CN102351783A - Synthesizing method of 1-benzyl-piperidone hydrochloride - Google Patents
Synthesizing method of 1-benzyl-piperidone hydrochloride Download PDFInfo
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Abstract
The invention discloses a synthesizing method of 1-benzyl-piperidone hydrochloride. The method comprises steps that: (1) 3-hydroxypyridine is added to an organic solvent, and is refluxed under a temperature of 100 to 110 DEG C; benzyl halide is dropped into the solution, and the refluxing reaction is continued for 2 to 4 hours, such that a product A is obtained; (2) the product A is added to an alcohol organic solvent; sodium borohydride is added to the solution under an ice bath; the temperature of the solution is recovered to room temperature; the solution is stirred for 10 to 15 hours; the reaction liquid is quenched by using water; the alcohol organic solvent is removed; the pH value of the solution is regulated to 1-2 by using strong acid; the solution is extracted by using an extractant, and a water phase is preserved; the pH value of the solution is regulated to 13-14 by using an alkali solution, such that a product B is obtained; (3) through a Swerns oxidation reaction, hydroxyl groups in the product B are oxidized into ketone groups; the product is washed; an organic phase is dried, filtered, and condensed; an ethyl acetate hydrochloride solution is added to the product until the pH value is 1-2; the product is stirred and cooled; when solid is completely precipitated, the product is filtered and dried by baking, such that 1-benzyl-piperidone hydrochloride is obtained. The invention is advantaged in low cost and safe operation.
Description
Technical field
The present invention relates to the synthesis method of 1-benzyl-3-piperidone hydrochloride.
Background technology
1-benzyl-3-piperidone hydrochloride is important in a building-up process intermediate, so the demand of 1-benzyl-3-piperidone hydrochloride is the impetus that maintains sustained and rapid growth.The route of synthesis of 1-benzyl-3-piperidone hydrochloride mainly contains following two at present:
(1) with the gamma-butyrolactone be raw material, through benzylamine aminolysis, hydrolysis, esterification, generate 1-benzyl-3-piperidone hydrochloride with ethyl bromoacetate condensation, cyclization, hydrolysis decarboxylation six-step process, reaction process is following:
This preparation method is published in Chinese Journal of Pharmaceuticals 2004,35 (7), and advantage is that per step reaction all is a popular response, does not have non routine operations such as High Temperature High Pressure, and per step yield is higher, and stable.The oversize total recovery that makes descends thereby shortcoming is general line, and total cost raises.
(2) be raw material with the 3-pyridone, use that hydrogenating reduction is the 3-hydroxy piperidine under the noble metal catalyst catalysis, again the latter and cylite reaction are generated 1-benzyl-3-hydroxy piperidine, again hydroxyl oxygen is changed into carbonyl, process is following:
This approach is the current technology of producing 1-benzyl-3-piperidone hydrochloride at present both at home and abroad; The producer that uses is more; Because of it has been taked such as noble metal catalysts such as platinum dioxide, platinum carbon, rhodium carbon; Greatly reduce requirement to hydrogen pressure; Usually can accomplish 5 reactions below the normal atmosphere; Requirement to equipment reduces, and the security of operation also is improved; But the cost of noble metal catalyst is very high, and the cost of whole operational path still is difficult to descend.（A?Mild?and?Facile?Method?for?Complete?Hydrogenation?of?Aromatic?Nuclei?in?Water.?SYNLETT;?2006,No.?9,?pp?1440-1442）。A kind of new synthesis process of 1-benzyl-3-piperidone hydrochloride with low cost is demanded urgently occurring.
Summary of the invention
The technical problem that the present invention will solve is to overcome existing defective, and a kind of synthesis method of 1-benzyl-3-piperidone hydrochloride with low cost is provided.
In order to solve the problems of the technologies described above, the invention provides following technical scheme:
The synthesis method of 1-benzyl-3-piperidone hydrochloride comprises the steps:
(1) raw material 3-pyridone is added in the organic solvent, under 100-110 ℃ of reflux state, drip the halogenation benzyl, continued back flow reaction 2-4 hour, get product A;
(2) product A is added in the alcohol organic solvent; Under the ice bath; After adding sodium borohydride; Recover the room temperature stirring reaction 10-15 hour, and added the shrend reaction solution that goes out again, remove alcohol organic solvent; Adding strong acid accent PH is 1-2; The extraction agent extraction keeps water, to 13-14, gets product B with the alkaline solution adjust pH;
(3) with oxalyl chloride with methylene dichloride dissolving back and after dimethyl sulfoxide (DMSO) is mixed; In mixing solutions, add with methylene dichloride dissolved product B; Add again with methylene dichloride dissolved triethylamine; It is ketone group with the hydroxyl oxidize in the product B that polite oxidizing reaction (SwernOxidation) takes place; Washing; Dry organic phase; Filter; Concentrate, adding hydrochloric ethyl acetate solution is 1-2 up to PH, stirs; Cooling; After treating that solid is separated out fully, filter, dry 1-benzyl of the present invention-3-piperidone hydrochloride.
