CN110105261A - A method of continuous, rapid synthesis and purification epiphysin using microreactor - Google Patents
A method of continuous, rapid synthesis and purification epiphysin using microreactor Download PDFInfo
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- CN110105261A CN110105261A CN201811584073.4A CN201811584073A CN110105261A CN 110105261 A CN110105261 A CN 110105261A CN 201811584073 A CN201811584073 A CN 201811584073A CN 110105261 A CN110105261 A CN 110105261A
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- Prior art keywords
- microreactor
- methoxytryptamine
- sodium carbonate
- epiphysin
- aqueous sodium
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
Abstract
The present invention relates to a kind of using microreactor continuous, rapid synthesis and the method for purifying epiphysin, this method dissolves 5- methoxytryptamine first with methylene chloride, again it is delivered in microreactor simultaneously with acetic anhydride and is reacted, reaction resulting material enters in liquid distributing device after mixing with the aqueous sodium carbonate that pumping comes to be extracted, gained lower layer organic phase is after vacuum distillation and recrystallization, as high-purity epiphysin.This method is mixed using methylene chloride promotion reactant and the separation of product and impurity, synthesis and the separating-purifying continuous quickly progress in microreactor, simpler efficient.
Description
Technical field
The present invention relates to medical synthesis technical fields, and in particular to a kind of to utilize continuous microreactor, rapid synthesis and mention
The method of pure epiphysin.
Background technique
Melatonin (chemical name n-acetyl-5-methoxytryptamine) is a kind of indoles of human brain pineal body secretion
Hormone, main function are to safeguard the circadian rhythm of Human Physiology, are conducive to sleep, can enhance immune function of human body, press down
The growth of tumour cell processed.Epiphysin Central nervous system also has inhibiting effect, is a kind of peroxide more more effective than vitamin E
Change base scavenger, the growth and development of people, reproductive function and many organs can be played regulatory role.
Microreactor is a kind of novel consersion unit also referred to as micro passage reaction.Microreactor, which usually contains, works as
The fluid flowing passage of diameter and the order of magnitude between micron and millimeter is measured, chemical reaction just occurs in these channels.With
The development of technology, microreactor be increasingly taken seriously, relative to conventional reactor, microreactor is had the advantages that
1) reaction time can accurately control.Reactant chemically reacts during continuously flowing in microreactor,
It can the accurate reaction time by control residence time of material；
2) material can instantaneously be mixed with precise proportions.It can be and then accurate by controlling the response parameter of microreactor
Control the precise proportions of reaction mass；
3) experimental result is easy to amplify.Continuous flowing is the most significant feature of microreaction technology, passes through continuous flow
It is dynamic to prepare a large amount of target products；
4) security performance is high.Carry out that can be safe in microreactor is some to explode under normal conditions in the past
Reaction.
Although microreactor has many advantages, such as, Product formation can not carry out simultaneously with separating-purifying, generally need
It first synthetic product and to be collected in microreactor, the product gathered is then sent into other equipment or subsequent work
Purification operations are carried out in skill.The synthesis and purification of existing microreactor product be it is separated, entire technique is simultaneously discontinuous, and centre can
There can be pause, whole production efficiency is lower.
Currently there are many reports about epiphysin synthesis technology.(Yang Jianwu, Cao Huilan take off black sharp Yang Jianwu etc.
Element synthesis and characterization [J] chemical research, 2003,14 (4): 42-44.) report one kind using 5- methoxytryptamine as raw material,
Acetic anhydride is the method that acylating reagent carries out reaction synthesis n-acetyl-5-methoxytryptamine, and it is long that this method has the acylated time
The problems such as (three more than hour), reaction speed are relatively slow, energy consumption is big, at high cost, is not appropriate for industrialized production.Miryam
Femandez-Suarez et al. (The development o f integrated microfluidic chemistry
platforms for lead optimization in the phar maceutical industry,Fourth
international conference on Nanochannels,Microchann els and Minichannels,
Miryam Femandez-Suarez, et al., Page 1-6) disclose a kind of side that epiphysin is prepared using microreactor
Method, although will drop to 12s the reaction time using microreactor, synthesis is still operated separately with separating, and there is no realizations
Continuous production.
