CN1740157A - Synthesis process of N-sustituent-4-piperidyl alcohol - Google Patents
Synthesis process of N-sustituent-4-piperidyl alcohol Download PDFInfo
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- CN1740157A CN1740157A CN 200510094194 CN200510094194A CN1740157A CN 1740157 A CN1740157 A CN 1740157A CN 200510094194 CN200510094194 CN 200510094194 CN 200510094194 A CN200510094194 A CN 200510094194A CN 1740157 A CN1740157 A CN 1740157A
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Abstract
The synthesis process of preparing N-substituent-4-piperidyl alcohol includes the following steps: 1. adding primary amine into ethyl acrylate to react to obtain the secondary addition product; 2. adding cyclizing agent into the secondary addition product and adding concentrated hydrochloric acid after finishing cyclization to obtain N-substituent-4-piperidone hydrochloride; 3. reducing N-substituent-4-piperidone hydrochloride with NaBH4-Amberlyst-15(H+) system and regulating pH value to extract N-substituent-4-piperidyl alcohol; and 4. recovering and treating resin for reuse. The present invention has wide raw material resource, mild reaction condition, simple operation, low production cost, high yields in different steps, and excellent industrial application foreground.
Description
Technical field
The present invention relates to the preparation method of a kind of N-substituting group-4-piperidines alcohol, these compounds belong to the pharmaceutical technology field as the effective constituent of preparation medicine.
Background technology
N-substituting group-4-piperidines alcohol is important pharmaceutical intermediate, is widely used in the synthetic of various medicines, uses more anti-allergic medicine Loratadine, azatadine, diphenylpyraline, Cyproheptadine, Case's booth as clinical treatment; The antasthmatic ketotifen; Methemoglobinemia medication P-4 sheet.
At present report is more is to synthesize this compounds by reducing corresponding piperidone.The raw material piperidone mainly is to make by reactions such as dibasic acid esters condensation, salify, hydrolysis, neutralizations, and reactions steps is more, and intermediate product is handled complicated, and the product loss is more, and yield is lower.On method of reducing, it is higher to adopt the catalytic hydrogenation method to reduce general productive rate, but needs shortening under high temperature, condition of high voltage, to the equipment requirements height, also has certain danger in the technological process; Adopt LiAlH
4Make reductive agent, though speed of response is fast, the productive rate height, price is high, needs to operate under water-less environment, can't industrialization promotion; Adopt NaBH
4Make reductive agent, price is with respect to LiAlH
4Reduced a lot, reaction conditions is gentle, and industrial operation is convenient, but productive rate is lower, and NaBH during reduction
4Requirement bigger, production cost is improved.
Other has document Helv Chem Acta, 1966,49 (1) 690-695 report is with pyrrolo-[1,2-α] pyridone is raw material through reducing to such an extent that get corresponding target compound with iodide generation substitution reaction again behind the 4-piperidines alcohol, its feedstock production of this method is complicated, the reduction yield is lower, and it is also more expensive to replace used iodide price, is not suitable for industrialization promotion.
Summary of the invention
Technical problem: the objective of the invention is to overcome the deficiencies in the prior art, provide a kind of economy, efficiently, the method for synthetic N-substituting group-4-piperidines alcohol quickly.
The technology case: the present invention is earlier with 1). primary amine is added ethyl propenoate, react the secondary affixture, 2). add cyclizing agent in the secondary adduct, cyclization finishes the back and adds concentrated hydrochloric acid, the salify decarboxylation gets the hydrochloride of N-substituting group-4-piperidone, 3). in protic solvent, use NaBH
4-Amberlyst-15 (H
+) hydrochloride of reduction system N-substituting group-4-piperidone, regulate pH value, extract and obtain N-substituting group-4-piperidines alcohol, 4). reclaim resin, handle the back cycling and reutilization.
