CN102731369A - Synthesis method for N-substituted-4-piperidone - Google Patents
Synthesis method for N-substituted-4-piperidone Download PDFInfo
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- CN102731369A CN102731369A CN2012101635544A CN201210163554A CN102731369A CN 102731369 A CN102731369 A CN 102731369A CN 2012101635544 A CN2012101635544 A CN 2012101635544A CN 201210163554 A CN201210163554 A CN 201210163554A CN 102731369 A CN102731369 A CN 102731369A
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- piperidone
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- propiones
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- -1 N-substituted-4-piperidone Chemical class 0.000 title abstract description 4
- 238000001308 synthesis method Methods 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 17
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 10
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000005977 Ethylene Substances 0.000 claims abstract description 8
- 150000003141 primary amines Chemical class 0.000 claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- APNSUHRNUVUCIP-UHFFFAOYSA-N 1-chloropentan-3-one Chemical class CCC(=O)CCCl APNSUHRNUVUCIP-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 13
- 239000007789 gas Substances 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000007259 addition reaction Methods 0.000 abstract description 2
- LYJQMHVYFFZQGY-UHFFFAOYSA-N 1,5-dichloropentan-3-one Chemical compound ClCCC(=O)CCCl LYJQMHVYFFZQGY-UHFFFAOYSA-N 0.000 abstract 3
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 abstract 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 abstract 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 abstract 1
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 229960001076 chlorpromazine Drugs 0.000 description 10
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000003068 static effect Effects 0.000 description 5
- 238000010025 steaming Methods 0.000 description 5
- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical compound CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000006114 decarboxylation reaction Methods 0.000 description 3
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 2
- WXIUBYCJAAEOFL-UHFFFAOYSA-N [S].ClOCl Chemical class [S].ClOCl WXIUBYCJAAEOFL-UHFFFAOYSA-N 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- VPGLFNOKHAIGEC-UHFFFAOYSA-N 1-phenylpiperidin-4-one Chemical compound C1CC(=O)CCN1C1=CC=CC=C1 VPGLFNOKHAIGEC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Hydrogenated Pyridines (AREA)
Abstract
The present invention relates to an N-substituted-4-piperidone compound and a synthesis method thereof. In the general formula of the compound, R is alkyl with a carbon number of 1-8, phenyl or benzyl, and other groups. Characteristics of the method of the present invention are: selecting appropriate primary amine and 1,5-dichloro-3-pentanone, and carrying out a ring closing reaction to prepare N-substituted-4-piperidone, wherein the selected 1,5-dichloro-3-pentanone can directly be purchased or synthesized by a two-step synthesis method, and the two-step synthesis method comprises: (1) adding thionyl chloride to acrylic acid, and carrying out an addition reaction and acyl chlorination under catalysis of N,N-dimethyl formamide to obtain 3-chloropropionyl chloride; (2) introducing ethylene gas to a dichloromethane solution of 3-chloropropionyl chloride, and carrying out a Friedel-Crafts reaction to obtain the 1,5-dichloro-3-pentanone. The method of the present invention has characteristics of wide raw material source, mild reaction conditions, simple operation, low production costs, high yield, and good industrial production prospect.
Description
Technical field
The present invention relates to the compound method of a kind of N-substituting group-4-piperidone compound, these compounds belong to the pharmaceutical technology field as the important intermediate of preparation medicine.
Background technology
N-substituting group-4-piperidone has important researching value as pharmaceutical intermediate at field of medicaments.It is widely used in easing pain, antianaphylaxis, hypertension, medicine such as antitumor synthetic, the research of this compounds has been become the synthetic hot research fields of medicine.Therefore it is extensive to seek raw material sources, and reaction conditions is gentle, and production cost is low, and the N-substituting group that yield is high-4-piperidone compound method is very attracting work.
