CN102875476B - Method for preparing metronidazole benzoate - Google Patents
Method for preparing metronidazole benzoate Download PDFInfo
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- CN102875476B CN102875476B CN201210344933.3A CN201210344933A CN102875476B CN 102875476 B CN102875476 B CN 102875476B CN 201210344933 A CN201210344933 A CN 201210344933A CN 102875476 B CN102875476 B CN 102875476B
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Abstract
The invention discloses a method for preparing metronidazole benzoate. The method comprises the following steps of: (1) dissolving metronidazole in a solvent, adding benzoyl chloride and performing esterification reaction at the temperature of 500 to 700 DEG C, wherein the solvent is selected from tributylamine, a tributylamine and toluene binary system compound, a tributylamine and acetone binary system compound and a tributylamine, toluene and acetone ternary system compound; (2) adding cooled unsalted water into an esterification reaction product to completely dissolve a solid, cooling an organic phase, and recrystallizing to obtain a crude metronidazole benzoate; and (3) putting the crude metronidazole benzoate into an ethanol solvent for dissolving, adding activated carbon, decoloring, filtering, cooling, recrystallizing, filtering, washing and drying to obtain a finished metronidazole benzoate. By the method, the metronidazole benzoate with high yield, high environment-friendly performance and high product quality is prepared.
Description
Technical field
The present invention relates to a kind of preparation method of benzoic methyl nitroazole, particularly relate to Tributylamine or its multicomponent system mixture as action solvent prepares the method for benzoic methyl nitroazole.
Background technology
Benzoic methyl nitroazole chemistry 1-(2-benzoxy ethyl)-2-5-nitro imidazole by name, has following structure:
Benzoic methyl nitroazole is a kind of for anti-trichomonal and anti-infectious medicine.Specifically may be used for urogenital system trichomoniasis, as trichomonal vaginitis etc.; Enteron aisle and the outer loeschiasis of intestines, as loeschiasis and amebic liver abscess etc.; Giardiasis; Various infection caused by responsive anerobe, as bacteriemia, septicemia, abdominal operation postoperative infection etc.; Prevention is by the microbial gynaecology of anaerobism, surgical postoperative infection etc.To sum up, benzoic methyl nitroazole has larger medical value, good profit prospect.
The existing method preparing benzoic methyl nitroazole is with metronidazole and Benzoyl chloride for raw material, with pyridine, or the mixture of pyridine and toluene, or the mixture of pyridine and acetone is solvent, obtains benzoic methyl nitroazole by esterification.
Particularly, be that in the patent of 88104656.6, benzoic methyl nitroazole preparation method is as follows at application number:
(1), metronidazole all dissolves 10 DEG C ~ 50 DEG C time in solvent, when being then cooled to 10 DEG C ~ 25 DEG C, dripping Benzoyl chloride, reacts 4 hours; Wherein, solvent is selected from the one in pyridine, pyridine and toluene mixture, pyridine and acetone mixture three kinds.
(2) add activated carbon decolorizing in solution, after the reaction, filter, pour the salt-free water of about 5 DEG C into, crystallize out, stirs 20 minutes, filter, dry must benzoic methyl nitroazole finished product.
Contriver is realizing in prior art, finds following problem:
(1), use the molar yield of prior art production benzoic methyl nitroazole on the low side, be only 86%, cause the high expensive producing product.
(2), use impurity in the product of prior art production benzoic methyl nitroazole higher, more than 0.25%, affect the quality of product.
(3), do acid binding agent with pyridine in prior art, produce unpleasant foul smell aborning, production environment is severe, is not suitable for scale operation.
(4), pyridine has extremely strong bio-toxicity, can impact in process of production, and can cause huge pollution to environment to the health of employee.
Summary of the invention
The present invention aims to provide the benzoic methyl nitroazole preparation method of a kind of high yield, high-environmental, high product quality.The embodiment of the present invention for raw material with metronidazole and Benzoyl chloride, instead of pyridine with Tributylamine and makes acid binding agent and solvent.The present invention with metronidazole and Benzoyl chloride for the route of Material synthesis benzoic methyl nitroazole is as follows:
Synthetic method of the present invention specifically comprises the following steps:
(1) metronidazole is dissolved in solvent, add Benzoyl chloride and carry out esterification, the temperature of esterification is 50 DEG C ~ 70 DEG C, described solvent is selected from the one in Tributylamine, Tributylamine-Toluene Binary System mixture, Tributylamine-acetone binary system mixture, Tributylamine-toluene-acetone ternary system mixture, in multicomponent system mixture, each solvent can use arbitrary proportion to mix;
(2) salt-free water adding cooling in esterification reaction product makes solid dissolve completely, gets organic phase, and described organic phase crystallisation by cooling is obtained benzoic methyl nitroazole crude product;
(3) described benzoic methyl nitroazole crude product is put in alcohol solvent dissolve, and add gac and decolour, after filtration, crystallisation by cooling, filtration, washing and drying, obtain benzoic methyl nitroazole finished product after decolouring, in described alcohol solvent, the volumn concentration of ethanol is 40% ~ 60%.
