CN110128486B - Synthesis method of tulathromycin - Google Patents
Synthesis method of tulathromycin Download PDFInfo
- Publication number
- CN110128486B CN110128486B CN201910533066.XA CN201910533066A CN110128486B CN 110128486 B CN110128486 B CN 110128486B CN 201910533066 A CN201910533066 A CN 201910533066A CN 110128486 B CN110128486 B CN 110128486B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- carrying
- dichloromethane
- weight ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
- Y02A40/70—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in livestock or poultry
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthesis method of tulathromycin. The preparation method comprises the steps of taking dihydrohomoerythromycin as a starting material, carrying out Cbz-Cl protection, oxidizing by Pfitzner-Moffatt to obtain corresponding dihydrohomoerythromycin aldehyde, carrying out Corey-Chaykovsky epoxidation, carrying out ring-opening addition on an epoxy compound and n-propylamine under the action of a catalyst, and simultaneously carrying out aminolysis deprotection to obtain tulathromycin. The method avoids ultralow temperature reaction during oxidation and epoxidation in the prior art, and the reaction conditions are mild; alcoholysis protecting groups are used for deprotection, so that a hydrogenation deprotection process is avoided, safety risk and production cost are reduced, and industrial production is facilitated.
Description
Technical Field
The invention belongs to the field of chemistry or pharmaceutical chemistry, and particularly relates to a synthesis method of tulathromycin.
Background
Tulathromycin (Tulathromycin) is named Tulathromycin and Tulathromycin, the registered trade name of Tulathromycin is Ruikexin, belongs to macrocyclic azalide compounds structurally, and is mainly applied to broad-spectrum antibiotics and antigen biological agents. The tulathromycin has the advantages of easy absorption, high bioactivity, low residue, long half-life period of decomposition, good water solubility, convenient preparation and the like, and becomes a research hotspot in the present year.
The chemical name of tulathromycin is (2R, 3S,4R,5R,8R,10R, 111R, 12S,13S, 14R) -13- [2,6-dideoxy-3-C-methyl-3-O-methyl-4-C- [ (enamine) methyl ] -a-L-ribo-hexopyranosyl ] -oxy ] -2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11 [ [3,4,6-trideoxy-3- (dimethylamino) -beta-D-xylo-hexopyranosyl ] oxy-1-oxa-6-azacyclopentadecan-15-one. The chemical structure of tulathromycin is complex and has 10 chiral centers. The tulathromycin has better water solubility and alkalescence due to the fact that the tulathromycin contains five hydroxyl groups, three amido groups and one large-ring cycloaliphatic group, and the tulathromycin can penetrate through cell membranes of bacteria and inhibit a transpeptidation process of the bacteria by the characteristic, so that the effect of an antigen is achieved. The structural formula of tulathromycin is shown as follows:
the tulathromycin is a pficine drug developed and marketed in 1999, has strong antigenicity to actinobacillus pneumoniae, pasteurella, haemophilus parasuis, bordetella and other germs, and is mainly used for treating symptoms of large livestock respiratory system diseases, pleuropneumonia, mycoplasma, bronchial septicemia and the like. The national Ministry of agriculture in 2008, 5 months, permits tulathromycin to be used domestically as an injection in the No. 957 bulletin.
The tulathromycin has larger synthesis difficulty due to the complexity of the structure. Patents US6329345 and US6420536 of the company pfeiri use demethyl azithromycin as a starting material, protect hydroxyl groups by benzyl chloroformate, then perform Swern oxidation and Corey-Chaykovsky epoxidation to obtain an epoxy compound, and perform hydrogenation deprotection and n-propylamine addition for a total of 6 steps to obtain telamycin. The synthetic route of daptomycin is shown below:
in the process, because the reaction conditions of Swern oxidation and Corey-Chaykovsky epoxidation are harsh (the reaction temperature is lower than minus 80 ℃), the synthesis cost of the tulathromycin is high, and the tulathromycin is not easy to be produced in an enlarged mode; meanwhile, in the hydrogenation process, due to the generation of dimethyl sulfide in the oxidation process of the previous step, the consumption of palladium carbon as a catalyst is large (the consumption is equal to the quality of an epoxy compound), the industrial production cannot be enlarged, and the production cost is high.
In view of the defects of the existing mebendazole transformation process, the method for synthesizing tulathromycin, which has mild reaction conditions, few steps and high yield and is suitable for production, is still to be explored and researched further.
Disclosure of Invention
Aiming at various defects of the above route, the invention aims to provide a synthesis method of tulathromycin which has mild reaction conditions, less steps and high yield and is suitable for production, and the specific technical scheme is as follows:
the synthesis method of tulathromycin is carried out by the following chemical reaction equation:
the reaction equation is prepared by the following steps:
(1) Hydroxyl protection: adopting dihydrohomoerythromycin (compound 1) as initial material, dichloromethane as solvent, triethylamine as acid-binding agent for catalysis, and dropwise adding chloroformate as protective agent at 0-5 deg.C
Carrying out condensation reaction on a dichloromethane solution, carrying out heat preservation reaction for 2-3h, carrying out water quenching on a reaction solution, standing, layering, washing with water, drying with anhydrous sodium sulfate, and carrying out reduced pressure concentration to obtain a compound 2; wherein the R substituent of the protective agent is at least one of p-nitrobenzyl, p-methylbenzyl, benzyl and allyl;
(2) And (3) oxidation: in an organic solvent, carrying out Pfitzner-Moffatt oxidation on hydroxyl of a compound 2 by an oxidant A under the action of a catalyst to convert the hydroxyl into carbonyl, carrying out water quenching on reaction liquid, standing, layering, washing with water, drying by anhydrous sodium sulfate, carrying out reduced pressure concentration, adding dichloromethane and methyl tert-butyl ether for dissolving, dropwise adding trifluoroacetic acid to form a salt at 25 ℃, and carrying out suction filtration to obtain a compound 3;
(3) Epoxidation: dissociating the compound 3 in dichloromethane by potassium carbonate, separating layers, drying by anhydrous sodium sulfate, and oxidizing the compound 3 into an epoxy compound (compound 4) by Corey epoxidation by an oxidant B in an organic solvent under the alkaline condition;
(4) Aminolysis and deprotection: in an organic solvent, carrying out ring-opening addition on the compound 4 and n-propylamine under the action of a catalyst, simultaneously carrying out aminolysis deprotection to obtain a crude product of the tulathromycin (compound 5), forming salt by phosphoric acid, dissociating by potassium carbonate in water and dichloromethane, layering, carrying out reduced pressure concentration, adding acetone with the weight ratio of the compound 4 being 3.4-4.0 times that of the compound, and carrying out crystallization to obtain a refined product of the tulathromycin (compound 5).
