CN102351783B - The synthetic method of 1-benzyl-3-piperidone hydrochloride - Google Patents
The synthetic method of 1-benzyl-3-piperidone hydrochloride Download PDFInfo
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- OVWSFXNSJDMRPV-UHFFFAOYSA-N 1-benzylpiperidin-3-one;hydron;chloride Chemical compound Cl.C1C(=O)CCCN1CC1=CC=CC=C1 OVWSFXNSJDMRPV-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000010189 synthetic method Methods 0.000 title claims abstract description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 138
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- 239000000243 solution Substances 0.000 claims abstract description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000012074 organic phase Substances 0.000 claims abstract description 29
- 238000003756 stirring Methods 0.000 claims abstract description 24
- 238000000605 extraction Methods 0.000 claims abstract description 20
- 238000001816 cooling Methods 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 239000007787 solid Substances 0.000 claims abstract description 13
- 238000005406 washing Methods 0.000 claims abstract description 12
- 239000008346 aqueous phase Substances 0.000 claims abstract description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 11
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 11
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 230000026030 halogenation Effects 0.000 claims abstract description 9
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 5
- 239000012670 alkaline solution Substances 0.000 claims abstract description 5
- 241001122315 Polites Species 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000000468 ketone group Chemical group 0.000 claims abstract description 3
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 100
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 239000000126 substance Substances 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 16
- 239000002994 raw material Substances 0.000 claims description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 9
- 229940073608 benzyl chloride Drugs 0.000 claims description 9
- 230000004044 response Effects 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000012535 impurity Substances 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- PXOIIZOTNBIMPZ-UHFFFAOYSA-N dichloromethane;oxalyl dichloride Chemical compound ClCCl.ClC(=O)C(Cl)=O PXOIIZOTNBIMPZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims 1
- 239000012141 concentrate Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007789 gas Substances 0.000 description 7
- 206010013786 Dry skin Diseases 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
- GKECDORWWXXNRY-UHFFFAOYSA-N 2h-pyridin-3-one Chemical class O=C1CN=CC=C1 GKECDORWWXXNRY-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229910000510 noble metal Inorganic materials 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UTTCOAGPVHRUFO-UHFFFAOYSA-N 1-benzylpiperidin-3-ol Chemical compound C1C(O)CCCN1CC1=CC=CC=C1 UTTCOAGPVHRUFO-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
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- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses the synthetic method of 1-benzyl-3-piperidone hydrochloride, comprise the steps: that 3-pyridone adds in organic solvent by (1), 100-110 DEG C of backflow, drip halogenation benzyl, continue back flow reaction 2-4 hour, obtain product A; (2) product A is added in alcohol organic solvent, under ice bath, after adding sodium borohydride, recover room temperature stirring reaction 10-15 hour, then add shrend and to go out reaction solution, remove alcohol organic solvent, adding strong acid adjusts PH to be 1-2, extraction agent extraction retains aqueous phase, adjusts PH to 13-14, obtain product B with alkaline solution; (3) be ketone group by polite oxidizing reaction by the hydroxyl oxidize in product B, washing, dry organic phase, filters, concentrated, add hydrochloric ethyl acetate solution until PH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain 1-benzyl-3-piperidone hydrochloride of the present invention.Of the present invention with low cost, operational safety.
Description
Technical field
The present invention relates to the synthetic method of 1-benzyl-3-piperidone hydrochloride.
Background technology
1-benzyl-3-piperidone hydrochloride is an intermediate important in building-up process, and therefore the demand of 1-benzyl-3-piperidone hydrochloride is in the impetus that maintains sustained and rapid growth.The route of synthesis of current 1-benzyl-3-piperidone hydrochloride mainly contains following two:
(1) take gamma-butyrolactone as 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 as follows:
This preparation method is published in Chinese Journal of Pharmaceuticals 2004,35(7), advantage is that often walking reaction is all popular response, does not have the non routine operations such as High Temperature High Pressure, often walks yield higher, and stable.Shortcoming is that general line is oversize thus total recovery is declined, and total cost raises.