Wherein, metronidazole described in step (1) is dissolved in the temperature of solvent is 90 DEG C ~ 115 DEG C.
Wherein, described in step (1), the reaction times of esterification is 2 ~ 6 hours.
Wherein, 4 ~ 10 times of the volume (L) of solvent described in step (1) quality (Kg) that is described metronidazole.
Wherein, described in step (1), the mol ratio of metronidazole and described Benzoyl chloride is 1:1.05 ~ 1.15.
Preferably, solvent described in step (1) is Tributylamine-Toluene Binary System mixture.
Wherein, described in step (2), the salt-free water of cooling is 0
oc ~ 10
othe distilled water of C, the temperature of described crystallisation by cooling is 0
oc ~ 10
oc.
Wherein, described in step (3), the mass ratio of benzoic methyl nitroazole crude product and described gac is 100:2 ~ 6.
Wherein, described in step (3), the temperature of drying operation is 50
oc ~ 75
oc.
Wherein, add alkali in aqueous phase remaining after getting organic phase in step (2), extraction obtains Tributylamine, can recycle Tributylamine, effectively reduce production cost.
The embodiment of the present invention does not adopt pyridine to do solvent, and adopt Tributylamine-toluene, the Tributylamine-acetone of Tributylamine or binary system, or any one in ternary system Tributylamine-toluene-acetone makes action solvent, make metronidazole and Benzoyl chloride carry out esterification and generate benzoic methyl nitroazole.The present invention's Tributylamine instead of pyridine and makes acid binding agent, and avoid bad smell and strong toxicity that pyridine has, production environment is good and free from environmental pollution.Another Tributylamine and water stratification, easy recycling, greatly reduces cost, reduces costs and can reach more than 7% in large-scale industrial is produced.Preparation method provided by the invention is that benchmark yield is greater than 93% by metronidazole, and product assay, more than 99.8%, improves quality product while reducing production cost.
Embodiment
For making the object, technical solutions and advantages of the present invention clearly, below embodiment of the present invention is described further in detail.
Embodiment 1
Embodiment 1 adopts Tributylamine to do action solvent, and the reaction process preparing benzoic methyl nitroazole is as follows:
20.00 grams of metronidazoles and 80ml Tributylamine are joined in 250ml four-hole boiling flask successively, is warmed up to 90
oc stirs insulation 1 hour, then cools to 50
oc, drops into Benzoyl chloride 17.25 grams and stirs insulation reaction 6 hours.After having reacted, add a certain amount of 0 while stirring in the reaction product
othe distilled water of C is used for dissolving Tributylamine hydrochloride, leaves standstill again and makes solution layering, separate supernatant liquid (organic phase), organic phase is cooled to 0 with separating funnel after Tributylamine hydrochloride dissolves completely
oc crystallization, filtration, drying obtain crude product 30.45 grams; Get lower floor's liquid (aqueous phase remaining after getting organic phase) of separating funnel, in aqueous phase, add alkali, proceed to separating funnel again after layering, extraction obtains Tributylamine, then can Reusability Tributylamine.Crude product is put into 120 milliliter 80
oin the alcohol solvent (mixture of ethanol and water, the volumn concentration of ethanol is 40%) of C, separately add 0.6 gram of gac, be incubated after 1 hour and filter, obtain the filtrate after decolouring, filtrate is cooled to 0
oc crystallisation by cooling is after 0.5 hour, through suction filtration, washing and 50
odry under C after 14 hours and obtain the product benzoic methyl nitroazole 30.11 grams after refining, productive rate is 93.6%, and characterizing product assay is after tested 99.83%.
Embodiment 2
Embodiment 2 adopts the Tributylamine-toluene of binary system to do action solvent, and the reaction process preparing benzoic methyl nitroazole is as follows:
17.00 grams of metronidazoles, 80ml Tributylamine liquid and 90ml toluene are joined in 250ml four-hole boiling flask successively, is warmed up to 115
oc stirs insulation 0.5 hour, then cools to 70
oc, drops into Benzoyl chloride 16.06 grams and stirs insulation reaction 2 hours.After having reacted, add a certain amount of 10 while stirring in the reaction product
othe distilled water of C is used for dissolving Tributylamine hydrochloride, leaves standstill again and makes solution layering, separate supernatant liquid (organic phase), organic phase is cooled to 10 with separating funnel after Tributylamine hydrochloride dissolves completely
oc crystallization, filtration, drying obtain crude product 26.14 grams; Get lower floor's liquid (aqueous phase remaining after getting organic phase) of separating funnel, in aqueous phase, add alkali, proceed to separating funnel again after layering, extraction obtains Tributylamine, then can Reusability Tributylamine.Crude product is put into 100 milliliter 60
oin the alcohol solvent (mixture of ethanol and water, the volumn concentration of ethanol is 60%) of C, separately add 1.6 grams of gacs, be incubated after 2 hours and filter, obtain the filtrate after decolouring, filtrate is cooled to 10
oc crystallisation by cooling is after 2 hours, through suction filtration, washing and 75
odry under C after 10 hours and obtain the product benzoic methyl nitroazole 25.73 grams after refining, productive rate is 94.1%, and characterizing product assay is after tested 99.81%.
Embodiment 3
Embodiment 3 adopts the Tributylamine-toluene of binary system to do action solvent, and the reaction process preparing benzoic methyl nitroazole is as follows:
18.50 grams of metronidazoles, 80ml Tributylamine liquid and 80ml toluene are joined in 250ml four-hole boiling flask successively, is warmed up to 100
oc stirs insulation 1 hour, then cools to 60
oc, drops into Benzoyl chloride 16.70 grams and stirs insulation reaction 4 hours.After having reacted, add a certain amount of 5 while stirring in the reaction product
othe distilled water of C is used for dissolving Tributylamine hydrochloride, leaves standstill again and makes solution layering, separate supernatant liquid (organic phase), organic phase is cooled to 5 with separating funnel after Tributylamine hydrochloride dissolves completely
oc crystallization, filtration, drying obtain crude product 28.71 grams; Get lower floor's liquid (aqueous phase remaining after getting organic phase) of separating funnel, in aqueous phase, add alkali, proceed to separating funnel again after layering, extraction obtains Tributylamine, then can Reusability Tributylamine.Crude product is put into 110 milliliter 70
oin the alcohol solvent (mixture of ethanol and water, the volumn concentration of ethanol is 55%) of C, separately add 1.1 grams of gacs, be incubated after 1 hour and filter, obtain the filtrate after decolouring, filtrate is cooled to 5
oc crystallisation by cooling is after 0.5 hour, through suction filtration, washing and 60
odry under C after 12 hours and obtain the product benzoic methyl nitroazole 28.26 grams after refining, productive rate is 95.0%, and characterizing product assay is after tested 99.88%.
Embodiment 4
Embodiment 4 adopts the Tributylamine-acetone of binary system to do action solvent, and the reaction process preparing benzoic methyl nitroazole is as follows:
17.60 grams of metronidazoles, 80ml Tributylamine liquid and 40ml acetone are joined in 250ml four-hole boiling flask successively, is warmed up to 95
oc stirs insulation 1 hour, then cools to 55
oc, drops into Benzoyl chloride 15.92 grams and stirs insulation reaction 4.5 hours.After having reacted, add a certain amount of 4 while stirring in the reaction product
othe distilled water of C is used for dissolving Tributylamine hydrochloride, leaves standstill again and makes solution layering, separate supernatant liquid (organic phase), organic phase is cooled to 8 with separating funnel after Tributylamine hydrochloride dissolves completely
oc crystallization, filtration, drying obtain crude product 26.94 grams; Get lower floor's liquid (aqueous phase remaining after getting organic phase) of separating funnel, in aqueous phase, add alkali, proceed to separating funnel again after layering, extraction obtains Tributylamine, then can Reusability Tributylamine.Crude product is put into 100 milliliter 55
oin the alcohol solvent (mixture of ethanol and water, the volumn concentration of ethanol is 50%) of C, separately add 1.4 grams of gacs, be incubated after 2.5 hours and filter, obtain the filtrate after decolouring, filtrate is cooled to 5
oc crystallisation by cooling is after 1 hour, through suction filtration, washing and 65
odry under C after 11 hours and obtain the product benzoic methyl nitroazole 26.58 grams after refining, productive rate is 93.9%, and characterizing product assay is after tested 99.92%.
