CN102766092A - Method for synthesizing optically active tetrahydroquinoline derivative in presence of chiral spiro phosphoric acid serving as catalyst - Google Patents
Method for synthesizing optically active tetrahydroquinoline derivative in presence of chiral spiro phosphoric acid serving as catalyst Download PDFInfo
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- CN102766092A CN102766092A CN2012102443363A CN201210244336A CN102766092A CN 102766092 A CN102766092 A CN 102766092A CN 2012102443363 A CN2012102443363 A CN 2012102443363A CN 201210244336 A CN201210244336 A CN 201210244336A CN 102766092 A CN102766092 A CN 102766092A
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- phosphoric acid
- optically active
- chiral spiro
- tetrahydroquinoline derivative
- alkyl
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Abstract
The invention discloses a method for synthesizing an optically active tetrahydroquinoline derivative in the presence of chiral spiro phosphoric acid serving as a catalyst. The method comprises the following steps of: reacting raw materials such as aldehyde, arylamine and N-carbobenzoxy vinylamine in an organic solvent in the presence of the chiral spiro phosphoric acid serving as the catalyst at the temperature of -30 to 50 DEG C for 1 to 5 hours, separating, and purifying to obtain the optically active tetrahydroquinoline derivative. Reaction conditions are mild, and the method is simple and is convenient to operate; and the obtained optically active tetrahydroquinoline derivative has high potential bioactivity and can be used as an intermediate of medicine synthesis.
Description
Technical field
The present invention relates to a kind of method of chiral spiro phosphoric acid catalyzed synthesis of optically active tetrahydroquinoline derivative, belong to the synthetic field of nitrogenous heterocyclic chirality.
Background technology
The optical activity tetrahydroquinoline derivative is a kind of active heterocycle of important biomolecule that has, and can be used as the important intermediate of pharmaceutical prod, also is present in some high-activity natural products, referring to (Tetrahedron, 1996,52,15031; Chem.Rev., 2011,111,7157).
Through asymmetric Povarov method synthesis of optically active tetrahydroquinoline derivative is one of classic methods; Recently some bibliographical informations various chiral catalysts can catalytic preparation optical activity tetrahydroquinoline derivatives; Referring to (Tetrahedron Lett.1996,37,7357; Org.Lett.2001,3,1973; Science, 2010,327,986; Angew.Chem., Int.Ed., 2010,49,3799; Angew.Chem., Int.Ed., 2011,50,1580; Chem.Eur.J., 2011,17,13800 J.Am.Chem.Soc., 2006,128,13070; J.Am.Chem.Soc., 2009,131,4598; J.Am.Chem.Soc., 2011,133,14804; Chem.Commun., 2010,46,327; Chem.Eur.J., 2012,18,5869; Org.Lett., 2012,14,3158; Chem.Commun., 2012,48,7738).These methods all relate to asymmetry catalysis, and the effect of catalyzer seriously relies on substrate in the asymmetric synthesis.Because present method substrate use range is narrow, uses some substrate, enantioselectivity is high not enough, and the therefore further preparation method of the high enantioselectivity efficiently of exploitation optical activity tetrahydroquinoline derivative is significant to new medicament screen etc.
Summary of the invention
The method that the purpose of this invention is to provide a kind of reaction temperature and, easy and simple to handle, chiral spiro phosphoric acid catalyzed synthesis of optically active tetrahydroquinoline derivative that enantioselectivity is high.
A kind of method of tetrahydroquinoline derivative of chiral spiro phosphoric acid catalyzed synthesis of optically active; It is characterized in that with aldehyde, arylamine and N-carbobenzoxy-(Cbz) vinyl-amine be raw material, is catalyzer with chiral spiro phosphoric acid, in organic solvent; Under the nitrogen protection; After 1～5 hour, obtain optically active tetrahydroquinoline derivative through the separation and purification process-30～50 ℃ of reactions, the mol ratio of described aldehyde, arylamine and N-carbobenzoxy-(Cbz) vinyl-amine is 1:1:1～1.2;
Reaction formula is:
In the formula: R
1Be selected from C
3～C
10Alkyl, benzyl, aryl or substituted aryl, heteroaryl, the substituting group on the said substituted aryl is halogen, nitro, trifluoromethyl, C
1～C
4Alkyl or C
1～C
4-oxyl in 1 or 2; R
2Be selected from hydrogen, halogen, trifluoromethyl, C
1～C
4Alkyl or C
1～C
4-oxyl.