(2) with 3-pyridone for raw material, be 3-hydroxy piperidine with hydrogenating reduction under noble metal catalyst catalysis, then the latter and cylite reacted and generate 1-benzyl-3-hydroxy piperidine, then hydroxyl oxygen is changed into carbonyl, process is as follows:
This approach is the current technique of producing 1-benzyl-3-piperidone hydrochloride at present both at home and abroad, the producer used is more, the noble metal catalysts such as such as platinum dioxide, platinum carbon, rhodium carbon are taken because of it, greatly reduce the requirement to hydrogen pressure, usually react below 5 normal atmosphere and can complete, reduce the requirement of equipment, the security of operation is also improved; But the cost of noble metal catalyst is very high, the cost of whole operational path is still difficult to decline.（AMildandFacileMethodforCompleteHydrogenationofAromaticNucleiinWater.SYNLETT;2006,No.9,pp1440-1442）。A kind of new synthesis process of 1-benzyl-3-piperidone hydrochloride with low cost urgently occurs.
Summary of the invention
The technical problem to be solved in the present invention overcomes existing defect, provides a kind of synthetic method of 1-benzyl-3-piperidone hydrochloride with low cost.
In order to solve the problems of the technologies described above, the invention provides following technical scheme:
The synthetic method of 1-benzyl-3-piperidone hydrochloride, comprises the steps:
(1) raw material 3-pyridone is added in organic solvent, under 100-110 DEG C of reflux state, drip halogenation benzyl, continue back flow reaction 2-4 hour, obtain product A;
(2) product A is added in alcohol organic solvent, under ice bath, after adding sodium borohydride, recover room temperature stirring reaction 10-15 hour, then add shrend and to go out reaction solution, remove alcohol organic solvent, adding strong acid adjusts PH to be 1-2, extraction agent extraction retains aqueous phase, with alkaline solution adjust pH to 13-14, obtains product B;
(3) after mixing with dimethyl sulfoxide (DMSO) after oxalyl chloride being dissolved with methylene dichloride, the product B of dissolving with methylene dichloride is added in mixing solutions, add the triethylamine dissolved with methylene dichloride again, polite oxidizing reaction (SwernOxidation) occurring by the hydroxyl oxidize in product B is ketone group, washing, dry organic phase, filter, concentrated, add hydrochloric ethyl acetate solution until PH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain 1-benzyl-3-piperidone hydrochloride of the present invention.
Further, described step (3) is for dissolve oxalyl chloride methylene dichloride, be cooled to-78-(-75) DEG C, dimethyl sulfoxide (DMSO) is dripped to it, the product B that step (2) is obtained is dissolved in methylene dichloride, slowly be added drop-wise to and be above-mentionedly mixed with in the solution of oxalyl chloride and dimethyl sulfoxide (DMSO), remain temperature-78-(-75) DEG C, dropwise rear reaction 0.5-1 hour, the triethylamine dissolved with methylene dichloride is added drop-wise in reaction solution, keep temperature-78-(-75) DEG C, dropwise reaction 0.5-1 hour, return to room temperature and place 10-15 hour, react completely, washing, dry organic phase, filter, concentrated, add hydrochloric ethyl acetate solution until pH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain 1-benzyl-3-piperidone hydrochloride of the present invention.
Further, in step (1), described organic solvent be selected from toluene, ethyl acetate, methylene dichloride, tetrahydrofuran (THF) one or more, described halogenation benzyl is Benzyl Chloride or cylite.
Further, in described step (1), raw material is 1:1-1.5 with the ratio of the amount of substance of halogenation benzyl.
Further, in described step (2), strong acid is one or more in concentrated hydrochloric acid, sulfuric acid, acetic acid, and alcohol organic solvent is selected from methyl alcohol or ethanol, extraction agent be selected from ethyl acetate, methylene dichloride, chloroform one or more.
