CN108586477A - A kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrates - Google Patents
A kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrates Download PDFInfo
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Abstract
The invention belongs to medical synthesis fields, specifically disclose a kind of method that micro passage reaction synthesizes 5 Isosorbide Mononitrates, nitrating agent and isobide liquid are pumped into micro passage reaction and carry out hybrid reaction by the present invention respectively, after the completion of reaction, product is exported from micro passage reaction to flow out, post-treated, isolate and purify to obtain 5 Isosorbide Mononitrate of purpose product.Method provided by the present invention, the reaction time is short, relative to traditional handicraft safety, and the yield of 5 Isosorbide Mononitrates is greatly improved.
Description
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a method of synthesis 5- Isosorbide Mononitrates, it is special
It is not related to a kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrates.
Background technology
5- Isosorbide Mononitrate (Isosorbide-5-Nitraes：3,6- bis- dehydrations-D-glucitol -5- nitrates, compound in structural formula such as Formulas I
1) it is Isosorbide Nitrate (Isosorbide-5-Nitrae：3,6- bis- dehydrations-D-glucitol -2,5- dinitrate, compound 2 in structural formula such as Formulas I)
Internal main metabolites, compared to Isosorbide Nitrate and 2- Isosorbide Mononitrate (Isosorbide-5-Nitraes：3,6- bis- dehydration-D- sorbs
Alcohol -2- nitrates, compound 3 in structural formula such as Formulas I), it have it is oral after without liver first-pass effect, bioavilability is high, secondary
The advantages that small and acting duration is long is acted on, was developed and is listed by German Boehringer Mannheim GmbH in 1981,
5- Isosorbide Mononitrates have been widely used in clinic at present, become the fiest-tire medication of antianginal.
The synthetic route report of 5- Isosorbide Mononitrates have it is very much, be broadly divided into direct nitrification process, selective reduction method,
Indirect nitrification process etc..The industrialized production route of mainstream is still to be based primarily upon the route of direct nitrification process using direct nitrification process
The advantages such as short, at low cost, easy to operate.
The direct specific route of nitrification process is：With isobide (Isosorbide-5-Nitrae：In 3,6- bis- dehydrations-D-glucitol, structural formula such as Formulas I
Compound 4) it is after the reaction of starting material and nitrating agent (such as nitric/sulfuric acid, nitric acid/acetic anhydride etc.) again by isolating and purifying
To target product.Document " Hayward, L.etal.Can.J.Chem., 1967,45,2191-2194 ", patent US3886186,
US4584391, JP5529996, CN103641840 etc. report this method.Reaction route is as follows：
But it is low to be mainly manifested in yield there is also many problems for direct nitrification process.In fact, for glycol and
The single nitric acid of polyol (such as 1,4-butanediol, glycerine etc.) is esterified, and can generally be faced with poor selectivity and the esterification of excessive nitric acid etc.
Problem, yield are generally difficult to reach 50%, this is because the active difference of each position hydroxyl often less caused by.Compared to right
Claiming the single nitric acid of glycol to be esterified, (such as 1,4-butanediol, 1- single nitric acid esterifications and 4- Mononitrates turn to same chemical combination
Object), two hydroxyls of isobide are asymmetrical, are target product when 5- hydroxyl nitric acid esterifications, and 2- hydroxyls
Nitric acid esterification products be 2- Isosorbide Mononitrates.So synthesizing 5- Isosorbide Mononitrate difficulty by direct nitrification process
Bigger, yield are lower.Currently, the yield of directly nitrification process synthesis 5- Isosorbide Mononitrates not can exceed that 40%.
Another main problem is that process safety risk is big existing for direct nitrification process synthesis 5- Isosorbide Mononitrates,
Since nitrating agent and nitric acid ester products itself all have explosivity, especially contain the Isosorbide there are two itrate group
Ester can be generated largely in the synthesis process, need strictly to control reaction condition (temperature, pressure), generally require low temperature, reaction certainly
Chain protective device is moved, but this can not effectively reduce security risk, especially when batch quantity expands, security risk is exponentially
Grade increases, this limits the amplification of production capacity to a certain extent.
In recent years, micro passage reaction can make reactant be more fully mixed because of its dimensional effect, and temperature control is accurate,
Side reaction and security risk caused by mass transfer, heat transfer are bad are reduced, and reaction liquid is to continue flow forward, this is just reduced
Due to " back-mixing " generation of overreaction.In addition microchannel system is much smaller compared to still reaction, this is just greatly reduced
Process risk hidden danger, due to may be implemented the reaction of uninterrupted flux, year flux can reach the scale of thousands of tons of.These advantages make
Micro passage reaction is obtained in field of medicine and chemical technology, is especially obtained greatly in the dangerous technique such as nitrification, hydrogenation, diazotising
Concern and use.
Invention content
Yield present in direct nitrification process is low in for the above-mentioned prior art, and reaction selectivity is poor, and technique has safety
The defect of hidden danger, inventor pass through a large amount of experimental study, and it is mono- to provide a kind of synthesis 5- safe efficient in micro passage reaction
The method of Isosorbide Nitrate.
Compared with the chemical reaction that popular response container carries out, micro passage reaction has the following advantages：
(1) microchannel width and depth are smaller in reactor, general tens to hundreds of microns, make between reactant diffusion away from
From greatly shortening, mass transfer velocity is fast, and reactant can be sufficiently mixed during flowing in the short time.
(2) large specific surface area of microchannel has prodigious heat exchanger effectiveness, even violent exothermic reaction, moment
Releasing a large amount of reaction heat can also remove in time, and maintaining reaction temperature is in safe range, since reaction-ure mixture is few, heat transfer
Soon, the danger of explosion is avoided especially suitable for the abnormal violent synthetic reaction of research.