Wherein in the reaction step (1), the dosage of the dichloromethane is 8-10 times of the weight of the dihydrohomoerythromycin, and the dosage of the triethylamine is 1.0-1.2 times of the molar ratio of the dihydrohomoerythromycin.
In the reaction step (2), the oxidant A is at least one of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, pyridinium chlorochromate and trifluoroacetic acid, and the molar ratio of the oxidant A to the compound 2 is 3-5: 1; the organic solvent is at least one of dimethyl sulfoxide, dichloromethane and tetrahydrofuran, and the weight ratio of the organic solvent to the compound 2 is 3-8: 1; the catalyst is trifluoroacetic acid pyridine; after decompression and concentration, the dosage of the added dichloromethane is 1.3 times of the weight ratio of the compound 2, the dosage of the methyl tert-butyl ether is 2.6 times of the weight ratio of the compound 2, and the dosage of the trifluoroacetic acid is 2 times of the molar ratio of the compound 2; the reaction temperature of the reaction step (2) is 0-25 ℃, and the reaction time is 10-15 h.
In the reaction step (3), the oxidant B is at least one of trimethyl sulfoxide iodide, trimethyl sulfoxide bromide and trimethyl sulfoxide chloride, and the molar ratio of the oxidant B to the compound 3 is 1-1.5: 1; the alkali is at least one of sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, sodium carbonate, potassium tert-butoxide, butyl lithium and tert-butyl lithium, and the molar ratio of the alkali to the compound 3 is 1.1-1.8: 1; the organic solvent is at least one of tetrahydrofuran, dimethyl sulfoxide and dichloromethane, and the weight ratio of the organic solvent to the compound 3 is 5-10; the amount of the water is 4.0-5.0 times of the weight ratio of the compound 3; the dosage of the dichloromethane is 6.5 to 8 times of the weight ratio of the compound 3; the dosage of the potassium carbonate is 3.0 to 4.5 times of the molar ratio of the compound 3; the reaction temperature of the reaction step (3) is-20 to 0 ℃, and the reaction time is 2 to 4 hours.
The catalyst in the reaction step (4) is at least one of potassium iodide, sodium iodide, potassium carbonate, sodium carbonate, potassium chloride and sodium chloride, and the molar ratio of the catalyst to the compound 4 is 3-5:1; the mol ratio of the compound 4 to the n-propylamine is 1; the organic solvent is at least one of methanol, ethanol and isopropanol, and the weight ratio of the organic solvent to the compound 4 is 5-10: 1; the dosage of the phosphoric acid is 1.0 to 1.5 times of the weight ratio of the compound 4; the amount of the water is 9.0 to 12.0 times of the weight ratio of the compound 4; the dosage of the dichloromethane is 9.0 to 12.0 times of the weight ratio of the compound 4; the using amount of the potassium carbonate is 0.5-0.65 time of the weight ratio of the compound 4; the reaction temperature of the reaction step (4) is 60-80 ℃, and the reaction time is 16-18 h.
The invention has the beneficial effects that:
1) The invention provides a synthesis method of tulathromycin, which improves an oxidation method for oxidizing a compound 2 into a compound 3, uses 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and other oxidants for oxidation, has mild reaction conditions (0-25 ℃), avoids low-temperature reaction (-70-80 ℃) in the original process, and reduces the production difficulty of industrial production.
2) The method uses the Corey epoxidation oxidant trimethyl sulfoxide iodide for epoxidation, has mild reaction conditions (-20-0 ℃), avoids low-temperature reaction (-70-80 ℃) in the prior art, and reduces the production difficulty of industrial production.
3) The deprotection method is improved, alcoholysis protection groups are used for deprotection, the hydrogenation deprotection process is avoided, the safety risk and the production cost are reduced, and the industrial production is easy to realize.
4) The invention provides a synthesis method of tulathromycin, the total yield reaches more than 50.0%, the HPLC content is more than 99.0%, the single impurity content is less than 0.5%, and the process is stable.
Drawings
FIG. 1 is a spectrum of a tylosin mass spectrum.
FIG. 2 is a mass spectrum of Compound 4.
Detailed Description
The invention is described in detail below by means of specific examples, which are intended to illustrate the invention without limiting it.