The compound method of having reported both at home and abroad at present mainly contains: 1. the condensation, the hydrolysis decarboxylation method that with the dibasic acid esters are raw material; Such as: with benzylamine, propenoate is basic raw material, synthesizes N-benzyl-4-piperidone through two keys and amino addition, ester group internal condensation, three steps of hydrochloric acid hydrolysis decarboxylation; This technology is industrialization at present, and the synthesis step reaction is comparatively ripe, and overall yield can be accepted, but process need is taken off alcohol radical, carboxyl, and Atom economy is poor, and cost is high, uses sodium Metal 99.5 dangerous high simultaneously; 2. with direct alkylated reaction such as 4-piperidone and benzyl bromide; This method yield is higher, and technology is simple, but initial feed is somewhat expensive, and is infeasible economically; 3. react, reduce with 4-piperidone and Benzoyl chloride 99min.; This method yield is higher, and technology is simple, and Benzoyl chloride 99min. is more cheap than benzyl bromide, but 4-piperidone raw material is more expensive, and has increased single step reaction, and is equally also infeasible economically.
Summary of the invention
The objective of the invention is to provides a kind of raw material sources extensive in order to overcome the shortcoming of above-mentioned technology, and reaction conditions is gentle, simple to operate, production cost is low, yield is high, have the N-substituting group-4-piperidone compound method of better industrial prospect of production.
To achieve these goals, the invention discloses the compound method of a kind of N-substituting group-4-piperidone compound, the structural formula of said N-substituting group-4-piperidone is:
Wherein: R is alkyl, phenyl or the benzyl of C1 ~ C8; N is a nitrogen, and O is a carbonyl, it is characterized in that said compound method may further comprise the steps:
(1) with 1,5-two chloro-propiones are dissolved in and obtain corresponding mixed solution among the proper amount of solvent A, stir this mixed solution, and are heated to 40-80 ℃;
(2) splash into primary amine more gradually, the primary amine consumption is 1, and the 0.4-1.0 of 5-two chloro-propiones doubly dropwises and continues to stir 4 hours, and cooling obtains N-substituting group-4-piperidone through aftertreatment, and its reaction formula is:
Wherein solvent orange 2 A is a kind of or their mixing solutions among methyl alcohol, ethanol, propyl alcohol, the DMF, used main raw material primary amine R-NH
2A kind of in methylamine, ethamine, butylamine, hexylamine, aniline, the benzylamine.
Compared with prior art, it is good that method of the present invention has an Atom economy, and selected operational path basically all is addition reaction; Want decarboxylation, dealcoholysis unlike primary amine-propenoate condensation route, reaction yield is higher, and operating procedure is simple; The building-up process normal pressure is accomplished; Service temperature 0-100 ℃ of scope takes hot and cold water-bath just can realize, is easy to industrialized advantage.
As further improvement of the present invention, said 1,5-two chloro-propiones are synthetic through following steps:
(1) mixed solution with vinylformic acid and catalyzer is heated to 60-70 ℃, drips chloride reagent, drips Bi Jixu and stirs half a hour, and underpressure distillation obtains the 3-chlorpromazine chloride, and its reaction formula is:
(2) (1) middle 3-chlorpromazine chloride product for preparing is cooled to below 5 ℃ in the presence of catalyzer 2 and solvent 1, feeds ethylene gas; Keep temperature to be lower than 10 ℃, ventilated 3-4 hour, with the Hydrogen chloride cancellation reaction of reaction solution with ice; The organic phase washing; Concentrate and obtain 1,5-two chloro-propiones, its reaction formula is:
Wherein, said catalyzer 1 is N, and dinethylformamide, its consumption are 0.05-0.15 times of vinylformic acid mole number; Employed acylating reagent is sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene, trichloromethylchloroformate; A kind of in the TRIPHOSGENE 99.5; Its consumption be the vinylformic acid mole number 1-1.5 doubly, said solvent B is a kind of or their mixing solutions in methylene dichloride, trichloromethane or the ethylene dichloride; Catalyst system therefor 2 is a kind of in aluminum trichloride (anhydrous), Zinc Chloride Anhydrous, the FERRIC CHLORIDE ANHYDROUS, and its consumption is the 1.1-1.5 of 3-chlorpromazine chloride mole number; The used Hydrogen chloride concentration of cancellation reaction is 8-12%.
