CN102532061A - Method for easily preparing aryl morpholine and aryl piperidine - Google Patents
Method for easily preparing aryl morpholine and aryl piperidine Download PDFInfo
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- CN102532061A CN102532061A CN2011104038112A CN201110403811A CN102532061A CN 102532061 A CN102532061 A CN 102532061A CN 2011104038112 A CN2011104038112 A CN 2011104038112A CN 201110403811 A CN201110403811 A CN 201110403811A CN 102532061 A CN102532061 A CN 102532061A
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Abstract
The invention relates to a method for easily preparing aryl morpholine (formula I) and aryl piperidine (formula II). The preparation method mainly comprises the following steps of: reacting morpholine (formula III) or piperidine (formula IV) with aryl bromide (formula V) in an organic solvent in the presence of a catalytic amount of palladium compound with a simple structure, a phosphorus (phosphonium) ligand with a simple structure and an alkali at a certain temperature for 3-10 hours; and performing column chromatography isolation to obtain aryl morpholine (formula I) or aryl piperidine (formula II). Compared with the conventional method for preparing aryl morpholine and aryl piperidine, the method has the advantages of easiness, readily-available catalysts and ligands, low preparation cost, high yield and the like.
Description
Technical field
The present invention relates to the method for a kind of easy manufacture aryl morpholine and Arylpiperidine, specifically, relate to a kind of through the Buchwald-Hartwig prepared in reaction aryl morpholine of simple system and the method for Arylpiperidine.
Background technology
Aryl morpholine, Arylpiperidine compounds are widely used in fields such as organic chemistry, pharmaceutical chemistry, Materials science.At synthetic organic dye, natural compounds, medicine intermediate, biologically active substance, functional material etc. more and more important effect is arranged.(B.B.Sniker，et?al.J.Am.Chem.Soc.1998，120，6417-6418；U.Scholz，et?al.Adv.Synth.Catal.2004，346，1599-1626)
The method of traditional synthesizing aryl morpholine/Arylpiperidine is that the compound with copper or copper is a catalyzer; But its reaction conditions is relatively harsh, a lot of limitation is arranged; Such as high temperature, normal catalyzer, also have basically only to iodo aromatic hydrocarbons effective (J.Hassan, et al.Chem.Rev.2002; 102,1359).The copper catalyzed reaction is seen Figure of description (Fig. 1) example.
It is the amination reaction of catalyzer with the palladium that nineteen ninety-five Buchward and Hartwig have developed a kind of respectively; Can be good at the reaction of aminated compoundss such as catalysis halogenated aryl hydrocarbon and morpholine, piperidines; Reaction conditions is gentle, and applicability is wider, becomes the important method of amination reaction.But wherein used palladium complex structure is complicated, for example Pd
2(dba)
3, Pd (PPh
3) Cl
2Deng, wherein used phosphine part is as (o-tol)
3P,
tBu
3P, dppf and BINAP etc., basically all to air-sensitive, cost an arm and a leg, complex structure.(L.Buchwald，et?al.Angew.Chem.Int.Ed.Engl.1995，34(12)，1348-1350.F.Hartwig，et?al.Tetrahedron?Letters.1995，63(21)，3609-3612)。The Buchwald-Hartwig amination reaction is seen Figure of description (Fig. 2) example.
Therefore, need to seek a kind of simple, convenient, economic, efficient, the stable catalystsystem catalysis synthesizing aryl morpholine and the method for Arylpiperidine.
Summary of the invention
Technical problem to be solved by this invention is to need complicated palladium complex and defectives such as instability, complex structure, expensive phosphine part in order to overcome existing preparation aryl morpholine and Arylpiperidine, and a kind of economy, easy, high yield and the method for preparing aryl morpholine and Arylpiperidine with practical value are provided.
Described preparing method's key step is: in the presence of phosphorus (phosphine) part of the palladium compound of the simple structure of catalytic amount and simple structure and alkali; By morpholine (formula III) or piperidines (formula IV) respectively with aryl bromide (formula V) in organic solvent; Under the certain temperature; React after 3-10 hour,, obtain aryl morpholine (formula I) or Arylpiperidine (formula II) through column chromatography for separation.The structure of formula I, II, III, IV, V is seen shown in the Figure of description (Fig. 3).
Catalyzer of the present invention is PdCl
2, K
2PdCl
4, Na
2PdCl
4, Pd (OAc)
2, Pd (CH
3CN)
2Cl
2One or more, that preferable is PdCl
2, its consumption is the 0.5-5mol% of formula V compound, that preferable is the 2mol% of formula V compound.
Phosphorus of the present invention (phosphine) part is one or more of triethyl-phosphite, triphenyl phosphite, triphenylphosphine, and preferable is triphenylphosphine, and its consumption is the 1-10mol% of formula V compound, and preferable consumption is the 4mol% of formula V compound.
The consumption of formula III compound of the present invention and formula IV compound be formula V compound molar weight 1-3 doubly, 1.5 times of V compound molar weight that preferable is
What reaction of the present invention was preferable carries out in nitrogen atmosphere.
Alkali of the present invention is one or more in sodium tert-butoxide, potassium tert.-butoxide, potassiumphosphate, the sodium hydride.Preferable is sodium tert-butoxide, and its consumption is 0.5-5mol, and that preferable is 1.5mol.
Organic solvent of the present invention is one or more of toluene, dioxane, THF, and preferable is toluene.
Temperature of reaction of the present invention is 25-130 ℃, and preferable is the reflux temperature of solvent.The described reaction times is 3-10 hour, and preferable is 5 hours.After reaction finished, preferable purified thick product through column chromatography.
All commercially available the getting of catalyzer, part, raw material, alkali and solvent that the present invention is used.
Positive progressive effect of the present invention is: the present invention has screened palladium catalyst and part; Making does not need complicated palladium complex and phosphine part unstable, complex construction with Buchwald-Hartwig prepared in reaction aryl morpholine or Arylpiperidine, reacts efficient, easy, economical, is prone to be applied to enlarge and produces.
Embodiment
Mode through embodiment further specifies the present invention below, but does not therefore limit the present invention among the described scope of embodiments.
The preparation of case study on implementation 1N-phenylmorpholine
Under the nitrogen protection, in 25ml Schlenk bottle, add 144mg (1.5mmol) sodium tert-butoxide, 3.6mg (0.02mmol) palladium chloride, 10.6mg (0.04mmol) triphenylphosphine, 157mg (1.0mmol) bromobenzene, 130.5mg (1.5mmol) morpholine, 5.0ml toluene successively, heating reflux reaction 5h; Add an amount of shrend reaction of going out, (3 * 10ml) extractions merge organic phase with ETHYLE ACETATE; Concentrate; Column chromatography for separation obtains white solid 141.7mg, yield 88.0%.mp?49-51℃。
1HNMR(400MHz，CDCl
3)δ3.07(t，J＝4.7Hz，4H)，3.77(t，J＝4.7Hz，4H)，6.89-6.73(m，3H)，7.18-7.20(m，2H)。
The preparation of embodiment 2 N-4-aminomethyl phenyl morpholines
Change reaction substrate into 171mg (1.0mmol) 4-methyl bromobenzene, all the other experiment conditions and operation obtain faint yellow solid 153.1mg, yield 86.0% with embodiment 1; Mp 48-50 ℃.
1H?NMR(400MHz，CDCl
3)δ2.20(s，3H)，3.03(t，J＝4.8Hz，4H)，3.78(t，J＝4.8Hz，4H)，6.76(d，J＝8.5Hz，2H)，7.01(d，J＝8.5Hz，2H)。
The preparation of case study on implementation 3 N-4-chloro-phenyl-morpholines
Change reaction substrate into 191.5mg (1.0mmol) 4-chloro-bromobenzene, all the other experiment conditions and operation obtain white solid 175.6mg, yield 88.9% with embodiment 1.mp?65-68℃。
1H?NMR(400MHz，CDCl
3)δ3.04(t，J＝4.8Hz，4H)，3.78(t，J＝4.8Hz，4H)，6.75(d，J＝8.9Hz，2H)，7.14(d，J＝8.9Hz，2H)。
The preparation of case study on implementation 4N-2-aminomethyl phenyl morpholine
Change reaction substrate into 171mg (1.0mmol) 2-methyl bromobenzene, all the other experiment conditions and operation obtain weak yellow liquid 156.8mg, yield 88.1% with embodiment 1.
1H?NMR(400MHz，CDCl
3)δ2.25(s，3H)，2.85(t，J＝4.8Hz，4H)，3.80(t，J＝4.8Hz，4H)，6.95-6.98(m，2H)，7.11-7.12(m，2H)。
The preparation of case study on implementation 5N-4-p-methoxy-phenyl morpholine
Change reaction substrate into 187mg (1.0mmol) 4-methoxyl group bromobenzene, all the other experiment conditions and operation obtain white solid 140.4mg, yield 73.1% with embodiment 1.mp?67-70℃。
1H?NMR(400MHz，CDCl
3)δ2.98(t，J＝4.9Hz，4H)，3.70(s，3H)，3.79(t，J＝4.7Hz，4H)，6.77-6.83(m，4H)。
The preparation of case study on implementation 6N-4-cyano-phenyl morpholine
Change reaction substrate into 182mg (1.0mmol) 4-cyanic acid bromobenzene, all the other experiment conditions and operation obtain white solid 174.8mg, yield 92.5% with embodiment 1.mp?79-81℃。
1H?NMR(400MHz，CDCl
3)δ3.20-3.22(m，4H)，3.77-3.78(m，4H)，6.79(d，J＝9.0Hz，2H)，7.45(d，J＝9.0Hz，2H)。
The preparation of case study on implementation 7N-Phenylpiperidine
Under the nitrogen protection; In 25ml Schlenk bottle, add 144mg (1.5mmol) sodium tert-butoxide, 3.6mg (0.02mmol) palladium chloride, 10.6mg (0.04mmol) triphenylphosphine, 157mg (1.0mmol) bromobenzene, 127.5mg (1.5mmol) piperidines, 5.0ml toluene successively, nitrogen protection.Back flow reaction 5h, TLC follows the tracks of.Reaction finishes, and adds proper amount of deionized water cancellation reaction, with ETHYLE ACETATE (3 * 10) extraction, merges organic phase, concentrates, and column chromatography for separation obtains weak yellow liquid 136.9mg, yield 85.1%.
1H?NMR(400MHz，CDCl
3)δ1.57-1.59(m，2H)，1.70-1.73(m，4H)，3.13-3.15(m，4H)，6.80-6.82(m，1H)，6.92-6.94(m，2H)，7.72-7.75(m，2H)。
The preparation of case study on implementation 8 N-4-anisole phenylpiperidines
Change reaction substrate into 187mg (1.0mmol) 4-methoxyl group bromobenzene, all the other experiment conditions and operation obtain white solid 138.9mg, yield 72.7% with embodiment 7.mp?62-65℃。
1H?NMR(400MHz，CDCl
3)δ1.50-1.56(m，2H)，1.69-1.74(m，4H)，3.00-3.03(m，4H)，3.75(s，3H)，6.82(d，J＝9.0Hz，2H)，6.91(d，J＝9.0Hz，2H)。
The preparation of case study on implementation 9 N-4-aminomethyl phenyl piperidines
Change reaction substrate into 171mg (1.0mmol) 4-methyl bromobenzene, all the other experiment conditions and operation obtain yellow liquid 155.4mg, yield 88.3% with embodiment 7.
1H?NMR(400MHz，CDCl
3)δ1.44-1.50(m，2H)，1.60-1.66(m，4H)，2.18(s，3H)，2.99-3.02(m，4H)，6.78(d，J＝8.4Hz，2H)，6.98(d，J＝8.4Hz，2H)。.
The preparation of case study on implementation 10N-2-tolyl piperidines
Change reaction substrate into 171mg (1.0mmol) 2-methyl bromobenzene, all the other experiment conditions and operation obtain yellow liquid 145.7mg, yield 82.8% with embodiment 7.
1H?NMR(400MHz，CDCl
3)δ1.46-1.52(m，2H)，1.60-1.66(m，4H)，2.22(s，3H)，2.74-2.77(m，4H)，6.87-6.89(m，1H)，6.91-6.93(m，1H)，7.05-7.08(m，2H)。
The preparation of case study on implementation 11 N-4-chloro-phenyl-piperidines
Change reaction substrate into 191.5mg (1.0mmol) 4-chloro-bromobenzene, all the other experiment conditions and operation obtain white solid 179.3mg, yield: 91.3% with embodiment 7.mp?62-65℃。1H?NMR(400MHz，CDCl
3)δ1.47-1.53(m，2H)，1.60-1.66(m，4H)，3.03-3.06(m，4H)，6.78(d，J＝8.9Hz，2H)，7.11(d，J＝8.9Hz，2H)。
The preparation of case study on implementation 12 N-4-cyano-phenyl piperidines
Change reaction substrate into 182mg (1.0mmol) 4-cyanic acid bromobenzene, all the other experiment conditions and operation obtain white solid 177.8mg, yield: 91.4% with embodiment 7.mp?43-45℃。
1H?NMR(400MHz，CDCl
3)δ1.56-158(m，6H)，3.24-3.26(m，4H)，6.77(d，J＝9.0Hz，2H)，7.39(d，J＝9.0Hz，2H)。
Claims (10)
1. the preparation method of an aryl morpholine (formula I) or Arylpiperidine (formula II) compound; It is characterized in that described preparing method's key step is: in the presence of phosphorus (phosphine) part of the palladium compound of the simple structure of catalytic amount and simple structure and alkali, by morpholine (formula III) or piperidines (formula IV) respectively with aryl bromide (formula V) in organic solvent; Under the certain temperature; React after 3-10 hour,, obtain aryl morpholine (formula I) or Arylpiperidine (formula II) through column chromatography for separation.
Formula I formula II formula III formula IV formula V
Wherein R is one or more of methyl, methoxyl group, cyanic acid, halogen or hydrogen.
2. preparation method as claimed in claim 1 is characterized in that, described palladium compound is PdCl
2, K
2PdCl
4, Na
2PdCl
4, Pd (OAc)
2, Pd (CH
3CN)
2Cl
2One or more, its consumption is the 0.5-5mol% of formula V compound.
3. preparation method as claimed in claim 1 is characterized in that, described phosphorus (phosphine) part is one or more of triethyl-phosphite, triphenyl phosphite, triphenylphosphine, and its consumption is the 1-10mol% of formula V compound.
4. preparation method as claimed in claim 1 is characterized in that, the consumption of described formula III compound or formula IV compound is 1-3 a times of formula V compound molar weight.
5. preparation method as claimed in claim 1 is characterized in that, described being reflected in the nitrogen atmosphere carried out.
6. preparation method as claimed in claim 1 is characterized in that, described alkali is one or more in sodium tert-butoxide, potassium tert.-butoxide, potassiumphosphate, the sodium hydride, and its consumption is 1-3 a times of formula V compound molar weight.
7. preparation method as claimed in claim 1 is characterized in that, the used organic solvent of described reaction is one or more in toluene, dioxane, the THF.
8. preparation method as claimed in claim 5 is characterized in that, described temperature of in organic solvent, reacting is 25～130 ℃.
9. preparation method as claimed in claim 1 is characterized in that, the time of described reaction is 3-10 hour.
10. preparation method as claimed in claim 1 is characterized in that, after described reaction finished, crude product was purified through column chromatography.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794448A (en) * | 2015-02-11 | 2018-11-13 | 四川科伦药物研究院有限公司 | The preparation method of one koji Ge Lieting and its salt |
-
2011
- 2011-12-07 CN CN2011104038112A patent/CN102532061A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| ANIL S. GURAM，ET AL,: "A Simple Catalytic Method for the Conversion of Aryl Bromides to Arylamines", 《ANGEW. CHEM.INT.ED.ENGL.》 * |
| JANIS LOUIE AND JOHN F. HARTWIG: "Palladium-Catalyzed Synthesis of Arylamines from Aryl Halides. Mechanistic Studies Lead to Coupling in the Absence of Tin Reagents", 《TETRAHEDRON LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794448A (en) * | 2015-02-11 | 2018-11-13 | 四川科伦药物研究院有限公司 | The preparation method of one koji Ge Lieting and its salt |
| CN108794448B (en) * | 2015-02-11 | 2021-01-26 | 四川科伦药物研究院有限公司 | Preparation method of trelagliptin and salt thereof |
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Application publication date: 20120704 |