CN103896810B - The synthetic method of bufexamac - Google Patents
The synthetic method of bufexamac Download PDFInfo
- Publication number
- CN103896810B CN103896810B CN201410135578.8A CN201410135578A CN103896810B CN 103896810 B CN103896810 B CN 103896810B CN 201410135578 A CN201410135578 A CN 201410135578A CN 103896810 B CN103896810 B CN 103896810B
- Authority
- CN
- China
- Prior art keywords
- kilograms
- bufexamac
- hydroxyphenylaceticacid
- add
- hours
- 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides synthetic method the method for a kind of bufexamac, comprise the following steps: 1) under esterifying catalyst effect, there is esterification in p-hydroxyphenylaceticacid and propyl carbinol in esterified solvent, obtains the positive butyl ester of p-hydroxyphenylaceticacid; 2) under alkylation catalyst effect, in alkylation solvent, be there is alkylated reaction in positive for hydroxyl phenylacetic acid butyl ester and 1-bromination of n-butane, obtain n-butoxy n-butyl phenylatate; 3) under ammonolysis catalyst effect, there is aminolysis reaction in n-butoxy n-butyl phenylatate and oxammonium hydrochloride, obtain bufexamac in aminolysis solvent.The yield of bufexamac can be increased to 71.7% by bufexamac synthetic method provided by the invention.
Description
Technical field
The present invention relates to technical field bufexamac synthetic method, in particular to a kind of synthetic method of bufexamac.
Background technology
Bufexamac is a kind of NSAID (non-steroidal anti-inflammatory drug), and chemical name is 4-n-butoxy-N-hydroxyphenylacetyl amine, also known as to fourth oxygen phenylacetamide hydroxamic acid.Divide formula C
12h
17o
3n, has divided amount 223.27.Be widely used in treatment various skin inflammation, since listing in 1973, be widely used in the world, this material is particularly suitable for treatment child skin inflammation.
With the antiphlogistic drug of bufexamac synthesis, be widely used in treatment rheumatoid arthritis, eczema and other various skin inflammation, act on quite with many cortin preparations (as Fluocet, BETAMETHASONE emulsifiable paste etc.).The preparation that this intermediate is made is nontoxic, and side effect is little.From 1973, this medicine was in succession in Britain, France, Germany, Japan and other countries listing.Nearest recent studies on shows that it also has reduction body temperature, extends sleep, promotes the functions such as natural on-off cycles of hair growth.After hydroxyl on bufexamac is replaced by basic metal, alkaline-earth metal, the salt generated has again purposes unique separately.
About the synthetic route of bufexamac, bibliographical information is less, mainly contains following several synthetic routes:
1) n-butoxy benzene and MeSCHClCO
2et is obtained by reacting p-BuOC
6h
5(SMe) CHCO
2et, then desulfurization obtains ester, then is obtained by reacting product with oxammonium hydrochloride, and this synthesis utilizes Fridel-Crafts reaction to carry out.Synthetic route is shown below.
2) in water, target compound is obtained by reacting with acyl chlorides and oxammonium hydrochloride.Synthetic route is shown below.
Said synthesis route only can realize preparing bufexamac, and yield is lower, and bufexamac cannot be made to realize suitability for industrialized production.
Summary of the invention
The present invention aims to provide a kind of synthetic method of bufexamac, to solve the problem that in prior art, bufexamac yield is low.
To achieve these goals, the invention provides a kind of synthetic method of bufexamac, comprise the following steps:
1) under esterifying catalyst effect, there is esterification in p-hydroxyphenylaceticacid and propyl carbinol in esterified solvent, obtains the positive butyl ester of p-hydroxyphenylaceticacid;
2) under alkylation catalyst effect, in alkylation solvent, be there is alkylated reaction in positive for hydroxyl phenylacetic acid butyl ester and 1-bromination of n-butane, obtain n-butoxy n-butyl phenylatate;
3) under ammonolysis catalyst effect, there is aminolysis reaction in n-butoxy n-butyl phenylatate and oxammonium hydrochloride, obtain bufexamac in aminolysis solvent.
Further, esterified solvent is toluene or benzene.
Further, esterified solvent is toluene.
Further, esterified solvent add-on is 4 ~ 10 times of p-hydroxyphenylaceticacid quality.
Further, esterified solvent add-on is 5 ~ 8 times of p-hydroxyphenylaceticacid quality.
Further, esterifying catalyst is any one in the vitriol oil, hydrogenchloride, hydrogen bromide, sodium pyrosulfate, sal enixum.
Further, esterifying catalyst is any one in the vitriol oil, sodium pyrosulfate, sal enixum.
Further, p-hydroxyphenylaceticacid and propyl carbinol are 1: 1 ~ 4 to react in molar ratio.
Further, p-hydroxyphenylaceticacid and propyl carbinol are 1: 1 ~ 2 to react in molar ratio.
Further, alkylation catalyst is salt of wormwood, and alkylation solvent is ethanol; Ammonolysis catalyst is potassium hydroxide, and aminolysis solvent is methyl alcohol.
Technique effect of the present invention is:
Bufexamac synthetic method provided by the invention is reacted using propyl carbinol as alcohols reactant and p-hydroxyphenylaceticacid, gained by product is second step reaction products therefrom, thus alcohols reactant and p-hydroxyphenylaceticacid generation side reaction in subsequent reactions process can be avoided to generate the ether material being difficult to remove, thus improving the yield of product, the yield of bufexamac can be increased to 71.7%.
Except object described above, feature and advantage, the present invention also has other object, feature and advantage.Below with reference to embodiment, the present invention is further detailed explanation.
Accompanying drawing explanation
The accompanying drawing forming a application's part is used to provide a further understanding of the present invention, and schematic description and description of the present invention, for explaining the present invention, does not form inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 is the high-efficient liquid phase chromatogram of preferred embodiment of the present invention product; And
Fig. 2 is the high-efficient liquid phase chromatogram of preferred embodiment of the present invention product.
Embodiment
It should be noted that, when not conflicting, the embodiment in the application and the feature in embodiment can combine mutually.The present invention is described in detail below in conjunction with embodiment.
A kind of synthetic method of bufexamac is provided in the present invention, on the basis of existing technology, the reaction raw materials of esterification is optimized, reacted by p-hydroxyphenylaceticacid and propyl carbinol and carry out esterification, the generation of ethers impurity can be avoided, prevent ethers impurity to the interference of later separation purification process, thus improve bufexamac yield.