The present invention can take oneself preparation 1; 5-two chloro-propione methods, N-substituting group-4-piperidone synthetic raw material sources are extensive like this, and price is more cheap; Main raw material vinylformic acid, ethene, hydrochloric acid etc. are the Essential Chemistry industrial goods, can reduce production costs.
The present invention be will help to understand through following specific embodiment, but content of the present invention and scope do not limited.
Embodiment
Embodiment 1
(1) with 73 gram (1.01 mol) vinylformic acid and 7.2 gram (0.1 mol) N, dinethylformamide joins in the reaction flask, heat temperature raising to 70 ℃; Constant temperature stirs down, drips 145 gram (1.05 mol) phosphorus trichlorides, in 5 hours, dropwises; Continue to react half a hour, reaction finishes.60 ℃/6kPa cut is collected in underpressure distillation, obtains 130 gram 3-chlorpromazine chlorides (content 90.2%, yield 83.6%);
(2) 277 gram (2.08 mol) aluminum chlorides are dissolved in the 250 mL ethylene dichloride, are cooled to 0 ℃, constant temperature stirs down; Dripped 200 gram (1.57 mol) 3-chlorpromazine chlorides 30 minutes; Maintain the temperature at below 5 ℃ and feed ethylene gas, ventilate and stir a moment after 3 hours, reaction finishes.Dispose 10% aqueous hydrochloric acid, be cooled to 0 ℃, stir and down reaction solution is slowly poured into, and maintain the temperature at below 10 ℃.Static layering is got organic phase washing (300 mL * 3), uses the anhydrous magnesium sulfate drying organic phase, filters, and obtains 226.3 grams 1,5-two chloro-propiones (content 85.6%, yield 93%) after concentrating;
(3) with 50 grams 1,5-two chloro-propiones (0.32mol) are dissolved in the methyl alcohol (120mL), and heat temperature raising to 60 ℃ stirs down, drip 17 gram benzylamines (0.16 mol), and controlled temperature drips Bi Jixu and stirred 4 hours at 60-67 ℃.Then reaction solution is poured in the water (500mL), used diatomite filtration, filtrating is concentrated into 200mL, add gac (1.7 g), stirred 30 minutes down at 50 ℃.Filter, filtrating is regulated pH to 10 with sodium hydroxide, and with methylene dichloride (50mL * 3) extraction, anhydrous magnesium sulfate drying is used in organic phase washing (30mL * 3), filters, and revolves to steam at 40 ℃ to obtain 28 gram N-benzyl-4-piperidone (content 88.2%, yield 92.1%).
Embodiment 2
(1) with 73 gram (1.01 mol) vinylformic acid and 7.2 gram (0.1 mol) N, dinethylformamide joins in the reaction flask, heat temperature raising to 70 ℃; Constant temperature stirs down, drips 125 gram (1.05 mol) sulfur oxychlorides, in 5 hours, dropwises; Continue to react half a hour, reaction finishes.60 ℃/6kPa cut is collected in underpressure distillation, obtains 130 gram 3-chlorpromazine chlorides (content 90.2%, yield 83.6%);
(2) 231 gram (1.73 mol) aluminum chlorides are dissolved in the 250 mL trichloromethanes, are cooled to 0 ℃, constant temperature stirs down; Dripped 200 gram (1.57 mol) 3-chlorpromazine chlorides 30 minutes; Maintain the temperature at below 5 ℃ and feed ethylene gas, ventilate and stir a moment after 3 hours, reaction finishes.Dispose 10% aqueous hydrochloric acid, be cooled to 0 ℃, stir and down reaction solution is slowly poured into, and maintain the temperature at below 10 ℃.Static layering is got organic phase washing (300 mL * 3), uses the anhydrous magnesium sulfate drying organic phase, filters, and obtains 226.3 grams 1,5-two chloro-propiones (content 85.6%, yield 93%) after concentrating;
(3) with 50 grams 1,5-two chloro-propiones (0.32mol) are dissolved in the methyl alcohol (120mL), and heat temperature raising to 60 ℃ stirs down, drip 15 gram aniline (0.16 mol), and controlled temperature drips Bi Jixu and stirred 4 hours at 60-67 ℃.Then reaction solution is poured in the water (500mL), used diatomite filtration, filtrating is concentrated into 200mL, add gac (1.7 g), stirred 30 minutes down at 50 ℃.Filter, filtrating is regulated pH to 10, layering with sodium hydroxide; With trichloromethane (50mL * 3) extraction, anhydrous magnesium sulfate drying is used in organic phase washing (30mL * 3); Filter, revolve steaming at 40 ℃ and obtain 25.2 gram N-phenyl-4-piperidone (content 85.7%, yield 90%).