Further, in described step (2), product A is 1:2-3 with the ratio of the amount of substance of reductive agent.
Further, in described step (2), the sodium hydroxide solution of alkaline solution to be mass percent be 10%-15%.
Further, in step (3), described hydrochloric ethyl acetate solution is by being passed in ethyl acetate by HCl gas, until saturated obtained.
Preferably, the synthetic method of 1-benzyl-3-piperidone hydrochloride, comprises the steps:
(1) take raw material 3-pyridone, add toluene, heating for dissolving, under 105 DEG C of reflux states, drip Benzyl Chloride, add in 30 minutes, continue back flow reaction 2 hours, react completely, question response drops to room temperature, suction filtration, dries to obtain 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 ethanol, under ice bath, slowly add sodium borohydride in batches, after adding, recover room temperature stirring reaction 10-15 hour, react completely, add shrend to go out reaction solution, spin off ethanol, add concentrated hydrochloric acid and adjust PH to be 1-2, be extracted with ethyl acetate impurity, aqueous phase, is extracted with ethyl acetate to 13-14 with 10% sodium hydroxide adjust pH, saturated nacl aqueous solution washes organic phase once, by anhydrous sodium sulfate drying organic phase 2 hours, filter, concentratedly to obtain product B; Wherein, product A is 1:2 with the ratio of the amount of substance of reductive agent;
(3) oxalyl chloride methylene dichloride is dissolved, be cooled to-78 DEG C, drip dimethyl sulfoxide (DMSO), product B is dissolved in methylene dichloride, slowly be added drop-wise to and be above-mentionedly mixed with in the solution of oxalyl chloride and dimethyl sulfoxide (DMSO), temperature remains at-78 DEG C, dropwise rear reaction 0.5 hour, the triethylamine dissolved with methylene dichloride is added drop-wise in reaction solution, temperature keeps-78 DEG C, dropwise reaction 0.5 hour, return to room temperature and place 10-15 hour, react completely, washing, organic phase anhydrous sodium sulfate drying, filter, concentrated, add hydrochloric ethyl acetate solution until pH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain 1-benzyl-3-piperidone hydrochloride of the present invention, wherein, product B is 1:1.1 with the amount of substance ratio of oxalyl chloride, and oxalyl chloride and dimethyl sulfoxide (DMSO) amount of substance are than being 1:2, and product B and triethylamine amount of substance are than being 1:4.6.
Reaction scheme of the present invention:
Beneficial effect of the present invention:
1. reduction step achieves normal temperature and pressure reaction, operational safety.
2. step is shorter, and total recovery is higher than traditional technology.In traditional technology, the route total recovery of 6 steps is 16.2%, and average yield of the present invention can reach 82%, adopts noble metal to reduce 3-pyridone route total recovery suitable in the present invention and 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 is only for instruction and explanation of the present invention, is not intended to limit the present invention.
embodiment 1
The synthetic method of 1-benzyl-3-piperidone hydrochloride, comprises the steps:
(1) take 30 grams of (0.32mol) raw material 3-pyridones, add 400 milliliters of toluene, heating for dissolving, at reflux, drip Benzyl Chloride 40(0.32mol) gram, add in 30 minutes, continue back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dries to obtain 65 grams of product A, yield 94%.
(2) product A of 65 grams of (0.29mol) the first steps is added 800 milliliters of ethanol, under ice bath, slowly adds sodium borohydride 22.33(0.59mol in batches) gram, after adding, recover stirring at room temperature 10-15 hour.TLC detects, and reacts completely, adds 200 ml water cancellation reaction solutions.Spin off ethanol, adding concentrated hydrochloric acid adjusts PH to be 1-2, with 100 milliliters of extraction into ethyl acetate impurity 2 times, leaving and taking aqueous phase 10% sodium hydroxide adjusts pH value to 13-14, and with 300 milliliters of extraction into ethyl acetate three times, 100 milliliters of saturated nacl aqueous solutions wash organic phase once, 50 grams of anhydrous sodium sulfate drying organic phases 2 hours, filter, concentrate to obtain 52 grams of product B, yield 94.5%.