The synthetic method of bufexamac provided by the invention comprises the following steps:
1) under esterifying catalyst effect, there is esterification in p-hydroxyphenylaceticacid and propyl carbinol in esterified solvent, obtains the positive butyl ester of p-hydroxyphenylaceticacid;
2) under alkylation catalyst effect, in alkylation solvent, be there is alkylated reaction in positive for hydroxyl phenylacetic acid butyl ester and 1-bromination of n-butane, obtain n-butoxy n-butyl phenylatate;
3) under ammonolysis catalyst effect, there is aminolysis reaction in n-butoxy n-butyl phenylatate and oxammonium hydrochloride, obtain bufexamac in aminolysis solvent.
The invention provides synthesis bufexamac reaction equation:
The reaction equation of esterification is I.From reaction equation I, the hydroxyl generation esterification in propyl carbinol and p-hydroxyphenylaceticacid, when react carry out according to formula I time, the positive butyl ester of p-hydroxyphenylaceticacid can be obtained.Simultaneously in esterification process, alcohols material also can send out following reaction with p-hydroxyphenylaceticacid:
When using other alcohols materials and p-hydroxyphenylaceticacid generation esterification, the hydrogen on another hydroxyl in side reaction on products therefrom substituted benzene ring, gained side reaction product structure does not meet the structure of bufexamac.This side reaction product, after subsequent alkylation and aminolysis, obtains
even if this impurity is once it also cannot remove by generation last recrystallization repeatedly effectively from bufexamac.Although the generation of such impurity can be reduced by shortening time of esterification, the shortening of whose esterification time of the transformation efficiency of esterification and reducing, and then reduce the total recovery of bufexamac.
In order to avoid the generation of above-mentioned impurity, the use propyl carbinol of the invention and p-hydroxyphenylaceticacid react, when reaction shown in propyl carbinol and p-hydroxyphenylaceticacid generating polynomial IV, products therefrom is exactly n-butoxy n-butyl phenylatate, i.e. products therefrom in reaction equation II, this material is products therefrom in alkylation process.To avoid in esterification process other generations being difficult to the impurity be separated by adopting propyl carbinol to carry out reacting, thus improve the yield of bufexamac.Obtaining of this replacement is so insignificant in retrospect, but when without any enlightenment, searches out propyl carbinol, inherently creationary embodiment from vast as the open sea alcohols material.
In esterification reaction process, esterified solvent used can be conventional esterification solvent, is preferably toluene or benzene.Be preferably toluene.When using the solvent of toluene as esterification, toluene at solubilizing reaction thing, for reactant and product solute effect is provided while can also play the effect of dewatering agent.The water that toluene can make esterification produce hightails reaction system, and promote that esterification forward carries out, Reaction time shorten, enhances productivity, and makes product yield in esterification reaction process be about 100%.Because esterification transformation efficiency is high, after esterification completes, remove catalyzer after filtration, after recycling design, gained material, without the need to through purification & isolation repeatedly, can directly drop in alkylation process.In conventionally, when adopting ethanol to carry out esterification, by products therefrom through reclaiming the ethanol in esterified solvent, adding acetic acid ethyl dissolution, after alkali cleaning, washing, drying, concentrated etc. aftertreatment technology process, could by the p-hydroxyphenylaceticacid in gained material positive butyl ester.Improve production efficiency.
The add-on of esterified solvent can add in the requirement of p-hydroxyphenylaceticacid esterification routinely, is preferably 4 ~ 10 times of p-hydroxyphenylaceticacid quality, is preferably 5 ~ 8 times of p-hydroxyphenylaceticacid quality, is more preferably 6 times of p-hydroxyphenylaceticacid quality.Add solvent in this ratio and not only can waste solvent but also can ensure that esterification is carried out smoothly fully.Can also ensure, the solvency action of solvent gives full play to, and works in coordination with onset simultaneously, thus improve yield and the purity of the positive butyl ester of p-hydroxyphenylaceticacid to greatest extent with the dehydration played needed for dissolving.
Esterifying catalyst can commonly use all kinds of catalyzer for p-hydroxyphenylaceticacid esterification.Be preferably the vitriol oil, hydrogenchloride, hydrogen bromide, sodium pyrosulfate, any one in sal enixum.It is high that the preferred esterifying catalyst of institute has catalytic efficiency, the effects such as reactive behavior is strong.Be more preferably in the vitriol oil, sodium pyrosulfate, sal enixum any one.Hydrogen sulfate salt material cost is cheap, safety non-toxic convenient operation.Most preferred is sodium pyrosulfate or sal enixum.And when selected catalyzer is the sulfate species of solid, the generation of formula I reaction more can be conducive to.
In esterification reaction process, p-hydroxyphenylaceticacid and propyl carbinol are 1: 1 ~ 4 add in reaction system in molar ratio, carry out esterification.Improve the add-on of propyl carbinol, reaction forward can be impelled to carry out completely.Preferred p-hydroxyphenylaceticacid and propyl carbinol are 1: 1 ~ 2 to react in molar ratio, and being more preferably p-hydroxyphenylaceticacid and propyl carbinol is to react at 1: 1.5 in molar ratio.
After esterification, alkylation and aminolysis reaction are carried out to products therefrom, can bufexamac be obtained.The positive butyl ester of p-hydroxyphenylaceticacid that the invention provides method obtained can carry out subsequent alkylation and aminolysis reaction by bufexamac synthesis technique routinely.Alkylated reaction equation is II.In preferred alkyl reaction process, alkylation catalyst is salt of wormwood, and alkylation solvent is the material dissolving each reactant in the alkylated reaction of formula II, as common solvent such as acetone, methyl alcohol, Virahols, is preferably ethanol.Aminolysis words reaction equation is III, and preferably wherein ammonolysis catalyst is potassium hydroxide, and aminolysis solvent is the solvent dissolving each reactant in the aminolysis reaction of formula III, can be methyl alcohol, ethanol, Virahol, acetone equal solvent, is preferably methyl alcohol.By this conditioned response, acquired results is optimum.
Embodiment
In following examples, each material used is commercially available and instrument and is commercially available.
Embodiment 1
The preparation of the positive butyl ester of p-hydroxyphenylaceticacid
In the reactor of 1500L, add toluene 900L, p-hydroxyphenylaceticacid 152KG, propyl carbinol 106KG, sodium pyrosulfate 5KG, wherein p-hydroxyphenylaceticacid and propyl carbinol mol ratio are 1: 1.5.Heating reflux reaction, phegma needs by water trap, and after 40 minutes, TLC detects and judges that reaction reaches stopped reaction after terminal, and reactant is down to room temperature by logical water coolant, filters, filtration catalizer, and filtrate concentrates, and can directly apply mechanically after toluene recovery.Obtain oily matter and the positive butyl ester 207.5KG of p-hydroxyphenylaceticacid.
The preparation of bufexamac
Getting the positive butyl ester of gained p-hydroxyphenylaceticacid joins in 1000 liters of glassed steel reaction vessels, add dehydrated alcohol 600kg, 150kg1-bromination of n-butane and 163kg salt of wormwood mix with the esterification products of last consignment of, are warming up to backflow, reflux temperature controls at 75 ~ 80 DEG C, is incubated 8 hours.Point plate monitoring raw material point primitive reaction is complete.Distillation recovery ethanol.Cooling, adds 600 premium on currency, stirs 10 minutes in retort, leaves standstill 2 hours, point water outlet, and water layer extracts 3 times by 300L ethyl acetate at every turn, merges organic layer.Organic layer is with after the washing once of 45kg5% sodium hydroxide solution.Be washed to terminal aqueous phase pH=7.Underpressure distillation, reclaim ethyl acetate, resistates is for aligning butyl phenyl ether n-butyl acetate.
In another 1000 liters of glassed steel reaction vessels, add 79.6kg oxammonium hydrochloride and 900L absolute methanol solution, open below frozen cooling to 10 DEG C, under stirring, add 112.8kg potassium hydroxide.Add again and align butyl phenyl ether n-butyl acetate, be heated to backflow, reflux temperature 64 ~ 72 DEG C, be incubated 2 hours, cool, be neutralized to pH=2 ~ 3 with sulfuric acid, stir 30 minutes, be cooled to 5 DEG C freezing 1 hour.Suction filtration, water washing filter cake to last filtrate is neutral.Suction filtration, to dry, dry more than 10 hours, obtains off-white powder and bufexamac crude product 206kg at 55 ~ 60 DEG C.
Add in reactor by bufexamac crude product, 1500L methyl alcohol, 1.5kgEDTA and 6kg gac, be heated to backflow, reflux temperature, at 64 ~ 72 DEG C, is incubated 1 hour, suction filtration while hot.About cooling water temperature to 50 DEG C, stop stirring, to open at frozen cooling to 5 DEG C 2 hours, centrifugal, washing, dries.55 ~ 60 DEG C of dryings, obtain bufexamac 160kg.
Embodiment 2
The preparation of the positive butyl ester of p-hydroxyphenylaceticacid
In the reactor of 1500L, add toluene 900L, p-hydroxyphenylaceticacid 152KG, propyl carbinol 106KG, vitriol oil 5KG, heating reflux reaction, phegma needs to pass through water trap.After 40 minutes, TLC detects and judges that reaction reaches stopped reaction after terminal, reactant is down to room temperature by logical water coolant, be washed till the aobvious alkalescence of water layer with the sodium carbonate solution of 1mol/L, then wash with water to neutrality, which floor has been got, anhydrous sodium sulfate drying more than 5 hours, filter, filtrate concentrates, and can directly apply mechanically after toluene recovery.Obtain oily matter and the positive butyl ester 204.6KG of p-hydroxyphenylaceticacid.
The preparation of bufexamac
Getting the positive butyl ester of gained p-hydroxyphenylaceticacid joins in 1000 liters of glassed steel reaction vessels, add dehydrated alcohol 600kg, 150kg1-bromination of n-butane and 163kg salt of wormwood mix with the esterification products of last consignment of, are warming up to backflow, reflux temperature controls at 75 ~ 80 DEG C, is incubated 8 hours.Point plate monitoring raw material point primitive reaction is complete.Distillation recovery ethanol.Cooling, adds 600 premium on currency, stirs 10 minutes in retort, leaves standstill 2 hours, point water outlet, and water layer extracts 3 times by 300L ethyl acetate at every turn, merges organic layer.Organic layer is with after the washing once of 45kg5% sodium hydroxide solution.Be washed to terminal aqueous phase pH=7.Underpressure distillation, reclaim ethyl acetate, resistates is for aligning butyl phenyl ether n-butyl acetate.
In another 1000 liters of glassed steel reaction vessels, add 79.6kg oxammonium hydrochloride and 900L absolute methanol solution, open below frozen cooling to 10 DEG C, under stirring, add 112.8kg potassium hydroxide.Add again and align butyl phenyl ether n-butyl acetate, be heated to backflow, reflux temperature 64 ~ 72 DEG C, be incubated 2 hours, cool, be neutralized to pH=2 ~ 3 with sulfuric acid, stir 30 minutes, be cooled to 5 DEG C freezing 1 hour.Suction filtration, water washing filter cake to last filtrate is neutral.Suction filtration, to dry, dry more than 10 hours, obtains off-white powder and bufexamac crude product 206kg at 55 ~ 60 DEG C.
Add in reactor by bufexamac crude product, 1500L methyl alcohol, 1.5kgEDTA and 6kg gac, be heated to backflow, reflux temperature, at 64 ~ 72 DEG C, is incubated 1 hour, suction filtration while hot.About cooling water temperature to 50 DEG C, stop stirring, to open at frozen cooling to 5 DEG C 2 hours, centrifugal, washing, dries.55 ~ 60 DEG C of dryings, obtain bufexamac 160kg.
Embodiment 3
The preparation of the positive butyl ester of p-hydroxyphenylaceticacid
In the reactor of 1500L, be to mix at 1: 1 in molar ratio, add the benzene of p-hydroxyphenylaceticacid quality 4 times of quality by propyl carbinol and p-hydroxyphenylaceticacid, logical hydrogen chloride gas, heating reflux reaction, phegma needs to pass through water trap.After 40 minutes, TLC detects and judges that reaction reaches stopped reaction after terminal, reactant is down to room temperature by logical water coolant, be washed till the aobvious alkalescence of water layer with the sodium carbonate solution of 1mol/L, then wash with water to neutrality, get organic layer, anhydrous sodium sulfate drying more than 5 hours, filter, filtrate concentrates, and can directly apply mechanically after toluene recovery.Obtain oily matter and the positive butyl ester 192KG of p-hydroxyphenylaceticacid.
