CN105646483B - The method that indolizine compounds are continuously prepared using micro passage reaction - Google Patents
The method that indolizine compounds are continuously prepared using micro passage reaction Download PDFInfo
- Publication number
- CN105646483B CN105646483B CN201610108387.1A CN201610108387A CN105646483B CN 105646483 B CN105646483 B CN 105646483B CN 201610108387 A CN201610108387 A CN 201610108387A CN 105646483 B CN105646483 B CN 105646483B
- Authority
- CN
- China
- Prior art keywords
- reaction
- micro passage
- indolizine
- passage reaction
- oxygen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
The invention belongs to chemosynthesis technical field, specially a kind of method that indolizine compounds are continuously prepared using micro passage reaction.The present invention with the enedioic acid dimethyl ester of 2 (subunit of pyrrolidines 2) methyl acetates and 3 chlorine penta 2 in the presence of an organic base, annulation is carried out by way of continuous charging in micro passage reaction, (the oxygen ethyl of 2 methoxyl group 2) 5 oxygen 1 of camptothecin derivative intermediate product indolizine compounds 7 are made, 2, the methyl formate of 3,5 indolizine 8.The present invention carries out the accurate control of inlet amount using the fabulous heat and mass efficiency of micro passage reaction and using plunger pump, greatly shorten the reaction time and lift the quality of product, simultaneously avoid cumbersome tower reactor device, can continuously continual production, there is great industrial application value.
Description
Technical field
The invention belongs to chemosynthesis technical field, and in particular to prepare camptothecin drug intermediate product indolizine compounds
The method of 7- (2- methoxyl group -2- oxygen ethyl) -5- oxygen -1,2,3,5- indolizine -8- methyl formates.
Background technology
Camptothecine (camptothecin, CPT) belongs to terpene indole class antineoplastic alkaloids, has two kinds of water solubilitys at present
Camptothecin derivative topotecan and irinotecans obtain U.S. FDA ratify be used for clinic, treat oophoroma and colon cancer etc..
Indolizine compounds 7- (2- methoxyl group -2- oxygen ethyl) -5- oxygen -1,2,3,5- indolizine -8- methyl formates are camplotheca acuminatas
The key intermediate of bases derivative synthesis, existing preparation method are reacted using batch, and its is cumbersome, and reaction condition is not easily-controllable
System, reaction time length, accessory substance is more, cost is high, pollution environment is big.
The content of the invention
It is an object of the invention to provide nitrogen in a kind of good product quality, the continuous preparation that accessory substance generates less, energy consumption is low
The method of indene compound 7- (2- methoxyl group -2- oxygen ethyl) -5- oxygen -1,2,3,5- indolizine -8- methyl formates.
It is provided by the invention continuously to prepare indolizine compounds 7- (2- methoxyl group -2- oxygen ethyl) -5- oxygen -1,2,3,
The method of 5- indolizine -8- methyl formates, using micro passage reaction, with 2- (pyrrolidines -2- subunits) methyl acetates with
The amyl- 2- enedioic acids dimethyl ester of 3- chlorine is raw material, is accurately controlled with reference to micro passage reaction heat and mass good efficiency, inlet amount
The advantages of, react to obtain the key intermediate indolizine compounds 7- of required camptothecin derivative synthesis through cycloaddition ring
(2- methoxyl group -2- oxygen ethyl) -5- oxygen -1,2,3,5- indolizine -8- methyl formates.React and fill with traditional batch
Put and compare, each point of reaction solution can be in identical physical environment and chemical environment, reduce the generation of accessory substance, lifting
Product quality, reduce energy consumption and waste discharge.The rapid scale of product can be promoted to produce.
The inventive method comprises the following steps that：
（1）2- (pyrrolidines -2- subunits) methyl acetate is well mixed in a solvent with organic base；
（2）By step（1）Mixed liquor, proportionally noted by plunger pump respectively with the amyl- 2- enedioic acids dimethyl ester of 3- chlorine
Enter micro passage reaction, reacted；
（3）Reaction terminates rear reaction solution and flowed out from micro passage reaction, is introduced into frozen water, by separating, filtering, obtains
7- (2- methoxyl group -2- oxygen ethyl) -5- oxygen -1,2,3,5- indolizine -8- methyl formate crude products, then be recrystallized to give
Sterling.
Step（1）In, described organic base may be selected from diethylamine, triethylamine, tri-n-butylamine, diisopropyl ethyl amine, second two
Amine, pyridine, piperidines, DMAP.