(3) oxalyl chloride 36.58(0.29mol is added in 1L there-necked flask) gram, dissolve with 250 milliliters of methylene dichloride, be cooled to-78 DEG C, drip 45 grams of (0.58mol) dimethyl sulfoxide (DMSO).The product B that 52 grams of (0.27mol) second steps are obtained is dissolved in 250 milliliters of methylene dichloride, and be slowly added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), temperature remains at-78 DEG C, dropwises rear reaction 0.5 hour.Be added drop-wise in reaction solution by 124 grams (1.23mol) with the triethylamine that methylene dichloride dissolves, temperature keeps-78 DEG C, dropwises reaction 0.5 hour, returns to room temperature placement 10-15 hour, TLC detection reaction complete.Add 500 milliliters of washings three times, organic phase 50 grams of anhydrous sodium sulfate dryings, filter, concentrate to obtain product 49 grams, add hydrochloric ethyl acetate solution until PH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain 1-benzyl-3-piperidone hydrochloride 55 grams of the present invention.Yield 90%, purity 98%.Wherein, hydrochloric ethyl acetate solution is by being passed in ethyl acetate by HCl gas, until saturated obtained.
embodiment 2
The synthetic method of 1-benzyl-3-piperidone hydrochloride, comprises the steps:
(1) 300(3.2mol is taken) gram raw material 3-pyridone, add 5000 milliliters of toluene, heating for dissolving, at reflux, drip Benzyl Chloride 390 grams (3.08mol), add in 60 minutes, continue back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dries to obtain 630 grams of product A, yield 90%.
(2) product A of 630 grams of (2.85mol) the first steps is added 8000 milliliters of ethanol, under ice bath, slowly add sodium borohydride 250 (6.6mol) gram in batches, after adding, recover stirring at room temperature 10-15 hour.TLC detects, and reacts completely.Add 2000 ml water cancellation reaction solutions.Spin off ethanol, adding concentrated hydrochloric acid adjusts PH to be 1-2, with 1000 milliliters of extraction into ethyl acetate impurity 2 times, leaving and taking aqueous phase 10% sodium hydroxide adjusts pH value to 13-14, and with 3000 milliliters of extraction into ethyl acetate three times, then 500 milliliters of saturated nacl aqueous solutions wash organic phase once, 500 grams of anhydrous sodium sulfate drying organic phases 2 hours, filter, concentrate to obtain 501 grams of product B, yield 92%.
(3) add oxalyl chloride 380 (2.99mol) gram in 5L there-necked flask, dissolve with 1500 milliliters of methylene dichloride, be cooled to-78 DEG C, drip 480 grams of (6.14mol) dimethyl sulfoxide (DMSO).The product B that 500 (2.62mol) gram second step is obtained is dissolved in 2500 milliliters of methylene dichloride, and be slowly added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), temperature remains at-78 DEG C, dropwises rear reaction 0.5 hour.Be added drop-wise in reaction solution by 1325 (13.10mol) grams with the triethylamine that methylene dichloride dissolves, temperature keeps-78 DEG C, dropwises reaction 0.5 hour, returns to room temperature placement 10-15 hour, TLC detection reaction complete.Add 1000 milliliters of washings three times, organic phase 500 grams of anhydrous sodium sulfate dryings, filter, concentrate to obtain product 425 grams.Add hydrochloric ethyl acetate solution until PH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain 1-benzyl-3-piperidone hydrochloride 455 grams of the present invention.Yield 77%, purity 90%.Wherein, hydrochloric ethyl acetate solution is by being passed in ethyl acetate by HCl gas, until saturated obtained.
embodiment 3
The synthetic method of 1-benzyl-3-piperidone hydrochloride, comprises the steps:
(1) take 1000 grams of (10.52mol) raw material 3-pyridones, add 5000 milliliters of toluene, heating for dissolving, at reflux, drip Benzyl Chloride 1280 grams (10.11mol), add in 60 minutes, continue back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dries to obtain 2165 grams of product A, yield 93%.