Embodiment 3
(1) with 73 gram (1.01 mol) vinylformic acid and 7.2 gram (0.1 mol) N, dinethylformamide joins in the reaction flask, heat temperature raising to 70 ℃; Constant temperature stirs down, drips 68 gram (0.53 mol) oxalyl chlorides, in 5 hours, dropwises; Continue to react half a hour, reaction finishes.60 ℃/6kPa cut is collected in underpressure distillation, obtains 130 gram 3-chlorpromazine chlorides (content 90.2%, yield 83.6%).
(2) 314 gram (2.36 mol) aluminum chlorides are dissolved in the 250 mL methylene dichloride, are cooled to 0 ℃, constant temperature stirs down; Dripped 200 gram (1.57 mol) 3-chlorpromazine chlorides 30 minutes; Maintain the temperature at below 5 ℃ and feed ethylene gas, ventilate and stir a moment after 3 hours, reaction finishes.Dispose 10% aqueous hydrochloric acid, be cooled to 0 ℃, stir and down reaction solution is slowly poured into, and maintain the temperature at below 10 ℃.Static layering is got organic phase washing (300 mL * 3), uses the anhydrous magnesium sulfate drying organic phase, filters, and obtains 226.3 grams 1,5-two chloro-propiones (content 85.6%, yield 93%) after concentrating.
(3) with 50 grams 1,5-two chloro-propiones (0.32mol) are dissolved in the methyl alcohol (120mL), and heat temperature raising to 40 ℃ stirs down, feeds methylamine gas, and controlled temperature ventilate 3 hours at 60-67 ℃, continued stirring 4 hours.Then reaction solution is poured in the water (500mL), used diatomite filtration, filtrating is concentrated into 200mL, add gac (1.7 g), stirred 30 minutes down at 50 ℃.Filter, filtrating is regulated pH to 10, layering with sodium hydroxide; With trichloromethane (50mL * 3) extraction, anhydrous magnesium sulfate drying is used in organic phase washing (30mL * 3); Filter; Revolve steaming at 40 ℃ and obtain 10.3 gram N-methyl-4-piperidone (content 80.7%, by 1, it is 28.3% that the amount of 5-two chloro-propiones is calculated yield).
Embodiment 4
(1) with 73 gram (1.01 mol) vinylformic acid and 7.2 gram (0.1 mol) N, dinethylformamide joins in the reaction flask, heat temperature raising to 70 ℃; Constant temperature stirs down, drips 104 gram (1.05 mol) TRIPHOSGENE 99.5s, in 5 hours, dropwises; Continue to react half a hour, reaction finishes.60 ℃/6kPa cut is collected in underpressure distillation, obtains 130 gram 3-chlorpromazine chlorides (content 90.2%, yield 83.6%).
(2) 277 gram (2.08 mol) aluminum chlorides are dissolved in the 250 mL methylene dichloride, are cooled to 0 ℃, constant temperature stirs down; Dripped 200 gram (1.57 mol) 3-chlorpromazine chlorides 30 minutes; Maintain the temperature at below 5 ℃ and feed ethylene gas, ventilate and stir a moment after 3 hours, reaction finishes.Dispose 10% aqueous hydrochloric acid, be cooled to 0 ℃, stir and down reaction solution is slowly poured into, and maintain the temperature at below 10 ℃.Static layering is got organic phase washing (300 mL * 3), uses the anhydrous magnesium sulfate drying organic phase, filters, and obtains 226.3 grams 1,5-two chloro-propiones (content 85.6%, yield 93%) after concentrating.
