CN101638378A - Synthetic method of N-alkyl substituted-3-piperidones - Google Patents
Synthetic method of N-alkyl substituted-3-piperidones Download PDFInfo
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- CN101638378A CN101638378A CN200910069437A CN200910069437A CN101638378A CN 101638378 A CN101638378 A CN 101638378A CN 200910069437 A CN200910069437 A CN 200910069437A CN 200910069437 A CN200910069437 A CN 200910069437A CN 101638378 A CN101638378 A CN 101638378A
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a synthetic method of N-alkyl substituted-3-piperidones. The method comprises the following steps of: opening the ring of brooethyl cyclopropyl ketone; protecting keto carbonyl group with proper protecting group; reacting with N-substituted primary amine; de-protecting; and directly preparing the N-alkyl substituted-3-piperidones. The method has simple and convenient operation (non-column chromatography separating, only one recrystallizing, and twice distilling by means of pressure reduction), less synthesis step, moderate condition, high yield coefficient (total yieldcoefficient is 80%), good purity, can obtain high-purity product for storing longer time, and is applicable for industrial industry.
Description
Technical field
The present invention relates to a kind of synthetic method of N-alkyl replacement-3-piperidone, it is with the synthetic method of a nitrogen-atoms as the N-alkyl replacement-3-piperidone of unique heterocyclic atom.
Background technology
N-alkyl replacement-3-piperidone is organic synthesis key intermediate (Synthesis, 2007,289-293; WO2006010577), in organic synthesis particularly medicine synthetic (WO 2005070407; WO 2005087751; WO2005079497; US 2005070534; Bioorg.﹠amp; Med.Chem.2004,12,2115-2137; Ibid 2005,13,4667-4678; Ibid 2007,15,350-364; Ibid 2007,15,6208-6226; Ibid 2008,116,8447-8465; Bioorg.﹠amp; Med.Chem.Lett.2005,15,4780-4785; Ibid 2008,18,188-193; J.Med.Chem., 1986,29,740-747; Ibid 1988,31,486-491) with natural product complete synthesis (J.Am.Chem.Soc.2008,130,7568-7569; Tetrahedron Lett.1995,36, be widely used in 2235-2238).At present, about the synthetic report of N-alkyl replacement-3-piperidone seldom, be shown below (Chinese Journal of Pharmaceuticals, 2004,35,385-388 of Chang Yong method relatively; Hel.Chim.Acta.1954,37,178-184; J.Am.Chem.Soc.1953,75,3727-3730; J.Am.Chem.Soc.1949,71,1680-1682; J.Am.Chem.Soc.1933,55,1233-1241), R is different substituting group, though this synthetic method has certain versatility,, thereby limited the application of this synthetic method because the yield of azanylization and the reaction of Dieckmann condensation and cyclization is generally lower.
Another synthesis strategy is following, and (Acta Chem.Scan.B 1976,30,884-888), this method synthesis yield is medium, but used raw material is expensive.
The N-alkyl replacement-3-piperidone synthetic method of other bibliographical information also is only applicable to laboratory synthetic on a small scale (Eur.J.Med.Chem.1981,16,163-169; Croatica Chem.Acta 1991,64,65-77; Biochem.﹠amp; Biophysical Res.Commun.1991,179,1368-1376; J.Chem.Soc.Perkin Trans.I 1999,2277-2280; J.Org.Chem.2007,72,2674-2677), be not suitable for the industrially scalable preparation.
Summary of the invention
Purpose of the present invention aims to provide a kind of synthetic method of new N-alkyl replacement-3-piperidone, can overcome the defective of prior art.With commercialized raw materials Cyclopropyl Methyl Ketone cheap and easy to get is raw material, the universal method of setting up efficiently, synthesizing N-alkyl replacement-3-piperidone 6 compactly.This synthetic method simple, convenient (no column chromatography is separated, only through a recrystallization, twice underpressure distillation), synthesis step is few, mild condition, product yield height (total recovery is 80%), purity is good, and resulting highly purified product can be preserved the long period, is applicable to suitability for industrialized production.