(2) product A of 2165 grams of (9.79mol) the first steps is added 15 liters of ethanol, under ice bath, slowly add sodium borohydride 800 grams (21.12mol) in batches, after adding, recover stirring at room temperature 10-15 hour.TLC detects, and reacts completely.Add 2000 ml water cancellation reaction solutions.Spin off ethanol, adding concentrated hydrochloric acid adjusts PH to be 1-2, with 2000 milliliters of extraction into ethyl acetate impurity 2 times, leaving and taking aqueous phase 10% sodium hydroxide adjusts pH value to 13-14, and with 10 liters of extraction into ethyl acetate products three times, 5000 milliliters of saturated nacl aqueous solutions wash organic phase once, 2000 grams of anhydrous sodium sulfate drying organic phases 2 hours, filter, concentrate to obtain 1683 grams of product B, yield 90%.
(3) add oxalyl chloride 1200 grams (9.45mol) in 20L there-necked flask, dissolve with 5000 milliliters of methylene dichloride, be cooled to-78 DEG C, drip 1440 grams of (18.43mol) dimethyl sulfoxide (DMSO).The product B that 1500 grams of (7.85mol) second steps are obtained is dissolved in 5000 milliliters of methylene dichloride, and be slowly added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), temperature remains at-78 DEG C, dropwises rear reaction 0.5 hour.Be added drop-wise in reaction solution by 3177 grams (31.40mol) with the triethylamine that methylene dichloride dissolves, temperature keeps-78 DEG C, dropwises reaction 0.5 hour, returns to room temperature and places 10-15 hour.TLC detection reaction is complete.Add 10 premium on currency and wash three times, organic phase 2000 grams of anhydrous sodium sulfate dryings, filter, concentrate to obtain product 1275 grams.Add hydrochloric ethyl acetate solution until PH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain 1-benzyl-3-piperidone hydrochloride 1365 grams of the present invention.Yield 77%, purity 90%.Wherein, hydrochloric ethyl acetate solution is by being passed in ethyl acetate by HCl gas, until saturated obtained.
embodiment 4
The synthetic method of 1-benzyl-3-piperidone hydrochloride, comprises the steps:
(1) take 30 grams of (0.32mol) raw material 3-pyridones, add 400 milliliters of toluene, heating for dissolving, at reflux, drip Benzyl Chloride 44.352(0.352mol) gram, add in 30 minutes, continue back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dries to obtain 67 grams of product A, yield 95%.
(2) product A of 67 grams of (0.303mol) the first steps is added 800 milliliters of ethanol, under ice bath, slowly adds sodium borohydride 34(0.909mol in batches) gram, after adding, recover stirring at room temperature 10-15 hour.TLC detects, and reacts completely, adds 200 ml water cancellation reaction solutions.Spin off ethanol, adding concentrated hydrochloric acid adjusts PH to be 1-2, with 100 milliliters of extraction into ethyl acetate impurity 2 times, leaving and taking aqueous phase 10% sodium hydroxide adjusts pH value to 13-14, and with 300 milliliters of extraction into ethyl acetate three times, 100 milliliters of saturated nacl aqueous solutions wash organic phase once, 50 grams of anhydrous sodium sulfate drying organic phases 2 hours, filter, concentrate to obtain 52 grams of product B, yield 90%.
(3) oxalyl chloride 36.58(0.29mol is added in 1L there-necked flask) gram, dissolve with 250 milliliters of tetrahydrofuran (THF)s, be cooled to-78 DEG C, drip 45 grams of (0.58mol) dimethyl sulfoxide (DMSO).The product B that 52 grams of (0.27mol) second steps are obtained is dissolved in 250 milliliters of methylene dichloride, and be slowly added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), temperature remains at-78 DEG C, dropwises rear reaction 0.5 hour.Be added drop-wise in reaction solution by 124 grams (1.23mol) with the triethylamine that methylene dichloride dissolves, temperature keeps-78 DEG C, dropwises reaction 0.5 hour, returns to room temperature placement 10-15 hour, TLC detection reaction complete.Add 500 milliliters of washings three times, organic phase 50 grams of anhydrous sodium sulfate dryings, filter, concentrate to obtain product 49 grams, add hydrochloric ethyl acetate solution until PH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain 1-benzyl-3-piperidone hydrochloride 55 grams of the present invention.Yield 90%, purity 98%.Wherein, hydrochloric ethyl acetate solution is by being passed in ethyl acetate by HCl gas, until saturated obtained.
embodiment 5
The synthetic method of 1-benzyl-3-piperidone hydrochloride, comprises the steps:
(1) take 30 grams of (0.32mol) raw material 3-pyridones, add 500 milliliters of methylene dichloride, heating for dissolving, at reflux, drip Benzyl Chloride 60(0.48mol) gram, add in 30 minutes, continue back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dries to obtain 63.6 grams of product A, yield 90%.
(2) product A of 63 grams of (0.285mol) the first steps is added 800 milliliters of ethanol, under ice bath, slowly adds sodium borohydride 21.66(0.57mol in batches) gram, after adding, recover stirring at room temperature 10-15 hour.TLC detects, and reacts completely, adds 200 ml water cancellation reaction solutions.Spin off ethanol, adding sulfuric acid adjusts PH to be 1-2, with 100 milliliters of chloroform extraction impurity 2 times, leaving and taking aqueous phase 10% sodium hydroxide adjusts pH value to 13-14, and with 300 milliliters of chloroform extractions three times, 100 milliliters of saturated nacl aqueous solutions wash organic phase once, 50 grams of anhydrous sodium sulfate drying organic phases 2 hours, filter, concentrate to obtain 50 grams of product B, yield 92%.
(3) oxalyl chloride 36.58(0.29mol is added in 1L there-necked flask) gram, dissolve with 250 milliliters of methylene dichloride, be cooled to-78 DEG C, drip 45 grams of (0.58mol) dimethyl sulfoxide (DMSO).The product B that 50 grams of (0.26mol) second steps are obtained is dissolved in 250 milliliters of methylene dichloride, and be slowly added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), temperature remains at-78 DEG C, dropwises rear reaction 0.5 hour.Be added drop-wise in reaction solution by 124 grams (1.23mol) with the triethylamine that methylene dichloride dissolves, temperature keeps-78 DEG C, dropwises reaction 0.5 hour, returns to room temperature placement 10-15 hour, TLC detection reaction complete.Add 500 milliliters of washings three times, organic phase 50 grams of anhydrous sodium sulfate dryings, filter, concentrate to obtain product 46 grams, add hydrochloric ethyl acetate solution until PH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain 1-benzyl-3-piperidone hydrochloride 50 grams of the present invention.Yield 85%, purity 98%.Wherein, hydrochloric ethyl acetate solution is by being passed in ethyl acetate by HCl gas, until saturated obtained.
embodiment 6
The synthetic method of 1-benzyl-3-piperidone hydrochloride, comprises the steps:
(1) 300(3.2mol is taken) gram raw material 3-pyridone, add 5000 milliliters of ethyl acetate, heating for dissolving, at reflux, drip cylite 390 grams (3.08mol), add in 60 minutes, continue back flow reaction 2 hours.TLC detects, and reacts completely.Question response drops to room temperature, suction filtration, dries to obtain 630 grams of product A, yield 90%.
