CN102442937A - Method for preparing 1-benzyl-4-aniline piperidine-4-carboxylic acid - Google Patents
Method for preparing 1-benzyl-4-aniline piperidine-4-carboxylic acid Download PDFInfo
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Abstract
The invention discloses a method for preparing 1-benzyl-4-aniline piperidine-4-carboxylic acid, which comprises the following steps that: (1) hydrocyanic acid is added into 1-benzyl-4-piperidone at 0 to 15 DEG C under the effect of base catalysis, then, the temperature of the reaction liquid is raised to that under the back flow state, aniline is added in a flowing way, the materials are cooled to the temperature below 5 DEG C after the reaction completion, glacial acetic acid is added, and 1-benzyl-4-cyan-4-aniline piperidine solid is obtained through crystal separation and filtering; (2) the solid obtained in the first step is added into 70 to 90 percent sulfuric acid, the stirring reaction is carried out for 50 to 90 hours at 20 to 50 DEG C, then, the reaction liquid is added into crushed ice solution, the pH value of the solution is regulated to 4 to 9 at 0 to 10 DEG C by stronger ammonia water, the crystal separation, the filtering and the water washing are carried out, and white powder solid is obtained; and (3) the solid obtained in the second step is added into concentrated hydrochloric acid, the temperature is raised to the boiling temperature, the backflow reaction is carried out for 10 to 20 hours, the materials are cooled to the temperature being 0 to 30 DEG C and are in still standing placement for 24 to 54 hours, and products are obtained after crystal separation, extraction filtering, water washing and drying. Through the optimization on each reaction step, a large number of organic solvents such as dichloromethane, isopropanol and the like are not used, the technical flow process is simplified, the environment pollution is reduced, the raw material cost is saved, and the product yield is improved.
Description
Technical field
The present invention relates to a kind of novel method of the key intermediate 1-benzyl-4-anilino piperidines-4-carboxylic acid of narcotic analgesic-remifentanil when ultrashort for preparing.
Background technology
1-benzyl-4-anilino piperidines-4-carboxylic acid is the important intermediate of preparation 3-[4-(methoxycarbonyl) 4-(N-Phenylpropionamide base)-1-piperidines] methyl propionate; It is a novel potent analgesia narcotic;, continuous intravenous extremely short because of its transformation period drip do not produce accumulate phenomenon, untoward reaction is little, become developed country in the recent period widely used comparatively ideal efficiently, fast, narcotic analgesic in short-term.Its preparation method and use is at " the synthetic and analgesic activity of 4-methoxycarbonyl-4-N-propionanilide phenylpiperidines 1 bit derivant " Acta Pharmaceutica Sinica 1990.25 (4): 253-29 " synthesizing of Alfentanil Hydrochloride " Chinese Pharmaceutical Journal 2002,12 (6) 354-356; Feldman PL, Brackeen MF.A novel route to the 4-anilido-4-(meThoxycarBoNyl)-iperdine class of anagetics [J] J Org Chem, 1990,55 (13): 4207-4209; Feldman PL; James M K; Brackeen MF; Et al.Design synthesis and armacological evaluation of ultrasthortto long-acting opioid analgtics [J] J Med Chem, 1991,34 (7): description is all arranged in the documents such as 2202-2208.
In the technology of existing synthesize benzyl-4-anilino piperidines-4-carboxylic acid especially with 1-benzyl-4-piperidone be starting raw material through addition, elimination, hydrolysis, in and the preparation method of the synthetic 1-benzyl of step-4-anilino piperidines-4-carboxylic acid such as crystallization use morely.But in the synthetic technology that these have been reported, have long reaction time, use auxiliary material various, product yield is low, and quantity of three wastes is big and be difficult to defective such as processing.
According to Yang Yulong; Zhu Xinwen; Zhu Guozheng; Deng people's report record in " 4-methoxycarbonyl-4-N-propionanilide phenylpiperidines 1 bit derivant synthetic and analgesic activity " literary composition, they with 1-benzyl-4-piperidone be starting raw material through addition, elimination, hydrolysis, in and step such as crystallization synthesized 1-benzyl-4-anilino piperidines-4-carboxylic acid, used a large amount of organic solvents such as acetic acid, chloroform, Virahol in reaction and the last handling process.The three-step reaction total recovery is merely 32.48%.
