Tai Le lactone
By tylosin 300kg, toluene 1565kg stirring and dissolving, then add piperidines 30.7kg, formic acid 62.1kg, is heated to 70-80 DEG C of stirring reaction 2.5h, and then adds 2.6kg piperidines, stirring reaction 1h again, product mixtures is cooled to 50 DEG C, makes 23-O-(6-deoxidation-2,3-bis--D-allose base)-20-piperidyl-5-O-mycaminose base-4 ＇-mycaminose Ji-Tai Le lactone;
(2) 23-O-(6-deoxidation-2,3-bis--D-allose base) preparation of-20-piperidyl-5-0-mycaminose Ji-Tai Le lactone
23-O-(6-deoxidation-2 prepared by (1), 3-bis--D-allose base)-20-piperidyl-5-O-mycaminose base-4 ＇-mycaminose Ji-Tai Le lactone adds 24wt% hydrobromic acid solution 80L, stir simultaneously and maintain this mixture temperature and be less than 40 DEG C, then use layering in 20 minutes, stratification temperature keeps 20～25 DEG C, the water HPLC of lower floor detects and confirms to have reacted, and makes 23-O-(6-deoxidation-2,3-bis--D-allose base)-20-piperidyl-5-0-mycaminose Ji-Tai Le lactone;
(3) 23-hydroxyl-20-piperidyl-5-0-mycaminose Ji-Tai Le lactone preparation
To 23-O-(6-deoxidation-2 that make in step (2), 3-bis--D-allose base) add 24wt% hydrobromic acid solution 1500L in-20-piperidyl-5-0-mycaminose Ji-Tai Le lactone, 56 DEG C of stirring reaction 2～4h, HPLC detection reaction completes, immediately cooling mixture, at 25～30 DEG C, by water extracting twice, 980kg/ time, water is cooled to 0 DEG C with methylene dichloride, and be less than at 5 DEG C, adjusting ph with sodium hydroxide solution is 10～10.5.At 20 DEG C with methylene dichloride by water extracting twice, 980kg/ time.Use NaHCO
3the aqueous solution is by the organic extractant phase 2 times merging, 1000kg/ time.Then vacuum concentration is removed methylene dichloride, recrystallization 2 times after enriched material adds t-butyl methyl ether to dissolve, 610kg/ time; Use t-butyl methyl ether washed twice, 40 DEG C of vacuum-dryings, obtain 23-hydroxyl-20-piperidyl-5-0-mycaminose Ji-Tai Le lactone 69kg.
(4) the iodo-20-piperidyl-5-0-of 23-mycaminose Ji-Tai Le lactone preparation
At room temperature, by triphenyl phosphorus 90kg, pyridine 30kg, is dissolved in methylene dichloride 1170kg, adds iodine 80kg, is stirred to whole dissolvings, and mixture is cooled to 13 DEG C, and this reaction solution is reaction solution a for subsequent use;
23-hydroxyl-20-piperidyl-5-0-mycaminose Ji-Tai Le lactone 69kg of preparation in (3) is added to methylene dichloride 1170kg stirring and dissolving, 15 DEG C drip the reaction solution a of above-mentioned preparation, 1h left and right dropwises, HLPC detects, reaction has been reacted at 2～2.5h, makes the iodo-20-piperidyl-5-0-of 23-mycaminose Ji-Tai Le lactone;
(5) 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone preparations
In the iodo-20-piperidyl-5-0-of 23-mycaminose Ji-Tai Le lactone of (4) middle preparation, add salt of wormwood 180kg, acetonitrile 1670kg, piperidinyl-1 10kg, be warming up to 78 DEG C, distillate methylene dichloride, exchange of solvent is acetonitrile, back flow reaction 2～2.5h simultaneously, be cooled to 25 DEG C, filter out salt of wormwood, with acetonitrile 280kg washing leaching cake, 50 DEG C of vacuum concentration solvents, resistates adds ethyl acetate 1580kg, and 0.5N hydrochloric acid 3560kg mixes.After stirring, 25 DEG C of layerings, ethyl acetate aqueous phase extracted three times 1580kg/ time; It is 11 that water layer adds 6N sodium hydroxide solution to adjust pH, uses dichloromethane extraction three times, 1870kg/ time; Combined dichloromethane layer, adds 530kg sodium sulfate, stirs 3h, filters 50 DEG C of vacuum concentrated filtrates.Resistates adds 2000kg acetonitrile recrystallization, filters cold acetonitrile washed twice, each 350kg.40 DEG C of vacuum-dryings of filter cake are spent the night, and obtain 20,23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone 36.6kg.Total molar yield 12.2%, purity 90%, total impurities 8.2%.