Inventor team (CN106622070A) discloses not long ago a kind of continuously prepares epiphysin using microreactor
Method is passed through long-term a large amount of experiment on this basis and is summarized, in line with the purpose for continuing optimization microreactor function, further
Have developed a kind of method that separation epiphysin is continuously synthesized using microreactor as carrier.This method not only simplifies operation, more
Uninterrupted production is realized, efficient separating-purifying, industrialization, automation journey can be carried out to it while synthesizing epiphysin
It spends higher.
Summary of the invention
It is an object of the invention to overcome reaction time length, low efficiency existing for existing epiphysin synthetic method, synthesis with
The deficiencies of separated progress of purification, product postprocessing very complicated, provides a kind of continuous, rapid synthesis and purification using microreactor
The method of epiphysin, method includes the following steps:
(a) 5- methoxytryptamine is dissolved in methylene chloride, obtains 5- methoxytryptamine-dichloromethane solution；Prepare one
Determine the aqueous sodium carbonate of concentration；(b) 5- methoxytryptamine-dichloromethane solution and acetic anhydride are pressed by microchannel in parallel
It conveys according to certain proportion into microreactor, while prepared aqueous sodium carbonate is delivered to microreactor exit, make it
It is mixed with the material after reacting, gained mixed material enters liquid separation in liquid distributing device, lower layer's organic phase is delivered to vacuum distillation
It is distilled in device, distillation gained liquid is recrystallized.
Further, 5- methoxytryptamine-dichloromethane solution concentration is 0.025-0.1g/mL.Select methylene chloride
Mainly utilize it with the immiscible characteristic of water convenient for later separation purification as solvent；If selecting ethyl alcohol, then subsequent point
It is difficult to effectively carry out from operation；If selecting THF, pipeline swelling set can be caused, destroy micro- reaction channel.
Further, the mass fraction of the aqueous sodium carbonate is 10%-30%.
Further, the mass ratio of required each material is 5- methoxytryptamine: acetic anhydride: sodium carbonate liquor=1 when reaction:
2-10:20-50.Acetic anhydride should be excessive, therefore its ratio is high compared with 5- methoxytryptamine-dichloromethane solution；For save the cost, carbon
Acid sodium solution should suitably excessive (the sum of the flow for being approximately equivalent to other two kinds of materials), convenient for excessive acetic anhydride is quenched, and
The acetic acid extraction that reaction is generated separates conducive to the complete acetic anhydride of byproduct of reaction and unreacted with product into inorganic phase.
Further, the microreactor is PTFE material, and wherein microtube length is 80-120cm.
Further, microreactor is placed in 20 DEG C of water-baths when reaction, while sonic oscillation is handled, mixed material is micro-
The residence time is 10-90s, flow velocity 1.18-47.1mL/h in reactor.
Further, the vacuum degree of vacuum distillation is 0.09MPa, and 40 DEG C of temperature, recrystallization temperature is -10 DEG C.
Compared with prior art, the beneficial effects are mainly reflected as follows the following aspects: (1) utilizing methylene chloride
Reaction solution is made in the dissolution of raw material 5- methoxytryptamine, in order to which it is preferably sufficiently mixed instead with another reaction solution acetic anhydride
It answers, and methylene chloride toxicity is relatively small, also helps the separation and purification of product and impurity；(2) material is in microreactor
The middle residence time is short, reaction sufficiently it is thorough, reacted material exit directly with aqueous sodium carbonate hybrid extraction, entirely
Process is more coherent, and extraction gained organic liquid phase obtains the epiphysin product of high-purity after vacuum distillation and crystallization；(3) existing
Have microreactor Product formation that cannot carry out simultaneously with separating-purifying, generally require first in microreactor synthetic product and by its
It collects, the product gathered is then subjected to next step purification operations, the synthesis and purification of product are separated, entire works
Skill is simultaneously discontinuous, and production efficiency is lower.The present invention successfully solves the above problem.
Detailed description of the invention
Fig. 1 is synthesizer schematic diagram of the present invention.
Specific embodiment
To make those of ordinary skill in the art fully understand technical solution of the present invention and beneficial effect, below in conjunction with specific
Embodiment is further described.
Device used in the present invention as shown in Figure 1, the microreactor entrance by two pipelines in parallel respectively with
Reaction solution A is connected with reaction solution B, and exit is connected by bypass line with solution C, and all reaction solutions are all by micro delivery pump
Accurate measurement conveying.Outlet material is delivered to liquid separation in liquid distributing device (separatory funnel) after mixing with solution C, lower layer is organic to subtract each other
It is high-purity product after pressure distillation, recrystallization.The microreactor is PTFE material, microtube length 100cm.
Embodiment 1
0.3g 5- methoxytryptamine is dissolved in 6mL methylene chloride, the 5- methoxy primary colours that concentration is 0.050g/mL are obtained
Amine-dichloromethane solution.1g sodium carbonate is dissolved in 9mL water, the aqueous sodium carbonate that mass fraction is 10% is obtained.
Microreactor is placed in 20 DEG C of water-bath, while opening sonic oscillation.5- methoxytryptamine-methylene chloride is molten
Liquid, acetic anhydride are pumped into microreactor simultaneously by inlet ductwork, and aqueous sodium carbonate is pumped to microreactor outlet at once
Place is mixed with outlet material.5- methoxytryptamine-dichloromethane solution flow is 37.7mL/h, and the flow of acetic anhydride is
9.4mL/h, the flow of aqueous sodium carbonate are 40mL/h, residence time of material 45s or so.
The material come out from microreactor enters separatory funnel after mixing with aqueous sodium carbonate, takes lower layer's dichloromethane layer
It is evaporated under reduced pressure (vacuum degree 0.09MPa, solvent is all evaporated by 40 DEG C of bath temperature).Distillation gained liquid is in -10 DEG C of weights
Crystallization, obtains 0.30g solid.Product yield known to calculating is 80.61%.The solid shows really black to take off through tests such as nuclear-magnetisms
Element.
Embodiment 2
0.3g 5- methoxytryptamine is dissolved in 4mL methylene chloride, the 5- methoxy primary colours that concentration is 0.075g/mL are obtained
Amine-dichloromethane solution.1g sodium carbonate is dissolved in 10mL water, the aqueous sodium carbonate that mass fraction is 10% is obtained.
Microreactor is placed in 20 DEG C of water-bath, while opening sonic oscillation.5- methoxytryptamine-methylene chloride is molten
Liquid, acetic anhydride are pumped into microreactor simultaneously by inlet ductwork, and aqueous sodium carbonate is pumped to microreactor outlet at once
Place is mixed with outlet material.5- methoxytryptamine-dichloromethane solution flow is 1.06mL/h, and the flow of acetic anhydride is
0.12mL/h, the flow of aqueous sodium carbonate are 5mL/h, residence time of material 45s or so.
The material come out from microreactor enters separatory funnel after mixing with aqueous sodium carbonate, takes lower layer's dichloromethane layer
It is evaporated under reduced pressure (vacuum degree 0.09MPa, solvent is all evaporated by 40 DEG C of bath temperature).Distillation gained liquid is at -10 DEG C
Recrystallization, obtains 0.28g solid.Product yield known to calculating is 73.7%.
Claims (7)
1. a kind of continuous, rapid synthesis using microreactor and the method for purifying epiphysin, which is characterized in that including following step
It is rapid:
(a) 5- methoxytryptamine is dissolved in methylene chloride, obtains 5- methoxytryptamine-dichloromethane solution；It prepares certain dense
The aqueous sodium carbonate of degree；
(b) by microchannel in parallel by 5- methoxytryptamine-dichloromethane solution and acetic anhydride convey according to a certain percentage into
Microreactor, while prepared aqueous sodium carbonate is delivered to microreactor exit, keep it mixed with the material after reacting
It closes, gained mixed material enters liquid separation in liquid distributing device, lower layer's organic phase is delivered in vacuum distillation apparatus and is distilled, will distill
Gained liquid recrystallization.
2. the method as described in claim 1, it is characterised in that: the concentration of the 5- methoxytryptamine-dichloromethane solution is
0.025-0.1g/mL。
3. the method as described in claim 1, it is characterised in that: the mass fraction for stating aqueous sodium carbonate is 10%-30%.