The above-mentioned chiral spiro phosphoric acid catalyst and the mol ratio of aldehyde are 1～15:100, and described chiral spiro phosphoric acid catalyst is levo form or the dextrorotatory form with compound of structural formula (1):
Formula (1),
In the formula: R is selected from C
3～C
10Alkyl, benzyl, naphthyl, anthryl, aryl or substituted aryl, the substituting group on the said substituted aryl is halogen, nitro, trifluoromethyl, C
1～C
4Alkyl or C
1～C
4-oxyl in 1～3.
Described organic solvent is methylene dichloride, chloroform, 1,2-ethylene dichloride, acetonitrile, THF, toluene or YLENE.
The present invention compares with existing compound method, has the following advantages:
1) reaction conditions is gentle;
2) reaction highly versatile, particularly alkanoic participated in this reaction and also can be obtained fabulous selectivity;
3) enantioselectivity is high.
Embodiment
Following examples will help to understand the present invention, but be not limited to content of the present invention:
Embodiment 1
Under nitrogen protection, at room temperature, 0.1 mmole p-bromobenzaldehyde, 0.1 mmole P-nethoxyaniline, 0.01 mmole (S)-O; O '-{ 7; 7 '-[6,6 '-two-(4-chloro-phenyl-)-1, the two dihydro indenes of 1 '-spiral shell] } phosphoric acid catalyst (1e) and 0.11 mmole N-carbobenzoxy-(Cbz) vinyl-amine are blended in 1 milliliter of dichloromethane solvent successively; React and finish after 1 hour to react to carry out aftertreatment; Obtain optical activity (2S, tetrahydroquinoline derivative 5a 4S), productive rate 88% through the silica-gel powder column chromatography.It is 96%ee that the product optical purity is measured with HPLC.White?solid;m.p.175-177°C;86%?yield;cis:trans>20:1;>96%ee,determined?by?HPLC[Daicel?Chiralcel?OD-H,n-hexane/i-propanol=70/30,1.0mL/min,λ=?254nm,t(major)=18.120min,t(minor)=23.121min].[á]
D 20=-15.4°(c=0.8,CHCl
3);
41HNMR(500MHz,CDCl
3)δ1.80(q,J＝14.5Hz,1H),2.37-2.41(m,1H),3.69(s,3H),3.78(br,1H),4.45(d,J＝12.0Hz,1H),4.94(d,J＝11.5Hz,1H),5.13-5.20(m,3H),6.50(d,J＝11.5Hz,1H),6.67(dd,J1=3.0Hz,J2=10.5Hz,1H),6.78(d,J＝2.0Hz,1H),7.26-7.36(m,7H),7.46(d,J＝10.5Hz,2H);MS(ESI)m/z?466.8([M+H]
+).
Product structure is:
Embodiment 2～8
Like embodiment 1 process that feeds intake, the structure of its hts catalyst can obtain the experimental result of table 1.
Table 1
Embodiment 9～16
Like embodiment 1 process that feeds intake, wherein change organic solvent or temperature of reaction or catalyst levels, can obtain the experimental result of table 2.
Table 2
Embodiment 17～32
Like embodiment 1 process that feeds intake, wherein change reaction substrate, temperature of reaction is-20 degree, and catalyst levels is 5%, and the reaction times follows the tracks of with TLC, can obtain the experimental result of table 3:
Claims (3)
1. the method for the tetrahydroquinoline derivative of a chiral spiro phosphoric acid catalyzed synthesis of optically active; It is characterized in that with aldehyde, arylamine and N-carbobenzoxy-(Cbz) vinyl-amine be raw material, is catalyzer with chiral spiro phosphoric acid, in organic solvent; Under the nitrogen protection; After 1～5 hour, obtain optically active tetrahydroquinoline derivative through the separation and purification process-30～50 ℃ of reactions, the mol ratio of described aldehyde, arylamine and N-carbobenzoxy-(Cbz) vinyl-amine is 1:1:1～1.2;
Reaction formula is:
In the formula: R
1Be selected from C
3～C
10Alkyl, benzyl, aryl or substituted aryl, heteroaryl, the substituting group on the said substituted aryl is halogen, nitro, trifluoromethyl, C
1～C
4Alkyl or C
1～C
4-oxyl in 1 or 2; R
2Be selected from hydrogen, halogen, trifluoromethyl, C
1～C
4Alkyl or C
1～C
4-oxyl.
2. the method for chiral spiro phosphoric acid catalyzed synthesis of optically active tetrahydroquinoline derivative according to claim 1; The mol ratio that it is characterized in that described chiral spiro phosphoric acid catalyst and aldehyde is 1～15:100, and described chiral spiro phosphoric acid catalyst is levo form or the dextrorotatory form with compound of structural formula (1):
Formula (1),
In the formula: R is selected from C
3～C
10Alkyl, benzyl, naphthyl, anthryl, aryl or substituted aryl, the substituting group on the said substituted aryl is halogen, nitro, trifluoromethyl, C
1～C
4Alkyl or C
1～C
4-oxyl in 1～3.
3. the method for chiral spiro phosphoric acid catalyzed synthesis of optically active tetrahydroquinoline derivative according to claim 1 is characterized in that described organic solvent is methylene dichloride, chloroform, 1,2-ethylene dichloride, acetonitrile, THF, toluene or YLENE.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420921A (en) * | 2013-08-07 | 2013-12-04 | 浙江大学 | Method for synthesizing optically-active 2,3-dihydro quinazolinone derivative by using chiral spiro phosphoric acid as catalyst |
| CN104710429A (en) * | 2015-02-04 | 2015-06-17 | 浙江大学 | Method for chiral spirocyclic phosphoric acid catalyzed synthesis of optically active quinoxaline derivative |
| CN105001159A (en) * | 2014-04-23 | 2015-10-28 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by chiral phosphoric acid |
| CN107033037A (en) * | 2017-04-27 | 2017-08-11 | 江西师范大学 | Asymmetric synthesis method of optical pure terpene alkaloid analogue catalyzed by chiral acid |
| CN111468183A (en) * | 2019-11-25 | 2020-07-31 | 天津大学 | Polyfluoro triaryl chiral spiro phosphoric acid catalyst, and preparation method and application thereof |
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| CN101466679A (en) * | 2006-03-30 | 2009-06-24 | 田边三菱制药株式会社 | A process for preparing tetrahydroquinoline derivatives |
| KR20100010229A (en) * | 2008-07-22 | 2010-02-01 | 영남대학교 산학협력단 | A novel method for preparing tetrahydroquinolines from 1,3-dicarbonyls |
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| CN101466679A (en) * | 2006-03-30 | 2009-06-24 | 田边三菱制药株式会社 | A process for preparing tetrahydroquinoline derivatives |
| KR20100010229A (en) * | 2008-07-22 | 2010-02-01 | 영남대학교 산학협력단 | A novel method for preparing tetrahydroquinolines from 1,3-dicarbonyls |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420921A (en) * | 2013-08-07 | 2013-12-04 | 浙江大学 | Method for synthesizing optically-active 2,3-dihydro quinazolinone derivative by using chiral spiro phosphoric acid as catalyst |
| CN105001159A (en) * | 2014-04-23 | 2015-10-28 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by chiral phosphoric acid |
| CN105001159B (en) * | 2014-04-23 | 2017-11-21 | 中国科学院大连化学物理研究所 | A kind of method of the outer amine of chiral phosphoric acid catalysis quinoline 3 amine asymmetric transfer hydrogenation synthesis of chiral ring |
| CN104710429A (en) * | 2015-02-04 | 2015-06-17 | 浙江大学 | Method for chiral spirocyclic phosphoric acid catalyzed synthesis of optically active quinoxaline derivative |
| CN104710429B (en) * | 2015-02-04 | 2017-02-22 | 浙江大学 | Method for chiral spirocyclic phosphoric acid catalyzed synthesis of optically active quinoxaline derivative |
| CN107033037A (en) * | 2017-04-27 | 2017-08-11 | 江西师范大学 | Asymmetric synthesis method of optical pure terpene alkaloid analogue catalyzed by chiral acid |
| CN111468183A (en) * | 2019-11-25 | 2020-07-31 | 天津大学 | Polyfluoro triaryl chiral spiro phosphoric acid catalyst, and preparation method and application thereof |
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Application publication date: 20121107 |