CN110283167A - A kind of preparation method of antiarrhythmic Agents Bu Tuopuluo piperazine - Google Patents
A kind of preparation method of antiarrhythmic Agents Bu Tuopuluo piperazine Download PDFInfo
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- CN110283167A CN110283167A CN201811351026.5A CN201811351026A CN110283167A CN 110283167 A CN110283167 A CN 110283167A CN 201811351026 A CN201811351026 A CN 201811351026A CN 110283167 A CN110283167 A CN 110283167A
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- compound
- tuopuluo
- piperazine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a kind of preparation methods of antiarrhythmic Agents molecule Bu Tuopuluo piperazine, comprising: (1) synthesizes compound II with pyridine, alpha-brominated acetanisole and amylene-4 acid methyl ester；(2) compound II progress de-ester reaction is obtained into compound III；(3) compound III progress demethylating reaction is obtained into compound IV；(4) by compound IV withN(3- chloropropyl) dibutylamine carries out nucleophilic substitution under alkaline condition and obtains compound I Bu Tuopuluo piperazine.Easily operated provided by the present invention for the preparation method of Bu Tuopuluo piperazine, side reaction is few, and yield is high, and practicability is stronger.
Description
Technical field
The invention belongs to pharmaceutical synthesis field more particularly to a kind of synthetic methods of Bu Tuopuluo piperazine.
Background technique
Bu Tuopuluo piperazine (Butoprozine) is a kind of drug molecule for treating arrhythmia cordis, and core skeleton structure is
Indolizine.Existing method synthesizes the drug molecule and needs to react by nitrogen ylide at salt, condensation cyclization, benzoylation, removes sulphur
Acyl group, monocyclopropanated and ammonification and etc. (US patent 4103012A).The present invention is obtained in acyl group using three component reactions
Benzazole skeleton structure, and Bu Tuopuluo piperazine molecule is obtained by the reaction of degreasing base, demethylating reaction and nucleophilic substitution.This
Preparation method of the invention for Bu Tuopuluo piperazine is easily operated, and side reaction is few, and yield is high, and practicability is stronger.
Summary of the invention
The present invention provides a kind of preparation methods of Bu Tuopuluo piperazine, comprising: (1) by pyridine, alpha-brominated to methoxybenzene
Ethyl ketone and amylene-4 acid methyl ester react to obtain compound II；(2) it reacts compound II progress degreasing base to obtain compound III；(3)
Compound III progress demethylation reaction is obtained into compound IV；(4) by compound IV withN(3- chloropropyl) dibutylamine
Reaction obtains Bu Tuopuluo piperazine compound I.
The Bu Tuopuluo piperazine is as shown in the formula (I):
(I)
The compound II structure is as shown in the formula (II):
(II)
The compound III structure is as shown in the formula (III):
(III)
The compound IV structure is as shown in formula (IV)
(IV)
The synthesis of compound II.Pyridine (0.4 mmol), alpha-brominated acetanisole (0.4 mmol), amylene-4 acid methyl ester
(0.2 mmol), Salicylaldoxime (0.6 mmol), potassium phosphate (0.8 mmol) are dissolved in 1 mLN, NSolvent dimethylformamide
In, 100oIt is reacted 12 hours under C.Saturated sodium chloride solution is added after the reaction was completed, then is extracted with ethyl acetate 3 times.Merge
It is dry with anhydrous sodium sulfate after organic layer, it is yellow that compound II is obtained by column chromatography for separation (petroleum ether: ethyl acetate 20:1)
Color liquid, yield 75%.1H NMR (400 MHz, Chloroform-d) δ 9.06 (d, J = 7.0 Hz, 1H),
8.30 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 8.0 Hz, 1H),
6.96 (d, J = 8.7 Hz, 2H), 6.85 (t, J = 6.8 Hz, 1H), 3.92 (s, 3H), 3.88 (s,
3H), 2.79 (q, J = 7.3 Hz, 2H), 1.02 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 187.30, 165.34, 163.24, 142.72, 139.39, 133.20, 131.50, 127.71,
126.27, 122.52, 119.69, 113.93, 113.90, 103.58, 55.62, 51.01, 20.06, 16.09.
LRMS (ESI) m/z (%) 360 (80) [M + Na]+, 697 (100) [2M+Na]+。
The synthesis of compound III.By compound II(0.3mmol), Salicylaldoxime (0.3mol), 1,10 Phens
(0.3 mmol), quinoline (0.3 mmol), NMP(0.9 mmol) it is added in sealing reaction tube, 180oC reaction is 15 small
When.Dilute hydrochloric acid solution is added after the reaction was completed, is then extracted with ethyl acetate 2-3 times, uses anhydrous sodium sulfate after merging organic layer
It is dry, compound III yellow liquid, yield 56% are obtained by column chromatography for separation (petroleum ether: ethyl acetate 20:1).1H
NMR (600 MHz, Chloroform-d) δ 9.47 (d, J = 7.1 Hz, 1H), 7.68 – 7.61 (m, 2H),
7.42 (d, J = 8.8 Hz, 1H), 7.05 (ddd, J = 8.8, 6.7, 1.1 Hz, 1H), 6.95 (d, J =
8.7 Hz, 2H), 6.74 (t, J = 6.3 Hz, 1H), 6.40 (s, 1H), 3.88 (s, 3H), 2.36 (q, J
= 7.5 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.02,
162.26, 141.08, 134.45, 130.90, 129.73, 128.21, 123.52, 117.92, 115.47,
113.70, 112.60, 102.54, 55.54, 22.01, 15.02. LRMS (ESI) m/z (%) 302 (35) [M +
Na]+, 581 (100) [2M+Na]+。
The synthesis of compound IV.Compound III(0.2mmol) is dissolved in methylene chloride (0.3mmol), 0oIt is dripped under C
Add Boron tribromide (0.9 mmol).Temperature is slowly increased to room temperature, ice water quenching reaction is added after the reaction was completed, adds saturation
Sodium chloride solution.It is extracted with ethyl acetate 2-3 times, it is dry with anhydrous sodium sulfate after merging organic layer, pass through column chromatography for separation (stone
Oily ether: ethyl acetate 5:1) obtain compound IV yellow solid, yield 95%.1H NMR (600 MHz, Methanol-d4)
δ 9.36 (d, J = 7.0 Hz, 1H), 7.53 – 7.49 (m, 3H), 7.13 (ddd, J = 8.8, 6.7, 1.1
Hz, 1H), 6.90 – 6.87 (m, 2H), 6.82 (td, J = 6.9, 1.4 Hz, 1H), 6.48 (s, 1H),
3.32 (p, J = 1.7 Hz, 4H), 2.38 (q, J = 7.5 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H).13C NMR (151 MHz, MeOD4) δ 187.91, 162.31, 142.85, 139.86, 134.00, 132.02,
128.90, 124.97, 122.18, 119.17, 116.19, 113.80, 104.03, 22.86, 15.36. LRMS
(ESI) m/z (%) 288 (36) [M + Na]+, 553 (100) [2M+Na]+。
The synthesis of compound I Bu Tuopuluo piperazine.By compound IV(0.1mmol), potassium carbonate (0.1mmol) andN,NDiformazan
Base formamide is added in sealing reaction tube.Reaction half an hour is stirred at room temperature, then adds potassium iodide (0.02
Mmol),N(3- chloropropyl) dibutylamine (0.15 mmol), in 150oIt is reacted under C.Unsaturated carbonate is added after the reaction was completed
Hydrogen sodium, it is dry with anhydrous sodium sulfate after merging organic layer after being extracted with ether, pass through column chromatography for separation (petroleum ether: ethyl acetate
Compound I Bu Tuopuluo piperazine yellow liquid, yield 65% are obtained for 10:1).1H NMR (600 MHz, Chloroform-d) δ
9.44 (d, J = 7.1 Hz, 1H), 7.63 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H),
7.05 – 7.01 (m, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.73 (t, J = 6.3 Hz, 1H), 6.39
(s, 1H), 4.09 (t, J = 6.3 Hz, 2H), 2.63 (t, J = 7.1 Hz, 2H), 2.46 – 2.43 (m,
4H), 2.37 (t, J = 7.5 Hz, 2H), 1.95 (p, J = 6.5 Hz, 2H), 1.46 – 1.40 (m, 4H),
1.30 (h, J = 7.5 Hz, 6H), 1.08 (t, J = 7.5 Hz, 3H), 0.90 (t, J = 7.3 Hz, 6H).13C NMR (151 MHz, CDCl3) δ 186.05, 161.85, 140.87, 137.94, 134.26, 130.91,
128.14, 123.35, 121.27, 117.91, 114.17, 112.50, 102.40, 66.50, 54.05, 50.51,
29.29,27.09,21.99,20.85,15.03,14.22.LRMS(ESI)m/z(%)435(100)[M+H]+。
Claims (5)
1. a kind of preparation method of antiarrhythmic drug molecule Bu Tuopuluo piperazine characterized by comprising (1) with pyridine, α-
Bromo acetanisole and amylene-4 acid methyl ester are Material synthesis compound II；(2) compound II is subjected to de-ester reaction
Obtain compound III；(3) compound III progress demethylating reaction is obtained into compound IV；(4) by compound IV withN(3-
Chloropropyl) dibutylamine carries out nucleophilic substitution under alkaline condition and obtains compound I Bu Tuopuluo piperazine.