Example 1
1) Preparation of compound 2:
A1L reaction flask was charged with 50g (68 mmol) of dihydrohomoerythromycin, 500g of dichloromethane and 8.2g of triethylamine, N 2 The displacement is carried out three times, 17g (82 mmol) of benzyl chloroformate solution in dichloromethane (50 g) is dripped at 0 ℃, the dripping temperature is controlled at 0-5 ℃, and the dripping time is controlled for 1-2 hours. After the dropwise addition, the mixture is kept warm and stirred for 2 to 3 hours, HPLC (high performance liquid chromatography) central control detection is carried out to ensure that the raw materials completely react, and the stirring is stopped. The reaction solution was slowly poured into 1L of water to quench, and after standing and layering, liquid separation was carried out, the organic phase was collected, washed with 1L of water for 2 times, and dried over anhydrous sodium sulfate. Filtration and rotary evaporation of the organic phase under reduced pressure gave 53.3g of a white solid in 90.2% yield with an HPLC content of 95.1%.
2) Preparation of Compound 3
A500 ml reaction flask was charged with 30g of Compound 2 (34.5 mmol), 100g of dimethyl sulfoxide, 11g of pyridine (136 mmol), and 26g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (136 mmol), and after mixing well, N was added 2 The substitution was carried out three times. 16g of trifluoroacetic acid (136 mmol) in dichloromethane (100 ml) is dripped into the reaction flask at 0 ℃, the dripping speed is controlled, the reaction temperature in the four-mouth flask is kept at 0-5 ℃, and the dripping is carried out for 1-2 hours. Stirring at constant temperature for 10-12h after the dropwise addition is finished, detecting that the raw materials are completely reacted, and stopping stirring. The reaction solution was slowly poured into 1L of water to quench, and after standing and layering, liquid separation was carried out, the organic phase was collected, washed with 100ml of water for 2 times, and dried over anhydrous sodium sulfate. Filtering, and carrying out reduced pressure rotary evaporation on the organic phase to obtain a yellow oily substance.
Adding 40g of dichloromethane and 80g of methyl tert-butyl ether into the yellow oily substance to dissolve the yellow oily substance to prepare a mixed solution, adding the mixed solution into a 250ml reaction bottle, dropwise adding 7.9g (69.3 mmol) of trifluoroacetic acid into the reaction bottle at 25 ℃, stirring at constant temperature for 1-2h after dropwise adding is finished for 30-60min, crystallizing, and performing suction filtration to obtain 34.8g of white solid, namely the compound 3, wherein the yield is 92.0%, and the HPLC content is 87.5%
3) Preparation of Compound 4
Adding 38g of compound 3 (34.7 mmol), 19.4g of potassium carbonate (136 mmol), 170g of water and 250g of dichloromethane into a 250ml reaction bottle, stirring at constant temperature of 25 ℃ for 1-2h, standing the reaction solution for layering after complete dissociation, separating liquid, collecting organic phase, and using Na for the organic phase 2 SO 4 And drying and then carrying out suction filtration for later use.
1g of sodium hydride (41 mmol) and 50ml of dimethyl sulfoxide are added into a 500ml reaction bottle, N2 is replaced for three times, the reaction bottle is cooled to 0 ℃, 9g of dimethyl sulfoxide (20 ml) solution of trimethyl sulfoxide iodide (41 mmol) is added into the reaction bottle dropwise at 0 ℃, and after dropwise addition is finished for 1-2h, the reaction bottle is stirred for 1-2h at constant temperature. And (3) dropwise adding a dichloromethane solution of the compound 3 into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. Detecting the reaction of the raw materials, slowly adding 100g of water into a reaction bottle to quench the reaction, stirring for 30-60min, and standing for layering. The organic phase was collected, washed 2 times with 150ml of water, 1 time with 150ml of saturated brine, and then dried over anhydrous sodium sulfate. Filtration and rotary evaporation of the organic phase under reduced pressure gave 25.1g of a yellow oil, compound 4, in 82.1% yield and 82.4% HPLC content.
The liquid quality detection [ M ] is 881.55 (the theoretical molecular weight is 881.10).
4) Preparation of tulathromycin
Adding 8.8g of compound 4 (10 mmol), 0.8g of potassium iodide and 23.6g of n-propylamine into a 250ml reaction bottle, heating to 60 ℃, sealing for reaction, stirring at constant temperature for 16-18h, detecting that the raw materials are completely reacted, carrying out suction filtration and reduced pressure rotary evaporation to obtain 12g of yellow oily matter, namely a crude product of the tulathromycin.
Dissolving 12g of crude tulathromycin in 120ml of methanol, adding the dissolved solution into a 250ml reaction bottle, dripping 11g of methanol (100 ml) solution of phosphoric acid at 25 ℃, stirring and crystallizing for 1-2h at constant temperature of 25 ℃ after dripping for 30-60 min. Vacuum-filtering, and vacuum-drying at 50 deg.C or below to obtain white solid (9.12 g), i.e. tulathromycin diphosphate.
Adding 85g of pure water and 5.2g of potassium carbonate into a 250ml four-mouth bottle, starting stirring, adding 9.12g of the tulathromycin phosphate and 85g of dichloromethane, stirring until the materials are clear, layering, distilling an organic layer under reduced pressure until the organic layer is dried, adding 30g of acetone, stirring, heating to 40 ℃, dropwise adding 45g of pure water, separating out a white solid, carrying out suction filtration, and carrying out vacuum drying at 50 ℃ to obtain 6.1g of tulathromycin, wherein the yield is 75.7%, the HPLC content is 99.0%, and the single impurity content is less than 0.5%.
The liquid quality detection [ M ] is 806.50 (the theoretical molecular weight is 806.08).
Example 2:
preparation of Compound 3
A500 ml reaction flask was charged with 30g of Compound 2 (34.5 mmol), 100g of dimethyl sulfoxide, 11g of pyridine (136 mmol), and 21g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (136 mmol), and after mixing well, N was added 2 The substitution was carried out three times. 16g of trifluoroacetic acid (136 mmol) in dichloromethane (100 ml) is dripped into the reaction flask at 0 ℃, the dripping speed is controlled, the reaction temperature in the four-mouth flask is kept at 0-5 ℃, and the dripping is carried out for 1-2 hours. Stirring at constant temperature for 10-12h after the dropwise addition is finished, detecting that the raw materials are completely reacted, and stopping stirring. The reaction solution was slowly poured into 1L of water to quench, and after standing and layering, liquid separation was carried out, the organic phase was collected, washed with 100ml of water for 2 times, and dried over anhydrous sodium sulfate. Filtering, and carrying out reduced pressure rotary evaporation on the organic phase to obtain a yellow oily substance.
Adding 40g of dichloromethane and 80g of methyl tert-butyl ether into the yellow oily substance to dissolve the yellow oily substance to prepare a mixed solution, adding the mixed solution into a 250ml reaction bottle, dropwise adding 7.9g (69.3 mmol) of trifluoroacetic acid into the reaction bottle at 25 ℃, stirring at constant temperature for 1-2h after dropwise adding is finished for 30-60min, crystallizing, and performing suction filtration to obtain 35.0g of a white solid, namely the bistrifluoroacetate salt of the compound 3, wherein the yield is 92.5%, and the HPLC content is 87.8%.
Example 3:
preparation of Compound 3
A500 ml reaction flask was charged with 29g of pyridinium chlorochromate (136 mmol) and 120g of tetrahydrofuran, and after mixing well, N 2 The substitution was carried out three times. 30g of a tetrahydrofuran (100 g) solution of Compound 2 (34.5 mmol) was added dropwise to a reaction flask at 0 ℃ while controlling the dropping rate to maintain the reaction in the flaskDropping at 0-5 deg.c for 1-2 hr. Stirring at constant temperature for 10-12h after the dropwise addition is finished, detecting that the raw materials are completely reacted, and stopping stirring. The reaction solution was slowly poured into 1L of water to quench, and after standing and layering, liquid separation was carried out, the organic phase was collected, washed with 100ml of water for 2 times, and dried over anhydrous sodium sulfate. Filtering, and performing reduced pressure rotary evaporation on the organic phase to obtain red oily matter.
Adding 40g of dichloromethane and 80g of methyl tert-butyl ether into the red oily substance, dissolving to prepare a mixed solution, adding the mixed solution into a 250ml reaction bottle, dropwise adding 7.9g (69.3 mmol) of trifluoroacetic acid into the reaction bottle at 25 ℃, stirring at constant temperature for 1-2h after dropwise adding is finished for 30-60min, crystallizing, and performing suction filtration to obtain 35.2g of a white solid, namely the bistrifluoroacetate salt of the compound 3, wherein the yield is 93.1%, and the HPLC content is 88.5%.
Example 4:
preparation of Compound 4
Adding 38g of compound 3 (34.7 mmol), 19.4g of potassium carbonate (136 mmol), 170g of water and 250g of dichloromethane into a 250ml reaction bottle, stirring at constant temperature of 25 ℃ for 1-2h, standing and demixing reaction liquid after complete dissociation, separating liquid, collecting organic phase, and using Na for the organic phase 2 SO 4 And drying and then carrying out suction filtration for later use.
1g of sodium hydride (41 mmol) and 50ml of tetrahydrofuran are added into a 500ml reaction bottle, N2 is replaced for three times, the reaction bottle is cooled to 0 ℃, 7g of tetrahydrofuran (20 ml) solution of trimethyl sulfoxide bromide (41 mmol) is dripped into the reaction bottle at the temperature of 0 ℃, after dripping for 1 to 2 hours, the reaction bottle is stirred for 1 to 2 hours at constant temperature. And (3) dropwise adding a dichloromethane solution of the compound 3 into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. Detecting that the raw materials are completely reacted, slowly adding 100g of water into a reaction bottle to quench the reaction, stirring for 30-60min, and standing for layering. The organic phase was collected, washed 2 times with 150ml of water, 1 time with 150ml of saturated brine, and then dried over anhydrous sodium sulfate. Filtration and rotary evaporation of the organic phase under reduced pressure gave 25.5g of a yellow oil, compound 4, in 83.5% yield and 82.8% HPLC content.
Example 5:
preparation of Compound 4
38g of Compound 3 (34.7 mmol), 19.4g of potassium carbonate (136 mmol), 170g of water, 250g of methylene chloride were charged into a 250ml reaction flaskStirring at constant temperature of 25 deg.C for 1-2 hr, standing for layering, separating, collecting organic phase with Na 2 SO 4 Drying and then carrying out suction filtration for later use.
1g of sodium hydride (41 mmol), 50ml of dichloromethane and N2 are added into a 500ml reaction bottle for three times of replacement, the reaction bottle is cooled to 0 ℃, 5.5g of dichloromethane (20 ml) solution of trimethyl thionyl chloride (41 mmol) is added into the reaction bottle dropwise at the temperature of 0 ℃, after the dropwise addition is finished for 1-2h, the reaction bottle is stirred for 1-2h at constant temperature. And (3) dropwise adding a dichloromethane solution of the compound 3 into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. Detecting the reaction of the raw materials, slowly adding 100g of water into a reaction bottle to quench the reaction, stirring for 30-60min, and standing for layering. The organic phase was collected, washed 2 times with 150ml of water, 1 time with 150ml of saturated brine, and then dried over anhydrous sodium sulfate. Filtration and rotary evaporation of the organic phase under reduced pressure gave 26.1g of a yellow oil, compound 4, in 85.4% yield with an HPLC content of 81.5%.
Example 6:
preparation of Compound 4
Adding 38g of compound 3 (34.7 mmol), 19.4g of potassium carbonate (136 mmol), 170g of water and 300g of dichloromethane into a 250ml reaction bottle, stirring at constant temperature of 25 ℃ for 1-2h, standing and demixing reaction liquid after complete dissociation, separating liquid, collecting organic phase, and using Na for the organic phase 2 SO 4 And drying and then carrying out suction filtration for later use.
1.6g of sodium hydroxide (41 mmol) and 50ml of dimethyl sulfoxide are added into a 500ml reaction bottle, N2 is replaced for three times, the mixture is cooled to 0 ℃, 9g of dimethyl sulfoxide (20 ml) solution of trimethyl sulfoxide iodide (41 mmol) is dripped into the reaction bottle at the temperature of 0 ℃, after dripping for 1-2h, the mixture is stirred for 1-2h at constant temperature. And (3) dropwise adding a dichloromethane solution of the compound 3 into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. Detecting the reaction of the raw materials, slowly adding 100g of water into a reaction bottle to quench the reaction, stirring for 30-60min, and standing for layering. The organic phase was collected, washed 2 times with 150ml of water, 1 time with 150ml of saturated brine, and then dried over anhydrous sodium sulfate. Filtration and rotary evaporation of the organic phase under reduced pressure gave 25.7g of a yellow oil, compound 4, in 84.1% yield and 83.5% HPLC content.
Example 7:
preparation of Compound 4
Adding 38g of compound 3 (34.7 mmol), 19.4g of potassium carbonate (136 mmol), 170g of water and 280g of dichloromethane into a 250ml reaction bottle, stirring at constant temperature of 25 ℃ for 1-2h, standing and demixing reaction liquid after complete dissociation, separating liquid, collecting organic phase, and using Na for the organic phase 2 SO 4 And drying and then carrying out suction filtration for later use.
6.5g of sodium carbonate (61 mmol) and 50ml of dimethyl sulfoxide are added into a 500ml reaction bottle, N2 is replaced for three times, the mixture is cooled to 0 ℃, 9g of dimethyl sulfoxide (20 ml) solution of trimethyl sulfoxide iodide (41 mmol) is dropwise added into the reaction bottle at the temperature of 0 ℃, after dropwise addition is finished for 1-2h, the mixture is stirred for 1-2h at constant temperature. And (3) dropwise adding a dichloromethane solution of the compound 3 into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. Detecting that the raw materials are completely reacted, slowly adding 100g of water into a reaction bottle to quench the reaction, stirring for 30-60min, and standing for layering. The organic phase was collected, washed 2 times with 150ml of water, 1 time with 150ml of saturated brine, and then dried over anhydrous sodium sulfate. Filtration and reduced pressure rotary evaporation of the organic phase gave 26.3g of yellow oil, compound 4, 86.0% yield and 82.0% HPLC content.
Example 8:
preparation of Compound 4
Adding 38g of compound 3 (34.7 mmol), 19.4g of potassium carbonate (136 mmol), 170g of water and 250g of dichloromethane into a 250ml reaction bottle, stirring at constant temperature of 25 ℃ for 1-2h, standing and demixing reaction liquid after complete dissociation, separating liquid, collecting organic phase, and using Na for the organic phase 2 SO 4 And drying and then carrying out suction filtration for later use.
4.2g of potassium carbonate (41 mmol) and 50ml of dimethyl sulfoxide are added into a 500ml reaction bottle, N2 is replaced for three times, the mixture is cooled to 0 ℃, 9g of dimethyl sulfoxide (20 ml) solution of trimethyl sulfoxide iodide (41 mmol) is dropwise added into the reaction bottle at the temperature of 0 ℃, after dropwise addition is finished for 1-2h, the mixture is stirred for 1-2h at constant temperature. And (3) dropwise adding a dichloromethane solution of the compound 3 into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. Detecting the reaction of the raw materials, slowly adding 100g of water into a reaction bottle to quench the reaction, stirring for 30-60min, and standing for layering. The organic phase was collected, washed 2 times with 150ml of water, 1 time with 150ml of saturated brine, and then dried over anhydrous sodium sulfate. After filtration and reduced pressure rotary evaporation of the organic phase, 25.2g of yellow oil, compound 4, was obtained in 82.4% yield and 83.3% HPLC content.
Example 9:
preparation of Compound 4
Adding 38g of compound 3 (34.7 mmol), 19.4g of potassium carbonate (136 mmol), 170g of water and 250g of dichloromethane into a 250ml reaction bottle, stirring at constant temperature of 25 ℃ for 1-2h, standing and demixing reaction liquid after complete dissociation, separating liquid, collecting organic phase, and using Na for the organic phase 2 SO 4 And drying and then carrying out suction filtration for later use.
A500 ml reaction flask was charged with 4.6g of potassium tert-butoxide (41 mmol), 50ml of dimethyl sulfoxide, N 2 Replacing three times, cooling to 0 ℃, dropwise adding 9g dimethyl sulfoxide (20 ml) solution of trimethyl sulfoxide iodide (41 mmol) into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. And (3) dropwise adding a dichloromethane solution of the compound 3 into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. Detecting the reaction of the raw materials, slowly adding 100g of water into a reaction bottle to quench the reaction, stirring for 30-60min, and standing for layering. The organic phase was collected, washed 2 times with 150ml of water, 1 time with 150ml of saturated brine, and then dried over anhydrous sodium sulfate. Filtration and rotary evaporation of the organic phase under reduced pressure gave 25.0g of a yellow oil, compound 4, in 81.8% yield and 85.4% HPLC content.
Example 10:
preparation of Compound 4
Adding 38g of compound 3 (34.7 mmol), 19.4g of potassium carbonate (136 mmol), 170g of water and 250g of dichloromethane into a 250ml reaction bottle, stirring at constant temperature of 25 ℃ for 1-2h, standing the reaction solution for layering after complete dissociation, separating liquid, collecting organic phase, and using Na for the organic phase 2 SO 4 And drying and then carrying out suction filtration for later use.
41ml of an N-butyllithium tetrahydrofuran solution (1M, 41mmol), 50ml of dimethyl sulfoxide, N 2 Replacing three times, cooling to 0 ℃, dropwise adding 9g dimethyl sulfoxide (20 ml) solution of trimethyl sulfoxide iodide (41 mmol) into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. And (3) dropwise adding a dichloromethane solution of the compound 3 into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. Detecting raw materialsAnd (3) after the reaction is complete, slowly adding 100g of water into the reaction bottle to quench the reaction, stirring for 30-60min, and standing for layering. The organic phase was collected, washed 2 times with 150ml of water, 1 time with 150ml of saturated brine, and then dried over anhydrous sodium sulfate. Filtration and rotary evaporation of the organic phase under reduced pressure gave 26.6g of a yellow oil, compound 4, in 87.0% yield and 80.5% HPLC content.
Example 11:
preparation of Compound 4
Adding 38g of compound 3 (34.7 mmol), 19.4g of potassium carbonate (136 mmol), 170g of water and 250g of dichloromethane into a 250ml reaction bottle, stirring at constant temperature of 25 ℃ for 1-2h, standing and demixing reaction liquid after complete dissociation, separating liquid, collecting organic phase, and using Na for the organic phase 2 SO 4 And drying and then carrying out suction filtration for later use.
A500 ml reaction flask was charged with 41ml of t-butyllithium tetrahydrofuran solution (1M, 41mmol), 50ml of dimethyl sulfoxide, N 2 Replacing three times, cooling to 0 ℃, dropwise adding 9g dimethyl sulfoxide (20 ml) solution of trimethyl sulfoxide iodide (41 mmol) into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. And (3) dropwise adding a dichloromethane solution of the compound 3 into the reaction bottle at 0 ℃, stirring for 1-2h at constant temperature after dropwise adding is finished for 1-2h. Detecting the reaction of the raw materials, slowly adding 100g of water into a reaction bottle to quench the reaction, stirring for 30-60min, and standing for layering. The organic phase was collected, washed 2 times with 150ml of water, 1 time with 150ml of saturated brine, and then dried over anhydrous sodium sulfate. After filtration and reduced pressure rotary evaporation of the organic phase, 25.6g of yellow oil, compound 4, was obtained in 83.7% yield and 83.8% HPLC content.
Example 12:
preparation of tulathromycin
Adding 8.8g of compound 4 (10 mmol), 0.6g of potassium carbonate and 17.8g (301.1 mmol) of n-propylamine into a 250ml reaction bottle, heating to 60 ℃, sealing for reaction, stirring at constant temperature for 16-18h, detecting the completion of the reaction of the raw materials, carrying out suction filtration, pressure reduction and rotary evaporation to obtain 16g of yellow oily matter, namely a crude product of the tulathromycin.
Dissolving 16g of crude tulathromycin in 120ml of methanol, adding the dissolved solution into a 250ml reaction bottle, dripping 8.8g of methanol (100 ml) solution of phosphoric acid at 25 ℃, stirring and crystallizing for 1-2h at the constant temperature of 25 ℃ after dripping for 30-60 min. The white solid, i.e. the tulathromycin diphosphate, 9.8g is obtained by suction filtration.
Adding 90g of pure water and 5.4g of potassium carbonate into a 250ml four-mouth bottle, starting stirring, adding 9.8g of the tulathromycin phosphate and 100g of dichloromethane, stirring until the materials are clear, layering, distilling an organic layer under reduced pressure until the organic layer is dried, adding 35g of acetone, stirring, heating to 40 ℃, dropwise adding 50g of pure water, separating out a white solid, carrying out suction filtration, and carrying out vacuum drying at 50 ℃ to obtain 6.3g of tulathromycin, wherein the yield is 78.2%, the HPLC content is 99.2%, and the single impurity content is less than 0.3%.
Example 13:
preparation of tulathromycin
Adding 8.8g of compound 4 (10 mmol), 0.5g of potassium chloride and 11.9g (201.3 mmol) of n-propylamine into a 250ml reaction bottle, heating to 60 ℃, sealing for reaction, stirring at constant temperature for 16-18h, detecting the completion of the reaction of the raw materials, and performing suction filtration, decompression and rotary evaporation to obtain 19g of yellow oily matter, namely a crude product of the tulathromycin.
Dissolving 19g of crude tulathromycin in 120ml of methanol, adding the dissolved solution into a 250ml reaction bottle, dripping 12g of methanol (100 ml) solution of phosphoric acid at 25 ℃, stirring and crystallizing for 1-2h at constant temperature of 25 ℃ after dripping for 30-60 min. The white solid, i.e. the tulathromycin diphosphate, 9.5g is obtained by suction filtration.
Adding 85g of pure water and 5.3g of potassium carbonate into a 250ml four-mouth bottle, starting stirring, adding 9.5g of the tulathromycin phosphate and 90g of dichloromethane, stirring until the materials are dissolved clearly, layering, distilling an organic layer under reduced pressure until the organic layer is dried, adding 32g of acetone, stirring, heating to 40 ℃, dropwise adding 47g of pure water, separating out a white solid, carrying out suction filtration, and carrying out vacuum drying at 50 ℃ to obtain 6.2g of tulathromycin, wherein the yield is 76.9%, the HPLC content is 99.3%, and the single impurity content is less than 0.3%.