Embodiment 5
Embodiment 5 adopts the Tributylamine-acetone of binary system to do action solvent, and the reaction process preparing benzoic methyl nitroazole is as follows:
18.69 grams of metronidazoles, 80ml Tributylamine liquid and 100ml acetone are joined in 250ml four-hole boiling flask successively, is warmed up to 105
oc stirs insulation 1 hour, then cools to 65
oc, drops into Benzoyl chloride 16.93 grams and stirs insulation reaction 3 hours.After having reacted, add a certain amount of 0 while stirring in the reaction product
othe distilled water of C is used for dissolving Tributylamine hydrochloride, leaves standstill again and makes solution layering, separate supernatant liquid (organic phase), organic phase is cooled to 10 with separating funnel after Tributylamine hydrochloride dissolves completely
oc crystallization, filtration, drying obtain crude product 28.83 grams; Get lower floor's liquid (aqueous phase remaining after getting organic phase) of separating funnel, in aqueous phase, add alkali, proceed to separating funnel again after layering, extraction obtains Tributylamine, then can Reusability Tributylamine.Crude product is put into 140 milliliter 75
oin the alcohol solvent (mixture of ethanol and water, the volumn concentration of ethanol is 52%) of C, separately add 0.7 gram of gac, be incubated after 1 hour and filter, obtain the filtrate after decolouring, filtrate is cooled to 0
oc crystallisation by cooling is after 0.9 hour, through suction filtration, washing and 70
odry under C after 10 hours and obtain the product benzoic methyl nitroazole 28.46 grams after refining, productive rate is 94.7%, and characterizing product assay is after tested 99.84%.
Embodiment 6
Embodiment 6 adopts the Tributylamine-toluene-acetone of ternary system to do action solvent, and the reaction process preparing benzoic methyl nitroazole is as follows:
18.00 grams of metronidazoles, 50ml Tributylamine liquid, 45ml toluene and 45ml acetone are joined in 250ml four-hole boiling flask successively, is warmed up to 110
oc stirs insulation 0.5 hour, then cools to 70
oc, drops into Benzoyl chloride 16.26 grams and stirs insulation reaction 2.5 hours.After having reacted, add a certain amount of 8 while stirring in the reaction product
othe distilled water of C is used for dissolving Tributylamine hydrochloride, leaves standstill again and makes solution layering, separate supernatant liquid (organic phase), organic phase is cooled to 4 with separating funnel after Tributylamine hydrochloride dissolves completely
oc crystallization, filtration, drying obtain crude product 27.87 grams; Get lower floor's liquid (aqueous phase remaining after getting organic phase) of separating funnel, in aqueous phase, add alkali, proceed to separating funnel again after layering, extraction obtains Tributylamine, then can Reusability Tributylamine.Crude product is put into 130 milliliter 65
oin the alcohol solvent (mixture of ethanol and water, the volumn concentration of ethanol is 55%) of C, separately add 0.8 gram of gac, be incubated after 2 hours and filter, obtain the filtrate after decolouring, filtrate is cooled to 7
oc crystallisation by cooling is after 1 hour, through suction filtration, washing and 55
odry under C after 13 hours and obtain the product benzoic methyl nitroazole 27.47 grams after refining, productive rate is 94.9%, and characterizing product assay is after tested 99.96%.
Embodiment 7
Embodiment 7 adopts the Tributylamine-toluene-acetone of ternary system to do action solvent, and the reaction process preparing benzoic methyl nitroazole is as follows:
19.50 grams of metronidazoles, 50ml Tributylamine liquid, 30ml toluene and 60ml acetone are joined in 250ml four-hole boiling flask successively, is warmed up to 100
oc stirs insulation 1 hour, then cools to 60
oc, drops into Benzoyl chloride 17.62 grams and stirs insulation reaction 4 hours.After having reacted, add a certain amount of 5 while stirring in the reaction product
othe distilled water of C is used for dissolving Tributylamine hydrochloride, leaves standstill again and makes solution layering, separate supernatant liquid (organic phase), organic phase is cooled to 10 with separating funnel after Tributylamine hydrochloride dissolves completely
oc crystallization, filtration, drying obtain crude product 30.07 grams; Get lower floor's liquid (aqueous phase remaining after getting organic phase) of separating funnel, in aqueous phase, add alkali, proceed to separating funnel again after layering, extraction obtains Tributylamine, then can Reusability Tributylamine.Crude product is put into 80 milliliter 80
oin the alcohol solvent (mixture of ethanol and water, the volumn concentration of ethanol is 55%) of C, separately add 1.2 grams of gacs, be incubated after 1 hour and filter, obtain the filtrate after decolouring, filtrate is cooled to 5
oc crystallisation by cooling is after 0.5 hour, through suction filtration, washing and 60
odry under C after 12 hours and obtain the product benzoic methyl nitroazole 29.60 grams after refining, productive rate is 94.4%, and characterizing product assay is after tested 99.87%.
