CN102276601A - Preparation method of indolizine derivative - Google Patents
Preparation method of indolizine derivative Download PDFInfo
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- CN102276601A CN102276601A CN2011101502800A CN201110150280A CN102276601A CN 102276601 A CN102276601 A CN 102276601A CN 2011101502800 A CN2011101502800 A CN 2011101502800A CN 201110150280 A CN201110150280 A CN 201110150280A CN 102276601 A CN102276601 A CN 102276601A
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- indolizine derivative
- indolizine
- pyridine
- alpha
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Abstract
The invention discloses a preparation method of an indolizine derivative. The method comprises the following steps: performing a reflux reaction by glyoxylate alkyl ester, alpha-phenacyl bromide and pyridine which serve as raw materials for 12-24 hours in an organic solvent in the presence of sodium carbonate; and performing washing, extracting, concentrating, column chromatography or recrystallization purification to prepare the indolizine derivative. The method has the advantages of mild reaction conditions, simple process and convenience in operation; and the prepared indolizine derivative has excellent potential biological activity, and can be used as an organic synthetic intermediate.
Description
Technical field
The present invention relates to a kind of preparation method of indolizine derivative.
Background technology
The indolizine analog derivative is a kind of active alkaloid of important biomolecule that has, can be used as the important intermediate of fine chemical product, in fields such as biology, medicine, agricultural chemicals, household chemicals, coating, weaving, printing and dyeing, papermaking, sensitive materials, macromolecular materials purposes is widely arranged, reference is seen
Synthesis 1976, 209; Michael, J. P.
Nat. Prod. Rep. 1995,
5, 535 – 552;
J. Org. Chem.
1996,
61, 2273.Contain indolizine skeleton developing new drug particularly successful be new calcium antagonist Fantofarone Fantofarone as (CAS:114432-13-2) vasodilator.
Particularly when three substituting groups were arranged on the indolizine ring, it just had the inhibition histamine H
3Pharmaceutical activitys such as acceptor, spasmolytic and anti-inflammatory, reference is seen
Bioorg. Med. Chem.
Lett 2003,
13, 1767;
Heterocycles 2001,
54, 185;
ARKIVOC 2002,
2, 30;
Synlett. 2002, 1547;
Arch.Pharm.Chem.Life.Sci. 2006, 339,133.By 1, the cycloaddition of 3-dipole can generate such indolizine compound, and what wherein generated when the pyridine ylide participates in reaction is to contain substituent indolizine compound (reference is seen
Synthesis 2000, 1733;
ARKIVOC 2002,
2, 30,
Perkin. Trans. 1 2001, 1820;
Org. Lett, 2003,
5, 435;
Synthesis 2003, 35;
Org. Lett.
2001,
3, 3297;
J. Med. Chem.
2002,
45, 5458).But because this class cyclisation synthetic reaction conditions requires than higher, Bora etc. have proposed to promote by microwave radiation the novel method of one kettle way reaction, have prepared 1,2, the trisubstituted indolizine derivative of 3-, and reference is seen
Org. Lett, 2003,
5, 435.
Because 1,2, what 3-three replaced the indolizine derivatives has higher biological activity usually, and often can be as the important intermediate of organic synthesis, and therefore the further preparation method efficiently of exploitation indolizine derivative is significant to new medicament screen.
Summary of the invention
The purpose of this invention is to provide a kind of reaction temperature and, the method for preparing the indolizine derivative easy and simple to handle.
The preparation method of indolizine derivative, the steps include: that with oxoethanoic acid alkyl ester, alpha-brominated acetophenone derivs and pyridine be raw material, in the presence of yellow soda ash, back flow reaction is 12～24 hours in organic solvent, through washing and extraction, concentrate, column chromatography or recrystallization purifying process obtain the indolizine derivative; Mol ratio between oxoethanoic acid alkyl ester, alpha-brominated acetophenone derivs, pyridine and the yellow soda ash is 1:2～2.2:2.5:2.5;
Reaction formula is:
In the formula: R
1Be selected from C
1～C
4Alkyl; R
2Be selected from C
1～C
4The aryl of alkyl, aryl or replacement; Substituting group on the aryl of described replacement is H, halogen, C
1～C
4Alkyl or C
1～C
4-oxyl.