(2) product A of 630 grams of (2.85mol) the first steps is added 8000 ml methanol, under ice bath, slowly add sodium borohydride 250 (6.6mol) gram in batches, after adding, recover stirring at room temperature 10-15 hour.TLC detects, and reacts completely.Add 2000 ml water cancellation reaction solutions.Spin off methyl alcohol, adding acetic acid adjusts PH to be 1-2, with 1000 milliliters of dichloromethane extraction impurity 2 times, leaving and taking aqueous phase 10% sodium hydroxide adjusts pH value to 13-14, and with 3000 milliliters of dichloromethane extractions three times, then 500 milliliters of saturated nacl aqueous solutions wash organic phase once, 500 grams of anhydrous magnesium sulfate drying organic phases 2 hours, filter, concentrate to obtain 501 grams of product B, yield 92%.
(3) add oxalyl chloride 380 (2.99mol) gram in 5L there-necked flask, dissolve with 1500 milliliters of methylene dichloride, be cooled to-78 DEG C, drip 480 grams of (6.14mol) dimethyl sulfoxide (DMSO).The product B that 500 (2.62mol) gram second step is obtained is dissolved in 2500 milliliters of methylene dichloride, and be slowly added drop-wise in the solution of above-mentioned oxalyl chloride and dimethyl sulfoxide (DMSO), temperature remains at-78 DEG C, dropwises rear reaction 0.5 hour.Be added drop-wise in reaction solution by 1325 (13.10mol) grams with the triethylamine that methylene dichloride dissolves, temperature keeps-78 DEG C, dropwises reaction 0.5 hour, returns to room temperature placement 10-15 hour, TLC detection reaction complete.Add 1000 milliliters of washings three times, organic phase 500 grams of anhydrous magnesium sulfate dryings, filter, concentrate to obtain product 425 grams.Add hydrochloric ethyl acetate solution until PH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain 1-benzyl-3-piperidone hydrochloride 455 grams of the present invention.Yield 77%, purity 90%.Wherein, hydrochloric ethyl acetate solution is by being passed in ethyl acetate by HCl gas, until saturated obtained.
Last it is noted that the foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment to invention has been detailed description, for a person skilled in the art, it still can be modified to the technical scheme described in foregoing embodiments, or carries out equivalent replacement to wherein portion of techniques feature.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 (10)
- The synthetic method of 1.1-benzyl-3-piperidone hydrochloride, is characterized in that, comprise the steps:(1) raw material 3-pyridone is added in organic solvent, under 100-110 DEG C of reflux state, drips halogenation benzyl, continue back flow reaction 2-4 hour, obtain product A, described organic solvent be selected from toluene, ethyl acetate, methylene dichloride one or more;(2) product A is added in alcohol organic solvent, under ice bath, after adding sodium borohydride, recover room temperature stirring reaction 10-15 hour, then add shrend and to go out reaction solution, remove alcohol organic solvent, adding strong acid adjusts pH to be 1-2, extraction agent extraction retains aqueous phase, with alkaline solution adjust pH to 13-14, obtains product B;(3) mix with dimethyl sulfoxide (DMSO) after oxalyl chloride being dissolved with methylene dichloride, in mixing solutions, add the product B of dissolving with methylene dichloride, then add the triethylamine dissolved with methylene dichloride, polite oxidizing reaction occurring by the hydroxyl oxidize in product B is ketone group, washing, dry organic phase, filter, concentrated, add hydrochloric ethyl acetate solution until pH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain described 1-benzyl-3-piperidone hydrochloride.
- 2. synthetic method according to claim 1, it is characterized in that: described step (3) is for dissolve oxalyl chloride methylene dichloride, be cooled to-78-(-75) DEG C, dimethyl sulfoxide (DMSO) is dripped to it, the product B that step (2) is obtained is dissolved in methylene dichloride, slowly be added drop-wise to and be above-mentionedly mixed with in the solution of oxalyl chloride and dimethyl sulfoxide (DMSO), remain temperature-78-(-75) DEG C, dropwise rear reaction 0.5-1 hour, the triethylamine dissolved with methylene dichloride is added drop-wise in reaction solution, keep temperature-78-(-75) DEG C, dropwise reaction 0.5-1 hour, return to room temperature and place 10-15 hour, react completely, washing, dry organic phase, filter, concentrated, add hydrochloric ethyl acetate solution until pH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain described 1-benzyl-3-piperidone hydrochloride.