Method of the present invention is achieved through the following technical solutions:
(1) preparation of dibasic acid esters
The mixed solution of solvent and ethyl propenoate is warming up to 60-70 ℃, to wherein dripping primary amine, dropwises back insulation 1-2 hour, air distillation gets high boiling secondary adduct after reclaiming low-boiling-point substance.Its reaction formula is:
Said solvent mainly is selected from triethylamine, 1,4-dioxane or tetrahydrofuran (THF) a kind of; The mol ratio of participating in each material of reaction is: primary amine: ethyl propenoate=(1: 2.5～3).
(2) preparation of the hydrochloride of N-substituting group-4-piperidone
Secondary adduct, cyclizing agent, solvent are put into reaction flask, reflux to the reaction system vapour temperature near the solvent boiling point temperature, constantly the mixed solution of ethanol and solvent is told with water trap in the reaction, cooling, it is quiet to half an hour to add concentrated hydrochloric acid, reactant is poured in the separating funnel, told organic layer, the decarboxylation of water layer reflux is to FeCl
3The test nondiscoloration through certain post-processing, gets the thick product of N-substituting group-4-piperidone hydrochloride, gets the hydrochloride of highly purified N-substituting group-4-piperidone for 2～3 times with ethanol-acetone mixed solution recrystallization by a certain percentage.Its reaction formula is:
Said solvent mainly is selected from benzene, toluene, a kind of in the toluene; Used cyclizing agent mainly is selected from a kind of in sodium, sodium methylate, sodium ethylate, the sodium hydride; Appropriate postprocessing is meant that decarboxylation finishes back pressure reducing and steaming sour water to thick shape, adds ethanol heating for dissolving after-filtration, and filtrate is steamed to gluey, reclaim ethanol, add acetone in jelly, have a large amount of white solids to separate out, filtering drying gets the thick product of N-substituting group-4-piperidone hydrochloride; The used mixed solvent of recrystallization is: ethanol: acetone=(1: 2.5～3); The mol ratio of participating in each material of reaction is: dibasic acid esters: cyclizing agent=(1: 1.5～2).
(3) preparation of N-substituting group-4-piperidines alcohol
N-methyl-4-piperidone hydrochloride is dissolved in the solvent, adds the macroporous resin stirring and evenly mixing, NaBH
4Powder slowly joins in the reactor, and normal temperature reacted 30-40 minute down, adds the dilute hydrochloric acid hydrolysis, regulates PH, and suction filtration is used the solvent wash filter residue, merging filtrate, and distillation concentrates, and extracts concentrated solution with mixed solvent, united extraction liquid, anhydrous Na
2SO
4Drying, reclaim under reduced pressure extraction agent get N-substituting group-4-piperidines alcohol.Its reaction formula is:
Used solvent mainly is selected from wherein a kind of of ethanol, a glyme, diglyme; Extraction agent is that ethyl acetate and ethanol were by 5: 1 blended proportioning liquid; The mol ratio of participating in each material of reaction is: N-substituting group-4-piperidone hydrochloride: NaBH
4=(1: 2～2.5); Every mole of piperidone needs 50～60g macroporous resin.
(4) reclaim resin, handle the back cycling and reutilization
The soluble solids on the spent resin is removed in washing, and with 3M salt acid soak 24h, 3MNaOH solution soaking 12h is used in washing then, uses 3M salt acid soak 12h after the washing again, is washed to neutrality at last, and baking is extremely half-dried, mixes can be recycled by a certain percentage with fresh resin.
It is better that resin that recycled and fresh resin recycle effect by 3: 1 proportionings.
Beneficial effect: the advantage that the present invention has compared with the prior art is: when (1) dibasic acid esters synthesizes, add appropriate solvent such as triethylamine, 1, and 4-dioxane or tetrahydrofuran (THF), the yield of two adducts is enhanced; Aftertreatment only needs the pressure reducing and steaming low-boiling-point substance to avoid molecular distillation, and the low-boiling-point substance of Hui Shouing can be recycled simultaneously, economizes in raw materials; (2) adding of concentrated hydrochloric acid can salify again for decarboxylation provides sour environment, efficient quick ground synthesizes the thick product of N-substituting group-4-piperidone hydrochloride, need not purifying, can be directly used in down the step reduction reaction; (3) adopt NaBH
4-Amberlyst-15 (H
+) hydrochloride of reduction system piperidone, the reaction conditions gentleness, speed is very fast, and product yield is higher, reductive agent NaBH
4Consumption also reduce to some extent, saved manufacturing cost; (4) the recyclable mixing with fresh resin after treatment again of exhausted resin utilized, and reduced manufacturing cost.