As can be seen from embodiment 1 to 7, the embodiment of the present invention does not adopt pyridine to do solvent, and adopt Tributylamine-toluene, the Tributylamine-acetone of Tributylamine or binary system, or any one in ternary system Tributylamine-toluene-acetone makes action solvent, make metronidazole and Benzoyl chloride carry out esterification and generate benzoic methyl nitroazole.The present invention's Tributylamine instead of pyridine and makes acid binding agent, and avoid bad smell and strong toxicity that pyridine has, production environment is good and free from environmental pollution.Another Tributylamine and water stratification, easy recycling, greatly reduces cost, reduces costs and can reach more than 7% in large-scale industrial is produced.Preparation method provided by the invention is that benchmark yield is greater than 93% by metronidazole, and product assay, more than 99.8%, improves quality product while reducing production cost.
Above embodiments of the invention are illustrated, but the present invention is not limited to above-described embodiment, in the ken that those of ordinary skill in the art possess, can also makes a variety of changes not departing under present inventive concept prerequisite.
Claims (9)
1. a preparation method for benzoic methyl nitroazole, is characterized in that, said method comprising the steps of:
(1) metronidazole is dissolved in solvent, add Benzoyl chloride and carry out esterification, the temperature of esterification is 50 DEG C ~ 70 DEG C, and described solvent is selected from the one in Tributylamine, Tributylamine-Toluene Binary System mixture, Tributylamine-acetone binary system mixture, Tributylamine-toluene-acetone ternary system mixture;
(2) salt-free water adding cooling in esterification reaction product makes solid dissolve completely, gets organic phase, and described organic phase crystallisation by cooling is obtained benzoic methyl nitroazole crude product, adds alkali in aqueous phase remaining after getting organic phase, and extraction obtains Tributylamine;
(3) described benzoic methyl nitroazole crude product is put in alcohol solvent dissolve, and add gac and decolour, after filtration, crystallisation by cooling, filtration, washing and drying, obtain benzoic methyl nitroazole finished product after decolouring, in described alcohol solvent, the volumn concentration of ethanol is 40% ~ 60%.
2. according to the preparation method described in claim 1, it is characterized in that: it is 90 DEG C ~ 115 DEG C that metronidazole described in step (1) is dissolved in the temperature of solvent.
3. according to the preparation method described in claim 1, it is characterized in that: the reaction times of esterification described in step (1) is 2-6 hour.
4. according to the preparation method described in claim 1, it is characterized in that: the volume of described solvent and the mass ratio of described metronidazole are 4 ~ 10, the dimension of described solvent volume is for rising, and the dimension of described metronidazole quality is kilogram.
5. according to the preparation method described in claim 1, it is characterized in that: the mol ratio of described metronidazole and described Benzoyl chloride is 1: 1.05 ~ 1.15.
6. according to the preparation method described in claim 1, it is characterized in that: described solvent is Tributylamine-Toluene Binary System mixture.
7. according to the preparation method described in claim 1, it is characterized in that: described in step (2), the salt-free water of cooling is the distilled water of 0 DEG C ~ 10 DEG C, and the temperature of described crystallisation by cooling is 0 DEG C ~ 10 DEG C.
8. according to the preparation method described in claim 1, it is characterized in that: the mass ratio of described benzoic methyl nitroazole crude product and described gac is 100:2 ~ 6.
9. according to the preparation method described in claim 1, it is characterized in that: the temperature of drying operation described in step (3) is 50 DEG C ~ 75 DEG C.
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Address after: 438600 Fengshan City, Huanggang province Luotian County, north of the town of water Yi Road, No. 428 Patentee after: HUBEI HONGYUAN PHARMACEUTICAL TECHNOLOGY CO., LTD. Address before: 438600 Fengshan City, Huanggang province Luotian County, north of the town of water Yi Road, No. 428 Patentee before: Hubei Hongyuan Pharmaceutical Co., Ltd. |
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Denomination of invention: A preparation method of benzoyl metronidazole Effective date of registration: 20220512 Granted publication date: 20150114 Pledgee: Industrial and Commercial Bank of China Limited Luotian sub branch Pledgor: HUBEI HONGYUAN PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Registration number: Y2022420000116 |
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