Said organic solvent is acetonitrile or ethylene dichloride.
The present invention compares with existing synthetic method, has the following advantages:
1) reaction conditions gentleness;
2) reaction highly versatile;
3) feed intake and aftertreatment all very simple;
4) the reaction starting raw material obtains easily.
Embodiment
Following examples will help to understand the present invention, but be not limited to content of the present invention:
Embodiment 1
Glyoxylic acid ethyl ester (10 mmole), alpha-brominated methyl phenyl ketone (21 mmole), pyridine (25 mmole) are placed reactor, add acetonitrile (20 milliliters), after fully mixing, add yellow soda ash (25 mmole), heating reflux reaction 18 hours, reaction finishes, process washing, ethylene dichloride extraction, organic phase are evaporated to dried, and spissated mixture obtains flaxen indolizine-1 by recrystallization purifying, 3-dibenzoyl-2-ethyl formate, productive rate 61%; The product physical data is m.p. 130 – 131
oC; IR (neat)
ν2977,1709,1603,1487,1420,1383,1223,1052,1020,891,862,793,761,697,654 cm
-1;
1H NMR (400 MHz, CDCl
3) δ 9.53 (d,
J=7.2 Hz, 1 H), 8.15 (d,
J=9.2 Hz, 1 H), 7.69 – 7.67 (m, 4 H), 7.51 – 7.46 (m, 2 H), 7.42 – 7.35 (m, 5 H), 7.11 – 7.08 (m, 1 H), 3.10 (q,
J=7.2 Hz, 2 H), 0.73 (t,
J=7.2 Hz, 3 H) ppm;
13C NMR (100 MHz, CDCl
3) δ 191.12,187.15,164.15,140.20,140.01,138.00,132.18,132.11,130.24,128.65,128.62,128.24,128.21,127.63,127.55,121.00,119.81,116.25,113.28,61.49,13.18 ppm; MS (ESI): m/z ([M+H]
+): 398; HRMS (EI): m/z calcd for (C
25H
19NO
4): 397.1314; Found:397.1317.
Embodiment 2
Glyoxylic acid ethyl ester (10 mmole), alpha-brominated (4-chloro-phenyl-) ethyl ketone (20 mmole), pyridine (25 mmole) are placed reactor, add acetonitrile (20 milliliters), after fully mixing, add yellow soda ash (25 mmole), heating reflux reaction 16 hours, reaction finishes, be evaporated to dried through washing, ethylene dichloride extraction, organic phase, spissated mixture passes through recrystallization purifying, obtain flaxen indolizine-1,3-two (4-chlorobenzene formacyl)-2-ethyl formate, productive rate 63%; The product physical data is m.p. 171 – 172
oC; IR (neat)
ν2987,1727,1617,1586,1491,1423,1382,1219,1080,1052,1013,868,830,776,750,683 cm
-1;
1H NMR (400 MHz, CDCl
3) δ 9.48 (d,
J=7.2 Hz, 1 H), 8.11 (d,
J=9.6 Hz, 1H), 7.64 (dd,
J=8.4,2.0 Hz, 4 H), 7.44 – 7.35 (m, 5 H), 7.14 – 7.10 (m, 1 H), 3.26 (q,
J=7.2 Hz, 2 H), 0.80 (t,
J=7.2 Hz, 3 H) ppm;
13C NMR (100 MHz, CDCl
3) δ 189.63,185.71,164.04,138.66,138.57,138.45,138.23,138.00,130.07,130.00,129.83,128.58,128.57,127.86,127.64,120.81,119.73,116.48,113.05,61.79,13.26 ppm; MS (ESI): m/z ([M+H]
+): 466; HRMS (EI): m/z calcd for (C
25H
17Cl
2NO
4): 465.0535; Found:465.0534.