Embodiment
Below will the present invention is further illustrated by embodiment:
Embodiment 1
(1) triethylamine with the ethyl propenoate (containing stopper) of 200g and 100ml adds in the reaction flask, heat temperature raising to 70 ℃, and constant temperature stirs and feeds the exsiccant methylamine gas down, stirs a moment behind the ventilation 3h, finishes reaction.Underpressure distillation recovery low-boiling-point substance steams to 120 ℃/3mmHg of interior temperature, and no distillate is chilled to room temperature, and sampling is made GC and analyzed, and dibasic acid esters content is 92.3%, gets orange liquid N, two (β-ethyl propenoate) methylamine 212.4g of N-, yield 84.6%.
(2) ethanol and the 3.5g sodium with 5ml adds in the reaction flask, add 70ml toluene behind the reaction 10min, be heated to backflow, stir and be added drop-wise to the 25g dibasic acid esters of above-mentioned preparation and the mixed solution of 30ml toluene in the reaction system at leisure down, after mixed solution dropwises, insulation refluxes, constantly toluene and alcoholic acid mixed solution are told in the reaction process with water trap, vapor temperature in the question response system finishes reaction during near 110 ℃, leave standstill and be cooled to room temperature, use concentrated hydrochloric acid (50ml * 3) to extract in batches, merge the hydrochloric acid reflux decarboxylation until using FeCl
3The test nondiscoloration, retort solution becomes syrupy shape, add dissolve with ethanol and reflux, filtered while hot, distillation filtrate is to gluey, reclaim ethanol, a large amount of white solids occurs add acetone in jelly after, filter, filter cake is with getting white needle-like crystals N-methyl-4-piperidone hydrochloride 13.2g behind the mixed solution recrystallization of ethanol-acetone, fusing point 88-90 ℃, yield 87.8%.
(3) 7.5g N-methyl-4-piperidone hydrochloride is dissolved in the 100ml ethanol, to wherein adding the 30g macroporous resin, stirring and evenly mixing, 3.0g NaBH
4Powder slowly joins in the reactor, and stirring reaction 1h obtains the oyster white turbid solution.The hydrochloric acid hydrolysis that adds 50ml 1M, NaOH regulates pH value to strong basicity in the ice bath, suction filtration, ethanol (60ml * 2) washing filter residue, merging filtrate, underpressure distillation concentrates, reclaim ethanol, press body (60ml * 4) the extraction concentrated solution of 5: 1 mixed, combining extraction liquid, anhydrous Na with ethyl acetate and ethanol
2SO
4Drying, extraction liquid is reclaimed in underpressure distillation, collects the cut 5.2g of 102 ℃/25mmHg, yield 85.1%.
Embodiment 2
(1) with 1 of the ethyl propenoate (containing stopper) of 200g and 100ml, the 4-dioxane adds in the reaction flask, and heat temperature raising to 70 ℃ stirs down and slowly drips 36g ethamine, dropwises back insulated and stirred 1h, finishes reaction.Low-boiling-point substance is reclaimed in underpressure distillation, steams to 120 ℃/3mmHg of interior temperature.No distillate is chilled to room temperature, and sampling is made GC and analyzed, and dibasic acid esters content is 90.6%, gets orange liquid N, two (β-ethyl propenoate) ethamine 173.4g of N-, yield 80.3%.
(2) methyl alcohol and the 3.5g sodium with 5ml adds in the reaction flask, add 70ml toluene behind the reaction 10min, be heated to backflow, stir and be added drop-wise to the 27g dibasic acid esters of above-mentioned preparation and the mixed solution of 30ml toluene in the reaction system at leisure down, after mixed solution dropwises, insulation refluxes, constantly the toluene and the mixed solution of alcohol are told in the reaction process with water trap, vapor temperature in the question response system finishes reaction during near 110 ℃, leave standstill and be cooled to room temperature, use concentrated hydrochloric acid (50ml * 3) to extract in batches, merge the hydrochloric acid reflux decarboxylation until using FeCl
3The test nondiscoloration, retort solution becomes syrupy shape, add dissolve with ethanol and reflux, filtered while hot, distillation filtrate is to gluey, reclaim ethanol, white solid occurs add acetone in jelly after, filter, filter cake is with getting white needle-like crystals N-ethyl-4-piperidone hydrochloride 14.8g behind the mixed solution recrystallization of ethanol-acetone, 98～100 ℃ of fusing points, yield 89.2%
(3) 8.3g N-ethyl-4-piperidone hydrochloride is dissolved in 100ml one glyme, to wherein adding the 30g macroporous resin, stirring and evenly mixing, 3.0g NaBH
4Powder slowly joins in the reactor, and stirring reaction 1h obtains the oyster white turbid solution.The hydrochloric acid hydrolysis that adds 50ml 1M, NaOH regulates pH value to strong basicity in the ice bath, suction filtration, one glyme (60ml * 2) washing filter residue, merging filtrate, underpressure distillation concentrates, reclaim a glyme, press liquid (60ml * 4) the extraction concentrated solution of 5: 1 mixed, combining extraction liquid, anhydrous Na with ethyl acetate and ethanol
2SO
4Drying, underpressure distillation, the cut 5.6g of 102～103 ℃/11mmHg of collection, yield 86.6%.
Embodiment 3
(1) tetrahydrofuran (THF) of the ethyl propenoate (containing stopper) of 200g and 100ml is added in the reaction flask heat temperature raising to 60 ℃, stir down and slowly drip the 85.6g benzylamine, dropwise back insulated and stirred 1h, finish reaction.Low-boiling-point substance is reclaimed in underpressure distillation, steams to 130 ℃/3mmHg of interior temperature.No distillate is chilled to room temperature, and sampling is made GC and analyzed, and dibasic acid esters content 90.8% gets orange liquid N, two (β-ethyl propenoate) benzylamine 238.0g of N-, yield 88.2%.
(2) ethanol and the 3.5g sodium with 5ml adds in the reaction flask, add 70ml benzene behind the reaction 10min, be heated to backflow, mixed solution with 34g dibasic acid esters and 30ml benzene under stirring is added drop-wise in the reaction system at leisure, after mixed solution dropwises, insulation refluxes, constantly benzene and alcoholic acid mixed solution are told in the reaction process with water trap, vapor temperature in the question response system finishes reaction during near 78 ℃, leave standstill and be cooled to room temperature, use concentrated hydrochloric acid (50ml * 3) to extract in batches, merge the hydrochloric acid reflux decarboxylation until using FeCl
3The test nondiscoloration, retort solution becomes syrupy shape, add dissolve with ethanol and reflux, filtered while hot, distillation filtrate is reclaimed ethanol to gluey, a large amount of white solids occurs add acetone in jelly after, filter the thick product 23g of N-benzyl-4-piperidone hydrochloride.
(3) 12.2g N-benzyl-4-piperidone hydrochloride is dissolved in the 100ml diglyme, to wherein adding the 30g macroporous resin, stirring and evenly mixing, 3.0g NaBH
4Powder slowly joins in the reactor, and stirring reaction 1 hour obtains the oyster white turbid solution.The hydrochloric acid hydrolysis half hour that adds 50ml 1M, NaOH regulates pH value to strong basicity in the ice bath, suction filtration, diglyme (60ml * 2) washing filter residue, merging filtrate, underpressure distillation concentrates, reclaim diglyme, press liquid (60ml * 4) the extraction concentrated solution of 5: 1 mixed, combining extraction liquid, anhydrous Na with ethyl acetate and ethanol
2SO
4Drying, underpressure distillation, the cut 8.0g of 127-128 ℃/12mmHg of collection.Yield 83.7%.