Step（1）In, described solvent may be selected from C1-C6Alcohols, tetrahydrofuran, dioxane.
Step（1）In, 2-（Pyrrolidines -2- subunits）The mol ratio of methyl acetate and organic base is 1:（0.5~4）, preferably
1:（1~2）.
Step（2）In, the amyl- 2- enedioic acids dimethyl ester of 3- chlorine and step（1）In mixture flow rate volume ratio be 1:（1~
10）, preferably 1:（3~7）.
Step（2）In, the internal diameter of described micro passage reaction is the mm of 0.5 mm~5.0, preferably 0.5 mm~2.0
mm；Reaction temperature is 0~50 DEG C, preferably 10~30 DEG C；Reaction time is 0.5~4 h, preferably 0.5~2 h.
The present invention can use micro passage reaction of the prior art, capable of automatic assembling or directly purchase from the market.
It is of the invention to be had the following advantages that compared with existing synthetic method：Reaction efficiency is high, and accessory substance is few, and the reaction time is short,
Cost is low, and product yield is high and product purity is high, and reaction three-waste pollution is few, beneficial to environmental protection.
Brief description of the drawings
Fig. 1 is the reaction scheme schematic diagram of the present invention.
Embodiment
According to following embodiments, the present invention may be better understood.It is however, as it will be easily appreciated by one skilled in the art that real
Apply the content described by example and be merely to illustrate the present invention, without the present invention described in detail in claims should be limited.
Micro passage reaction model EHRFELD slit-plate mixer used in following examples（Reactor body
Product is 20 mL；Reactor inside diameter is 2.0 mm）Or Vapourtec R4/R2+（Reactor volume is 10 mL；Reactor inside diameter
For 1.0 mm）.
Embodiment 1~15
By 2-（Pyrrolidines -2- subunits）Methyl acetate is well mixed in a solvent with organic base, with the amyl- 2- enedioic acids of 3- chlorine
Dimethyl ester respectively by plunger pump according to a certain percentage（V1：V2）Micro passage reaction is injected into, in 0~50oC reactions 0.5~4
h.Reaction solution is introduced into frozen water, separating and filtering obtains 7- after micro passage reaction outflow（2- methoxyl group -2- oxygen ethyls）-
5- oxygen -1,2,3,5- indolizine -8- methyl formate crude products, then through being recrystallized to give sterling.Vapourtec R4/R2+
Reaction utensil concrete conditions in the establishment of a specific crime and it the results are shown in Table 1, EHRFELD slit-plate mixer and inlet amount volume need to only be doubled, its
His condition is almost suitable with table 1, reaction effect and Vapourtec R4/R2+ reactors.
The reaction condition of table 1 and result
。
Claims (6)
1. one kind continuously prepares indolizine compounds 7- (2- methoxyl group -2- oxygen ethyl) -5- oxygen -1 using micro passage reaction,
The method of 2,3,5- indolizine -8- methyl formates, it is characterised in that comprise the following steps that：
（1）2- (pyrrolidines -2- subunits) methyl acetate is well mixed in a solvent with organic base；
（2）By step（1）Mixed liquor, proportionally injected by plunger pump respectively with the amyl- 2- enedioic acids dimethyl ester of 3- chlorine micro-
Channel reactor, reacted,
Wherein, the amyl- 2- enedioic acids dimethyl ester of 3- chlorine and step（1）Obtained mixture flow rate volume ratio is 1:1~10, it is described
The internal diameter of micro passage reaction is the mm of 0.5 mm~5.0, and reaction temperature is 0~50 DEG C, and the reaction time is 0.5~4 h；
（3）After reaction terminates, reaction solution flows out from micro passage reaction, is introduced into frozen water, by separating, filtering, obtains 7-
(2- methoxyl group -2- oxygen ethyl) -5- oxygen -1,2,3,5- indolizine -8- methyl formate crude products, then be recrystallized to give pure
Product.
2. according to the method for claim 1, it is characterised in that step（1）Described in organic base be selected from diethylamine, three second
Amine, tri-n-butylamine, diisopropyl ethyl amine, ethylenediamine, pyridine, piperidines, DMAP；Described solvent is selected from C1-C6Alcohol
Class, tetrahydrofuran, dioxane.
3. method according to claim 1 or 2, it is characterised in that step（1）In, 2-（Pyrrolidines -2- subunits）Acetic acid first
The mol ratio of ester and organic base is 1:0.5~4.