Embodiment 3
Glyoxylic acid ethyl ester (10 mmole), alpha-brominated-2-butanone (21 mmole), pyridine (25 mmole) are placed reactor, add ethylene dichloride (20 milliliters), after fully mixing, add yellow soda ash (25 mmole), heating reflux reaction 18 hours, reaction finishes, process washing, ethylene dichloride extraction, organic phase are evaporated to dried, and spissated mixture obtains lurid indolizine-1 by recrystallization purifying, 3-two propionyls-2-ethyl formate, productive rate 32%; The product physical data is IR (neat)
ν2979,2938,1728,1643,1492,1427,1383,1232,1180,1160,1113,1056,1020,900,816,761 cm
-1;
1H NMR (400 MHz, CDCl
3) δ 10.05 (d,
J=7.6 Hz, 1 H), 8.39 (d,
J=9.2 Hz, 1 H), 7.47 (t,
J=7.6 Hz, 1 H), 7.47 (t,
J=6.8 Hz, 1 H), 4.55 (q,
J=7.2 Hz, 2 H), 2.91 – 2.85 (m, 4 H), 1.46 (t,
J=7.2 Hz, 3 H), 1.27 – 1.21 (m, 6 H) ppm;
13C NMR (100 MHz, CDCl
3) δ 194.64,191.50,167.90,137.19,129.86,129.36,128.50,120.11,119.77,116.05,112.99,62.71,34.47,33.03,13.87,8.19,7.99 ppm; MS (ESI): m/z ([M+Na]
+): 330; HRMS (EI): m/z calcd for (C
17H
19NO
4): 301.1314; Found:301.1409.
Claims (2)
1. the preparation method of an indolizine derivative, the steps include: that with oxoethanoic acid alkyl ester, alpha-brominated acetophenone derivs and pyridine be raw material, in the presence of yellow soda ash, back flow reaction is 12～24 hours in organic solvent, through washing and extraction, concentrate, column chromatography or recrystallization purifying process obtain the indolizine derivative; Mol ratio between oxoethanoic acid alkyl ester, alpha-brominated acetophenone derivs, pyridine and the yellow soda ash is 1:2～2.2:2.5:2.5;
Reaction formula is:
In the formula: R
1Be selected from C
1～C
4Alkyl; R
2Be selected from C
1～C
4The aryl of alkyl, aryl or replacement; Substituting group on the aryl of described replacement is H, halogen, C
1～C
4Alkyl or C
1～C
4-oxyl.
2. the method for preparing the indolizine derivative according to claim 1 is characterized in that said organic solvent is acetonitrile or ethylene dichloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530442A (en) * | 2018-04-04 | 2018-09-14 | 安徽师范大学 | 1,2,3- tri- replaces Indoli zine derivatives and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101423572A (en) * | 2007-11-01 | 2009-05-06 | 中国石油天然气股份有限公司 | Catalytic component for olefin polymerization and catalyst thereof |
| CN102070503A (en) * | 2010-12-07 | 2011-05-25 | 浙江大学 | Method for preparing pyrrole derivative |
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2011
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101423572A (en) * | 2007-11-01 | 2009-05-06 | 中国石油天然气股份有限公司 | Catalytic component for olefin polymerization and catalyst thereof |
| CN102070503A (en) * | 2010-12-07 | 2011-05-25 | 浙江大学 | Method for preparing pyrrole derivative |
Non-Patent Citations (3)
| Title |
|---|
| 《Bioorganic & Medicinal Chemistry Letters》 20060609 Karim Bedjeguelal, et al. Discovery of protein-protein binding disruptors using multi-component condensations small molecules 3998-4001 1-2 第16卷, * |
| KARIM BEDJEGUELAL, ET AL.: "Discovery of protein–protein binding disruptors using multi-component condensations small molecules", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| UTPAL BORA,ET AL.: "A Novel Microwave-Mediated One-Pot Synthesis of Indolizines via a Three-Component Reaction", 《ORGANIC LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530442A (en) * | 2018-04-04 | 2018-09-14 | 安徽师范大学 | 1,2,3- tri- replaces Indoli zine derivatives and preparation method thereof |
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