Embodiment 4
(1) operation is with embodiment 1.
(2) operation is with embodiment 1.
(3) embodiment 1 used resin is reclaimed, the soluble solids on the spent resin is removed in washing, with 3M salt acid soak 24h, 3M NaOH solution soaking 12h is used in washing then, use 3M salt acid soak 12h after the washing again, be washed to neutrality at last, baking is to half-dried, and weighing gets 23g, to wherein adding the 8g fresh resin, stir evenly.
7.5g N-methyl-4-piperidone hydrochloride is dissolved in the 100ml ethanol, to wherein adding the above-mentioned blended macroporous resin of 30g, stirring and evenly mixing, 3.0g NaBH
4Powder slowly joins in the reactor, and stirring reaction 1h obtains the oyster white turbid solution.The hydrochloric acid hydrolysis half hour that adds 50ml 1M, NaOH regulates pH value to strong basicity in the ice bath, suction filtration, ethanol (60ml * 2) washing filter residue, merging filtrate, underpressure distillation concentrates, reclaim ethanol, press liquid (60ml * 4) the extraction concentrated solution of 5: 1 mixed, combining extraction liquid, anhydrous Na with ethyl acetate and ethanol
2SO
4Drying, underpressure distillation, the cut 4.7g of 102 ℃/25mmHg of collection, yield 83.2%.
Embodiment 5
(1) operation is with embodiment 1.
(2) operation is with embodiment 1.
(3) embodiment 4 used resins are reclaimed, the soluble solids on the spent resin is removed in washing, with 3M salt acid soak 24h, 3M NaOH solution soaking 12h is used in washing then, use 3M salt acid soak 12h after the washing again, be washed to neutrality at last, baking is to half-dried, and weighing gets 23.6g, to wherein adding the 6g fresh resin, stir evenly.
3.8g N-methyl-4-piperidone hydrochloride is dissolved in the 50ml ethanol, to the macroporous resin that wherein adds the above-mentioned recycling of 15g, stirring and evenly mixing, 1.5g NaBH
4Powder slowly joins in the reactor, and stirring reaction 1h obtains the oyster white turbid solution.The hydrochloric acid hydrolysis half hour that adds 25ml 1M, NaOH regulates pH value to strong basicity in the ice bath, suction filtration, ethanol (30ml * 2) washing filter residue, merging filtrate, underpressure distillation concentrates, reclaim ethanol, press liquid (30ml * 4) the extraction concentrated solution of 5: 1 mixed, combining extraction liquid, anhydrous Na with ethyl acetate and ethanol
2SO
4Drying, underpressure distillation, the cut 2.2g of 102 ℃/25mmHg of collection.Yield 78.6%.
Need not further to elaborate, believe and adopt the disclosed content in front, those skilled in the art can use the present invention to greatest extent.Therefore, the embodiment of front is interpreted as only illustrating, but not limits the scope of the invention by any way.
Claims (4)
1. the synthetic method of N-substituting group-4-piperidines alcohol is characterized in that the structural formula of N-substituting group-4-piperidines alcohol is:
Wherein: R is C
1～C
8Alkyl, benzyl or styroyl, N are the nitrogen base, OH is a hydroxyl, synthetic method may further comprise the steps:
The first step: the preparation of ester
With certain solvent be warming up to 60-70 ℃ after ethyl propenoate mixes, to wherein slowly dripping primary amine, dropwise back insulation 1-2 hour, distillation is reclaimed low-boiling-point substance and is got high boiling secondary adduct, its reaction formula is:
Second step: the preparation of N-substituting group-4-piperidone hydrochloride
Secondary adduct, cyclizing agent, solvent are put into reaction flask, reflux to the reaction system vapour temperature near the solvent boiling point temperature, constantly the mixed solution of ethanol and solvent is told with water trap in the reaction, cooling, it is quiet to half an hour to add concentrated hydrochloric acid, reactant is poured in the separating funnel, told organic layer, the decarboxylation of water layer reflux is to FeCl
3Test nondiscoloration, pressure reducing and steaming sour water add ethanol heating for dissolving after-filtration to thick shape, and filtrate is steamed to gluey, reclaim ethanol, add acetone in jelly, have a large amount of white solids to separate out, and filtering drying gets the thick product of N-substituting group-4-piperidone hydrochloride; With ethanol-acetone mixed solution recrystallization by a certain percentage 2～3 times the hydrochloride of highly purified N-substituting group-4-piperidone, its reaction formula is:
The 3rd step: the preparation of N-substituting group-4-piperidines alcohol
N-methyl-4-piperidone hydrochloride is dissolved in the solvent, adds Amberlyst-15 (H
+) stirring and evenly mixing, with NaBH
4Powder slowly joins in the reactor, and normal temperature reacted 1 hour down, adds the dilute hydrochloric acid hydrolysis, regulates PH, suction filtration is used the solvent wash filter residue, merging filtrate, and distillation concentrates, ethanol and ethyl acetate are mixed according to a certain percentage as extraction agent extraction concentrated solution, united extraction liquid, anhydrous Na
2SO
4Drying, the reclaim under reduced pressure extraction agent gets colourless liquid N-substituting group-4-piperidines alcohol, and its reaction formula is:
The 4th step: reclaim resin, the soluble solids on the spent resin is removed in washing, with 3M salt acid soak 24 hours, washing, use 3M NaOH solution soaking 12 hours then, use 3M salt acid soak 12 hours after the washing again, be washed to neutrality at last, baking is to half-dried, with fresh resin 3～4: 1 mixed cycle use in proportion.
2. the synthetic method of N-substituting group according to claim 1-4-piperidines alcohol, it is characterized in that said certain solvent of the first step reaction refers to be selected from triethylamine, 1, wherein a kind of of 4-dioxane or tetrahydrofuran (THF), add-on is advisable to add the 50ml solvent in each mol propylene acetoacetic ester; The mol ratio of participating in each material of reaction is: primary amine: ethyl propenoate=1: 2.5～3.
3. the synthetic method of N-substituting group according to claim 1-4-piperidines alcohol is characterized in that: the said solvent of the second step reaction is selected from benzene, toluene, a kind of in the toluene; Used cyclizing agent is selected from a kind of in sodium, sodium methylate, sodium ethylate, the sodium hydride; The used mixed solvent of recrystallization refers to that ethanol and acetone are by the mixed solution of forming at 1: 3; The mol ratio of participating in each material of reaction is: dibasic acid esters: cyclizing agent=1: 1～1.5.
4. the synthetic method of N-substituting group according to claim 1-4-piperidines alcohol is characterized in that: the used solvent of three-step reaction is selected from wherein a kind of of ethanol, a glyme, diglyme; Extraction agent is ethyl acetate and the ethanol mixed solution by 5: 1 proportionings; The mol ratio of participating in each material of reaction is: N-substituting group-4-piperidone hydrochloride: NaBH
4=1: 2～2.5; Every mole of piperidone needs 50～60g macroporous resin.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102417478A (en) * | 2011-09-14 | 2012-04-18 | 启东金美化学有限公司 | Synthesis method of 1-allyl-2,2,6,6-tetramethyl-piperidinol |
| CN108047126A (en) * | 2017-12-19 | 2018-05-18 | 苏州艾缇克药物化学有限公司 | A kind of preparation method of N- methyl -4- piperidones |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101886269B (en) * | 2010-07-20 | 2012-04-25 | 河北师范大学 | Method for non-membrane electrochemical synthesis of 2,2,6,6-tetramethyl-piperidinol |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102417478A (en) * | 2011-09-14 | 2012-04-18 | 启东金美化学有限公司 | Synthesis method of 1-allyl-2,2,6,6-tetramethyl-piperidinol |
| CN108047126A (en) * | 2017-12-19 | 2018-05-18 | 苏州艾缇克药物化学有限公司 | A kind of preparation method of N- methyl -4- piperidones |
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