CN105646483A - Method for preparing indolizine compound continuously through micro-channel reactor - Google Patents
Method for preparing indolizine compound continuously through micro-channel reactor Download PDFInfo
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- CN105646483A CN105646483A CN201610108387.1A CN201610108387A CN105646483A CN 105646483 A CN105646483 A CN 105646483A CN 201610108387 A CN201610108387 A CN 201610108387A CN 105646483 A CN105646483 A CN 105646483A
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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 belongs to the technical field of chemical synthesis, in particular to a method for preparing a indolizine compound continuously through a micro-channel reactor. 2-(pyrrolidine-2-subunit)methyl acetate and C7H9ClO4 have a cyclization reaction in a continuous feeding manner in the micro-channel reactor in the presence of organic alkali, and camptothecin derivative intermediate products, namely, the indolizine compound 7-(2-methoxy-2-yloxyethyl)-5-oxygen-1,2,3,5-tetrahydroindolizine-8-methyl formate, are prepared. The feeding capacity is accurately controlled by a plunger pump by the aid of good heat and mass transfer efficiency of the micro-channel reactor, the reaction time is greatly shortened, the quality of the product is improved, a complicated column reactor device is avoided, continuous production can be realized, and the method has important industrial application value.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to prepare camptothecin drug intermediate product indolizine compounds 7-(2-methoxyl group-2-oxygen ethyl)-5-oxygen-1, the method for 2,3,5-indolizine-8-methyl formates.
Background technology
Camptothecine (camptothecin, CPT) belongs to terpene indole class antineoplastic alkaloids, and existing two kinds of water miscible camptothecin derivative topotecans and irinotecans obtain U.S. FDA approval for clinic at present, treat ovarian cancer and colon cancer etc. Indolizine compounds 7-(2-methoxyl group-2-oxygen ethyl)-5-oxygen-1,2,3,5-indolizine-8-methyl formate is the key intermediate of camptothecin derivant synthesis, existing preparation method adopts a batch reaction, its complex operation, and reaction condition is wayward, response time is long, and by-product is many, cost is high, contaminated environment is big.
Summary of the invention
It is an object of the invention to provide a kind of good product quality, the method preparing indolizine compounds 7-(2-methoxyl group-2-oxygen ethyl)-5-oxygen-1,2,3,5-indolizine-8-methyl formate continuously that by-product generates less, energy consumption is low.
Provided by the invention prepare indolizine compounds 7-(2-methoxyl group-2-oxygen ethyl)-5-oxygen-1 continuously, 2, 3, the method of 5-indolizine-8-methyl formate, utilize micro passage reaction, with 2-(pyrrolidine-2-subunit) methyl acetate and 3-chlorine penta-2-enedioic acid dimethyl ester for raw material, in conjunction with micro passage reaction heat and mass good efficiency, the advantage that inlet amount is accurately controlled, key intermediate indolizine compounds 7-(2-methoxyl group-2-oxygen the ethyl)-5-oxygen-1 of required camptothecin derivant synthesis it is obtained by reacting through cycloaddition ring, 2, 3, 5-indolizine-8-methyl formate. compared with traditional batch reaction unit, each point of reactant liquor can be in identical physical environment and chemical environment, reduces the generation of by-product, Improving The Quality of Products, reduces energy consumption and waste discharge. the rapid scale that can promote product produces.
Specifically comprising the following steps that of the inventive method
(1) 2-(pyrrolidine-2-subunit) methyl acetate is mixed homogeneously in a solvent with organic base;
(2) by the mixed liquor of step (1), proportionally inject micro passage reaction with 3-chlorine penta-2-enedioic acid dimethyl ester respectively through plunger displacement pump, react;
(3) reaction terminates rear reactant liquor from micro passage reaction outflow, is introduced in frozen water, by separating, filtering, obtain 7-(2-methoxyl group-2-oxygen ethyl)-5-oxygen-1,2,3,5-indolizine-8-methyl formate crude product, then recrystallization obtains sterling.
In step (1), described organic base is selected from diethylamine, triethylamine, tri-n-butylamine, diisopropyl ethyl amine, ethylenediamine, pyridine, piperidines, DMAP.
In step (1), described solvent is selected from C1-C6Alcohols, oxolane, dioxane.
In step (1), 2-(pyrrolidine-2-subunit) mol ratio of methyl acetate and organic base is 1:(0.5��4), it is preferable that 1:(1��2).
In step (2), 3-chlorine penta-2-enedioic acid dimethyl ester is 1:(1��10 with the mixture flow rate volume ratio in step (1)), it is preferable that 1:(3��7).
In step (2), the internal diameter of described micro passage reaction is 0.5mm��5.0mm, it is preferable that 0.5mm��2.0mm; Reaction temperature is 0��50 DEG C, it is preferable that 10��30 DEG C; Response time is 0.5��4h, it is preferable that 0.5��2h.
The present invention can adopt micro passage reaction of the prior art, capable of automatic assembling or directly buy from the market.
The present invention has the advantage that compared with existing synthetic method reaction efficiency is high, and by-product is few, and the response time is short, and cost is low, and product yield is high and product purity is high, and reaction three-waste pollution is few, is beneficial to environmental conservation.
Accompanying drawing explanation
Fig. 1 is the reaction scheme schematic diagram of the present invention.
Detailed description of the invention
According to following embodiment, it is possible to be more fully understood that the present invention. But, as it will be easily appreciated by one skilled in the art that the content described by embodiment is merely to illustrate the present invention, and should not limit the present invention described in detail in claims.
The micro passage reaction model that following example use is EHRFELDslit-platemixer(reactor volume is 20mL; Reactor inside diameter is 2.0mm) or VapourtecR4/R2+(reactor volume be 10mL; Reactor inside diameter is 1.0mm).
Embodiment 1��15
By 2-(pyrrolidine-2-subunit) methyl acetate mixs homogeneously in a solvent with organic base, with 3-chlorine penta-2-enedioic acid dimethyl ester respectively through plunger displacement pump (V according to a certain percentage1: V2) it is injected into micro passage reaction, in 0��50oC reacts 0.5��4h. Reactant liquor is introduced in frozen water after flowing out from micro passage reaction, and separating and filtering obtains 7-(2-methoxyl group-2-oxygen ethyl)-5-oxygen-1,2,3,5-indolizine-8-methyl formate crude products, obtain sterling then through recrystallization. Inlet amount volume only need to be doubled by VapourtecR4/R2+ reactor actual conditions and result in Table 1, EHRFELDslit-platemixer, and other conditions are with table 1, and reaction effect is almost suitable with VapourtecR4/R2+ reactor.
Table 1 reaction condition and result
��
Claims (8)
1. one kind utilizes micro passage reaction to prepare indolizine compounds 7-(2-methoxyl group-2-oxygen ethyl)-5-oxygen-1, the method for 2,3,5-indolizine-8-methyl formates, it is characterised in that specifically comprise the following steps that continuously
(1) 2-(pyrrolidine-2-subunit) methyl acetate is mixed homogeneously in a solvent with organic base;
(2) by the mixed liquor of step (1), proportionally inject micro passage reaction with 3-chlorine penta-2-enedioic acid dimethyl ester respectively through plunger displacement pump, react;
(3), after reaction terminates, reactant liquor flows out from micro passage reaction, is introduced in frozen water, by separating, filtering, obtain 7-(2-methoxyl group-2-oxygen ethyl)-5-oxygen-1,2,3,5-indolizine-8-methyl formate crude products, then recrystallization obtains sterling.
2. method according to claim 1, it is characterised in that the organic base described in step (1) is selected from diethylamine, triethylamine, tri-n-butylamine, diisopropyl ethyl amine, ethylenediamine, pyridine, piperidines, DMAP; Described solvent is selected from C1-C6Alcohols, oxolane, dioxane.
3. method according to claim 1 and 2, it is characterised in that in step (1), 2-(pyrrolidine-2-subunit) mol ratio of methyl acetate and organic base is 1:(0.5��4).
4. method according to claim 1 and 2, it is characterised in that in step (2), 3-chlorine penta-2-enedioic acid dimethyl ester is 1:(1��10 with the mixture flow rate volume ratio in step (1)).
5. method according to claim 1 and 2, it is characterised in that in step (2), the internal diameter of described micro passage reaction is 0.5mm��5.0mm; Reaction temperature is 0��50 DEG C; Response time is 0.5��4h.
6. the mol ratio of method according to claim 3, it is characterised in that in step (1), 2-(pyrrolidine-2-subunit) methyl acetate and organic base is 1:1��2.
7. method according to claim 4, it is characterised in that in step (2), the mixture flow rate volume ratio that 3-chlorine penta-2-enedioic acid dimethyl ester prepares with step (1) is 1:3��7.
8. method according to claim 5, it is characterised in that in step (2), the internal diameter of micro passage reaction is 0.5mm��2.0mm, and reaction temperature is 10��30 DEG C, and the response time is 0.5��2h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5446047A (en) * | 1992-07-23 | 1995-08-29 | Sloan-Kettering Institute For Cancer Research | Camptothecin analogues |
| CN103641827A (en) * | 2013-12-10 | 2014-03-19 | 广西师范大学 | Purrocoline derivative and synthetic method and application thereof |
-
2016
- 2016-02-29 CN CN201610108387.1A patent/CN105646483B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5446047A (en) * | 1992-07-23 | 1995-08-29 | Sloan-Kettering Institute For Cancer Research | Camptothecin analogues |
| CN103641827A (en) * | 2013-12-10 | 2014-03-19 | 广西师范大学 | Purrocoline derivative and synthetic method and application thereof |
Non-Patent Citations (5)
| Title |
|---|
| LAWRENCE SNYDER ET AL.: ""Synthesis of 18-Noranhydrocamptothecin Analogs Which Retain Topoisomerase I Inhibitory Function"", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| NATACHA MALECKI ET AL.: ""Studies on pyrrolidinones. Synthesis of new α-pyridones derivatives"", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
| THIERRY BRUNIN ET AL.: ""Towards new camptothecins. Part 2: Synthesis of the ABCD ring scaffold substituted by a carboxyl group in the 5-position"", 《TETRAHEDRON》 * |
| WANG SHEN ET AL.: ""Concise total syntheses of dl-camptothecin and related anticancer drugs"", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| 刘兆利 等: ""微反应器在化学化工领域中的应用"", 《化工进展》 * |
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