The preparation of bufexamac
Getting the positive butyl ester of gained p-hydroxyphenylaceticacid joins in 1000 liters of glassed steel reaction vessels, add dehydrated alcohol 600kg, 150kg1-bromination of n-butane and 163kg salt of wormwood mix with the esterification products of last consignment of, are warming up to backflow, reflux temperature controls at 75 ~ 80 DEG C, is incubated 8 hours.Point plate monitoring raw material point primitive reaction is complete.Distillation recovery ethanol.Cooling, adds 600 premium on currency, stirs 10 minutes in retort, leaves standstill 2 hours, point water outlet, and water layer extracts 3 times by 300L ethyl acetate at every turn, merges organic layer.Organic layer is with after the washing once of 45kg5% sodium hydroxide solution.Be washed to terminal aqueous phase pH=7.Underpressure distillation, reclaim ethyl acetate, resistates is for aligning butyl phenyl ether n-butyl acetate.
In another 1000 liters of glassed steel reaction vessels, add 79.6kg oxammonium hydrochloride and 900L absolute methanol solution, open below frozen cooling to 10 DEG C, under stirring, add 112.8kg potassium hydroxide.Add again and align butyl phenyl ether n-butyl acetate, be heated to backflow, reflux temperature 64 ~ 72 DEG C, be incubated 2 hours, cool, be neutralized to pH=2 ~ 3 with sulfuric acid, stir 30 minutes, be cooled to 5 DEG C freezing 1 hour.Suction filtration, water washing filter cake to last filtrate is neutral.Suction filtration, to dry, dry more than 10 hours, obtains off-white powder and bufexamac crude product 197.6kg at 55 ~ 60 DEG C.
Add in reactor by bufexamac crude product, 1500L methyl alcohol, 1.5kgEDTA and 6kg gac, be heated to backflow, reflux temperature, at 64 ~ 72 DEG C, is incubated 1 hour, suction filtration while hot.About cooling water temperature to 50 DEG C, stop stirring, to open at frozen cooling to 5 DEG C 2 hours, centrifugal, washing, dries.55 ~ 60 DEG C of dryings, obtain bufexamac 152.5kg.
Embodiment 4
The preparation of the positive butyl ester of p-hydroxyphenylaceticacid
In the reactor of 1500L, be to mix at 1: 4 in molar ratio by propyl carbinol and p-hydroxyphenylaceticacid, add the benzene of p-hydroxyphenylaceticacid quality 10 times of quality, vitriol oil 5KG, heating reflux reaction, phegma needs to pass through water trap.After 40 minutes, TLC detects and judges that reaction reaches stopped reaction after terminal, reactant is down to room temperature by logical water coolant, be washed till the aobvious alkalescence of water layer with the sodium carbonate solution of 1mol/L, then wash with water to neutrality, which floor has been got, anhydrous sodium sulfate drying more than 5 hours, filter, filtrate concentrates, and can directly apply mechanically after toluene recovery.Obtain oily matter and the positive butyl ester 198.0KG of p-hydroxyphenylaceticacid.
The preparation of bufexamac
Getting the positive butyl ester of gained p-hydroxyphenylaceticacid joins in 1000 liters of glassed steel reaction vessels, add dehydrated alcohol 600kg, 150kg1-bromination of n-butane and 163kg salt of wormwood mix with the esterification products of last consignment of, are warming up to backflow, reflux temperature controls at 75 ~ 80 DEG C, is incubated 8 hours.Point plate monitoring raw material point primitive reaction is complete.Distillation recovery ethanol.Cooling, adds 600 premium on currency, stirs 10 minutes in retort, leaves standstill 2 hours, point water outlet, and water layer extracts 3 times by 300L ethyl acetate at every turn, merges organic layer.Organic layer is with after the washing once of 45kg5% sodium hydroxide solution.Be washed to terminal aqueous phase pH=7.Underpressure distillation, reclaim ethyl acetate, resistates is for aligning butyl phenyl ether n-butyl acetate.
In another 1000 liters of glassed steel reaction vessels, add 79.6kg oxammonium hydrochloride and 900L absolute methanol solution, open below frozen cooling to 10 DEG C, under stirring, add 112.8kg potassium hydroxide.Add again and align butyl phenyl ether n-butyl acetate, be heated to backflow, reflux temperature 64 ~ 72 DEG C, be incubated 2 hours, cool, be neutralized to pH=2 ~ 3 with sulfuric acid, stir 30 minutes, be cooled to 5 DEG C freezing 1 hour.Suction filtration, water washing filter cake to last filtrate is neutral.Suction filtration, to dry, dry more than 10 hours, obtains off-white powder and bufexamac crude product 199.2kg at 55 ~ 60 DEG C.
Add in reactor by bufexamac crude product, 1500L methyl alcohol, 1.5kg EDTA and 6kg gac, be heated to backflow, reflux temperature, at 64 ~ 72 DEG C, is incubated 1 hour, suction filtration while hot.About cooling water temperature to 50 DEG C, stop stirring, to open at frozen cooling to 5 DEG C 2 hours, centrifugal, washing, dries.55 ~ 60 DEG C of dryings, obtain bufexamac 154kg.
Embodiment 5
The preparation of the positive butyl ester of p-hydroxyphenylaceticacid
In the reactor of 1500L, be to mix at 1: 2 in molar ratio by propyl carbinol and p-hydroxyphenylaceticacid, add the benzene of p-hydroxyphenylaceticacid quality 5 times of quality, sodium pyrosulfate 5KG, heating reflux reaction, phegma needs to pass through water trap.After 40 minutes, TLC detects and judges that reaction reaches stopped reaction after terminal, and filter, filtrate concentrates, and can directly apply mechanically after toluene recovery.Obtain oily matter and the positive butyl ester 203.8KG of p-hydroxyphenylaceticacid.
The preparation of bufexamac
Getting the positive butyl ester of gained p-hydroxyphenylaceticacid joins in 1000 liters of glassed steel reaction vessels, add dehydrated alcohol 600kg, 150kg1-bromination of n-butane and 163kg salt of wormwood mix with the esterification products of last consignment of, are warming up to backflow, reflux temperature controls at 75 ~ 80 DEG C, is incubated 8 hours.Point plate monitoring raw material point primitive reaction is complete.Distillation recovery ethanol.Cooling, adds 600 premium on currency, stirs 10 minutes in retort, leaves standstill 2 hours, point water outlet, and water layer extracts 3 times by 300L ethyl acetate at every turn, merges organic layer.Organic layer is with after the washing once of 45kg5% sodium hydroxide solution.Be washed to terminal aqueous phase pH=7.Underpressure distillation, reclaim ethyl acetate, resistates is for aligning butyl phenyl ether n-butyl acetate.
In another 1000 liters of glassed steel reaction vessels, add 79.6kg oxammonium hydrochloride and 900L absolute methanol solution, open below frozen cooling to 10 DEG C, under stirring, add 112.8kg potassium hydroxide.Add again and align butyl phenyl ether n-butyl acetate, be heated to backflow, reflux temperature 64 ~ 72 DEG C, be incubated 2 hours, cool, be neutralized to pH=2 ~ 3 with sulfuric acid, stir 30 minutes, be cooled to 5 DEG C freezing 1 hour.Suction filtration, water washing filter cake to last filtrate is neutral.Suction filtration, to dry, dry more than 10 hours, obtains off-white powder and bufexamac crude product 205.2kg at 55 ~ 60 DEG C.
Add in reactor by bufexamac crude product, 1500L methyl alcohol, 1.5kgEDTA and 6kg gac, be heated to backflow, reflux temperature, at 64 ~ 72 DEG C, is incubated 1 hour, suction filtration while hot.About cooling water temperature to 50 DEG C, stop stirring, to open at frozen cooling to 5 DEG C 2 hours, centrifugal, washing, dries.55 ~ 60 DEG C of dryings, obtain bufexamac 159.0kg.
Embodiment 6
The preparation of the positive butyl ester of p-hydroxyphenylaceticacid
In the reactor of 1500L, be to mix at 1: 1.3 in molar ratio by propyl carbinol and p-hydroxyphenylaceticacid, add the toluene of p-hydroxyphenylaceticacid quality 8 times of quality, sal enixum 5KG, heating reflux reaction, phegma needs to pass through water trap.After 40 minutes, TLC detects and judges that reaction reaches stopped reaction after terminal, reactant is down to room temperature by logical water coolant, be washed till the aobvious alkalescence of water layer with the sodium carbonate solution of 1mol/L, then wash with water to neutrality, which floor has been got, anhydrous sodium sulfate drying more than 5 hours, filter, filtrate concentrates, and can directly apply mechanically after toluene recovery.Obtain oily matter and the positive butyl ester 203.8KG of p-hydroxyphenylaceticacid.
The preparation of bufexamac
Getting the positive butyl ester of gained p-hydroxyphenylaceticacid joins in 1000 liters of glassed steel reaction vessels, add dehydrated alcohol 600kg, 150kg1-bromination of n-butane and 163kg salt of wormwood mix with the esterification products of last consignment of, are warming up to backflow, reflux temperature controls at 75 ~ 80 DEG C, is incubated 8 hours.Point plate monitoring raw material point primitive reaction is complete.Distillation recovery ethanol.Cooling, adds 600 premium on currency, stirs 10 minutes in retort, leaves standstill 2 hours, point water outlet, and water layer extracts 3 times by 300L ethyl acetate at every turn, merges organic layer.Organic layer is with after the washing once of 45kg5% sodium hydroxide solution.Be washed to terminal aqueous phase pH=7.Underpressure distillation, reclaim ethyl acetate, resistates is for aligning butyl phenyl ether n-butyl acetate.
In another 1000 liters of glassed steel reaction vessels, add 79.6kg oxammonium hydrochloride and 900L absolute methanol solution, open below frozen cooling to 10 DEG C, under stirring, add 112.8kg potassium hydroxide.Add again and align butyl phenyl ether n-butyl acetate, be heated to backflow, reflux temperature 64 ~ 72 DEG C, be incubated 2 hours, cool, be neutralized to pH=2 ~ 3 with sulfuric acid, stir 30 minutes, be cooled to 5 DEG C freezing 1 hour.Suction filtration, water washing filter cake to last filtrate is neutral.Suction filtration, to dry, dry more than 10 hours, obtains off-white powder and bufexamac crude product 205.2kg at 55 ~ 60 DEG C.
Add in reactor by bufexamac crude product, 1500L methyl alcohol, 1.5kgEDTA and 6kg gac, be heated to backflow, reflux temperature, at 64 ~ 72 DEG C, is incubated 1 hour, suction filtration while hot.About cooling water temperature to 50 DEG C, stop stirring, to open at frozen cooling to 5 DEG C 2 hours, centrifugal, washing, dries.55 ~ 60 DEG C of dryings, obtain bufexamac 159.2kg.
Comparative example 1
The preparation of 4-hydroxyphenylacetic acid ethyl ether
In the reactor of 1500L, add ethanol 900L, vitriol oil 5KG, p-hydroxyphenylaceticacid 152KG, propyl carbinol 106KG, sodium pyrosulfate 5KG, heating reflux reaction, after 10 hours, TLC detects and judges that reaction reaches stopped reaction after terminal, concentrated, reclaims ethanol.Gained oily matter adds ethyl acetate 600L, after stirring and dissolving, is washed till the aobvious alkalescence of water layer, is washing with water to neutrality with the sodium carbonate solution of 1mol/L, which floor is got, anhydrous sodium sulfate drying more than 5 hours, filtered, concentrated, obtain 4-hydroxyphenylacetic acid ethyl ether 120KG, yield 75%.
The preparation of bufexamac
Getting gained 4-hydroxyphenylacetic acid ethyl ether joins in 1000 liters of glassed steel reaction vessels, add dehydrated alcohol 600kg, 123kg1-bromination of n-butane and 120kg salt of wormwood mix with the esterification products of last consignment of, are warming up to backflow, reflux temperature controls at 75 ~ 80 DEG C, is incubated 8 hours.Point plate monitoring raw material point primitive reaction is complete.Distillation recovery ethanol.Cooling, adds 600 premium on currency, stirs 10 minutes in retort, leaves standstill 2 hours, point water outlet, and water layer extracts 3 times by 300L ethyl acetate at every turn, merges organic layer.Organic layer is with after the washing once of 45kg5% sodium hydroxide solution.Be washed to terminal aqueous phase pH=7.Underpressure distillation, reclaim ethyl acetate, resistates is for aligning butyl phenyl ether ethyl acetate.
In another 1000 liters of glassed steel reaction vessels, add 60kg oxammonium hydrochloride and 900L absolute methanol solution, open below frozen cooling to 10 DEG C, under stirring, add 84.2kg potassium hydroxide.Add again and align butyl phenyl ether ethyl acetate, be heated to backflow, reflux temperature 64 ~ 72 DEG C, be incubated 2 hours, cool, be neutralized to pH=2 ~ 3 with sulfuric acid, stir 30 minutes, be cooled to 5 DEG C freezing 1 hour.Suction filtration, water washing filter cake to last filtrate is neutral.Suction filtration, to dry, dry more than 10 hours, obtains off-white powder and bufexamac crude product 130kg at 55 ~ 60 DEG C.
Bufexamac crude product, 1000L methyl alcohol, 1.3kgEDTA and 6kg gac are added refinery decolorization tank, and be heated to backflow, reflux temperature, at 64 ~ 72 DEG C, is incubated 1 hour, suction filtration while hot.About cooling water temperature to 50 DEG C, stop stirring, to open at frozen cooling to 5 DEG C 2 hours, centrifugal, washing, dries.55 ~ 60 DEG C of dryings, obtain bufexamac 104kg.Total recovery counts 46.6% with p-hydroxyphenylaceticacid.
Comparative example 2
By the synthetic method synthesis bufexamac mentioned in " meticulous and specialty chemicals " 2004,12 (19): 5-6 " synthetic method that bufexamac is new and application ", products therefrom cannot obtain bufexamac by separating-purifying.
Comparative example 3
Be that the add-on of esterified solvent is 11 times of p-hydroxyphenylaceticacid quality with the difference of embodiment 1.
Comparative example 4
Be that the add-on of esterified solvent is 3 times of p-hydroxyphenylaceticacid quality with the difference of embodiment 1.
Comparative example 5
Press
React.
Bufexamac total recovery is in p-hydroxyphenylaceticacid.Embodiment 1 ~ 6 and the positive butyl ester of p-hydroxyphenylaceticacid of comparative example 1 ~ 4 and the yield of bufexamac are listed in table 1.
The yield detected result table of the positive butyl ester of table 1 p-hydroxyphenylaceticacid and bufexamac
In embodiment 1, the high-efficient liquid phase chromatogram of gained bufexamac as shown in Figure 1.In embodiment 2, the high-efficient liquid phase chromatogram of gained bufexamac as shown in Figure 2.As seen from the figure, in embodiment 1 and 2, the characteristic peak of products therefrom and the characteristic peak of bufexamac standard fit like a glove, and illustrate that the chemical purity of products therefrom can reach 99% close to 100%.
From table 1 by comparative example 1, adopt ethanol be raw material react produce bufexamac time, the existence due to by product of product and interference, the yield of 4-hydroxyphenylacetic acid ethyl ether and bufexamac is all lower, is only 75% and 46.6%.In embodiment 1 ~ 6, the yield of the positive butyl ester of p-hydroxyphenylaceticacid is close to 100%.Illustrate that after adopting propyl carbinol to substitute ethanol, not only generated by product is the product of second step, and the yield of 4-hydroxyphenylacetic acid ethyl ether is also greatly improved.In embodiment 1 ~ 6, the yield of bufexamac can reach about 70%, illustrates that synthesizing bufexamac by method provided by the invention can effectively improve its yield, makes to be suitable for industrial applicability far above the yield in comparative example 1 ~ 4.Comparative example 2 is for synthesizing by method disclosed in existing document, and owing to not protecting hydroxyl, leading alkylation, thus makes side reaction in product uncontrollable, cannot obtain product, and disclosed in actual tests result and document, result greatly differs from each other.Comparative example 3 and 4 is when the situation of esterified solvent add-on not when the application provides in scope.From this comparative example, the add-on due to esterified solvent exceedes or lower than limited range of the present invention, makes moisture in reaction process depart from effect and declines, reactant and product solute effect not good, cause gained bufexamac purity and yield all to decline.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (4)
1. a synthetic method for bufexamac, is characterized in that comprising the following steps:
(1) under esterifying catalyst effect, there is esterification in p-hydroxyphenylaceticacid and propyl carbinol in esterified solvent, obtains the positive butyl ester of p-hydroxyphenylaceticacid; (2) under alkylation catalyst effect, in alkylation solvent, be there is alkylated reaction in positive for hydroxyl phenylacetic acid butyl ester and 1-bromination of n-butane, obtain n-butoxy n-butyl phenylatate; (3) under ammonolysis catalyst effect, there is aminolysis reaction in n-butoxy n-butyl phenylatate and oxammonium hydrochloride, obtain bufexamac in aminolysis solvent; Its preparation feedback is as follows:
Wherein, esterifying catalyst is selected from: sodium pyrosulfate or sal enixum; Esterified solvent is selected from: toluene or benzene; Alkylation catalyst is selected from: salt of wormwood; Alkylation solvent is selected from: dehydrated alcohol; Ammonolysis catalyst is selected from: potassium hydroxide; Aminolysis solvent is selected from: anhydrous methanol; Total recovery 71.3% ~ 71.7%; Purity 99% ~ 99.9%.
2. method according to claim 1, is characterized in that bufexamac is prepared as follows:
(1) in the reactor of 1500L, add toluene 900L, p-hydroxyphenylaceticacid 152 kilograms, propyl carbinol 106 kilograms, sodium pyrosulfate 5 kilograms, wherein p-hydroxyphenylaceticacid and propyl carbinol mol ratio are 1: 1.5; Heating reflux reaction, phegma needs by water trap, and after 40 minutes, TLC detects and judges that reaction reaches stopped reaction after terminal, and reactant is down to room temperature by logical water coolant, filters, filtration catalizer, and filtrate concentrates, and can directly apply mechanically after toluene recovery; Obtain oily matter and the positive butyl ester of p-hydroxyphenylaceticacid 207.5 kilograms;
(2) getting the positive butyl ester of gained p-hydroxyphenylaceticacid joins in 1000 liters of glassed steel reaction vessels, add dehydrated alcohol 600 kilograms, 150 kilograms of 1-bromination of n-butane and 163 kilograms of salt of wormwood mix with the esterification products of last consignment of, be warming up to backflow, reflux temperature controls at 75 ~ 80 DEG C, is incubated 8 hours; Point plate monitoring raw material point primitive reaction is complete; Distillation recovery ethanol; Cooling, adds 600 premium on currency, stirs 10 minutes in retort, leaves standstill 2 hours, point water outlet, and water layer extracts 3 times by 300L ethyl acetate at every turn, merges organic layer; Organic layer is with after 45 kilogram of 5% sodium hydroxide solution washing once; Be washed to terminal aqueous phase pH=7; Underpressure distillation, reclaim ethyl acetate, resistates is for aligning butyl phenyl ether n-butyl acetate;
(3) in another 1000 liters of glassed steel reaction vessels, add 79.6 kilograms of oxammonium hydrochlorides and 900L absolute methanol solution, open below frozen cooling to 10 DEG C, under stirring, add 112.8 kilograms of potassium hydroxide; Add again and align butyl phenyl ether n-butyl acetate, be heated to backflow, reflux temperature 64 ~ 72 DEG C, be incubated 2 hours, cool, be neutralized to pH=2 ~ 3 with sulfuric acid, stir 30 minutes, be cooled to 5 DEG C freezing 1 hour; Suction filtration, water washing filter cake to last filtrate is neutral; Suction filtration, to dry, dry more than 10 hours, obtains off-white powder and bufexamac crude product 206 kilograms at 55 ~ 60 DEG C;
Add in reactor by bufexamac crude product, 1500L methyl alcohol, 1.5 kilograms of EDTA and 6 kilogram gacs, be heated to backflow, reflux temperature, at 64 ~ 72 DEG C, is incubated 1 hour, suction filtration while hot; About cooling water temperature to 50 DEG C, stop stirring, to open at frozen cooling to 5 DEG C 2 hours, centrifugal, washing, dries; 55 ~ 60 DEG C of dryings, obtain bufexamac 160 kilograms; Purity 99%, total recovery 71.7%.
3. method according to claim 1, is characterized in that bufexamac is prepared as follows:
(1) in the reactor of 1500L, by propyl carbinol with p-hydroxyphenylaceticacid in molar ratio for 1:2 mixes, add the benzene of p-hydroxyphenylaceticacid quality 5 times of quality, sodium pyrosulfate 5 kilograms, heating reflux reaction, phegma needs to pass through water trap; After 40 minutes, TLC detects and judges that reaction reaches stopped reaction after terminal, and filter, filtrate concentrates, and can directly apply mechanically after toluene recovery; Obtain oily matter and the positive butyl ester of p-hydroxyphenylaceticacid 203.8 kilograms;
(2) getting the positive butyl ester of gained p-hydroxyphenylaceticacid joins in 1000 liters of glassed steel reaction vessels, add dehydrated alcohol 600 kilograms, 150 kilograms of 1-bromination of n-butane and 163 kilograms of salt of wormwood mix with the esterification products of last consignment of, be warming up to backflow, reflux temperature controls at 75 ~ 80 DEG C, is incubated 8 hours; Point plate monitoring raw material point primitive reaction is complete; Distillation recovery ethanol; Cooling, adds 600 premium on currency, stirs 10 minutes in retort, leaves standstill 2 hours, point water outlet, and water layer extracts 3 times by 300L ethyl acetate at every turn, merges organic layer; Organic layer is with after 45 kilogram of 5% sodium hydroxide solution washing once; Be washed to terminal aqueous phase pH=7; Underpressure distillation, reclaim ethyl acetate, resistates is for aligning butyl phenyl ether n-butyl acetate;
(3) in another 1000 liters of glassed steel reaction vessels, add 79.6 kilograms of oxammonium hydrochlorides and 900L absolute methanol solution, open below frozen cooling to 10 DEG C, under stirring, add 112.8 kilograms of potassium hydroxide; Add again and align butyl phenyl ether n-butyl acetate, be heated to backflow, reflux temperature 64 ~ 72 DEG C, be incubated 2 hours, cool, be neutralized to pH=2 ~ 3 with sulfuric acid, stir 30 minutes, be cooled to 5 DEG C freezing 1 hour; Suction filtration, water washing filter cake to last filtrate is neutral; Suction filtration, to dry, dry more than 10 hours, obtains off-white powder and bufexamac crude product 205.2 kilograms at 55 ~ 60 DEG C;
Add in reactor by bufexamac crude product, 1500L methyl alcohol, 1.5 kilograms of EDTA and 6 kilogram gacs, be heated to backflow, reflux temperature, at 64 ~ 72 DEG C, is incubated 1 hour, suction filtration while hot; About cooling water temperature to 50 DEG C, stop stirring, to open at frozen cooling to 5 DEG C 2 hours, centrifugal, washing, dries; 55 ~ 60 DEG C of dryings, obtain bufexamac 159.0 kilograms; Purity 99.8%, total recovery 71.3%.