4. the method as described in claim 1, it is characterised in that: the mass ratio of each material needed for reacting is 5- methoxytryptamine:
Acetic anhydride: sodium carbonate liquor=1:2-10:20-50.
5. the method as described in claim 1, it is characterised in that: the microreactor is PTFE material, and wherein microtube length is
80-120cm。
6. the method as described in claim 1, it is characterised in that: microreactor is placed in 20 DEG C of water-baths when reaction, is surpassed simultaneously
Sound oscillation processing, mixed material residence time in microreactor is 10-90s, flow velocity 1.18-47.1mL/h.
7. the method as described in claim 1, it is characterised in that: the vacuum degree of vacuum distillation is 0.09MPa, 40 DEG C of temperature, heavy
Crystallization temperature is -10 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811584073.4A CN110105261A (en) | 2018-12-24 | 2018-12-24 | A method of continuous, rapid synthesis and purification epiphysin using microreactor |
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| CN201811584073.4A CN110105261A (en) | 2018-12-24 | 2018-12-24 | A method of continuous, rapid synthesis and purification epiphysin using microreactor |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113230993A (en) * | 2021-05-18 | 2021-08-10 | 山东科加工业技术研究院有限公司 | Device for preparing dilute acid or mixed acid by utilizing RTB reactor, method and application thereof |
| CN115650891A (en) * | 2022-10-27 | 2023-01-31 | 常熟市滨江化工有限公司 | Method for purifying tert-butyl peroxybenzoate by using microchannel reactor |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3105850A1 (en) * | 1981-02-18 | 1982-08-19 | Horst, Hans Jörg, Priv.Doz.Dr., 2057 Reinbek | Agent for treating tumours |
| JPS6445361A (en) * | 1983-07-01 | 1989-02-17 | Nestle Sa | Manufacture of n-acetylserotonin |
| US6436984B1 (en) * | 1998-12-18 | 2002-08-20 | Centre National De La Recherche Scientifique (Cnrs) | Melatonin derivatives and medicine containing same |
| CN102329263A (en) * | 2011-10-17 | 2012-01-25 | 上海化学试剂研究所 | Preparation method of N-acetyl-5-methoxytryptamine |
| CN106622070A (en) * | 2016-12-26 | 2017-05-10 | 武汉工程大学 | Method for continuously preparing melatonin by using microreactor |
-
2018
- 2018-12-24 CN CN201811584073.4A patent/CN110105261A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3105850A1 (en) * | 1981-02-18 | 1982-08-19 | Horst, Hans Jörg, Priv.Doz.Dr., 2057 Reinbek | Agent for treating tumours |
| JPS6445361A (en) * | 1983-07-01 | 1989-02-17 | Nestle Sa | Manufacture of n-acetylserotonin |
| US6436984B1 (en) * | 1998-12-18 | 2002-08-20 | Centre National De La Recherche Scientifique (Cnrs) | Melatonin derivatives and medicine containing same |
| CN102329263A (en) * | 2011-10-17 | 2012-01-25 | 上海化学试剂研究所 | Preparation method of N-acetyl-5-methoxytryptamine |
| CN106622070A (en) * | 2016-12-26 | 2017-05-10 | 武汉工程大学 | Method for continuously preparing melatonin by using microreactor |
Non-Patent Citations (2)
| Title |
|---|
| 万宁等: ""美乐托宁的合成新工艺研究"", 《西北药学杂志》 * |
| 杨昭等: ""美乐托宁微反应合成***的开发"", 《武汉工程大学学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113230993A (en) * | 2021-05-18 | 2021-08-10 | 山东科加工业技术研究院有限公司 | Device for preparing dilute acid or mixed acid by utilizing RTB reactor, method and application thereof |
| CN115650891A (en) * | 2022-10-27 | 2023-01-31 | 常熟市滨江化工有限公司 | Method for purifying tert-butyl peroxybenzoate by using microchannel reactor |
| CN115650891B (en) * | 2022-10-27 | 2024-05-03 | 常熟市滨江化工有限公司 | Method for purifying tert-butyl peroxybenzoate by using microchannel reactor |
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