Further; Said step (3) is for to dissolve oxalyl chloride with methylene dichloride; Be cooled to-78-(75) ℃, drip dimethyl sulfoxide (DMSO) to it, the product B that step (2) is made is dissolved in the methylene dichloride; Slowly be added drop-wise in the above-mentioned solution that is mixed with oxalyl chloride and dimethyl sulfoxide (DMSO); Remain temperature-78-(75) ℃, dropwised afterreaction 0.5-1 hour, will be added drop-wise in the reaction solution with methylene dichloride dissolved triethylamine; Keep temperature-78-(75) ℃; Dropwise reaction 0.5-1 hour, return to room temperature and placed 10-15 hour, react completely; Washing; Dry organic phase is filtered, and concentrates; Adding hydrochloric ethyl acetate solution is 1-2 up to pH; Stir, cooling, treat that solid is separated out fully after; Filter, dry 1-benzyl of the present invention-3-piperidone hydrochloride.
Further, in the step (1), described organic solvent is selected from one or more in toluene, ethyl acetate, methylene dichloride, the tetrahydrofuran (THF), and described halogenation benzyl is Benzyl Chloride or cylite.
Further, in the said step (1), raw material is 1:1-1.5 with the ratio of the amount of substance of halogenation benzyl.
Further, in the said step (2), strong acid is one or more in concentrated hydrochloric acid, sulfuric acid, the acetic acid, and alcohol organic solvent is selected from methyl alcohol or ethanol, and extraction agent is selected from one or more in ethyl acetate, methylene dichloride, the chloroform.
Further, in the said step (2), product A is 1:2-3 with the ratio of the amount of substance of reductive agent.
Further, in the said step (2), alkaline solution be that mass percent is the sodium hydroxide solution of 10%-15%.
Further, in the step (3), said hydrochloric ethyl acetate solution is through hydrochloric acid gas being fed in the ethyl acetate, makes up to saturated.
Preferably, the synthesis method of 1-benzyl-3-piperidone hydrochloride comprises the steps:
(1) take by weighing raw material 3-pyridone, add toluene, heating for dissolving under 105 ℃ of reflux states, drips Benzyl Chloride, adds in 30 minutes, continues back flow reaction 2 hours, reacts completely, and question response drops to room temperature, suction filtration, dry product A; Wherein, raw material is 1:1.1 with the ratio of the amount of substance of halogenation benzyl;
(2) product A is added in the ethanol, under the ice bath, slowly add sodium borohydride in batches; After adding finishes, recovered the room temperature stirring reaction 10-15 hour, react completely; Add the shrend reaction solution that goes out, spin off ethanol, adding concentrated hydrochloric acid, to transfer PH be 1-2; Use ethyl acetate extraction impurity, water to 13-14, is used ethyl acetate extraction with 10% sodium hydroxide adjust pH; Saturated nacl aqueous solution is washed organic phase once; With anhydrous sodium sulfate drying organic phase 2 hours, filter, concentrate product B; Wherein, product A is 1:2 with the ratio of the amount of substance of reductive agent;
(3) oxalyl chloride is dissolved with methylene dichloride; Be cooled to-78 ℃; Drip dimethyl sulfoxide (DMSO); Product B is dissolved in the methylene dichloride, slowly is added drop-wise in the above-mentioned solution that is mixed with oxalyl chloride and dimethyl sulfoxide (DMSO), temperature remains at-78 ℃; Dropwised afterreaction 0.5 hour; To be added drop-wise in the reaction solution with methylene dichloride dissolved triethylamine, temperature keeps-78 ℃, dropwises reaction 0.5 hour; Returning to room temperature placed 10-15 hour; React completely washing, organic phase anhydrous sodium sulfate drying; Filter; Concentrate, adding hydrochloric ethyl acetate solution is 1-2 up to pH, stirs; Cooling; After treating that solid is separated out fully, filter, dry 1-benzyl of the present invention-3-piperidone hydrochloride; Wherein, product B is 1:1.1 with the amount of substance ratio of oxalyl chloride, and oxalyl chloride is 1:2 with dimethyl sulfoxide (DMSO) amount of substance ratio, and product B is 1:4.6 with triethylamine amount of substance ratio.
Reaction scheme of the present invention:
Beneficial effect of the present invention:
1. reduction step has realized normal temperature and pressure reaction, operational safety.
2. step is shorter, and total recovery is higher than traditional technology.The route total recovery in 6 steps is 16.2% in the traditional technology, and average yield of the present invention can reach 82%, adopts noble metal reduction 3-pyridone route total recovery suitable in the present invention and the traditional technology.The purity of target product of the present invention is higher, and average purity can reach 98%.
3. do not use valuable metal catalyst, cost reduces.
Embodiment
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for explanation and explains the present invention, and be not used in qualification the present invention.
Embodiment 1
The synthesis method of 1-benzyl-3-piperidone hydrochloride comprises the steps:
(1) take by weighing 30 gram (0.32mol) raw material 3-pyridones, add 400 milliliters of toluene, heating for dissolving under reflux state, drips Benzyl Chloride 40 (0.32mol) gram, adds in 30 minutes, continues back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dry 65 the gram product A, yield 94%.
(2) product A with 65 gram (0.29mol) the first step systems adds 800 milliliters of ethanol, under the ice bath, slowly adds sodium borohydride 22.33 (0.59mol) gram in batches, after adding finishes, recovers stirring at room 10-15 hour.TLC detects, and reacts completely, and adds 200 ml water cancellation reaction solutions.Spin off ethanol; Adding concentrated hydrochloric acid accent PH is 1-2; With 100 milliliters of ethyl acetate extraction impurity 2 times; Leave and take water and transfer pH value to 13-14 with 10% sodium hydroxide, with 300 milliliters of ethyl acetate extractions three times, 100 milliliters of saturated nacl aqueous solutions are washed organic phase once; 50 gram anhydrous sodium sulfate drying organic phases 2 hours; Filter, concentrate 52 gram product B, yield 94.5%.
(3) add oxalyl chloride 36.58 (0.29mol) gram in the 1L there-necked flask,, be cooled to-78 ℃, drip 45 gram (0.58mol) dimethyl sulfoxide (DMSO) with 250 milliliters of methylene dichloride dissolvings.The product B that second step of 52 grams (0.27mol) is made is dissolved in 250 milliliters of methylene dichloride, slowly is added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), and temperature remains at-78 ℃, dropwises afterreaction 0.5 hour.124 grams (1.23mol) are added drop-wise in the reaction solution with methylene dichloride dissolved triethylamine, and temperature keeps-78 ℃, dropwises reaction 0.5 hour, returns to room temperature and places 10-15 hour, and the TLC detection reaction is complete.Add 500 ml waters and give a baby a bath on the third day after its birth time, organic phase is filtered with 50 gram anhydrous sodium sulfate dryings, concentrates to such an extent that product 49 restrains; Adding hydrochloric ethyl acetate solution is 1-2 up to PH, stirs cooling; After treating that solid is separated out fully, filter, dry to such an extent that 1-benzyl of the present invention-3-piperidone hydrochloride 55 restrains.Yield 90%, purity 98%.Wherein, hydrochloric ethyl acetate solution is through hydrochloric acid gas being fed in the ethyl acetate, makes up to saturated.
Embodiment 2
The synthesis method of 1-benzyl-3-piperidone hydrochloride comprises the steps:
(1) take by weighing 300 (3.2mol) gram raw material 3-pyridone, add 5000 milliliters of toluene, heating for dissolving under reflux state, drips Benzyl Chloride 390 grams (3.08mol), adds in 60 minutes, continues back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dry 630 the gram product A, yield 90%.
(2) product A with 630 gram (2.85mol) the first step systems adds 8000 milliliters of ethanol, under the ice bath, slowly adds sodium borohydride 250 (6.6mol) gram in batches, after adding finishes, recovers stirring at room 10-15 hour.TLC detects, and reacts completely.Add 2000 ml water cancellation reaction solutions.Spin off ethanol; Adding concentrated hydrochloric acid accent PH is 1-2; With 1000 milliliters of ethyl acetate extraction impurity 2 times; Leave and take water and transfer pH value to 13-14 with 10% sodium hydroxide, with 3000 milliliters of ethyl acetate extractions three times, 500 milliliters of saturated nacl aqueous solutions are washed organic phase once then; 500 gram anhydrous sodium sulfate drying organic phases 2 hours; Filter, concentrate 501 gram product B, yield 92%.
(3) add oxalyl chloride 380 (2.99mol) gram in the 5L there-necked flask,, be cooled to-78 ℃, drip 480 gram (6.14mol) dimethyl sulfoxide (DMSO) with 1500 milliliters of methylene dichloride dissolvings.The product B that second step of 500 (2.62mol) gram is made is dissolved in 2500 milliliters of methylene dichloride, slowly is added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), and temperature remains at-78 ℃, dropwises afterreaction 0.5 hour.1325 (13.10mol) gram is added drop-wise in the reaction solution with methylene dichloride dissolved triethylamine, and temperature keeps-78 ℃, dropwises reaction 0.5 hour, returns to room temperature and places 10-15 hour, and the TLC detection reaction is complete.Add 1000 ml waters and give a baby a bath on the third day after its birth time, organic phase is filtered with 500 gram anhydrous sodium sulfate dryings, concentrates to such an extent that product 425 restrains.Adding hydrochloric ethyl acetate solution is 1-2 up to PH, stir, cooling, treat that solid is separated out fully after, filter, dry 1-benzyl of the present invention-3-piperidone hydrochloride 455 grams.Yield 77%, purity 90%.Wherein, hydrochloric ethyl acetate solution is through hydrochloric acid gas being fed in the ethyl acetate, makes up to saturated.
Embodiment 3
The synthesis method of 1-benzyl-3-piperidone hydrochloride comprises the steps:
(1) take by weighing 1000 gram (10.52mol) raw material 3-pyridones, add 5000 milliliters of toluene, heating for dissolving under reflux state, drips Benzyl Chloride 1280 grams (10.11mol), adds in 60 minutes, continues back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dry 2165 the gram product A, yield 93%.
(2) product A with 2165 gram (9.79mol) the first step systems adds 15 liters of ethanol, under the ice bath, slowly adds sodium borohydride 800 grams (21.12mol) in batches, after adding finishes, recovers stirring at room 10-15 hour.TLC detects, and reacts completely.Add 2000 ml water cancellation reaction solutions.Spin off ethanol; Adding concentrated hydrochloric acid accent PH is 1-2; With 2000 milliliters of ethyl acetate extraction impurity 2 times; Leave and take water and transfer pH value to 13-14 with 10% sodium hydroxide, with 10 liters of ethyl acetate extraction products three times, 5000 milliliters of saturated nacl aqueous solutions are washed organic phase once; 2000 gram anhydrous sodium sulfate drying organic phases 2 hours; Filter, concentrate 1683 gram product B, yield 90%.
(3) add oxalyl chloride 1200 grams (9.45mol) in the 20L there-necked flask,, be cooled to-78 ℃, drip 1440 gram (18.43mol) dimethyl sulfoxide (DMSO) with 5000 milliliters of methylene dichloride dissolvings.The product B that second step of 1500 grams (7.85mol) is made is dissolved in 5000 milliliters of methylene dichloride, slowly is added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), and temperature remains at-78 ℃, dropwises afterreaction 0.5 hour.3177 grams (31.40mol) are added drop-wise in the reaction solution with methylene dichloride dissolved triethylamine, and temperature keeps-78 ℃, dropwises reaction 0.5 hour, returns to room temperature and places 10-15 hour.The TLC detection reaction is complete.Add 10 premium on currency and give a baby a bath on the third day after its birth time, organic phase is filtered with 2000 gram anhydrous sodium sulfate dryings, concentrates to such an extent that product 1275 restrains.Adding hydrochloric ethyl acetate solution is 1-2 up to PH, stir, cooling, treat that solid is separated out fully after, filter, dry 1-benzyl of the present invention-3-piperidone hydrochloride 1365 grams.Yield 77%, purity 90%.Wherein, hydrochloric ethyl acetate solution is through hydrochloric acid gas being fed in the ethyl acetate, makes up to saturated.
Embodiment 4
The synthesis method of 1-benzyl-3-piperidone hydrochloride comprises the steps:
(1) take by weighing 30 gram (0.32mol) raw material 3-pyridones, add 400 milliliters of toluene, heating for dissolving under reflux state, drips Benzyl Chloride 44.352 (0.352mol) gram, adds in 30 minutes, continues back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dry 67 the gram product A, yield 95%.
(2) product A with 67 gram (0.303mol) the first step systems adds 800 milliliters of ethanol, under the ice bath, slowly adds sodium borohydride 34 (0.909mol) gram in batches, after adding finishes, recovers stirring at room 10-15 hour.TLC detects, and reacts completely, and adds 200 ml water cancellation reaction solutions.Spin off ethanol; Adding concentrated hydrochloric acid accent PH is 1-2; With 100 milliliters of ethyl acetate extraction impurity 2 times; Leave and take water and transfer pH value to 13-14 with 10% sodium hydroxide, with 300 milliliters of ethyl acetate extractions three times, 100 milliliters of saturated nacl aqueous solutions are washed organic phase once; 50 gram anhydrous sodium sulfate drying organic phases 2 hours; Filter, concentrate 52 gram product B, yield 90%.
(3) add oxalyl chloride 36.58 (0.29mol) gram in the 1L there-necked flask,, be cooled to-78 ℃, drip 45 gram (0.58mol) dimethyl sulfoxide (DMSO) with 250 milliliters of tetrahydrofuran (THF) dissolvings.The product B that second step of 52 grams (0.27mol) is made is dissolved in 250 milliliters of methylene dichloride, slowly is added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), and temperature remains at-78 ℃, dropwises afterreaction 0.5 hour.124 grams (1.23mol) are added drop-wise in the reaction solution with methylene dichloride dissolved triethylamine, and temperature keeps-78 ℃, dropwises reaction 0.5 hour, returns to room temperature and places 10-15 hour, and the TLC detection reaction is complete.Add 500 ml waters and give a baby a bath on the third day after its birth time, organic phase is filtered with 50 gram anhydrous sodium sulfate dryings, concentrates to such an extent that product 49 restrains; Adding hydrochloric ethyl acetate solution is 1-2 up to PH, stirs cooling; After treating that solid is separated out fully, filter, dry to such an extent that 1-benzyl of the present invention-3-piperidone hydrochloride 55 restrains.Yield 90%, purity 98%.Wherein, hydrochloric ethyl acetate solution is through hydrochloric acid gas being fed in the ethyl acetate, makes up to saturated.
Embodiment 5
The synthesis method of 1-benzyl-3-piperidone hydrochloride comprises the steps:
(1) take by weighing 30 gram (0.32mol) raw material 3-pyridones, add 500 milliliters of methylene dichloride, heating for dissolving under reflux state, drips Benzyl Chloride 60 (0.48mol) gram, adds in 30 minutes, continues back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dry 63.6 the gram product A, yield 90%.
(2) product A with 63 gram (0.285mol) the first step systems adds 800 milliliters of ethanol, under the ice bath, slowly adds sodium borohydride 21.66 (0.57mol) gram in batches, after adding finishes, recovers stirring at room 10-15 hour.TLC detects, and reacts completely, and adds 200 ml water cancellation reaction solutions.Spin off ethanol; Adding sulfuric acid accent PH is 1-2; With 100 milliliters of chloroform extraction impurity 2 times; Leave and take water and transfer pH value to 13-14 with 10% sodium hydroxide, with 300 milliliters of chloroform extractions three times, 100 milliliters of saturated nacl aqueous solutions are washed organic phase once; 50 gram anhydrous sodium sulfate drying organic phases 2 hours; Filter, concentrate 50 gram product B, yield 92%.
(3) add oxalyl chloride 36.58 (0.29mol) gram in the 1L there-necked flask,, be cooled to-78 ℃, drip 45 gram (0.58mol) dimethyl sulfoxide (DMSO) with 250 milliliters of methylene dichloride dissolvings.The product B that second step of 50 grams (0.26mol) is made is dissolved in 250 milliliters of methylene dichloride, slowly is added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), and temperature remains at-78 ℃, dropwises afterreaction 0.5 hour.124 grams (1.23mol) are added drop-wise in the reaction solution with methylene dichloride dissolved triethylamine, and temperature keeps-78 ℃, dropwises reaction 0.5 hour, returns to room temperature and places 10-15 hour, and the TLC detection reaction is complete.Add 500 ml waters and give a baby a bath on the third day after its birth time, organic phase is filtered with 50 gram anhydrous sodium sulfate dryings, concentrates to such an extent that product 46 restrains; Adding hydrochloric ethyl acetate solution is 1-2 up to PH, stirs cooling; After treating that solid is separated out fully, filter, dry to such an extent that 1-benzyl of the present invention-3-piperidone hydrochloride 50 restrains.Yield 85%, purity 98%.Wherein, hydrochloric ethyl acetate solution is through hydrochloric acid gas being fed in the ethyl acetate, makes up to saturated.
Embodiment 6
The synthesis method of 1-benzyl-3-piperidone hydrochloride comprises the steps:
(1) take by weighing 300 (3.2mol) gram raw material 3-pyridone, add 5000 milliliters of ethyl acetate, heating for dissolving under reflux state, drips cylite 390 grams (3.08mol), adds in 60 minutes, continues back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dry 630 the gram product A, yield 90%.
(2) product A with 630 gram (2.85mol) the first step systems adds 8000 ml methanol, under the ice bath, slowly adds sodium borohydride 250 (6.6mol) gram in batches, after adding finishes, recovers stirring at room 10-15 hour.TLC detects, and reacts completely.Add 2000 ml water cancellation reaction solutions.Spin off methyl alcohol; Adding acetic acid accent PH is 1-2; With 1000 milliliters of dichloromethane extraction impurity 2 times; Leave and take water and transfer pH value to 13-14 with 10% sodium hydroxide, with 3000 milliliters of dichloromethane extractions three times, 500 milliliters of saturated nacl aqueous solutions are washed organic phase once then; 500 gram anhydrous magnesium sulfate drying organic phases 2 hours; Filter, concentrate 501 gram product B, yield 92%.
(3) add oxalyl chloride 380 (2.99mol) gram in the 5L there-necked flask,, be cooled to-78 ℃, drip 480 gram (6.14mol) dimethyl sulfoxide (DMSO) with 1500 milliliters of methylene dichloride dissolvings.The product B that second step of 500 (2.62mol) gram is made is dissolved in 2500 milliliters of methylene dichloride, slowly is added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), and temperature remains at-78 ℃, dropwises afterreaction 0.5 hour.1325 (13.10mol) gram is added drop-wise in the reaction solution with methylene dichloride dissolved triethylamine, and temperature keeps-78 ℃, dropwises reaction 0.5 hour, returns to room temperature and places 10-15 hour, and the TLC detection reaction is complete.Add 1000 ml waters and give a baby a bath on the third day after its birth time, organic phase is filtered with 500 gram anhydrous magnesium sulfate dryings, concentrates to such an extent that product 425 restrains.Adding hydrochloric ethyl acetate solution is 1-2 up to PH, stir, cooling, treat that solid is separated out fully after, filter, dry 1-benzyl of the present invention-3-piperidone hydrochloride 455 grams.Yield 77%, purity 90%.Wherein, hydrochloric ethyl acetate solution is through hydrochloric acid gas being fed in the ethyl acetate, makes up to saturated.
What should illustrate at last is: the above only is the preferred embodiments of the present invention; Be not limited to the present invention; Although the present invention has been carried out detailed explanation with reference to previous embodiment; For a person skilled in the art; It still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.All within spirit of the present invention and principle, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1.1-the synthesis method of benzyl-3-piperidone hydrochloride is characterized in that, comprises the steps:
(1) raw material 3-pyridone is added in the organic solvent, under 100-110 ℃ of reflux state, drip the halogenation benzyl, continued back flow reaction 2-4 hour, get product A;
(2) product A is added in the alcohol organic solvent; Under the ice bath; After adding sodium borohydride; Recover the room temperature stirring reaction 10-15 hour, and added the shrend reaction solution that goes out again, remove alcohol organic solvent; Adding strong acid accent PH is 1-2; The extraction agent extraction keeps water, transfers pH value to 13-14 with alkaline solution, gets product B;
(3) oxalyl chloride is mixed with dimethyl sulfoxide (DMSO) with methylene dichloride dissolving back, in mixing solutions, add, add again with methylene dichloride dissolved triethylamine with methylene dichloride dissolved product B; It is ketone group with the hydroxyl oxidize in the product B that polite oxidizing reaction takes place, washing, dry organic phase; Filter; Concentrate, adding hydrochloric ethyl acetate solution is 1-2 up to pH, stirs; Cooling; After treating that solid is separated out fully, filter, dry 1-benzyl of the present invention-3-piperidone hydrochloride.
2. synthesis method according to claim 1; It is characterized in that: said step (3) is for to dissolve oxalyl chloride with methylene dichloride; Be cooled to-78-(75) ℃; Drip dimethyl sulfoxide (DMSO) to it; The product B that step (2) is made is dissolved in the methylene dichloride; Slowly be added drop-wise in the above-mentioned solution that is mixed with oxalyl chloride and dimethyl sulfoxide (DMSO); Remain temperature-78-(75) ℃, dropwised afterreaction 0.5-1 hour, will be added drop-wise in the reaction solution with methylene dichloride dissolved triethylamine; Keep temperature-78-(75) ℃; Dropwise reaction 0.5-1 hour, return to room temperature and placed 10-15 hour, react completely; Washing; Dry organic phase is filtered, and concentrates; Adding hydrochloric ethyl acetate solution is 1-2 up to PH; Stir, cooling, treat that solid is separated out fully after; Filter, dry 1-benzyl of the present invention-3-piperidone hydrochloride.
3. synthesis method according to claim 1 is characterized in that: in the step (1), described organic solvent is selected from one or more in toluene, ethyl acetate, methylene dichloride, the tetrahydrofuran (THF), and described halogenation benzyl is Benzyl Chloride or cylite.
4. synthesis method according to claim 1 is characterized in that: in the said step (1), raw material is 1:1-1.5 with the ratio of the amount of substance of halogenation benzyl.
5. synthesis method according to claim 1; It is characterized in that: in the said step (2); Strong acid is one or more in concentrated hydrochloric acid, sulfuric acid, the acetic acid, and alcohol organic solvent is selected from methyl alcohol or ethanol, and extraction agent is selected from one or more in ethyl acetate, methylene dichloride, the chloroform.
6. synthesis method according to claim 1 is characterized in that: in the said step (2), product A is 1:2-3 with the ratio of the amount of substance of reductive agent.
7. synthesis method according to claim 1 is characterized in that: in the said step (2), alkaline solution is that mass percent is the sodium hydroxide solution of 10%-15%.
8. synthesis method according to claim 1 and 2; It is characterized in that: in the said step (3); Product B is 1:1-1.2 with the amount of substance ratio of oxalyl chloride, and oxalyl chloride is 1:2 with dimethyl sulfoxide (DMSO) amount of substance ratio, and product B is 1:4-5 with triethylamine amount of substance ratio.
9. synthesis method according to claim 1 and 2 is characterized in that: in the step (3), said hydrochloric ethyl acetate solution is through hydrochloric acid gas being fed in the ethyl acetate, makes up to saturated.
10. according to each described synthesis method of claim 1-7, it is characterized in that, comprise the steps:
(1) take by weighing raw material 3-pyridone, add toluene, heating for dissolving under 105 ℃ of reflux states, drips Benzyl Chloride, adds in 30 minutes, continues back flow reaction 2 hours, reacts completely, and question response drops to room temperature, suction filtration, dry product A; Wherein, raw material is 1:1.1 with the ratio of the amount of substance of halogenation benzyl;
(2) product A is added in the ethanol, under the ice bath, slowly add sodium borohydride in batches; After adding finishes, recovered the room temperature stirring reaction 10-15 hour, react completely; Add the shrend reaction solution that goes out, spin off ethanol, adding concentrated hydrochloric acid, to transfer pH be 1-2; Use ethyl acetate extraction impurity, water to 13-14, is used ethyl acetate extraction with 10% sodium hydroxide adjust pH; Saturated nacl aqueous solution is washed organic phase once; With anhydrous sodium sulfate drying organic phase 2 hours, filter, concentrate product B; Wherein, product A is 1:2 with the ratio of the amount of substance of reductive agent;
(3) oxalyl chloride is dissolved with methylene dichloride; Be cooled to-78 ℃; Drip dimethyl sulfoxide (DMSO); Product B is dissolved in the methylene dichloride, slowly is added drop-wise in the above-mentioned solution that is mixed with oxalyl chloride and dimethyl sulfoxide (DMSO), temperature remains at-78 ℃; Dropwised afterreaction 0.5 hour; To be added drop-wise in the reaction solution with methylene dichloride dissolved triethylamine, temperature keeps-78 ℃, dropwises reaction 0.5 hour; Returning to room temperature placed 10-15 hour; React completely washing, organic phase anhydrous sodium sulfate drying; Filter; Concentrate, adding hydrochloric ethyl acetate solution is 1-2 up to pH, stirs; Cooling; After treating that solid is separated out fully, filter, dry 1-benzyl of the present invention-3-piperidone hydrochloride; Wherein, product B is 1:1.1 with the amount of substance ratio of oxalyl chloride, and oxalyl chloride is 1:2 with dimethyl sulfoxide (DMSO) amount of substance ratio, and product B is 1:4.6 with triethylamine amount of substance ratio.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103204801A (en) * | 2013-04-12 | 2013-07-17 | 兰州远辉生物科技有限公司 | Synthesis method for N-Boc-3-piperidone |
| CN103304472A (en) * | 2013-06-15 | 2013-09-18 | 扬州天和药业有限公司 | Method for synthesizing 1-BOC-3-piperidone |
| CN104529872A (en) * | 2014-12-10 | 2015-04-22 | 天津孚音生物科技发展有限公司 | Synthetic method for benidipine hydrochloride intermediate |
| CN105693598A (en) * | 2014-11-28 | 2016-06-22 | 中国科学院大连化学物理研究所 | Method for synthesis of 3-piperidone derivatives through iridium catalytic hydrogenation |
| CN105949113A (en) * | 2016-05-24 | 2016-09-21 | 苏州艾缇克药物化学有限公司 | Method for efficiently synthesizing 1-Boc-3-piperidone |
| CN115073358A (en) * | 2022-07-21 | 2022-09-20 | 安徽德诺医药股份有限公司 | Preparation method of N-benzyl-4-ethyl piperidine formate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1450993A (en) * | 1999-07-20 | 2003-10-22 | 道农业科学公司 | Fungicidal heterocyclic aromatic amides and their compositions methods of use and preparation |
| WO2005026145A2 (en) * | 2003-09-12 | 2005-03-24 | Warner-Lambert Company Llc | Quinolone antibacterial agents |
| US20060074087A1 (en) * | 2003-01-31 | 2006-04-06 | Ashton Wallace T | 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| CN102070514A (en) * | 2011-02-23 | 2011-05-25 | 南通远航医药化工有限公司 | Method for preparing halofuginone intermediate |
| CN101759630B (en) * | 2010-01-28 | 2011-12-28 | 浙江大学 | Method for synthesizing N-benzyl-4-methyl-3-piperidone |
-
2011
- 2011-08-23 CN CN201110242392.9A patent/CN102351783B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1450993A (en) * | 1999-07-20 | 2003-10-22 | 道农业科学公司 | Fungicidal heterocyclic aromatic amides and their compositions methods of use and preparation |
| US20060074087A1 (en) * | 2003-01-31 | 2006-04-06 | Ashton Wallace T | 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| WO2005026145A2 (en) * | 2003-09-12 | 2005-03-24 | Warner-Lambert Company Llc | Quinolone antibacterial agents |
| CN101759630B (en) * | 2010-01-28 | 2011-12-28 | 浙江大学 | Method for synthesizing N-benzyl-4-methyl-3-piperidone |
| CN102070514A (en) * | 2011-02-23 | 2011-05-25 | 南通远航医药化工有限公司 | Method for preparing halofuginone intermediate |
Non-Patent Citations (3)
| Title |
|---|
| ISELIN, B. M.; HOFFMANN, K.: "Alkylenimine derivatives. Synthesis of 3-aryl-3-hydroxy-piperidines", 《HELVETICA CHIMICA ACTA》 * |
| 郝宝玉等: "1-叔丁羰基-4-甲基-3-哌啶酮的合成研究", 《高等化学工程学报》 * |
| 郝宝玉等: "1-叔丁羰基-4-甲基-3-哌啶酮的合成研究", 《高等化学工程学报》, vol. 25, no. 6, 15 December 2011 (2011-12-15), pages 1021 - 1025 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103204801A (en) * | 2013-04-12 | 2013-07-17 | 兰州远辉生物科技有限公司 | Synthesis method for N-Boc-3-piperidone |
| CN103304472A (en) * | 2013-06-15 | 2013-09-18 | 扬州天和药业有限公司 | Method for synthesizing 1-BOC-3-piperidone |
| CN105693598A (en) * | 2014-11-28 | 2016-06-22 | 中国科学院大连化学物理研究所 | Method for synthesis of 3-piperidone derivatives through iridium catalytic hydrogenation |
| CN105693598B (en) * | 2014-11-28 | 2017-12-19 | 中国科学院大连化学物理研究所 | A kind of method that iridium catalytic hydrogenation synthesizes 3 derivative of piperidone |
| CN104529872A (en) * | 2014-12-10 | 2015-04-22 | 天津孚音生物科技发展有限公司 | Synthetic method for benidipine hydrochloride intermediate |
| CN104529872B (en) * | 2014-12-10 | 2018-07-10 | 天津长源医药科技有限公司 | A kind of synthetic method of benidipine hydrochloride intermediate |
| CN105949113A (en) * | 2016-05-24 | 2016-09-21 | 苏州艾缇克药物化学有限公司 | Method for efficiently synthesizing 1-Boc-3-piperidone |
| CN115073358A (en) * | 2022-07-21 | 2022-09-20 | 安徽德诺医药股份有限公司 | Preparation method of N-benzyl-4-ethyl piperidine formate |
| CN115073358B (en) * | 2022-07-21 | 2023-09-26 | 安徽德诺医药股份有限公司 | Preparation method of N-benzyl-4-ethyl piperidine formate |
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