(3) with 31 grams 1,5-two chloro-propiones (0.20mol) are dissolved in the methyl alcohol (120mL), and heat temperature raising to 70 ℃ stirs down, splash into 12 gram n-Butyl Amine 99s (0.16 mol), and controlled temperature continues to stir 4 hours at 65-75 ℃.Then reaction solution is poured in the water (500mL), used diatomite filtration, filtrating is concentrated into 200mL, add gac (1.7 g), stirred 30 minutes down at 50 ℃.Filter, filtrating is regulated pH to 10, layering with sodium hydroxide; With ethylene dichloride (50mL * 3) extraction, anhydrous magnesium sulfate drying is used in organic phase washing (30mL * 3); Filter, revolve steaming at 40 ℃ and obtain 18.6 gram N-methyl-4-piperidone (content 89.2%, yield 75.2%).
Embodiment 5
(1) with 73 gram (1.01 mol) vinylformic acid and 7.2 gram (0.1 mol) N, dinethylformamide joins in the reaction flask, heat temperature raising to 70 ℃; Constant temperature stirs down, drips 125 gram (1.05 mol) sulfur oxychlorides, in 5 hours, dropwises; Continue to react half a hour, reaction finishes.60 ℃/6kPa cut is collected in underpressure distillation, obtains 130 gram 3-chlorpromazine chlorides (content 90.2%, yield 83.6%).
(2) 277 gram (2.08 mol) aluminum chlorides are dissolved in the 250 mL methylene dichloride, are cooled to 0 ℃, constant temperature stirs down; Dripped 200 gram (1.57 mol) 3-chlorpromazine chlorides 30 minutes; Maintain the temperature at below 5 ℃ and feed ethylene gas, ventilate and stir a moment after 3 hours, reaction finishes.Dispose 10% aqueous hydrochloric acid, be cooled to 0 ℃, stir and down reaction solution is slowly poured into, and maintain the temperature at below 10 ℃.Static layering is got organic phase washing (300 mL * 3), uses the anhydrous magnesium sulfate drying organic phase, filters, and obtains 226.3 grams 1,5-two chloro-propiones (content 85.6%, yield 93%) after concentrating.
(3) with 50 grams 1,5-two chloro-propiones (0.32mol) are dissolved in the methyl alcohol (120mL), and heat temperature raising to 80 ℃ stirs down, splash into 16 gram normal hexyl Amines (0.16 mol), and controlled temperature continues to stir 4 hours at 70-80 ℃.Then reaction solution is poured in the water (500mL), used diatomite filtration, filtrating is concentrated into 200mL, add gac (1.7 g), stirred 30 minutes down at 50 ℃.Filter, filtrating is regulated pH to 10, layering with sodium hydroxide; With methylene dichloride (50mL * 3) extraction, anhydrous magnesium sulfate drying is used in organic phase washing (30mL * 3); Filter, revolve steaming at 40 ℃ and obtain 23.5 gram N-methyl-4-piperidone (content 91.2%, yield 80.2%).
Embodiment 6
With 31 grams 1,5-two chloro-propiones (0.20mol) are dissolved in the methyl alcohol (120mL), and heat temperature raising to 70 ℃ stirs down, splash into 15 gram n-Butyl Amine 99s (0.20 mol), and controlled temperature continues to stir 4 hours at 65-75 ℃.Then reaction solution is poured in the water (500mL), used diatomite filtration, filtrating is concentrated into 200mL, add gac (1.7 g), stirred 30 minutes down at 50 ℃.Filter, filtrating is regulated pH to 10, layering with sodium hydroxide; With ethylene dichloride (50mL * 3) extraction, anhydrous magnesium sulfate drying is used in organic phase washing (30mL * 3); Filter, revolve steaming at 40 ℃ and obtain 19.1 gram N-methyl-4-piperidone (content 89.2%, yield 78.2%).
Claims (3)
1. the compound method of N-substituting group-4-piperidone compound, the structural formula of said N-substituting group-4-piperidone is:
Wherein: R is alkyl, phenyl or the benzyl of C1 ~ C8; N is a nitrogen, and O is a carbonyl, it is characterized in that said compound method may further comprise the steps:
With 1,5-two chloro-propiones are dissolved in and obtain corresponding mixed solution among the proper amount of solvent A, stir this mixed solution, and are heated to 40-80 ℃;
Splash into primary amine more gradually, the primary amine consumption is 1, and the 0.4-1.0 of 5-two chloro-propiones doubly dropwises and continues to stir 4 hours, and cooling obtains N-substituting group-4-piperidone through aftertreatment, and its reaction formula is:
Wherein solvent orange 2 A is a kind of or their mixing solutions among methyl alcohol, ethanol, propyl alcohol, the DMF, used main raw material primary amine R-NH
2A kind of in methylamine, ethamine, butylamine, hexylamine, aniline, the benzylamine.
2. require the compound method of 1 described N-substituting group-4-piperidone compound according to right, it is characterized in that its mixed solution Heating temperature is 60-70 ℃.
3. require the compound method of 1 described N-substituting group-4-piperidone compound according to right, it is characterized in that saidly 1,5-two chloro-propiones are synthetic through following steps:
(1) mixed solution with vinylformic acid and catalyzer is heated to 60-70 ℃, drips chloride reagent, drips Bi Jixu and stirs half a hour, and underpressure distillation obtains the 3-chlorpromazine chloride, and its reaction formula is:
(2) (1) middle 3-chlorpromazine chloride product for preparing is cooled to below 5 ℃ in the presence of catalyzer 2 and solvent 1, feeds ethylene gas; Keep temperature to be lower than 10 ℃, ventilated 3-4 hour, with the Hydrogen chloride cancellation reaction of reaction solution with ice; The organic phase washing; Concentrate and obtain 1,5-two chloro-propiones, its reaction formula is:
Wherein, said catalyzer 1 is N, and dinethylformamide, its consumption are 0.05-0.15 times of vinylformic acid mole number; Employed acylating reagent is sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene, trichloromethylchloroformate; A kind of in the TRIPHOSGENE 99.5; Its consumption be the vinylformic acid mole number 1-1.5 doubly, said solvent B is a kind of or their mixing solutions in methylene dichloride, trichloromethane or the ethylene dichloride; Catalyst system therefor 2 is a kind of in aluminum trichloride (anhydrous), Zinc Chloride Anhydrous, the FERRIC CHLORIDE ANHYDROUS, and its consumption is the 1.1-1.5 of 3-chlorpromazine chloride mole number; The used Hydrogen chloride concentration of cancellation reaction is 8-12%.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116874413A (en) * | 2023-07-07 | 2023-10-13 | 南通华祥医药科技有限公司 | A kind of synthetic method of 1-tert-butylpiperidin-4-one |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3149155A (en) * | 1958-06-03 | 1964-09-15 | Basf Ag | Production of acid chlorides |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3149155A (en) * | 1958-06-03 | 1964-09-15 | Basf Ag | Production of acid chlorides |
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| 《Organic Process Research & Development》 20080621 Minoru Ishikawa et al. A Scalable Synthesis of MN-447, an Antagonist for Integrins alphavbeta3 and alphaⅡbbeta3 第596-602页 1-3 第12卷, 第4期 * |
| MINORU ISHIKAWA ET AL.: "A Scalable Synthesis of MN-447, an Antagonist for Integrins αvβ3 and αⅡbβ3", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》, vol. 12, no. 4, 21 June 2008 (2008-06-21), pages 596 - 602 * |
| T. SCHERER ET AL.: "Synthesis and exploratory photophysical investigation of donor-bridge-acceptor systems derived from N-substituted 4-piperidones", 《RED. TRAV. CHIM. PAYS-BAS》, vol. 112, no. 10, 31 October 1993 (1993-10-31), pages 535 - 548 * |
| 李炜坤: "哌啶酮及其衍生物合成方法研究", 《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》, no. 5, 31 May 2010 (2010-05-31), pages 016 - 18 * |
Cited By (1)
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|---|---|---|---|---|
| CN116874413A (en) * | 2023-07-07 | 2023-10-13 | 南通华祥医药科技有限公司 | A kind of synthetic method of 1-tert-butylpiperidin-4-one |
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