4. method according to claim 1, is characterized in that bufexamac is prepared as follows:
(1) in the reactor of 1500L, by propyl carbinol with p-hydroxyphenylaceticacid in molar ratio for 1:1.3 mixes, add the toluene of p-hydroxyphenylaceticacid quality 8 times of quality, sal enixum 5 kilograms, heating reflux reaction, phegma needs to pass through water trap; After 40 minutes, TLC detects and judges that reaction reaches stopped reaction after terminal, reactant is down to room temperature by logical water coolant, be washed till the aobvious alkalescence of water layer with the sodium carbonate solution of 1mol/L, then wash with water to neutrality, which floor has been got, anhydrous sodium sulfate drying more than 5 hours, filter, filtrate concentrates, and can directly apply mechanically after toluene recovery; Obtain oily matter and the positive butyl ester of p-hydroxyphenylaceticacid 203.8 kilograms;
(2) getting the positive butyl ester of gained p-hydroxyphenylaceticacid joins in 1000 liters of glassed steel reaction vessels, add dehydrated alcohol 600 kilograms, 150 kilograms of 1-bromination of n-butane and 163 kilograms of salt of wormwood mix with the esterification products of last consignment of, be warming up to backflow, reflux temperature controls at 75 ~ 80 DEG C, is incubated 8 hours; Point plate monitoring raw material point primitive reaction is complete; Distillation recovery ethanol; Cooling, adds 600 premium on currency, stirs 10 minutes in retort, leaves standstill 2 hours, point water outlet, and water layer extracts 3 times by 300L ethyl acetate at every turn, merges organic layer; Organic layer is with after 45 kilogram of 5% sodium hydroxide solution washing once; Be washed to terminal aqueous phase pH=7; Underpressure distillation, reclaim ethyl acetate, resistates is for aligning butyl phenyl ether n-butyl acetate;
(3) in another 1000 liters of glassed steel reaction vessels, add 79.6 kilograms of oxammonium hydrochlorides and 900L absolute methanol solution, open below frozen cooling to 10 DEG C, under stirring, add 112.8 kilograms of potassium hydroxide; Add again and align butyl phenyl ether n-butyl acetate, be heated to backflow, reflux temperature 64 ~ 72 DEG C, be incubated 2 hours, cool, be neutralized to pH=2 ~ 3 with sulfuric acid, stir 30 minutes, be cooled to 5 DEG C freezing 1 hour; Suction filtration, water washing filter cake to last filtrate is neutral; Suction filtration, to dry, dry more than 10 hours, obtains off-white powder and bufexamac crude product 205.2 kilograms at 55 ~ 60 DEG C;
Add in reactor by bufexamac crude product, 1500L methyl alcohol, 1.5 kilograms of EDTA and 6 kilogram gacs, be heated to backflow, reflux temperature, at 64 ~ 72 DEG C, is incubated 1 hour, suction filtration while hot; About cooling water temperature to 50 DEG C, stop stirring, to open at frozen cooling to 5 DEG C 2 hours, centrifugal, washing, dries; 55 ~ 60 DEG C of dryings, obtain bufexamac 159.2 kilograms; Purity 99.9%, total recovery 71.4%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410135578.8A CN103896810B (en) | 2014-04-04 | 2014-04-04 | The synthetic method of bufexamac |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410135578.8A CN103896810B (en) | 2014-04-04 | 2014-04-04 | The synthetic method of bufexamac |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103896810A CN103896810A (en) | 2014-07-02 |
| CN103896810B true CN103896810B (en) | 2015-09-16 |
Family
ID=50988435
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410135578.8A Active CN103896810B (en) | 2014-04-04 | 2014-04-04 | The synthetic method of bufexamac |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103896810B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104920360B (en) * | 2015-06-18 | 2017-04-12 | 青岛农业大学 | Application of bufexamac in preparation of bactericide used for controlling plant disease caused by phytopathogen |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5777646A (en) * | 1980-10-31 | 1982-05-15 | Kanto Kagaku Kk | Preparation of hydroxamic acid |
| CN103360225A (en) * | 2013-06-28 | 2013-10-23 | 大连大学 | Method for preparing p-hydroxy phenyl ethyl ketone compound through rearrangement reaction under catalysis of acidic ionic liquid |
-
2014
- 2014-04-04 CN CN201410135578.8A patent/CN103896810B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5777646A (en) * | 1980-10-31 | 1982-05-15 | Kanto Kagaku Kk | Preparation of hydroxamic acid |
| CN103360225A (en) * | 2013-06-28 | 2013-10-23 | 大连大学 | Method for preparing p-hydroxy phenyl ethyl ketone compound through rearrangement reaction under catalysis of acidic ionic liquid |
Non-Patent Citations (2)
| Title |
|---|
| 丁苯羟酸合成方法的改进;李庆明等;《广东药学院学报》;19990603;第15卷(第02期);92-93 * |
| 丁苯羟酸新的合成方法及应用;孙文等;《精细与专用化学品》;20050706;第12卷(第19期);5-6、15 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103896810A (en) | 2014-07-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104151152B (en) | A kind of three circulating methods preparing phenoxy acetic acid without waste water | |
| CN103724261A (en) | Novel industrial production method for hydroxychloroquine sulfate | |
| CN107118069A (en) | A kind of method that utilization isobutyl dehydration of alcohols prepares isobutene | |
| CN102731349B (en) | Aromatic sulfinic acid compound preparation method | |
| CN105418421A (en) | Synthesizing method for 3-methoxyacrylate | |
| CN101906209B (en) | Method for synthesizing polyethylene glycol monomethacrylate from solid superacid by catalytic esterification | |
| CN101337870A (en) | Method for synthesizing 4-(4'-n-alkyl cyclohexyl)cyclohexanone | |
| CN108912062A (en) | A kind of preparation method of triazolinthione derivative | |
| CN103896810B (en) | The synthetic method of bufexamac | |
| CN105218544A (en) | A kind of synthetic method of Eliquis intermediate | |
| CN106699594A (en) | Preparation method of iopromide | |
| CN103880699B (en) | Method for synthesizing imides compounds | |
| CN106565621A (en) | Isoxaflutole synthesizing method | |
| CN102381947A (en) | Synthesis method of chiral 2,2 '- di-alkoxy-1, 1'-binaphthyl | |
| CN102382050A (en) | Preparation method of substituted 1, 2, 3 and 4- tetrahydroquinoline -4-one hydrochloride | |
| CN106117118A (en) | A kind of preparation technology of bupivacaine hydrochloride | |
| CN106674135A (en) | Uracil synthesizing method | |
| CN103113234B (en) | Method for synthesizing N-methyl paranitroaniline | |
| CN104876806A (en) | Novel method for synthesizing bisoprolol importance intermediate | |
| CN105272957B (en) | A kind of green synthesis method of neutral ion liquid catalyst glycerine converting carbonic ester | |
| CN108047001A (en) | A kind of method for synthesizing 2,5- xylenols | |
| CN102093301B (en) | Solvothermal synthesis method of sartanbiphenyltetrazole | |
| CN209508101U (en) | A kind of preparation system of efficient and environment-friendly type quinolones sand star drug | |
| CN103012087A (en) | Green synthetic method of alpha, alpha'-double benzylidene cycloalkanone compound | |
| CN103224452A (en) | 2-bromine-4,6-dichloroaniline preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 410005 Kangping Road, Liuyang economic and Technological Development Zone, Changsha, Hunan, 165 Patentee after: HUNAN DINUO PHARMACEUTICAL Co.,Ltd. Address before: 410329 Huan Yuan East Road, Liuyang biological pharmaceutical industrial park, Changsha, Hunan Patentee before: HUNAN DINUO PHARMACEUTICAL Co.,Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Synthesis of butyryl hydroxylic acid Effective date of registration: 20221213 Granted publication date: 20150916 Pledgee: China Construction Bank Corporation Liuyang sub branch Pledgor: HUNAN DINUO PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980026992 |