CN102276601B - Preparation method of indolizine derivative - Google Patents
Preparation method of indolizine derivative Download PDFInfo
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- CN102276601B CN102276601B CN201110150280A CN201110150280A CN102276601B CN 102276601 B CN102276601 B CN 102276601B CN 201110150280 A CN201110150280 A CN 201110150280A CN 201110150280 A CN201110150280 A CN 201110150280A CN 102276601 B CN102276601 B CN 102276601B
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- pyrrocoline
- preparation
- verivate
- 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 pyrrocoline verivate.
Background technology
The pyrrocoline analog derivative is a kind of active vegeto-alkali 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 pyrrocoline skeleton developing new drug particularly successful be new calcium antagonist SR-33557 Fantofarone as (CAS:114432-13-2) vasodilator.
Particularly when three substituting groups were arranged on the pyrrocoline 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.Through 1, the cycloaddition of 3-dipole can generate such pyrrocoline compound, and what wherein when the pyridine ylide is participated in reaction, generated is to contain substituent pyrrocoline 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 type cyclisation synthetic reaction conditions requires than higher, Bora etc. have proposed to promote through microwave radiation the novel method of one kettle way reaction, have prepared 1,2, the trisubstituted pyrrocoline verivate of 3-, and reference is seen
Org. Lett, 2003,
5, 435.
Because 1,2, what 3-three replaced the pyrrocoline verivates 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 pyrrocoline verivate 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 pyrrocoline verivate easy and simple to handle.
The preparation method of pyrrocoline verivate; 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 pyrrocoline verivate; 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
4Alkyl, aryl or substituted aryl; Substituting group on the said substituted aryl 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 compound method, has the following advantages:
1) reaction conditions is gentle;
2) reaction highly versatile;
3) feed intake with 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
Place reaction kettle to glyoxylic acid ethyl ester (10 mmole), alpha-brominated methyl phenyl ketone (21 mmole), pyridine (25 mmole), 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 pyrrocoline-1 through 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
Place reaction kettle to glyoxylic acid ethyl ester (10 mmole), alpha-brominated (4-chloro-phenyl-) ethyl ketone (20 mmole), pyridine (25 mmole), add acetonitrile (20 milliliters), after fully mixing; Add yellow soda ash (25 mmole); Heating reflux reaction 16 hours, reaction finishes, and is evaporated to dried through washing, ethylene dichloride extraction, organic phase; Spissated mixture passes through recrystallization purifying; Obtain flaxen pyrrocoline-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
Place reaction kettle to glyoxylic acid ethyl ester (10 mmole), alpha-brominated-2-butanone (21 mmole), pyridine (25 mmole), 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 pyrrocoline-1 through recrystallization purifying; 3-two propionyl groups-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 a pyrrocoline verivate; 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, extraction, concentrated, and utilizes column chromatography or recrystallization purifying process to obtain the pyrrocoline verivate; 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 phenyl or substituted phenyl; Substituting group on the said substituted phenyl is halogen, C
1～C
4Alkyl or C
1～C
4-oxyl.
2. the preparation method of pyrrocoline verivate according to claim 1 is characterized in that said organic solvent is acetonitrile or ethylene dichloride.
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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 | Catalyst 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 | Catalyst 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 (5)
| Title |
|---|
| A Novel Microwave-Mediated One-Pot Synthesis of Indolizines via a Three-Component Reaction;Utpal Bora,et al.;《Organic Letters》;20030123;第5卷(第4期);435-438 * |
| Karim Bedjeguelal, et al..Discovery of protein–protein binding disruptors using multi-component condensations small molecules.《Bioorganic & Medicinal Chemistry Letters》.2006,第16卷3998–4001. |
| Karim Bedjeguelal, et al..Discovery of protein–protein binding disruptors using multi-component condensations small molecules.《Bioorganic & * |
| Medicinal Chemistry Letters》.2006,第16卷3998–4001. * |
| Utpal Bora,et al..A Novel Microwave-Mediated One-Pot Synthesis of Indolizines via a Three-Component Reaction.《Organic Letters》.2003,第5卷(第4期),435-438. |
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