The reactions steps that the synthetic method of N-alkyl replacement-3-piperidone provided by the invention comprises (in the statement hereinafter, specific synthetic product is according to the numbering in the structural formula, represents with Arabic numerals):
X＝Cl、Br、I，R
1＝CH
3、CH
3CH
2、CH
2CH
2，R
2＝CH
3、CH
3CH
2、C
6H
5CH
2、4-CH
3O-C
6H
4CH
2、C
6H
5、2-CH
3O-C
6H
4、4-CH
3O-C
6H
4.
Concrete steps are:
Step 1: compound 2 reacted in hydrogen halide solution 0.5～2 hour, 0 ℃～80 ℃ of temperature of reaction, preferably 20 ℃～60 ℃, through extraction, dry, concentrate, with obtaining compound 3 behind the organic solvent recrystallization.Described hydrogen halide is selected from hydrogen bromide, hydrogenchloride especially preferably from hydrogenchloride, hydrogen bromide, hydrogen iodide.Described organic solvent is ester class, ethers, alcohol compound, is selected from ether especially.Compound 2 is 1: 3～5 with the mol ratio of hydrogen halide.
Step 2: compound 3 reacted under the effect of acid or lewis acid catalyst 15～30 hours with alcohol or ester in inert organic solvents, 50 ℃～110 ℃ of temperature of reaction, preferred 70 ℃～100 ℃, through extraction, dry, obtain compound 4 after concentrating.Described inert organic solvents is selected from benzene, toluene.Described alcohol can be methyl alcohol, ethanol, ethylene glycol, is selected from ethylene glycol especially.Described ester can be trimethyl orthoformate, trimethyl orthoacetate, triethyl orthoformate, triethly orthoacetate, is selected from trimethyl orthoformate especially.Described acid is sulfuric acid, hydrochloric acid, tosic acid, methylsulfonic acid, trifluoromethanesulfonic acid or boron trifluoride, trifluoromethanesulfonic acid trimethylsilyl group, is selected from tosic acid especially.The mol ratio of compound 3, alcohol or ester and catalyzer is 1: 5～7: 0.05～0.2.
Step 3: compound 4 reacted in the presence of alkali 0.5～2 hour with primary amine under inert organic solvents or solvent-free state, 50 ℃～110 ℃ of temperature of reaction, preferred 70 ℃～100 ℃, through filtration, concentrate, underpressure distillation obtains compound 5.Described organic solvent can be C
2～C
4Fatty ethers or alicyclic ether, be selected from ether or tetrahydrofuran (THF) especially.Halogenated hydrocarbon is selected from C
1～C
4Halohydrocarbon, be selected from methylene dichloride or trichloromethane especially.This reaction can be selected from reaction under the solvent-free conditions especially.Described alkali can be amine or mineral alkali, is selected from benzylamine especially, triethylamine or salt of wormwood.Described primary amine can be aryl amine quiberon, benzylamine, kiber alkyl amine.Be selected from CH especially
3NH
2, CH
3CH
2NH
2, C
6H
5CH
2NH
2, 4-CH
3O-C
6H
4CH
2NH
2, C
6H
5NH
2, 2-CH
3O-C
6H
4NH
2, 4-CH
3O-C
6H
4NH
2. the mol ratio of compound 4, primary amine and alkali is 1: 3～6: 3～5.
Step 4: compound 5 reacted in inorganic aqueous acid 10～20 hours, 70 ℃～140 ℃ of temperature of reaction, preferred 90 ℃～120 ℃, through neutralization, extraction, dry, concentrate, underpressure distillation obtains compound 6.Described acid can be sulfuric acid, hydrochloric acid, rare nitric acid.Be selected from hydrochloric acid especially.Compound 5 is 1: 10～15 with the mineral acid mol ratio.
(synthetic method is seen document Tetrahedron with compound cheap and easy to get 2 in the present invention, 1987,43,4609-4619) be raw material, succinctly (4 steps altogether), efficient (total recovery is 80.5%), convenient (no column chromatography separation, only through a recrystallization, secondary underpressure distillation) the synthetic N-alkyl replacement-3-piperidone 6 that obtains.Synthesis step is few, mild condition, and product yield height (total recovery is 80%), purity is good, and resulting highly purified product can be preserved the long period, is applicable to suitability for industrialized production.
Embodiment
Below the invention will be further described in conjunction with the embodiments again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 11,5-two bromo-2 pentanones 7 synthetic
In the 1L flask, add 110 and digest compound 2 and 40% Hydrogen bromide (340mL), 50 ℃, 0.5 hour, extracted with diethyl ether, saturated common salt is washed once, and anhydrous magnesium sulfate drying is spin-dried for solvent and gets 159 gram white solids 7, yield 97%, recrystallization obtains white needle-like crystals in ether, 29～30 ℃ of fusing points.
1H NMR (400MHz, CDCl
3) δ 2.15-2.21 (2H, m), 2.88 (2H, t, J=6.8Hz), 3.46 (2H, t, J=6.4Hz), 3.9 (2H, s) ppm.
Embodiment 21, and 5-two bromo-2-ethylene glycol contract synthesizing of pentanone 8
In the 2L flask, add 83 and digest compound 7 and 132 gram ethylene glycol, 5.9 gram tosic acid, benzene (1100mL), reflux water-dividing 20 hours.Boil off benzene, use extracted with diethyl ether, saturated common salt is washed once, and anhydrous magnesium sulfate drying is spin-dried for solvent and gets colourless liquid 95 grams, yield 97%.
1H NMR (400MHz, CDCl
3) δ 1.96-2.02 (4H, m), 3.37 (2H, s), 3.43 (2H, t, J=6.0Hz), 3.98-4.09 (4H, m) ppm.
Embodiment 3 N-benzyl-3-ethylene glycol contracts synthesizing of piperidone 9
Add 98 and digest compound 8 and 187 gram benzylamines in the 500mL flask, 80 ℃ were heated 1 hour.The ether dilution.After the filtration, solid is the hydrobromate of benzylamine, is reclaimed.Filtrate elder generation normal pressure steams solvent, and water pump removes benzylamine under reduced pressure again, and 120 ℃ of cuts are collected in oil pump decompression then during 5～6Pa.Get colourless liquid 74 grams, yield 94%.
1H NMR (400MHz, CDCl
3) δ 1.60 (2H, t, J=6.8Hz), 1.70-1.76 (2H, m), 2.37 (2H, s), 2.40 (2H, t, J=5.2Hz), 3.60 (2H, s), 3.87-3.97 (4H, m), 7.31 (5H, br) ppm.
Synthesizing of embodiment 4 N-benzyl-3-piperidone 10
In the 2L flask, add 42 and digest compound 9 and 1M hydrochloric acid (1500mL), refluxed 15 hours.Transfer to alkalescence with sodium bicarbonate after being chilled to room temperature, ethyl acetate extraction, saturated common salt is washed once, and anhydrous sodium sulfate drying is spin-dried for solvent and gets light yellow liquid, becomes solid during-20 ℃ of left and right sides.Underpressure distillation, the cut of collecting 110 ℃ during 60Pa gets product 31 grams, yield 91%.
1H NMR (400MHz, CDCl
3) δ 1.91-1.97 (2H, m), 2.36 (2H, t, J=6.8Hz), 2.64 (2H, t, J=5.6Hz), 3.00 (2H, s), 3.58 (2H, s), 7.31 (5H, br) ppm.
Claims (9)
1, a kind of synthetic method of N-alkyl replacement-3-piperidone is characterized in that the step that it comprises:
X＝Cl、Br、I，R
1＝CH
3、CH
3CH
2、CH
2CH
2，R
2＝CH
3、CH
3CH
2、C
6H
5CH
2、4-CH
3O-C
6H
4CH
2、C
6H
5、2-CH
3O-C
6H
4、4-CH
3O-C
6H
4.
Concrete steps are:
1) compound 2 reacted in hydrogen halide solution 0.5～2 hour, 0 ℃～80 ℃ of temperature of reaction, through extraction, dry, concentrate, with obtaining compound 3 behind the organic solvent recrystallization;
2) compound 3 reacted under the effect of acid or lewis acid catalyst 15～30 hours with alcohol or ester in inert organic solvents, 50 ℃～110 ℃ of temperature of reaction, through extraction, dry, obtain compound 4 after concentrating;
3) compound 4 reacted in the presence of alkali 0.5～2 hour with primary amine under inert organic solvents or solvent-free state, 50 ℃～110 ℃ of temperature of reaction, through filtration, concentrate, underpressure distillation obtains compound 5;
4) compound 5 reacted in inorganic aqueous acid 10～20 hours, 70 ℃～140 ℃ of temperature of reaction, through neutralization, extraction, dry, concentrate, underpressure distillation obtains compound 6.
2, synthetic method according to claim 1 is characterized in that the described hydrogen halide of step 1) is selected from hydrogenchloride, hydrogen bromide, hydrogen iodide; Described organic solvent is an ether; Compound 2 is 1: 3～5 with the mol ratio of hydrogen halide.
3, synthetic method according to claim 2 is characterized in that described hydrogen halide is a hydrogen bromide.
4, synthetic method according to claim 1 is characterized in that step 2) described organic solvent is selected from benzene, toluene; Described alcohol is methyl alcohol, ethanol, ethylene glycol; Described ester is trimethyl orthoformate, trimethyl orthoacetate, triethyl orthoformate, triethly orthoacetate; Described acid is sulfuric acid, hydrochloric acid, tosic acid, methylsulfonic acid, trifluoromethanesulfonic acid or boron trifluoride, trifluoromethanesulfonic acid trimethylsilyl group; The mol ratio of compound 3, alcohol or ester and catalyzer is 1: 5～7: 0.05～0.2.
5, synthetic method according to claim 4 is characterized in that described alcohol is ethylene glycol.
6, synthetic method according to claim 1 is characterized in that the described organic solvent of step 3) is ether or tetrahydrofuran (THF), methylene dichloride or trichloromethane; Described alkali is selected from benzylamine, triethylamine or salt of wormwood; Described primary amine is selected from CH
3NH
2, CH
3CH
2NH
2, C
6H
5CH
2NH
2, 4-CH
3O-C
6H
4CH
2NH
2, C
6H
5NH
2, 2-CH
3O-C
6H
4NH
2, 4-CH
3O-C
6H
4NH
2The mol ratio of compound 4, primary amine and alkali is 1: 3～6: 3～5.
7, synthetic method according to claim 6 is characterized in that described primary amine is a benzylamine.
8, synthetic method according to claim 1 is characterized in that the described acid of step 4) is sulfuric acid, hydrochloric acid, rare nitric acid; Compound 5 is 1: 10～15 with the mineral acid mol ratio.
9, synthetic method according to claim 7 is characterized in that described acid is hydrochloric acid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483376A (en) * | 2019-09-11 | 2019-11-22 | 陈建江 | A kind of synthetic method of intermediate N phenyl -4- piperidones |
| CN111362853A (en) * | 2020-04-27 | 2020-07-03 | 安徽大学 | Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester |
-
2009
- 2009-06-25 CN CN200910069437XA patent/CN101638378B/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483376A (en) * | 2019-09-11 | 2019-11-22 | 陈建江 | A kind of synthetic method of intermediate N phenyl -4- piperidones |
| CN110483376B (en) * | 2019-09-11 | 2020-11-03 | 山西智创药研科技有限公司 | Synthesis method of intermediate N-phenyl-4-piperidone |
| CN111362853A (en) * | 2020-04-27 | 2020-07-03 | 安徽大学 | Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester |
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| Publication number | Publication date |
|---|---|
| CN101638378B (en) | 2011-06-15 |
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Assignee: Zhejiang Top Medicine Co., Ltd. Assignor: Zhejiang Huineng Animal Medicine Co., Ltd. Contract record no.: 2011330001195 Denomination of invention: Synthetic method of N-alkyl substituted-3-piperidones Granted publication date: 20110615 License type: Common License Open date: 20100203 Record date: 20110930 |
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