4. according to the method for claim 3, it is characterised in that step（1）In, 2- (pyrrolidines -2- subunits) methyl acetate
Mol ratio with organic base is 1:1~2.
5. according to the method for claim 1, it is characterised in that step（2）In, the amyl- 2- enedioic acids dimethyl ester of 3- chlorine and step
Suddenly（1）Obtained mixture flow rate volume ratio is 1:3~7.
6. according to the method for claim 1, it is characterised in that step（2）In, the internal diameter of micro passage reaction is 0.5 mm
~2.0 mm, reaction temperature are 10~30 DEG C, and the reaction time is 0.5~2h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610108387.1A CN105646483B (en) | 2016-02-29 | 2016-02-29 | The method that indolizine compounds are continuously prepared using micro passage reaction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610108387.1A CN105646483B (en) | 2016-02-29 | 2016-02-29 | The method that indolizine compounds are continuously prepared using micro passage reaction |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105646483A CN105646483A (en) | 2016-06-08 |
| CN105646483B true CN105646483B (en) | 2018-02-27 |
Family
ID=56489926
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610108387.1A Active CN105646483B (en) | 2016-02-29 | 2016-02-29 | The method that indolizine compounds are continuously prepared using micro passage reaction |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105646483B (en) |
Family Cites Families (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 |
| CN103641827B (en) * | 2013-12-10 | 2015-04-29 | 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
Also Published As
| Publication number | Publication date |
|---|---|
| CN105646483A (en) | 2016-06-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107820487A (en) | Prepare (Z) 3 [[4 [methyl [2 (piperazinyl of 4 methyl 1) acetyl group] amino] phenyl] amino] phenylmethylene) Oxoindole 6 carboxylate methyl ester (Nintedanib, Ning Tedani) method | |
| CN104447443A (en) | Preparation method for apremilast and intermediate of apremilast | |
| CN108295782A (en) | A kind of micro passage reaction and in the micro passage reaction three kinds of acetylization reactions method | |
| CN110437228A (en) | A kind of preparation method of Tadalafei and its intermediate | |
| CN103864748B (en) | A kind of purification process of 4- chloromethyl -5- methyl-1,3-dioxy heterocyclic pentene -2- ketone | |
| CN103664896B (en) | A kind of synthetic process of crizotinib serving as antitumor molecular targeting medicament | |
| CN113200996A (en) | Continuous flow synthesis method of valerate | |
| CN105801491B (en) | The synthetic method of 3,4 dihydro-pyrimidin ketones derivants | |
| CN105646483B (en) | The method that indolizine compounds are continuously prepared using micro passage reaction | |
| CN108610293B (en) | Method for preparing dorvitinib intermediate by adopting microchannel reaction device | |
| CN104561170B (en) | A kind of method of lipase-catalyzed online synthesis of acetic acid 1 (6 nitrobenzimidazole base) ethyl ester | |
| CN106824269A (en) | A kind of pyrazoles [5,4 b] γ pyran derivates and preparation method thereof and catalyst for preparing | |
| CN105017238A (en) | Method for chiral spirophosphonate catalyzed synthesis of optically active 2H-1,4-benzoxazine-2-one derivative | |
| CN107266311B (en) | Method for continuously preparing α -keto ester by using microfluid chip reactor | |
| CN106831549B (en) | A kind of method of asymmetric synthesis of Claritin carbinoxamine | |
| CN105481865B (en) | A kind of preparation method of pyrimido [1,6-a] indole Hete rocyclic derivatives | |
| CN104130125A (en) | Method for synthesizing glycerol triacetate through microchannel reactor | |
| CN102250103B (en) | Synthesis method of SN38 or intermediate thereof | |
| CN108586477A (en) | A kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrates | |
| CN104030984A (en) | Method for preparing pyrazole derivative | |
| CN104496938B (en) | A kind of preparation method of 2-acetyl phenothiazine | |
| CN108546266B (en) | Synthesis method of 1,4,6, 7-tetrahydropyrane [4,3-C ] pyrazole-3-carboxylic acid | |
| CN108003030B (en) | Method and device for continuously preparing 5-nitro-1, 4-dihydro-1, 4-methano-naphthalene in pipelining manner | |
| CN104561173B (en) | A kind of method of lipase-catalyzed online synthesis palmitic acid 1- (6- nitrobenzimidazoles base) ethyl ester | |
| CN103333106B (en) | The novel method of vinyl cyanide and substituted-phenyl schiff base reaction synthesis substd quinolines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |