CN103193662A - Method for preparing Beta-amino ester through copper-catalyzed three-component coupling reaction - Google Patents
Method for preparing Beta-amino ester through copper-catalyzed three-component coupling reaction Download PDFInfo
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- CN103193662A CN103193662A CN2013101359943A CN201310135994A CN103193662A CN 103193662 A CN103193662 A CN 103193662A CN 2013101359943 A CN2013101359943 A CN 2013101359943A CN 201310135994 A CN201310135994 A CN 201310135994A CN 103193662 A CN103193662 A CN 103193662A
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- amino ester
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- imines
- linked reaction
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- KDXOPXXFGBEPJB-UHFFFAOYSA-N B(C(CC1)C11CC=CC1)c1ccccc1 Chemical compound B(C(CC1)C11CC=CC1)c1ccccc1 KDXOPXXFGBEPJB-UHFFFAOYSA-N 0.000 description 1
- OQTNIRUGJWTMSW-UHFFFAOYSA-N C(C1)C(B2c3ccccc3)C11C2CC1 Chemical compound C(C1)C(B2c3ccccc3)C11C2CC1 OQTNIRUGJWTMSW-UHFFFAOYSA-N 0.000 description 1
- QDIANZRZEUAGPH-UHFFFAOYSA-N CCOC(C(C)(C(C(C)(C)C)NC(OC)=O)c1ccccc1)=O Chemical compound CCOC(C(C)(C(C(C)(C)C)NC(OC)=O)c1ccccc1)=O QDIANZRZEUAGPH-UHFFFAOYSA-N 0.000 description 1
- FQGYIIAXHJMRLC-JXMROGBWSA-N COC(/N=C/c1ccccc1)=O Chemical compound COC(/N=C/c1ccccc1)=O FQGYIIAXHJMRLC-JXMROGBWSA-N 0.000 description 1
- JAKIVOWSQQYYEE-UHFFFAOYSA-N COC(C(C(c1cc2ccccc2cc1)NC(OC)=O)(c1ccccc1)c1ccccc1)=O Chemical compound COC(C(C(c1cc2ccccc2cc1)NC(OC)=O)(c1ccccc1)c1ccccc1)=O JAKIVOWSQQYYEE-UHFFFAOYSA-N 0.000 description 1
- KASWPDSOXKQVOZ-UHFFFAOYSA-N COC(C(c1ccccc1)=N)=O Chemical compound COC(C(c1ccccc1)=N)=O KASWPDSOXKQVOZ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a method for preparing Beta-amino ester through copper-catalyzed three-component coupling reaction. The method is the method for synthesizing the Beta-amino ester with high efficiency and high yield, which successfully realizes efficient catalysis of the three-component coupling reaction by utilizing a plurality of copper salts. The method comprises the following steps of: dissolving 0.005 to 0.10 parts by mol of copper catalyst into 1 to 5mL solvent; adding 0.5 to 10 parts by mol of borane; adding 0.5 to 10 parts by mol of diazoester; finally adding 0.5 to 10 parts by mol of imine; and reacting for 1 to 24 hours at 20 to 40 DEG C, thus obtaining the Beta-amino ester. Compared with the existing method, the method provided by the invention has the advantages of being mild in reaction condition and low in price; and the catalytic system has high yield, product selectivity and diastereoselectivity. Compared with the conventional method, the method provided by the invention greatly increases the yield, decreases the amount of after-treatment steps and shows complete selectivity respect to a Beta-amino ester product.
Description
Technical field
The present invention relates to the technical matters that a kind of copper catalyzed three-component linked reaction prepares the beta-amino ester.
Background technology
Beta-amino ester and deprotection product beta-amino acids thereof are important chemical productss, have biologic medical activity and effect widely.Conventional synthesizing mean need could obtain amino acid and amino ester through multistep, relates to repeatedly post-reaction treatment, to the wasting of resources greatly and discharge a large amount of organic solvents, does not meet the energy-saving and emission-reduction requirement of current country.Therefore, utilize the polycomponent linked reaction, in single reaction vessel the plurality of raw materials coupling is got up, a step forms several new C-Cs, can simplify reaction process, reduces environmental pollution, for realizing that cleaner production is significant.
Though just begin effective polycomponent linked reaction is studied little high-level efficiency, the polycomponent coupling method report of the preparation beta-amino ester that suitability is strong both at home and abroad from the sixties.The polycomponent coupling method extensively exists productive rate low, and selectivity is low, the problem that by product is many.Hooz etc. have reported a kind of method of three component couplings, but this reaction system substrate type applicatory is less, and cis-selectivity is low.Mukaiyama etc. have reported the method for another kind of three component couplings, but this reaction system only can be applicable to the aldehydes substrate, can't be for the synthesis of amino acid and amino ester.All there is the narrow problem of applicable surface in above-mentioned two kinds of polycomponent coupling methods, and in the face of the problem that exists at present, we wish out the polycomponent linked reaction that a class is novel, make it have the productive rate height, selectivity height, advantage such as adaptability is wide.
The present invention is catalyzer with the cupric salt, and with borine, diazonium fat, imines are raw material, successful realization a series of three catalytic linked reactions, and have good cis-selectivity and very high productive rate.
Summary of the invention
One of purpose of the present invention is three component linked reaction methods of new and effective copper catalysis.
Two of purpose of the present invention is the shortcoming that exists at prior art, provides that a kind of catalysts is inexpensive, the method for the synthetic beta-amino ester of mild condition, compatible broad variety substrate.
Success of the present invention with several cupric salts, successfully the catalysis of the efficient catalytic of three component linked reactions three component linked reactions, a kind of synthetic method of efficient high yield of beta-amino ester is provided.Concrete technical scheme of the present invention is as follows: the copper catalyst of 0.005～0.10 molar part is dissolved in the solvent of 1～5mL, the borine that adds 0.5～10 molar part then, the diazo ester that then adds 0.5～10 molar part again, the imines that adds 0.5～10 molar part at last reacts, temperature of reaction is 20～40 ° of C, and the reaction times is that 1～24h obtains the beta-amino ester.
Further, the copper catalyst of 0.005～0.10 molar part is dissolved in the solvent of 1～5mL, adds the borine of 0.5～10 molar part then, slowly add diazo ester then, have a large amount of nitrogen bubble to emerge, treat that bubble stops after, the imines that adds 0.5～10 molar part reacts.
Preferably, the rate of addition of described diazo ester is got 5-20 second/is dripped.
Preferably, described borine and diazo ester add-on are 1:1.
Copper catalyst described in the present invention comprises: cupric chloride, cupric fluoride, cupric nitrate, a kind of in copper sulfate or the copper trifluoromethanesulfcomposite.
Described raw material borine comprises: phenyl-9-boron two ring [3.3.1] nonanes, 4-p-methoxy-phenyl-9-boron two ring [3.3.1] nonanes, styryl-9-boron two ring [3.3.1] nonanes, a kind of in triphenylborane or the boron triethyl.The preferred phenyl of borine in the aforesaid method-9-boron two ring [3.3.1] nonanes.
Described raw material imines comprises: phenyl aldehyde imines, 4-methoxybenzaldehyde imines, 4-fluorobenzaldehyde imines, a kind of in tertiary butyl imines or the 2-naphthaldehyde imines.Solvent comprises methylene dichloride, trichloromethane, toluene, tetrahydrofuran (THF), acetonitrile.Described raw material diazo ester comprises: phenyl ethyl diazoacetate, phenyl diazoacetic acid methyl esters, 4-p-methoxy-phenyl diazoacetic acid methyl esters, 4-fluorophenyl diazoacetic acid methyl esters, a kind of in methyl ethyl diazoacetate or the ethyl ethyl diazoacetate.
Compare with prior art, the present invention has following useful result:
1, the present invention utilizes the synthetic beta-amino acids of three component linked reactions and amino ester, compares with traditional method, has significantly improved productive rate, has reduced the step number of aftertreatment.
2, the present invention has selectivity of product completely for beta-amino acids and amino ester product.
Embodiment
Embodiment 1
Phenyl-9-boron two of 0.5mmol is encircled the copper trifluoromethanesulfcomposite catalyst dissolution of [3.3.1] nonanes and 0.005mmol among the methylene dichloride of 1mL, the phenyl diazo ester that slowly adds 0.5mmol then, can observe a large amount of nitrogen bubble emerges, after bubble stops, the phenyl aldehyde imines that adds 0.5mmol, in reaction flask, mix, remain on 25 ° of C of room temperature, reaction times 12h.Above-mentioned reaction formula is as follows:
Reaction product is separated by chromatography column, and proton nmr spectra detects purity, and the transformation efficiency of beta-amino ester is 85%, and selectivity of product is 99%.
Embodiment 2
The bluestone catalyst of the triphenylborane of 0.5mmol and 0.01mmol is dissolved among the toluene of 2mL, the phenyl diazo ester that slowly adds 0.6mmol then, can observe a large amount of nitrogen bubble emerges, after bubble stops, the naphthaldehyde imines that adds 0.6mmol, in reaction flask, mix, remain on 25 ° of C of room temperature, reaction times 12h.Above-mentioned reaction formula is as follows:
Reaction product is separated by chromatography column, and proton nmr spectra detects purity, and the transformation efficiency of beta-amino ester is 89%, and selectivity of product is 99%.
Embodiment 3
Phenyl-9-boron two of 1mmol is encircled the copper trifluoromethanesulfcomposite catalyst dissolution of [3.3.1] nonanes and 0.015mmol among the tetrahydrofuran (THF) of 3mL, the methyl diazo ester that slowly adds 1.2mmol then, can observe a large amount of nitrogen bubble emerges, after bubble stops, the tertiary butyl imines that adds 1.2mmol, in reaction flask, mix, remain on 25 ° of C of room temperature, reaction times 12h.Above-mentioned reaction formula is as follows:
Reaction product is separated by chromatography column, and proton nmr spectra detects purity, and the transformation efficiency of beta-amino ester is 82%, and selectivity of product is 99%, and cis-selectivity is 99%.
Claims (10)
1. a copper catalyzed three-component linked reaction prepares the method for beta-amino ester, it is characterized in that, comprise the steps: the copper catalyst of 0.005 ~ 0.10 molar part is dissolved in the solvent of 1 ~ 5mL, the borine that adds 0.5 ~ 10 molar part then, the diazo ester that then adds 0.5 ~ 10 molar part again, the imines that adds 0.5 ~ 10 molar part at last reacts, and temperature of reaction is 20 ~ 40
oC, the reaction times is that 1 ~ 24 h obtains the beta-amino ester.
2. prepare the method for beta-amino ester according to claim 1 copper catalyzed three-component linked reaction, it is characterized in that described copper catalyst is cupric chloride, cupric fluoride, cupric nitrate, a kind of in copper sulfate or the copper trifluoromethanesulfcomposite.
3. the method for preparing the beta-amino ester according to claim 1 copper catalyzed three-component linked reaction, it is characterized in that, described raw material borine comprises: phenyl-9-boron two ring [3.3.1] nonanes, 4-p-methoxy-phenyl-9-boron two ring [3.3.1] nonanes, styryl-9-boron two ring [3.3.1] nonanes, a kind of in triphenylborane or the boron triethyl.
4. prepare the method for beta-amino ester according to claim 3 copper catalyzed three-component linked reaction, it is characterized in that, described borine is phenyl-9-boron two ring [3.3.1] nonanes.
5. prepare the method for beta-amino ester according to claim 1 copper catalyzed three-component linked reaction, it is characterized in that described raw material imines comprises: the phenyl aldehyde imines, 4-methoxybenzaldehyde imines, 4-fluorobenzaldehyde imines, tertiary butyl imines, a kind of in the 2-naphthaldehyde imines.
6. prepare the method for beta-amino ester according to claim 1 copper catalyzed three-component linked reaction, it is characterized in that described solvent comprises methylene dichloride, trichloromethane, toluene, tetrahydrofuran (THF), a kind of in the acetonitrile.
7. the method for preparing the beta-amino ester according to claim 1 copper catalyzed three-component linked reaction, it is characterized in that, described diazo ester comprises: the phenyl ethyl diazoacetate, phenyl diazoacetic acid methyl esters, 4-p-methoxy-phenyl diazoacetic acid methyl esters, 4-fluorophenyl diazoacetic acid methyl esters, methyl ethyl diazoacetate, a kind of in the ethyl ethyl diazoacetate.
8. the method for preparing the beta-amino ester according to the copper catalyzed three-component linked reaction described in claim 1 or 2 or 3 or 5 or 6 or 7, it is characterized in that, the copper catalyst of 0.005 ~ 0.10 molar part is dissolved in the solvent of 1 ~ 5mL, the borine that adds 0.5 ~ 10 molar part then, slowly add diazo ester then, have a large amount of nitrogen bubble to emerge, treat that bubble stops after, the imines that adds 0.5 ~ 10 molar part reacts.
9. the copper catalyzed three-component linked reaction described in according to Claim 8 prepares the method for beta-amino ester, it is characterized in that, the rate of addition of described diazo ester is got 5-20 second/dripped.
10. the copper catalyzed three-component linked reaction described in according to Claim 8 prepares the method for beta-amino ester, it is characterized in that described borine and diazo ester add-on are 1:1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050107633A1 (en) * | 2001-12-21 | 2005-05-19 | Michel Vaultier | (Aryl)(amino) borane compounds, method for preparing same |
| CN101531606A (en) * | 2009-04-13 | 2009-09-16 | 华东师范大学 | Method for synthesizing alpha-alkoxyl-beta-amino ester derivative |
| CN102153488A (en) * | 2011-02-14 | 2011-08-17 | 华东师范大学 | Alpha,beta-diamino acid derivative, synthetic method thereof and application thereof |
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2013
- 2013-04-18 CN CN2013101359943A patent/CN103193662A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050107633A1 (en) * | 2001-12-21 | 2005-05-19 | Michel Vaultier | (Aryl)(amino) borane compounds, method for preparing same |
| CN101531606A (en) * | 2009-04-13 | 2009-09-16 | 华东师范大学 | Method for synthesizing alpha-alkoxyl-beta-amino ester derivative |
| CN102153488A (en) * | 2011-02-14 | 2011-08-17 | 华东师范大学 | Alpha,beta-diamino acid derivative, synthetic method thereof and application thereof |
Non-Patent Citations (6)
| Title |
|---|
| 《Organic Letters》 20110407 Luan Yi等 "Multicomponent Mannich Reactions with Boron Enolates Derived from Diazo Esters and 9-BBN" 第2510-2513页, Table 4, Supporting Information 1-10 第13卷, 第9期 * |
| 《Tetrahedron Letters》 19831231 John Hooz等 "A New Regio- and Stereocontrolled Synthesis of Enol Silyl Ethers" 第5695-5698页 1-10 第24卷, 第51期 * |
| 《Tetrahedron Letters》 20110806 Pavel K. Elkin等 "Reactions of CF3-substituted boranes with alpha-diazocarbonyl compounds" 第5259-5263页 1-10 第52卷, 第41期 * |
| JOHN HOOZ等: ""A New Regio- and Stereocontrolled Synthesis of Enol Silyl Ethers"", 《TETRAHEDRON LETTERS》 * |
| LUAN YI等: ""Multicomponent Mannich Reactions with Boron Enolates Derived from Diazo Esters and 9-BBN"", 《ORGANIC LETTERS》 * |
| PAVEL K. ELKIN等: ""Reactions of CF3-substituted boranes with α-diazocarbonyl compounds"", 《TETRAHEDRON LETTERS》 * |
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Application publication date: 20130710 |