What report in " Alfentanil Hydrochloride synthetic " literary composition of being delivered by Bi Xiaoling etc. is that people's such as its preparation process and Yang Yulong in the method for the synthetic 1-benzyl of starting raw material-4-anilino piperidines-4-carboxylic acid the practice is basic identical with 1-benzyl-4-piperidone.Just when preparation 1-benzyl-4-cyanic acid-4-anilino piperidines, changed raw material Potssium Cyanide wherein into sodium cyanide; Post processing mode when synthetic 1-benzyl-4-carbamyl-4-anilino piperidines is different.Though improve to some extent.But the total recovery of its three-step reaction also is merely about 41%.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of 1-benzyl-4-anilino piperidines-4-carboxylic acid of high yield, and this preparation method uses auxilliary material few, and product yield is high, more economically, environmental protection.
It is following that the present invention solves the problems of the technologies described above the technical scheme that is adopted: prepare the method for 1-benzyl-4-anilino piperidines-4-carboxylic acid, comprise the steps:
(1) according to 1-benzyl-4-piperidone: prussic acid: the mol ratio of alkaline catalysts is the ratio proportioning of 1:1 ~ 1.05:0.5 ~ 1.05; After earlier 1-benzyl-4-piperidone being cooled to 0 ~ 15 ℃; Add the methanol solution that contains massfraction 10 ~ 20% prussic acid, stream adds the methanol solution that massfraction is 3 ~ 10% alkaline catalystss in 0.5 ~ 3h then, after stream adds end insulation 0.5 ~ 3h; Again above-mentioned reaction solution is warmed up under the reflux state; According to 1-benzyl-4-piperidone: aniline: the mol ratio of Glacial acetic acid min. 99.5 is the ratio proportioning of 1:1 ~ 1.05:1.0 ~ 3.5, and under reflux state, stream adds aniline in 0.5 ~ 2.5h; After adding aniline insulation 0.5 ~ 3h, reaction solution is poured in the frozen water that 5 ~ 15 times of own vols contain 60 ~ 80% trash ices, and remained on that stream adds the Glacial acetic acid min. 99.5 crystallization in 0 ~ 15 ℃, crystal is filtered obtain 1-benzyl-4-cyanic acid-4-anilino piperidines solid then;
(2) the 1-benzyl-4-cyanic acid-4-anilino piperidines solid that step (1) is prepared; In 1-benzyl-4-cyanic acid-4-anilino piperidines: the vitriolic mol ratio is the ratio proportioning of 1:10 ~ 25; Under whipped state, joining the vitriolic massfraction is in 70 ~ 95% aqueous solution; Charge temperature remains on 20 ~ 50 ℃, and stirring reaction 40 ~ 90h is continued in the reinforced back that finishes in this temperature, then reaction solution is poured in the frozen water that 5 ~ 15 times of own vols contain 60 ~ 80% trash ices; And in 0 ~ 10 ℃ with pH value to 4 ~ 9 crystallizatioies of 20 ~ 40% ammoniacal liquor regulator solutions, with crystal filter, wash 1-benzyl-4-carbamyl-4-anilino piperidines white powder solid;
(3) the 1-benzyl-4-carbamyl-4-anilino piperidines white powder solid that step (2) is prepared; By 1-benzyl-4-carbamyl-4-anilino piperidines: the mol ratio of hydrochloric acid is the proportioning of 1:20 ~ 35; Join in the concentrated hydrochloric acid in 20 ~ 35 ℃; After adding material reaction system slowly is warmed up to boiling temperature back flow reaction 5 ~ 20h, reaction end postcooling reaction solution to 0 ~ 30 ℃ of static placement 48h crystallizatioies, filtration crystal, washing, drying obtain 1-benzyl-4-anilino piperidines-4-carboxylic acid white crystal product.
Above-mentioned steps (1) is in the reactor drum that has stirring and reflux exchanger, to react, and reaction is made solvent with methyl alcohol, is dissolved in prussic acid to be made into the danger that methanol solution can reduce operation in the methyl alcohol.Be dissolved in the methyl alcohol methanol solution of proportionaling alkali-forming to alkali and flow and add, help keeping the stability of system acidity.Adopt lesser temps to help suppressing the volatilization that prussic acid takes place and prevents in side reaction in the first step; In 0 ~ 10 ℃ the aqueous solution, carrying out acid out after reaction is accomplished is in order to prevent that the acid out process from generating by product.In the above-mentioned steps (2), the hydrolysis reaction that replaces pure 98% the vitriol oil more to help cyanic acid with the vitriol oil that contains certain water yield carries out; Reaction finishes the back and in containing the trash ice aqueous solution, neutralizes with ammoniacal liquor and help absorbing rapidly the great amount of heat energy that neutralization reaction is emitted, and reduces the generation of by product.In the above-mentioned steps (3), be hydrolyzed, help the purpose product and separate out, need not to carry out the alkali neutralization after reaction finishes and just can direct filtration obtain product with the form of its hydrochloride with concentrated hydrochloric acid.
Further preferred as each reaction parameter in above-mentioned preparation 1-benzyl-4-anilino piperidines-4-carboxylic acid method, said alkaline catalysts is a kind of or at least two kinds of mixtures that mix to constitute with arbitrary proportion in sodium hydroxide, Pottasium Hydroxide, yellow soda ash or the volatile salt.
In the said step (1) 1-benzyl-4-piperidone is cooled to add after 0 ~ 10 ℃ the methanol solution that contains massfraction 10 ~ 20% prussic acid; The temperature of stirring reaction is 20 ~ 35 ℃ in the step (2), and in 0 ~ 8 ℃ with the pH value of 20 ~ 40% ammoniacal liquor regulator solutions; 1-benzyl in the step (3)-4-carbamyl-4-anilino piperidines joins in the concentrated hydrochloric acid at 20 ~ 25 ℃, and reaction finishes postcooling reaction solution to 0 ~ 15 ℃ of crystallizatioies.
It is 0.5 ~ 2h that the middle alkaline catalysts stream of said step (1) adds the time, and the time that stream adds aniline is 0.8 ~ 1.5h; The time of the stirring reaction in the step (2) is 50-80h; Reflux time in the step (3) is 10 ~ 20h.
PH value to 5 ~ 7 crystallizatioies of regulator solution in the said step (2).
The ammonia concn scope is 25 ~ 35% in the said step (2).
Compared with prior art, the present invention has following beneficial effect:
The present invention is through with 1-benzyl-4-piperidone being the optimization of each step of the synthetic 1-benzyl of starting raw material-4-anilino piperidines-4-carboxylic acid; Do not re-use a large amount of organic solvent such as methylene dichloride, Virahol in the process, simplified technical process, reduced environmental pollution, practiced thrift raw materials cost, improved product yield.
Embodiment
Through embodiment the present invention is specifically described below; Be necessary to be pointed out that at this; Following examples only are used for the present invention is further described; Can not be interpreted as the restriction to protection domain of the present invention, the technician in this field can make some nonessential improvement and adjustment to the present invention according to the foregoing invention content.
Embodiment 1
Elder generation packs 94.63g1-benzyl-4-piperidone in the four-hole reaction flask that has reflux cooling device and whisking appliance; After stirring is cooled to 5 ℃, add the methanol solution 100g that contains 14.0g prussic acid, remain on then in 5 ~ 10 ℃; Stream adds that to contain massfraction be 5% sodium hydrate methanol solution 400g in 2h; Stream add finish insulation 1h after, above-mentioned reaction solution is warmed up under the reflux state stream adds 47g aniline in 0.8h, and under reflux temperature, is incubated 1.5h.Reaction is poured reaction solution in the 3500g frozen water that contains trash ice 70% into after finishing, and in 5 ~ 10 ℃ of temperature, adds Glacial acetic acid min. 99.5 75g crystallization, crystal is filtered obtain solid pure product 143.07g.(is 98.2% through calculated yield)
Earlier 70g water is joined in the four-hole reaction flask that has whisking appliance; Stream adds the 700g vitriol oil and is made into aqueous sulfuric acid in reaction flask again; This aqueous solution is cooled to 20 ℃; And add to go up the step reaction in 20 ~ 25 ℃ and obtain solid pure product 143.07g, keep its temperature stirring reaction 70h then, after insulation finishes reaction solution added and contain in the 4500g frozen water of trash ice 70%; And to keep system temperature be 0 ~ 5 ℃, use mass concentration be 25% ammoniacal liquor regulator solution pH value to 6.5 crystallizatioies, with crystal filter, wash white powder solid pure product 129.88g.(is 85.5% through calculated yield)
Concentrated hydrochloric acid adding with 1200g earlier has in the four-hole reaction flask of whisking appliance; In 25 ~ 30 ℃, the solid of 129.88g is joined in the reaction flask again; After slowly being warmed up to boiling temperature back flow reaction 12h, reaction end then; Cooling reaction liquid to 15 ℃, and in 15 ~ 20 ℃ static placement 48h crystallization, filter crystal, washing, dry the pure article 126.13g of white crystal.(is 96.8% through calculated yield)
The total recovery of above-mentioned three-step reaction is: 81.27%.
Embodiment 2
Earlier 94.63g1-benzyl-4-piperidone is packed into after stirring is cooled to 0 ℃ in the four-hole reaction flask that has reflux cooling device and whisking appliance; Add the methanol solution 100mL that contains 13.5g prussic acid; Remain on then in 0 ~ 5 ℃; Stream adds that to contain massfraction be 3% yellow soda ash methanol solution 350g in 1h, stream add finish back insulation 3h after, above-mentioned reaction solution is warmed up under the reflux state stream adds 48.8g aniline and is incubated 1.5h in 0.5h.Reaction is poured reaction solution in the 3500g frozen water that contains trash ice 80% into after finishing, and in 10 ~ 15 ℃, adds Glacial acetic acid min. 99.5 105g crystallization, crystal is filtered obtain solid pure product 140.6g.(96.5%)
Earlier 63g water is joined in the four-hole reaction flask that has whisking appliance; Add the 1200g vitriol oil to reaction flask stream again and be made into aqueous sulfuric acid; This aqueous solution is cooled to 20 ℃; And in 20 ~ 25 ℃, add to go up the step reaction and obtain solid pure product 140.6g, keep its temperature stirring reaction 50h then, after insulation finishes reaction solution added and contain in the 4500g frozen water of trash ice 60%; And to keep system temperature be 0 ~ 5 ℃, use mass concentration be 35% ammoniacal liquor regulator solution pH value to 5.5 crystallizatioies, filtration, wash white powder solid pure product 125.71g.（84.21%）
Concentrated hydrochloric acid adding with 1500g earlier has in the four-hole reaction flask of whisking appliance; To go up the 125.71g solid pure product that step reaction obtains in 20 ~ 25 ℃ again joins in the reaction flask; Slowly be warmed up to boiling temperature back flow reaction 10h, reaction then and finish postcooling reaction solution to 0 ℃; And in 0 ~ 5 ℃ static placement 48h crystallization, filter crystal, washing, dry the pure article 120.21g of white crystal.（95.32%）
The total recovery of three-step reaction is: 77.46%.
Embodiment 3
Earlier 94.63g1-benzyl-4-piperidone is packed into after a bottle stirring is cooled to below 5 ~ 10 ℃ in the four-hole reaction that has reflux cooling device and whisking appliance; Add the methanol solution 100mL that contains 14.2g prussic acid; Remain on 5 ~ 10 ℃ then; Stream adds that to contain massfraction be 10% potassium hydroxide methanol solution 280g in 0.5h, stream add finish insulation 3h after, above-mentioned reaction solution is warmed up under the reflux state stream adds 46.5g aniline and is incubated 3h in 1.5h.Insulation is poured reaction solution in the 3500g frozen water that contains trash ice 60% into after finishing, and in 0 ~ 5 ℃, adds Glacial acetic acid min. 99.5 60g crystallization, crystal is filtered obtain solid pure product 139.14g.(95.5%)
Earlier 210g water is joined in the four-hole reaction flask that has whisking appliance; Add the 490g vitriol oil to reaction flask stream again and be made into aqueous sulfuric acid; This aqueous solution is cooled to 30 ℃ and remain in 30 ~ 35 ℃ to add and go up the step reaction and obtain solid pure product 139.14g; Keep its temperature stirring reaction 80h then; After insulation finishes reaction solution is poured in the 4500g frozen water that contains trash ice 80%, and to keep system temperature be 0 ~ 5 ℃, use mass concentration be 30% ammoniacal liquor regulator solution pH value to 7.0 crystallizatioies, filtration, wash white powder solid pure product 125.21g.（84.75%）
Concentrated hydrochloric acid adding with 1100g earlier has in the four-hole reaction flask of whisking appliance; In 20 ~ 25 ℃, will go up the solid pure product 125.21g that step reaction obtains again joins in the reaction flask; Slowly be warmed up to boiling temperature back flow reaction 20h, reaction then and finish postcooling reaction solution to 10 ℃; And in 10 ~ 5 ℃ static placement 48h crystallization, filter crystal, washing, dry the pure article 120.08g of white crystal.（95.6%）
The total recovery of three-step reaction is: 77.38%.
Embodiment 4
According to 1-benzyl-4-piperidone: prussic acid: the mol ratio of alkaline catalysts is 1: (1 or 1.05 or 1.03): the ratio proportioning of (0.5 or 1.05 or 0.76); After earlier 1-benzyl-4-piperidone being cooled to 0 ℃ or 15 ℃ or 10 ℃; Add the methanol solution that contains massfraction 10 ~ 20% prussic acid; Stream adds the methanol solution that massfraction is 3 ~ 10% alkaline catalystss in 0.5 h or 2 h or 3h then; Stream add finish insulation 0.5h or 1.9h or 3h after, more above-mentioned reaction solution is warmed up under the reflux state, according to 1-benzyl-4-piperidone: aniline: the mol ratio of Glacial acetic acid min. 99.5 is 1: (1 or 1.02 or 1.05): the ratio proportioning of (1 or 3.4 or 2.1); Under reflux state, stream adds aniline in 0.8h or 1.5h or 2.4h; After adding aniline insulation 0.5h or 2h or 3h; Reaction solution is poured in the frozen water that 5 ~ 15 times of own vols contain 60 ~ 80% trash ices; And remain in 0 ℃ or 5 ℃ or 15 ℃ stream and add the Glacial acetic acid min. 99.5 crystallization, crystal is filtered obtain 1-benzyl-4-cyanic acid-4-anilino piperidines solid then;
1-benzyl-4-cyanic acid-4-anilino piperidines solid with above-mentioned preparation; In 1-benzyl-4-cyanic acid-4-anilino piperidines: the vitriolic mol ratio is the ratio proportioning of 1:10 or 16 or 25; Under whipped state, joining the vitriolic massfraction is in 70 ~ 95% aqueous solution; Charge temperature remains on 20 ℃ or 28 ℃ or 50 ℃; Stirring reaction 40h or 60h or 80h or 90h are continued in the reinforced back that finishes in this temperature; Then reaction solution is poured in the frozen water that 5 ~ 15 times of own vols contain 60 ~ 80% trash ices, and in 0 ℃ or 5 ℃ or 10 ℃ with the pH value to 4 or 5 or 7 or 9 crystallizatioies of 20 ~ 40% ammoniacal liquor regulator solutions, with crystal filter, wash 1-benzyl-4-carbamyl-4-anilino piperidines white powder solid;
(3) the 1-benzyl-4-carbamyl-4-anilino piperidines white powder solid that step (2) is prepared; By 1-benzyl-4-carbamyl-4-anilino piperidines: the mol ratio of hydrochloric acid is the proportioning of 1:20 or 26 or 34; Join in the concentrated hydrochloric acid in 20 ℃ or 27 ℃ or 35 ℃; Add behind the material with reaction system slowly be warmed up to boiling temperature back flow reaction 5h 15 or 20h, reaction finish postcooling reaction solution to 0 ℃ or 15 ℃ or 30 ℃ of static placements 48h crystallizatioies, filtration crystal, washing, drying obtain 1-benzyl-4-anilino piperidines-4-carboxylic acid white crystal product.
The reaction formula of above-mentioned three steps is following:
Present embodiment selects above-mentioned parameter to carry out orthogonal test, and test-results shows that the average total recovery for preparing the three-step reaction of 1-benzyl-4-anilino piperidines-4-carboxylic acid by present embodiment is: 79.38%.
As stated, embodiment of the present invention preferably.
Claims (6)
1. prepare the method for 1-benzyl-4-anilino piperidines-4-carboxylic acid, it is characterized in that, comprise the steps:
(1) according to 1-benzyl-4-piperidone: prussic acid: the mol ratio of alkaline catalysts is the ratio proportioning of 1:1～1.05:0.5～1.05; After earlier 1-benzyl-4-piperidone being cooled to 0～15 ℃; Add the methanol solution that contains massfraction 10～20% prussic acid, stream adds the methanol solution that massfraction is 3～10% alkaline catalystss in 0.5～3h then, after stream adds end insulation 0.5～3h; Again above-mentioned reaction solution is warmed up under the reflux state; According to 1-benzyl-4-piperidone: aniline: the mol ratio of Glacial acetic acid min. 99.5 is the ratio proportioning of 1:1～1.05:1.0～3.5, and under reflux state, stream adds aniline in 0.5～2.5h; After adding aniline insulation 0.5～3h, reaction solution is poured in the frozen water that 5～15 times of own vols contain 60～80% trash ices, and remained on that stream adds the Glacial acetic acid min. 99.5 crystallization in 0～15 ℃, crystal is filtered obtain 1-benzyl-4-cyanic acid-4-anilino piperidines solid then;
(2) the 1-benzyl-4-cyanic acid-4-anilino piperidines solid that step (1) is prepared; In 1-benzyl-4-cyanic acid-4-anilino piperidines: the vitriolic mol ratio is the ratio proportioning of 1:10～25; Under whipped state, joining the vitriolic massfraction is in 70～95% aqueous solution; Charge temperature remains on 20～50 ℃, and stirring reaction 40～90h is continued in the reinforced back that finishes in this temperature, then reaction solution is poured in the frozen water that 5～15 times of own vols contain 60～80% trash ices; And in 0～10 ℃ with pH value to 4～9 crystallizatioies of 20～40% ammoniacal liquor regulator solutions, with crystal filter, wash 1-benzyl-4-carbamyl-4-anilino piperidines white powder solid;
(3) the 1-benzyl-4-carbamyl-4-anilino piperidines white powder solid that step (2) is prepared; By 1-benzyl-4-carbamyl-4-anilino piperidines: the mol ratio of hydrochloric acid is the proportioning of 1:20～35; Join in the concentrated hydrochloric acid in 20～35 ℃; After adding material reaction system slowly is warmed up to boiling temperature back flow reaction 5～20h, reaction end postcooling reaction solution to 0～30 ℃ of static placement 48h crystallizatioies, filtration crystal, washing, drying obtain 1-benzyl-4-anilino piperidines-4-carboxylic acid white crystal product.
2. the method for preparing 1-benzyl-4-anilino piperidines-4-carboxylic acid according to claim 1; It is characterized in that said alkaline catalysts is a kind of or at least two kinds of mixtures that mix to constitute with arbitrary proportion in sodium hydroxide, Pottasium Hydroxide, yellow soda ash or the volatile salt.
3. the method for preparing 1-benzyl-4-anilino piperidines-4-carboxylic acid according to claim 1 is characterized in that, in the said step (1) 1-benzyl-4-piperidone is cooled to add after 0～10 ℃ the methanol solution that contains massfraction 10～20% prussic acid; The temperature of stirring reaction is 20～35 ℃ in the step (2), and in 0～8 ℃ with the pH value of 20～40% ammoniacal liquor regulator solutions; 1-benzyl in the step (3)-4-carbamyl-4-anilino piperidines joins in the concentrated hydrochloric acid at 20～25 ℃, and reaction finishes postcooling reaction solution to 0～15 ℃ of crystallizatioies.
4. according to any described method for preparing 1-benzyl-4-anilino piperidines-4-carboxylic acid of claim 1 to 3, it is characterized in that it is 0.5～2h that the middle alkaline catalysts stream of said step (1) adds the time, the time that stream adds aniline is 0.8～1.5h; The time of the stirring reaction in the step (2) is 50-80h; Reflux time in the step (3) is 10～20h.
5. according to any described method for preparing 1-benzyl-4-anilino piperidines-4-carboxylic acid of claim 1 to 3, it is characterized in that pH value to 5～7 crystallizatioies of regulator solution in the said step (2).
6. according to any described method for preparing 1-benzyl-4-anilino piperidines-4-carboxylic acid of claim 1 to 3, it is characterized in that the mass percentage concentration of ammoniacal liquor is 25～35% in the said step (2).
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107589192A (en) * | 2017-10-24 | 2018-01-16 | 宜昌人福药业有限责任公司 | A kind of method for improving remifentanil hydrochloride product quality |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008005423A1 (en) * | 2006-07-03 | 2008-01-10 | Cambrex Charles City, Inc. | Improved method of making sufentanil |
| CN102127007A (en) * | 2011-01-21 | 2011-07-20 | 浙江新华制药有限公司 | Method for preparing 4-(N-phenylpropionamide)-4-methoxymethyl-piperidine hydrochloride |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008005423A1 (en) * | 2006-07-03 | 2008-01-10 | Cambrex Charles City, Inc. | Improved method of making sufentanil |
| CN102127007A (en) * | 2011-01-21 | 2011-07-20 | 浙江新华制药有限公司 | Method for preparing 4-(N-phenylpropionamide)-4-methoxymethyl-piperidine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| DOUGLASS F. TABER ET AL.: "Amide to Ester Conversion: A Practical Route to the Carfentanil Class of Analgetics", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107589192A (en) * | 2017-10-24 | 2018-01-16 | 宜昌人福药业有限责任公司 | A kind of method for improving remifentanil hydrochloride product quality |
| CN107589192B (en) * | 2017-10-24 | 2020-10-09 | 宜昌人福药业有限责任公司 | Method for improving quality of remifentanil hydrochloride product |
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