- 3. synthetic method according to claim 1, is characterized in that: in step (1), and described halogenation benzyl is Benzyl Chloride or cylite.
- 4. synthetic method according to claim 1, is characterized in that: in described step (1), and raw material is 1:1-1.5 with the ratio of the amount of substance of halogenation benzyl.
- 5. synthetic method according to claim 1, it is characterized in that: in described step (2), strong acid is one or more in concentrated hydrochloric acid, sulfuric acid, acetic acid, and alcohol organic solvent is selected from methyl alcohol or ethanol, extraction agent be selected from ethyl acetate, methylene dichloride, chloroform one or more.
- 6. synthetic method according to claim 1, is characterized in that: in described step (2), and product A is 1:2-3 with the ratio of the amount of substance of reductive agent.
- 7. synthetic method according to claim 1, is characterized in that: in described step (2), the sodium hydroxide solution of alkaline solution to be mass percent be 10%-15%.
- 8. synthetic method according to claim 1 and 2, it is characterized in that: in described step (3), product B is 1:1-1.2 with the amount of substance ratio of oxalyl chloride, and oxalyl chloride and dimethyl sulfoxide (DMSO) amount of substance are than being 1:2, and product B and triethylamine amount of substance are than being 1:4-5.
- 9. synthetic method according to claim 1 and 2, is characterized in that: in step (3), and described hydrochloric ethyl acetate solution is by being passed in ethyl acetate by HCl gas, until saturated obtained.
- 10. the synthetic method according to any one of claim 1-7, is characterized in that, comprises the steps:(1) take raw material 3-pyridone, add toluene, heating for dissolving, under 105 DEG C of reflux states, drip Benzyl Chloride, add in 30 minutes, continue back flow reaction 2 hours, react completely, question response drops to room temperature, suction filtration, dries to obtain 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 ethanol, under ice bath, slowly add sodium borohydride in batches, after adding, recover room temperature stirring reaction 10-15 hour, react completely, add shrend to go out reaction solution, spin off ethanol, add concentrated hydrochloric acid and adjust pH to be 1-2, be extracted with ethyl acetate impurity, aqueous phase, is extracted with ethyl acetate to 13-14 with 10% sodium hydroxide adjust pH, saturated nacl aqueous solution washes organic phase once, by anhydrous sodium sulfate drying organic phase 2 hours, filter, concentratedly to obtain product B; Wherein, product A is 1:2 with the ratio of the amount of substance of reductive agent;(3) oxalyl chloride methylene dichloride is dissolved, be cooled to-78 DEG C, drip dimethyl sulfoxide (DMSO), product B is dissolved in methylene dichloride, slowly be added drop-wise to and be above-mentionedly mixed with in the solution of oxalyl chloride and dimethyl sulfoxide (DMSO), temperature remains at-78 DEG C, dropwise rear reaction 0.5 hour, the triethylamine dissolved with methylene dichloride is added drop-wise in reaction solution, temperature keeps-78 DEG C, dropwise reaction 0.5 hour, return to room temperature and place 10-15 hour, react completely, washing, organic phase anhydrous sodium sulfate drying, filter, concentrated, add hydrochloric ethyl acetate solution until pH is 1-2, stir, cooling, after solid is separated out completely, filter, dry to obtain described 1-benzyl-3-piperidone hydrochloride, wherein, product B is 1:1.1 with the amount of substance ratio of oxalyl chloride, and oxalyl chloride and dimethyl sulfoxide (DMSO) amount of substance are than being 1:2, and product B and triethylamine amount of substance are than being 1:4.6.
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| 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 |
| 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 |
| 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 |
| 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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