2. Bu Tuopuluo piperazine described in is as shown in the formula (I):
(I)
The compound II structure is as shown in the formula (II):
(II)
The compound III structure is as shown in the formula (III):
(III)
The compound IV structure is as shown in formula (IV)
(IV)
The preparation method of Bu Tuopuluo piperazine according to claim 1, which is characterized in that with pyridine, alpha-brominated to methoxyl group
Acetophenone and amylene-4 acid methyl ester existN,NDimethylformamide is as solvent, temperature 100oCompound II is synthesized under C.
3. the preparation method of Bu Tuopuluo piperazine according to claim 1, which is characterized in that compound II existsNMethylpyrrole
Alkanone is as solvent, temperature 180oCompound III is synthesized under C.
4. the preparation method of Bu Tuopuluo piperazine according to claim 1, which is characterized in that compound III is in methylene chloride
As solvent, temperature 0oIt reacts to obtain compound IV with Boron tribromide under C.
5. the preparation method of Bu Tuopuluo piperazine according to claim 1, which is characterized in that compound IV is in potassium carbonate and iodine
In the presence of changing potassium,N,NDimethylformamide is as solvent, temperature 150oBu Tuopuluo piperazine is synthesized under C.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4103012A (en) * | 1976-02-19 | 1978-07-25 | Labaz | Indolizine derivatives, pharmaceutical compositions and methods containing same |
| US4400387A (en) * | 1979-07-06 | 1983-08-23 | S. A. Labaz-Sanofi N.V. | Indolizine derivatives and uses in therapeutics |
| CN102093355A (en) * | 2011-02-09 | 2011-06-15 | 浙江大学 | C-3 acylated indolizine compound and preparation method thereof |
| CN102603735A (en) * | 2012-02-06 | 2012-07-25 | 浙江新和成股份有限公司 | Preparation method of C-2 arylation indolizine compound |
| CN107759588A (en) * | 2016-08-19 | 2018-03-06 | 江苏新元素医药科技有限公司 | A kind of phenyl (base of pyrazolo [1,5 a] pyridine 3) ketone derivatives |
-
2018
- 2018-11-14 CN CN201811351026.5A patent/CN110283167A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4103012A (en) * | 1976-02-19 | 1978-07-25 | Labaz | Indolizine derivatives, pharmaceutical compositions and methods containing same |
| US4400387A (en) * | 1979-07-06 | 1983-08-23 | S. A. Labaz-Sanofi N.V. | Indolizine derivatives and uses in therapeutics |
| CN102093355A (en) * | 2011-02-09 | 2011-06-15 | 浙江大学 | C-3 acylated indolizine compound and preparation method thereof |
| CN102603735A (en) * | 2012-02-06 | 2012-07-25 | 浙江新和成股份有限公司 | Preparation method of C-2 arylation indolizine compound |
| CN107759588A (en) * | 2016-08-19 | 2018-03-06 | 江苏新元素医药科技有限公司 | A kind of phenyl (base of pyrazolo [1,5 a] pyridine 3) ketone derivatives |
Non-Patent Citations (3)
| Title |
|---|
| HUAYOU HU ET AL.: "Copper acetate monohydrate: a cheap but efficient oxidant for synthesizing multi-substituted indolizines from pyridinium ylides and electron deficient alkenes", 《RSC ADVANCES》 * |
| JEANNE FICHEZ ET AL.: "Reductive Cleavage of Aromatic and Heteroaromatic Ester Functions via Copper-Catalyzed Proto-Decarbomethoxylation", 《ORG. LETT.》 * |
| SHOUJUN CHEN ET AL.: "Novel indolizine compounds as potent inhibitors of phosphodiesterase IV (PDE4): structure–activity relationship", 《MED. CHEM. COMMUN.》 * |
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