The present invention is not limited to the above-described embodiments, and any simple, equivalent changes or modifications made to the above-described embodiments in accordance with the technical spirit of the present invention fall within the technical scope of the present invention.
Claims (1)
1. A synthesis method of tulathromycin is characterized by comprising the following steps: prepared via the following chemical reaction equation:
the reaction equation is prepared by the following steps:
(1) Hydroxyl protection: adopting dihydrohomoerythromycin, namely a compound 1 as an initial raw material, dichloromethane as a solvent, triethylamine as an acid-binding agent for catalysis, and dropwise adding a protective agent chloroformate at 0-5 ℃, namely
Carrying out condensation reaction on a dichloromethane solution, carrying out heat preservation reaction for 2-3h, carrying out water quenching on a reaction solution, standing, layering, washing with water, drying with anhydrous sodium sulfate, and carrying out reduced pressure concentration to obtain a compound 2; wherein the R substituent of the protective agent is at least one of p-nitrobenzyl, p-methylbenzyl, benzyl and allyl;
(2) And (3) oxidation: in an organic solvent, carrying out Pfitzner-Moffatt oxidation on hydroxyl of a compound 2 by an oxidant A under the action of a catalyst to change the hydroxyl into carbonyl, carrying out water quenching on reaction liquid, standing, layering, washing with water, drying by anhydrous sodium sulfate, carrying out reduced pressure concentration, adding dichloromethane and methyl tert-butyl ether for dissolving, dropwise adding trifluoroacetic acid to form a salt at 25 ℃, and carrying out suction filtration to obtain a compound 3;
(3) Epoxidation: dissociating the compound 3 in water and dichloromethane by using potassium carbonate, layering, drying by using anhydrous sodium sulfate, and oxidizing the compound 3 into an epoxy compound, namely a compound 4 by performing Corey epoxidation by using an oxidant B in an organic solvent under the alkaline condition;
(4) Aminolysis and deprotection: in an organic solvent, carrying out ring-opening addition on a compound 4 and n-propylamine under the action of a catalyst, simultaneously carrying out aminolysis deprotection to obtain a crude compound 5 of the tulathromycin, carrying out salification by phosphoric acid, carrying out potassium carbonate liberation in water and dichloromethane, layering, carrying out reduced pressure concentration, adding acetone with the weight ratio of the compound 4 being 3.4-4.0, and carrying out crystallization to obtain the tulathromycin, namely a refined compound 5 of the compound 5;
in the reaction step (1), the dosage of the dichloromethane is 8 to 10 times of the weight of the dihydrohomoerythromycin, and the dosage of the triethylamine is 1.0 to 1.2 times of the molar ratio of the dihydrohomoerythromycin;
in the reaction step (2), the oxidant A is at least one of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, pyridinium chlorochromate and trifluoroacetic acid, and the molar ratio of the oxidant A to the compound 2 is 3-5: 1; the organic solvent is at least one of dimethyl sulfoxide, dichloromethane and tetrahydrofuran, and the weight ratio of the organic solvent to the compound 2 is 3-8: 1; the catalyst is trifluoroacetic acid pyridine; the dosage of dichloromethane added after decompression concentration is 1.3 times of the weight ratio of the compound 2, the dosage of methyl tert-butyl ether is 2.6 times of the weight ratio of the compound 2, and the dosage of trifluoroacetic acid is 2 times of the molar ratio of the compound 2; the reaction temperature of the reaction step (2) is 0-25 ℃, and the reaction time is 10-15 h;
in the reaction step (3), the oxidant B is at least one of trimethyl sulfoxide iodide, trimethyl sulfoxide bromide and trimethyl sulfoxide chloride, and the molar ratio of the oxidant B to the compound 3 is 1-1.5: 1; the alkali is at least one of sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, sodium carbonate, potassium tert-butoxide, butyl lithium and tert-butyl lithium, and the molar ratio of the alkali to the compound 3 is 1.1-1.8: 1; the organic solvent is at least one of tetrahydrofuran, dimethyl sulfoxide and dichloromethane, and the weight ratio of the organic solvent to the compound 3 is 5-10; the amount of the water is 4.0-5.0 times of the weight ratio of the compound 3; the dosage of the dichloromethane is 6.5 to 8 times of the weight ratio of the compound 3; the dosage of the potassium carbonate is 3.0 to 4.5 times of the molar ratio of the compound 3; the reaction temperature of the reaction step (3) is-20 to 0 ℃, and the reaction time is 2 to 4 hours;
the catalyst in the reaction step (4) is at least one of potassium iodide, sodium iodide, potassium carbonate, sodium carbonate, potassium chloride and sodium chloride, and the molar ratio of the catalyst to the compound 4 is 3-5:1; the mol ratio of the compound 4 to the n-propylamine is 1; the organic solvent is at least one of methanol, ethanol and isopropanol, and the weight ratio of the organic solvent to the compound 4 is 5-10: 1; the dosage of the phosphoric acid is 1.0 to 1.5 times of the weight ratio of the compound 4; the amount of the water is 9.0 to 12.0 times of the weight ratio of the compound 4; the dosage of the dichloromethane is 9.0 to 12.0 times of the weight ratio of the compound 4; the using amount of the potassium carbonate is 0.5-0.65 time of the weight ratio of the compound 4; the reaction temperature of the reaction step (4) is 60-80 ℃, and the reaction time is 16-18 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910533066.XA CN110128486B (en) | 2019-06-19 | 2019-06-19 | Synthesis method of tulathromycin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910533066.XA CN110128486B (en) | 2019-06-19 | 2019-06-19 | Synthesis method of tulathromycin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110128486A CN110128486A (en) | 2019-08-16 |
| CN110128486B true CN110128486B (en) | 2022-12-02 |
Family
ID=67577986
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910533066.XA Active CN110128486B (en) | 2019-06-19 | 2019-06-19 | Synthesis method of tulathromycin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110128486B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072730B (en) * | 2019-12-16 | 2021-01-12 | 浙江国邦药业有限公司 | Preparation method and application of tulathromycin intermediate salt |
| CN111253447B (en) * | 2020-03-26 | 2021-03-02 | 苏州正永生物医药有限公司 | Preparation method of tulathromycin |
| CN115960145A (en) * | 2023-01-17 | 2023-04-14 | 陕西师范大学 | Synthesis method of tulathromycin intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260306A (en) * | 2011-07-22 | 2011-11-30 | 山东鲁抗舍里乐药业有限公司 | Novel method for preparing tulathromycin |
| WO2012038372A1 (en) * | 2010-09-20 | 2012-03-29 | Novartis Ag | Novel process for the preparation of 9-deoxo-9a-aza- 9a-homoerythromycin a modified in the c-4'' of the cladinose ring by an epoxide group |
| CN105492004A (en) * | 2013-02-08 | 2016-04-13 | 罗达制药有限公司 | Methods of treating topical microbial infections |
| CN106939029A (en) * | 2017-04-28 | 2017-07-11 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of Tulathromycin |
-
2019
- 2019-06-19 CN CN201910533066.XA patent/CN110128486B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012038372A1 (en) * | 2010-09-20 | 2012-03-29 | Novartis Ag | Novel process for the preparation of 9-deoxo-9a-aza- 9a-homoerythromycin a modified in the c-4'' of the cladinose ring by an epoxide group |
| CN102260306A (en) * | 2011-07-22 | 2011-11-30 | 山东鲁抗舍里乐药业有限公司 | Novel method for preparing tulathromycin |
| CN105492004A (en) * | 2013-02-08 | 2016-04-13 | 罗达制药有限公司 | Methods of treating topical microbial infections |
| CN106939029A (en) * | 2017-04-28 | 2017-07-11 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of Tulathromycin |
Non-Patent Citations (1)
| Title |
|---|
| "Synthesis and Activity of a Novel Class of Tribasic Macrocyclic Antibiotics: The Triamilides";Michael A. Letavic et al.;《Bioorganic & Medicinal Chemistry Letters》;20021231;第12卷;第2771-2774页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110128486A (en) | 2019-08-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110128486B (en) | Synthesis method of tulathromycin | |
| CN102295672B (en) | Synthetic method for tylosin | |
| HU228005B1 (en) | 4"-substituted-9-deoxo-9a-aza-9a-homoerythromycin derivatives and pharmaceutical compositions containing them | |
| CN102786569A (en) | Tulathromycin intermediate and preparation method thereof, as well as preparation method of tulathromycin | |
| CN112812107B (en) | Preparation method of SGLT-2 inhibitor and intermediate | |
| CN112062712A (en) | Preparation method of 2- (5-bromo-3-methylpyridin-2-yl) acetic acid hydrochloride | |
| IE57564B1 (en) | Antibacterial homoerythromycin a derivatives and intermediates therefore | |
| CN104861018A (en) | Preparation method of draxxin | |
| SE448385B (en) | 4 "-DEOXI-4" ACYLAMIDO DERIVATIVES OF ERYTHROMYCIN-A | |
| CN109553539B (en) | Preparation method of benzalkonium chloride | |
| IE46394B1 (en) | Oleandomycin derivatives | |
| CN111116533B (en) | Zanamivir and ranamivir intermediate and synthesis method thereof | |
| CN111040000A (en) | Method for preparing intermediate of gliflozin hypoglycemic drug | |
| CN107056730B (en) | A kind of synthetic method and its application of bupropion hydrochloride sustained release tablets impurity isomers | |
| CN108929253B (en) | Pleuromutilin compound and preparation method and application thereof | |
| CN111574416B (en) | Method for preparing tiamulin from isothiourea salt and pleuromutilin p-toluenesulfonate | |
| CN101848911A (en) | Acid addition salts of synthetic intermediates for carbapenem antibiotics and processes for preparing the same | |
| CN114907304A (en) | Preparation method of tocopherol retinoic acid ester | |
| US4098993A (en) | Semi-synthetic 4-ureido-oleandomycin derivatives | |
| CN108822162B (en) | Synthetic method of tildipirosin intermediate | |
| CN112225769A (en) | Method for synthesizing and purifying tulathromycin impurity E | |
| WO2009011551A2 (en) | Process for the efficient preparation of 3-hydroxy pyrrolidine and derivatives thereof | |
| US4124755A (en) | 11-Alkanoyl-4"-deoxy-4"-isonitrilo-oleandomycin derivatives | |
| CN111484418A (en) | Preparation method of 4-amino-2-cyclopentene-1-methanol hydrochloride | |
| CN101440076A (en) | Process for synthesizing optical activity 2-(1'(Z) alkenyl iodo-alkyl) tetrahydrofuran |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 213127 No. 18 Jinlong Road, Xinbei District, Jiangsu, Changzhou Applicant after: CHANGZHOU YABANG-QH PHARMACHEM CO.,LTD. Applicant after: Inner Mongolia Qihui Pharmaceutical Co.,Ltd. Applicant after: LIANYUNGANG YAHUI PHARMACHEM Co.,Ltd. Address before: 213127 No. 18 Jinlong Road, Xinbei District, Jiangsu, Changzhou Applicant before: CHANGZHOU YABANG-QH PHARMACHEM Co.,Ltd. Applicant before: INNER MONGOLIA QIHUI CHEMICAL Co.,Ltd. Applicant before: LIANYUNGANG YAHUI PHARMACHEM Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |