CN102442937B - 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 method of the key intermediate 1-benzyl-4-aniline piperidine-4-carboxylic acid of narcotic analgesic-remifentanil while preparing new super-short.
Background technology
The 1-benzyl-4-aniline piperidine-4-carboxylic acid is preparation 3-[4-(methoxycarbonyl) 4-(N-Phenylpropionamide base)-the 1-piperidines] important intermediate of methyl propionate, it is a novel potent analgesia narcotic, because its transformation period is extremely short, continuous intravenous infusion 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): in the documents such as 2202-2208, description is arranged.
In the technology of existing synthesize benzyl-4-aniline piperidine-4-carboxylic acid especially take 1-benzyl-4-piperidone as starting raw material through addition, elimination, hydrolysis, in and the preparation method of the synthetic 1-benzyl-4-aniline piperidine-4-carboxylic acid of step such as crystallization apply 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 large and be difficult to the defect such as processing.
According to Yang Yulong, Zhu Xinwen, Zhu Guozheng, Deng people's report record in " the synthetic and analgesic activity of 4-methoxycarbonyl-4-N-propionanilide phenylpiperidines 1 bit derivant " literary composition, they take 1-benzyl-4-piperidone as starting raw material through addition, elimination, hydrolysis, in and the step such as crystallization synthesized the 1-benzyl-4-aniline piperidine-4-carboxylic acid, used a large amount of organic solvents such as acetic acid, chloroform, Virahol in reaction and last handling process.The three-step reaction total recovery is only 32.48%.
In the method for synthetic 1-benzyl-4-aniline piperidine-4-carboxylic acid take 1-benzyl-4-piperidone as starting raw material of reporting in " Alfentanil Hydrochloride synthetic " literary composition of being delivered by Bi Xiaoling etc., the people's such as its preparation process and Yang Yulong the practice is basic identical.Just changed raw material potassium cyanide wherein into sodium cyanide when preparation 1-benzyl-4-cyano group-4-aniline piperidine; Post processing mode when synthetic 1-benzyl-4-amine formyl-4-aniline piperidine is different.Although improve to some extent.But the total recovery of its three-step reaction is only also 41% left and right.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of preparation method of 1-benzyl-4-aniline piperidine-4-carboxylic acid of high yield, and this preparation method uses auxiliary material few, and product yield is high, more economically, environmental protection.
It is as follows that the present invention solves the problems of the technologies described above the technical scheme that adopts: prepare the method for 1-benzyl-4-aniline piperidine-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 first 1-benzyl-4-piperidone being cooled to 0 ~ 15 ℃, add the methanol solution that contains massfraction 10 ~ 20% prussic acid, then stream adds the methanol solution that massfraction is 3 ~ 10% alkaline catalystss in 0.5 ~ 3h, after stream adds end insulation 0.5 ~ 3h, again above-mentioned reaction solution is warmed up under reflux state, according to 1-benzyl-4-piperidone: aniline: the mol ratio of Glacial acetic acid is the ratio proportioning of 1:1 ~ 1.05:1.0 ~ 3.5, 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 stream in 0 ~ 15 ℃ and add the Glacial acetic acid crystallization, then crystal is filtered and obtains 1-benzyl-4-cyano group-4-aniline piperidine solid,
(2) with the 1-benzyl of step (1) preparation-4-cyano group-4-aniline piperidine solid, in 1-benzyl-4-cyano group-4-aniline piperidine: the mol ratio of sulfuric acid is the ratio proportioning of 1:10 ~ 25, the massfraction that joins sulfuric acid under whipped state is in 70 ~ 95% aqueous solution, charge temperature remains on 20 ~ 50 ℃, continue stirring reaction 40 ~ 90h after reinforced complete 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 the pH value to 4 of 20 ~ 40% ammoniacal liquor regulator solutions ~ 9 crystallizatioies, crystal is filtered, wash to obtain 1-benzyl-4-amine formyl-4-aniline piperidine white powder solid,
(3) with the 1-benzyl of step (2) preparation-4-amine formyl-4-aniline piperidine white powder solid; by 1-benzyl-4-amine formyl-4-aniline piperidine: the mol ratio of hydrochloric acid is the proportioning of 1:20 ~ 35; join in concentrated hydrochloric acid in 20 ~ 35 ℃; after adding material, reaction system slowly is warmed up to boiling temperature back flow reaction 5 ~ 20h; cooling reaction solution to 0 after reaction finishes ~ 30 ℃ of static placement 48h crystallizatioies, filtration crystal, washing, drying obtain 1-benzyl-4-aniline piperidine-4-carboxylic acid white crystal product.
Above-mentioned steps (1) be with stir and the reactor of reflux exchanger in react, react and make solvent with methyl alcohol, prussic acid is dissolved in methyl alcohol and is made into methanol solution and can reduces the danger of operation.The methanol solution that alkali is dissolved in proportionaling alkali-forming in methyl alcohol carries out stream and adds, and is conducive to keep the stability of system acidity.Adopt lesser temps to be conducive to suppress side reaction in the first step volatilization of prussic acid occurs and prevents; Carrying out acid out after reaction is completed in the aqueous solution of 0 ~ 10 ℃ is in order to prevent that the acid out process from generating by product.In above-mentioned steps (2), with the hydrolysis reaction that the vitriol oil that contains certain water yield replaces pure 98% the vitriol oil more to be conducive to cyano group, carry out; Reaction neutralizes and is conducive to absorb rapidly a large amount of heat energy that neutralization reaction is emitted with ammoniacal liquor after finishing in containing the trash ice aqueous solution, reduce the generation of by product.In above-mentioned steps (3), with concentrated hydrochloric acid, be hydrolyzed, be conducive to the purpose product and separate out with the form of its hydrochloride, need not to carry out the alkali neutralization after reaction finishes and just can direct filtration obtain product.
Further preferred as each reaction parameter in above-mentioned preparation 1-benzyl-4-aniline piperidine-4-carboxylic acid method, described alkaline catalysts is a kind of or at least two kinds of mixtures that mix to form with arbitrary proportion in sodium hydroxide, potassium hydroxide, sodium carbonate or volatile salt.
In described step (1), 1-benzyl-4-piperidone is cooled to after 0 ~ 10 ℃ add the methanol solution that contains massfraction 10 ~ 20% prussic acid; The temperature of stirring reaction is 20 ~ 35 ℃ in step (2), and in 0 ~ 8 ℃ with the pH value of 20 ~ 40% ammoniacal liquor regulator solutions; 1-benzyl in step (3)-4-amine formyl-4-aniline piperidine is in 20 ~ 25 ℃ join concentrated hydrochloric acid, and reaction finishes rear cooling reaction solution to 0 ~ 15 ℃ of crystallizatioies.
It is 0.5 ~ 2h that the middle alkaline catalysts stream of described step (1) adds the time, and the time that stream adds aniline is 0.8 ~ 1.5h; The time of the stirring reaction in step (2) is 50-80h; Reflux time in step (3) is 10 ~ 20h.
The pH value to 5 of regulator solution ~ 7 crystallizatioies in described step (2).
In described step (2), the ammonia concn scope is 25 ~ 35%.
Compared with prior art, the present invention has following beneficial effect:
The present invention is by the optimization of each step of synthetic 1-benzyl-4-aniline piperidine-4-carboxylic acid take 1-benzyl-4-piperidone as starting raw material, do not re-use a large amount of organic solvent such as methylene dichloride, Virahol in process, simplified technical process, reduced environmental pollution, saved raw materials cost, improved product yield.
Embodiment
Below by embodiment, the present invention is specifically described; be necessary to be pointed out that at this; following examples are only for the present invention is further illustrated; can not be interpreted as limiting the scope of the invention, the person skilled in art can make some nonessential improvement and adjustment to the present invention according to the foregoing invention content.
Embodiment 1
First 94.63g1-benzyl-4-piperidone is packed in four-hole reaction flask with reflux cooling device and agitator, after stirring is cooled to 5 ℃, add the methanol solution 100g that contains 14.0g prussic acid, then remain in 5 ~ 10 ℃, stream adds that to contain massfraction be 5% sodium hydrate methanol solution 400g in 2h, after stream adds and finishes insulation 1h, above-mentioned reaction solution is warmed up under reflux state stream in 0.8h adds 47g aniline, and be incubated 1.5h under reflux temperature.Reaction is poured reaction solution in the 3500g frozen water that contains trash ice 70% into after finishing, and adds Glacial acetic acid 75g crystallization in 5 ~ 10 ℃ of temperature, and crystal is filtered and obtains solid pure product 143.07g.(yield is 98.2% as calculated)
First 70g water is joined in the four-hole reaction flask with agitator, add the 700g vitriol oil to stream in reaction flask again and be made into aqueous sulfuric acid, this aqueous solution is cooled to 20 ℃, and add the step reaction to obtain solid pure product 143.07g in 20 ~ 25 ℃, then keep its temperature stirring reaction 70h, insulation adds reaction solution in the 4500g frozen water that contains trash ice 70% after finishing, and to keep system temperature be 0 ~ 5 ℃, with mass concentration be the pH value of 25% ammoniacal liquor regulator solution to 6.5 crystallizatioies, with the crystal filtration, wash to obtain white powder solid pure product 129.88g.(yield is 85.5% as calculated)
First the concentrated hydrochloric acid of 1200g is added in the four-hole reaction flask with agitator, in 25 ~ 30 ℃, the solid of 129.88g is joined in reaction flask again, then after slowly being warmed up to boiling temperature back flow reaction 12h, reaction end, cooling reaction solution to 15 ℃, and in 15 ~ 20 ℃ static placement 48h crystallization, filter crystal, washing, dry white crystal sterling 126.13g.(yield is 96.8% as calculated)
The total recovery of above-mentioned three-step reaction is: 81.27%.
Embodiment 2
First 94.63g1-benzyl-4-piperidone is packed into after stirring in the four-hole reaction flask of reflux cooling device and agitator and being cooled to 0 ℃, add the methanol solution 100mL that contains 13.5g prussic acid, then remain in 0 ~ 5 ℃, stream adds that to contain massfraction be 3% sodium carbonate methanol solution 350g in 1h, stream add finish after after insulation 3h, above-mentioned reaction solution is warmed up under reflux state stream in 0.5h adds 48.8g aniline and be incubated 1.5h.Reaction is poured reaction solution in the 3500g frozen water that contains trash ice 80% into after finishing, and adds Glacial acetic acid 105g crystallization in 10 ~ 15 ℃, and crystal is filtered and obtains solid pure product 140.6g.(96.5%)
First 63g water is joined in the four-hole reaction flask with agitator, 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 add the reaction of upper step to obtain solid pure product 140.6g in 20 ~ 25 ℃, then keep its temperature stirring reaction 50h, insulation adds reaction solution in the 4500g frozen water that contains trash ice 60% after finishing, and to keep system temperature be 0 ~ 5 ℃, with mass concentration be the pH value of 35% ammoniacal liquor regulator solution to 5.5 crystallizatioies, filtration, wash to obtain white powder solid pure product 125.71g.（84.21%）
First the concentrated hydrochloric acid of 1500g is added in the four-hole reaction flask with agitator, join in reaction flask in 20 ~ 25 ℃ of 125.71g solid pure product that the reaction of upper step is obtained again, then slowly be warmed up to boiling temperature back flow reaction 10h, the rear cooling reaction solution to 0 ℃ of reaction end, and in 0 ~ 5 ℃ static placement 48h crystallization, filter crystal, washing, dry white crystal sterling 120.21g.（95.32%）
The total recovery of three-step reaction is: 77.46%.
Embodiment 3
First 94.63g1-benzyl-4-piperidone is packed into after in the four-hole reaction of reflux cooling device and agitator, the bottle stirring is cooled to below 5 ~ 10 ℃, add the methanol solution 100mL that contains 14.2g prussic acid, then remain on 5 ~ 10 ℃, stream adds that to contain massfraction be 10% potassium hydroxide methanol solution 280g in 0.5h, after stream adds and finishes insulation 3h, above-mentioned reaction solution is warmed up under reflux state stream in 1.5h adds 46.5g aniline and be incubated 3h.Insulation is poured reaction solution in the 3500g frozen water that contains trash ice 60% into after finishing, and adds Glacial acetic acid 60g crystallization in 0 ~ 5 ℃, and crystal is filtered and obtains solid pure product 139.14g.(95.5%)
First 210g water is joined in the four-hole reaction flask with agitator, 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 ℃ and add upper step reaction to obtain solid pure product 139.14g, then keep its temperature stirring reaction 80h, insulation is poured reaction solution in the 4500g frozen water that contains trash ice 80% into after finishing, and to keep system temperature be 0 ~ 5 ℃, with mass concentration be the pH value of 30% ammoniacal liquor regulator solution to 7.0 crystallizatioies, filtration, wash to obtain white powder solid pure product 125.21g.（84.75%）
First the concentrated hydrochloric acid of 1100g is added in the four-hole reaction flask with agitator, the solid pure product 125.21g that in 20 ~ 25 ℃, the reaction of upper step is obtained again joins in reaction flask, then slowly be warmed up to boiling temperature back flow reaction 20h, the rear cooling reaction solution to 10 ℃ of reaction end, and in 10 ~ 5 ℃ static placement 48h crystallization, filter crystal, washing, dry white crystal sterling 120.08g.（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 first 1-benzyl-4-piperidone being cooled to 0 ℃ or 15 ℃ or 10 ℃, add the methanol solution that contains massfraction 10 ~ 20% prussic acid, then stream adds the methanol solution that massfraction is 3 ~ 10% alkaline catalystss in 0.5 h or 2 h or 3h, after stream adds end insulation 0.5h or 1.9h or 3h, again above-mentioned reaction solution is warmed up under reflux state, according to 1-benzyl-4-piperidone: aniline: the mol ratio of Glacial acetic acid 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 on stream in 0 ℃ or 5 ℃ or 15 ℃ and add the Glacial acetic acid crystallization, then crystal is filtered and obtains 1-benzyl-4-cyano group-4-aniline piperidine solid,
with the 1-of above-mentioned preparation benzyl-4-cyano group-4-aniline piperidine solid, in 1-benzyl-4-cyano group-4-aniline piperidine: the mol ratio of sulfuric acid is the ratio proportioning of 1:10 or 16 or 25, the massfraction that joins sulfuric acid under whipped state is in 70 ~ 95% aqueous solution, charge temperature remains on 20 ℃ or 28 ℃ or 50 ℃, continue stirring reaction 40h or 60h or 80h or 90h after reinforced complete 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 pH value to 4 or 5 or 7 or 9 crystallizatioies of 20 ~ 40% ammoniacal liquor regulator solutions, crystal is filtered, wash to obtain 1-benzyl-4-amine formyl-4-aniline piperidine white powder solid,
(3) with the 1-benzyl of step (2) preparation-4-amine formyl-4-aniline piperidine white powder solid; by 1-benzyl-4-amine formyl-4-aniline piperidine: the mol ratio of hydrochloric acid is the proportioning of 1:20 or 26 or 34; join in concentrated hydrochloric acid in 20 ℃ or 27 ℃ or 35 ℃; add after material reaction system slowly is warmed up to boiling temperature back flow reaction 5h 15 or 20h, reaction finish after cooling reaction solution to 0 ℃ or 15 ℃ or 30 ℃ of static placements 48h crystallizatioies, filtration crystal, washing, drying obtain 1-benzyl-4-aniline piperidine-4-carboxylic acid white crystal product.
The reaction formula of above-mentioned three steps is as follows:
The present embodiment selects above-mentioned parameter to carry out orthogonal test, and test-results shows, the average total recovery for preparing the three-step reaction of 1-benzyl-4-aniline piperidine-4-carboxylic acid by the present embodiment is: 79.38%.
As mentioned above, can implement preferably the present invention.
Claims (6)
1. prepare the method for 1-benzyl-4-aniline piperidine-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 first 1-benzyl-4-piperidone being cooled to 0～15 ℃, add the methanol solution that contains massfraction 10～20% prussic acid, then stream adds the methanol solution that massfraction is 3～10% alkaline catalystss in 0.5～3h, after stream adds end insulation 0.5～3h, again above-mentioned reaction solution is warmed up under reflux state, according to 1-benzyl-4-piperidone: aniline: the mol ratio of Glacial acetic acid is the ratio proportioning of 1:1～1.05:1.0～3.5, 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 stream in 0～15 ℃ and add the Glacial acetic acid crystallization, then crystal is filtered and obtains 1-benzyl-4-cyano group-4-aniline piperidine solid,
(2) with the 1-benzyl of step (1) preparation-4-cyano group-4-aniline piperidine solid, in 1-benzyl-4-cyano group-4-aniline piperidine: the mol ratio of sulfuric acid is the ratio proportioning of 1:10～25, the massfraction that joins sulfuric acid under whipped state is in 70～95% aqueous solution, charge temperature remains on 20～50 ℃, continue stirring reaction 40～90h after reinforced complete 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 the pH value to 4 of 20～40% ammoniacal liquor regulator solutions～9 crystallizatioies, crystal is filtered, wash to obtain 1-benzyl-4-amine formyl-4-aniline piperidine white powder solid,
(3) with the 1-benzyl of step (2) preparation-4-amine formyl-4-aniline piperidine white powder solid; by 1-benzyl-4-amine formyl-4-aniline piperidine: the mol ratio of hydrochloric acid is the proportioning of 1:20～35; join in concentrated hydrochloric acid in 20～35 ℃; after adding material, reaction system slowly is warmed up to boiling temperature back flow reaction 5～20h; cooling reaction solution to 0 after reaction finishes～30 ℃ of static placement 48h crystallizatioies, filtration crystal, washing, drying obtain 1-benzyl-4-aniline piperidine-4-carboxylic acid white crystal product.
2. the method for preparing the 1-benzyl-4-aniline piperidine-4-carboxylic acid according to claim 1, it is characterized in that, described alkaline catalysts is a kind of or at least two kinds of mixtures that mix to form with arbitrary proportion in sodium hydroxide, potassium hydroxide, sodium carbonate or volatile salt.
3. the method for preparing the 1-benzyl-4-aniline piperidine-4-carboxylic acid according to claim 1, is characterized in that, in described step (1), 1-benzyl-4-piperidone is cooled to after 0～10 ℃ add the methanol solution that contains massfraction 10～20% prussic acid; The temperature of stirring reaction is 20～35 ℃ in step (2), and in 0～8 ℃ with the pH value of 20～40% ammoniacal liquor regulator solutions; 1-benzyl in step (3)-4-amine formyl-4-aniline piperidine is in 20～25 ℃ join concentrated hydrochloric acid, and reaction finishes rear cooling reaction solution to 0～15 ℃ of crystallizatioies.
4. the described method for preparing the 1-benzyl-4-aniline piperidine-4-carboxylic acid of according to claim 1 to 3 any one, is characterized in that, it is 0.5～2h that the middle alkaline catalysts stream of described step (1) adds the time, and the time that stream adds aniline is 0.8～1.5h; The time of the stirring reaction in step (2) is 50-80h; Reflux time in step (3) is 10～20h.
5. the described method for preparing the 1-benzyl-4-aniline piperidine-4-carboxylic acid of according to claim 1 to 3 any one, is characterized in that, the pH value to 5 of regulator solution～7 crystallizatioies in described step (2).
6. the described method for preparing the 1-benzyl-4-aniline piperidine-4-carboxylic acid of according to claim 1 to 3 any one, is characterized in that, in described step (2), the mass percentage concentration of ammoniacal liquor is 25～35%.
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| 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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| Title |
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| Amide to Ester Conversion: A Practical Route to the Carfentanil Class of Analgetics;Douglass F. Taber et al.;《The Journal of Organic Chemistry》;19921231;第57卷;4037-4038 * |
| Douglass F. Taber et al..Amide to Ester Conversion: A Practical Route to the Carfentanil Class of Analgetics.《The Journal of Organic Chemistry》.1992,第57卷4037-4038. |
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