Interpretation of result
1, comparative example 1 only has single step reaction, its reaction raw materials 20,23-bis-iodos-5-O-mycaminose Ji-Tai Le lactone does not have commercially available prod, although therefore reaction is simple, but also need the raw material in preparation feedback, and not mentioned preparation method in this patent, prior art is also more difficult synthetic, and the finished product need to obtain by column chromatography, are not suitable for industrial production.
2, the present invention and comparative example 2 material used and product content contrast
Produce 1kg 20, the contrast of 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone desired raw material is as shown in table 1:
Table 1
| Material | This patent | Comparative example 2 |
| Tylosin | 2.4kg | 8.2kg |
| Methylene dichloride | 6.1kg | 324.3kg |
| Piperidines | 0.34kg | 3.9kg |
| Formic acid | 0.1kg | 1.7kg |
| Anhydrous magnesium sulfate | 1.5kg | |
| Triphenyl phosphorus | 0.5kg | 2.5kg |
| Imidazoles | 0.13kg | |
| Iodine | 0.24kg | 2.2kg |
| Ethyl acetate | 6.3kg | 43.2kg |
| Sodium carbonate | 0.32kg | |
| Salt of wormwood | 4.9kg | |
| Toluene | 42.76kg | |
| Methyl tertiary butyl ether | 33.3kg | |
| Pyridine | 0.82kg | |
| Acetonitrile | 127.0kg | |
| Molar yield | 58.7% | 12.2% |
| Product purity | 98% | 90% |
By upper table analysis, productive rate of the present invention increases substantially, and raw material consumption significantly reduces, and product purity is higher, is more suitable for suitability for industrialized production compared with comparative example 2.
Claims (10)
1. one kind 20, the preparation method of 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone, is characterized in that, step is as follows:
(1) by tylosin tartrate 1:(15～20 in mass ratio) soluble in water, then keeping temperature is to add acid under the condition of 50～100 DEG C, tylosin tartrate and sour mol ratio are 1:(5～10), hydrolysis reaction 6～8h, makes 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone;
Described acid is one of sulfuric acid, hydrochloric acid, Hydrogen bromide, tosic acid, trifluoroacetic acid or the mixing more than both;
(2) in the 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone reaction liquid making to step (1), add solvent, the mass ratio of 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone and solvent is 1:(5～6), adjust pH to 8～12, layering, get organic layer, add piperidines, formic acid, 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone, formic acid, piperidines mol ratio are 1:(1～3): (1～3), be heated to 39～41 DEG C, back flow reaction 5～6h, makes 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone;
Described solvent is one of methylene dichloride, ethyl acetate, trichloromethane or toluene;
(3) 1:(5～6 in mass ratio in the 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone reaction liquid making to step (2)) adding water stirs, adjust pH to 8～10, layering, get organic layer, add anhydrous magnesium sulfate to stir dehydration, filter, in filtrate, add triphenylphosphine and imidazoles, be cooled to-10～0 DEG C, then add iodine, reaction 2～3h, add sodium sulfite solution, static layering, take off a layer organic phase and add anhydrous magnesium sulfate dehydration, cross leaching filtrate, through vacuum concentration, obtain the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone,
Above-mentioned 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone, triphenylphosphine, imidazoles, iodine mol ratio are: 1:(1～3): (1～3): (1～3);
(4) the iodo-5-O-mycaminose Ji-Tai Le lactone of 20-piperidyl-23-1:(5～6 in mass ratio that step (3) made) be dissolved in ethyl acetate, then add piperidines and sodium carbonate, be warming up to 77～79 DEG C, back flow reaction 5～6h, cross leaching filtrate, add and the isopyknic water of ethyl acetate, adjust pH to 3.5～5.0, layering, water intaking phase, sodium hydroxide solution adjust pH to 10～11, crystallization, after filtration, filter cake is dissolved in 10 times of water, hydrochloric acid adjust pH to 3.5～5.0, after dissolving, sodium hydroxide adjust pH to 8～10, secondary crystallization, filtration makes 20, 23-dipiperidino-5-O mycaminose Ji-Tai Le lactone compound,
The mol ratio of the iodo-5-O-mycaminose Ji-Tai Le of above-mentioned 20-piperidyl-23-lactone, piperidines, sodium carbonate is 1:(1～2): (3～6).
2. preparation method as claimed in claim 1, is characterized in that, in described step (1), tylosin tartrate is 1:18 with quality ratio; Tylosin tartrate, sulfuric acid mol ratio are: 1:6.
3. preparation method as claimed in claim 1, is characterized in that, the acid in described step (1) is sulfuric acid, and the mass concentration of sulfuric acid is 40%.
4. preparation method as claimed in claim 1, is characterized in that, in described step (2), (3) and (4), with the sodium hydroxide solution of 5mol/L or 2mol/L and the hydrochloric acid adjust pH of 4mol/L.
5. preparation method as claimed in claim 1, is characterized in that, in described step (2), 23-hydroxyl-5-O mycaminose Ji-Tai Le lactone, formic acid, piperidines mol ratio are 1:2:2.
6. preparation method as claimed in claim 1, is characterized in that, the solvent in described step (2) is methylene dichloride.
7. preparation method as claimed in claim 1, is characterized in that, in described step (3), 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone, triphenylphosphine, pyridine, iodine mol ratio are: 1:2:2.5:2.
8. preparation method as claimed in claim 1, is characterized in that, in described step (3), the mass concentration of sodium sulfite solution is 10%; Preferably, in described step (3), the temperature of vacuum concentration is 18～22 DEG C.
9. preparation method as claimed in claim 1, is characterized in that, in described step (4), the mol ratio of the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone, piperidines, sodium carbonate is 1:1.2:4.
10. preparation method as claimed in claim 1, is characterized in that, step is as follows:
(1) tylosin tartrate 300kg is dissolved in 4500～6000kg purified water, then keeping temperature is that under the condition of 90 DEG C, to add mass percent be 20～98% sulfuric acid 742kg～302kg, hydrolysis reaction 6～8h; 23-hydroxyl-5-O-mycaminose Ji-Tai Le the lactone making;
(2) that gets that step (1) makes adds methylene dichloride 755kg containing in 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 130～150kg reaction solution, the sodium hydroxide solution of 5mol/L regulates pH value to 10～12, layering, get organic layer, add piperidines 21.5～43kg, anhydrous formic acid 11.5～26kg, be heated to 40 DEG C, back flow reaction 5～6h, HPLC detects 23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone content and is less than 2g/L, makes 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone;
(3) what make to step (2) adds purified water 800kg to stir containing in 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone 138～149kg reaction solution, molten adjust pH to 8～10 of 5mol/L sodium hydroxide, layering, water layer is taken away impurity, get organic layer, add anhydrous magnesium sulfate 90kg to stir dehydration, filter, in filtrate, add triphenylphosphine 61～182.8kg and imidazoles 16～48kg, be cooled to-10～0 DEG C, then add solid iodine 30～90kg in 1h, to add in three batches, reaction 2～3h, HPLC detects 20-piperidyl-23-hydroxyl-5-O-mycaminose Ji-Tai Le lactone and is less than 3g/L, add 10～15wt% sodium sulfite solution 700kg, static layering, take off a layer organic phase and add anhydrous magnesium sulfate 90kg dehydration, cross leaching filtrate, through 20 DEG C of vacuum concentration, obtain the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone,
(4) the iodo-5-O-mycaminose Ji-Tai Le of 20-piperidyl-23-lactone 141.5～153.5kg step (3) being made is dissolved in 780kg ethyl acetate, then add piperidines 20.2～60kg and sodium carbonate 40～120kg, be warming up to 78 DEG C, back flow reaction 5～6h, cross leaching filtrate, add 800kg purified water, hydrochloric acid adjust pH to 4.0, layering, water intaking phase, 2mol/L sodium hydroxide adjust pH to 10～11, crystallization filters, filter cake adds 800kg purified water, 4mol/L hydrochloric acid adjust pH to 4.0, stirring and dissolving, 2mol/L sodium hydroxide adjust pH to 10～11, secondary crystallization, filtration makes 20, 23-dipiperidino-5-O-mycaminose Ji-Tai Le lactone compound.
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| CN103554203A (en) * | 2013-08-17 | 2014-02-05 | 齐鲁动物保健品有限公司 | Amorphous crystal of tylonolide, and preparation method thereof |
| CN104922140B (en) * | 2014-03-20 | 2018-08-31 | 洛阳惠中兽药有限公司 | A kind of tylonolide composition and its application in treating or preventing fowl upper disease |
| CN104447919B (en) * | 2014-11-28 | 2017-03-08 | 武汉回盛生物科技股份有限公司 | A kind of process for purification of 20,23 dipiperidino, 5 O mycaminose Ji Taile lactone bulk drug |
| CN104478974B (en) * | 2014-11-28 | 2016-08-17 | 武汉回盛生物科技有限公司 | A kind of 20, the synthetic method of 23-dipiperidino-5-O-mycamino syl-tylono lide |
| CN104497082B (en) * | 2015-01-13 | 2017-12-12 | 中国兽医药品监察所 | A kind of synthetic method of tylonolide |
| CN104672287B (en) * | 2015-03-26 | 2017-02-22 | 宁夏泰瑞制药股份有限公司 | Method for purifying crude Tildipirosin product |
| CN104892704B (en) * | 2015-04-07 | 2017-08-08 | 中牧实业股份有限公司 | The preparation method of the O mycaminose Ji Taile lactones of 20,23 dipiperidino 5 |
| CN105384788A (en) * | 2015-12-14 | 2016-03-09 | 天津市中升挑战生物科技有限公司 | Tildipirosin preparation method |
| CN108822162B (en) * | 2018-08-22 | 2020-03-17 | 山东久隆恒信药业有限公司 | Synthetic method of tildipirosin intermediate |
| CN111349130A (en) * | 2018-12-21 | 2020-06-30 | 齐鲁动物保健品有限公司 | Tildipirosin crystal form B and preparation method thereof |
| CN110981926B (en) * | 2019-12-12 | 2023-05-16 | 河北远征药业有限公司 | Purification method of crude product of tylosin |
| CN110940751B (en) * | 2019-12-13 | 2022-11-18 | 河北远征药业有限公司 | Tildipirosin bulk drug and detection method of related substances in preparation thereof |
| CN113121625B (en) * | 2019-12-31 | 2023-05-23 | 湖北龙翔药业科技股份有限公司 | Preparation method of tylosin |
| CN114920789B (en) * | 2022-07-07 | 2024-06-14 | 京山瑞生制药有限公司 | Preparation method of tylosin key intermediate |
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| US6514946B1 (en) * | 1999-08-30 | 2003-02-04 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Macrolide antibiotics and treatment and prophylaxis of pasteurellosis using the same |
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| US6514946B1 (en) * | 1999-08-30 | 2003-02-04 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Macrolide antibiotics and treatment and prophylaxis of pasteurellosis using the same |
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