(3) when carrying out synthetic reaction in micro passage reaction, need reactant dosage little, can not only reduce it is expensive,
Toxic, adverse reaction object dosage, the environmental contaminants generated in reaction process are also few, are that a kind of environmental-friendly, synthesis is ground
Study carefully the technology platform of novel substance.
(4) when carrying out synthetic reaction in micro passage reaction, reactant ratio, temperature, pressure, reaction time and flow velocity
Etc. easy control of reaction conditions.Reactant reacts in flow process, and concentration constantly reduces, and product concentration constantly carries
Height, side reaction are less.
(5) it is reacted by the way of continuously flowing in micro passage reaction, for the chemistry of reaction speed quickly
Reaction can accurately control their reactions in micro passage reaction by the length of adjusting reactant flow velocity and microchannel
Time.
Direct nitrification process higher to difficulty asymmetric diol structure safe efficiently is utilized in micro passage reaction
Isobide carries out nitric acid esterification, and then it is the direction that we study to synthesize 5- Isosorbide Mononitrates.Direct nitrification process yield
Mainly due to 2- hydroxyls of isobide and 5- hydroxyl activities are not much different, two hydroxyls are likely to by nitric acid low reason
Esterification, higher yield, needs the activity for improving 5- hydroxyls of isobide, inventor to be ground by further experiment in order to obtain
Study carefully discovery, reduces reaction temperature and be conducive to improve the activity of 5- hydroxyls of isobide, and then improve purpose product 5- single nitric acids
The yield of Soquad.
Inventor also found the addition by-product Isosorbide Nitrate into reaction system, can effectively reduce Isosorbide
The generation of ester side reaction；So that isobide nitrification is Isosorbide Mononitrate, the utilization rate of raw material isobide is improved.
Prepared nitrating agent and isobide liquid are pumped into micro passage reaction and carry out hybrid reaction by the present invention respectively,
By the molar ratio of feed liquor flow control isobide and nitrating agent, by the temperature control medium control for being integrated in micro passage reaction
Reaction temperature processed；Reaction time of the reaction solution in micro passage reaction is controlled by concatenated reaction plate quantity.From micro-
Channel reactor outlet outflow reaction solution it is post-treated, isolate and purify to obtain 5- Isosorbide Mononitrates.
Nitrating agent of the present invention is fuming nitric aicd and acetic anhydride.Isobide liquid is that isobide is dissolved in acetic acid,
However the fusing point of acetic acid is 16.6 DEG C, at a lower temperature, solution system, which can solidify, then blocks microchannel tubing.Therefore it needs
Secondary solvent dilution isobide liquid is added to reduce the freezing point of solution system.Inventor is unexpected to send out by a large amount of experiment
The solvent containing furan nucleus is now added not only can dilute isobide liquid can also greatly improve the activity of its 5- hydroxyl, into
And the yield of target product 5- Isosorbide Mononitrates is improved, reduce the generation of by-product 2- Isosorbide Mononitrates.
What the goal of the invention of the present invention was realized in：
A kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrates, includes the following steps, by nitrating agent with
Isobide liquid, which is pumped into respectively in micro passage reaction, carries out hybrid reaction, and after the completion of reaction, product goes out from micro passage reaction
Mouthful outflow, it is post-treated, isolate and purify to obtain target product 5- Isosorbide Mononitrates.
Specifically, a kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrates, includes the following steps：
(1) preparation of nitrating agent：At 0~10 DEG C, fuming nitric aicd is slowly dropped in acetic anhydride, heat preservation is spare.
(2) preparation of isobide liquid：Isobide and Isosorbide Nitrate are dissolved into acetic acid and secondary solvent, stirred
It mixes to dissolving completely, it is spare.
(3) reaction temperature is set, above-mentioned nitrating agent and isobide liquid are pumped into respectively in micro passage reaction and carried out
Hybrid reaction, product is flowed out from reactor outlet after the completion of reaction, obtains efflux.
(4) by efflux is post-treated obtained by step (3), isolates and purifies to obtain target product 5- Isosorbide Mononitrates.
In one embodiment, the molar ratio of step (1) fuming nitric aicd and acetic anhydride is 1: 1~2；It is preferred at another
In embodiment, the molar ratio of step (1) fuming nitric aicd and acetic anhydride is 1: 1~1.5.
In step (2), the mass ratio of isobide and Isosorbide Nitrate is 1: 0.05~0.3.
The selection principle of step (2) described secondary solvent is to be not involved in reaction, and reduce reaction solution freezing point；Secondary solvent
Selected from one or more of acetone, ethyl acetate, dichloromethane, tetrahydrofuran and 2- methyltetrahydrofurans.Implement at one
In example, the secondary solvent described in step (2) is tetrahydrofuran and acetone, the mixed solution of ethyl acetate or dichloromethane；Another
In one embodiment, the secondary solvent described in step (2) is 2- methyltetrahydrofurans and acetone, ethyl acetate or dichloromethane
Mixed solution；In a preferred embodiment, the secondary solvent described in step (2) is tetrahydrofuran or 2- methyl tetrahydrochysene furans
It mutters；In an optimal embodiment, the secondary solvent described in step (2) is 2- methyltetrahydrofurans, is contained in secondary solvent
When tetrahydrofuran or 2- methyltetrahydrofurans, the activity of 5- hydroxyls of isobide, which is significantly higher than in secondary solvent, does not contain furans
The activity of isobide 5- hydroxyl when the solvent of ring.
In one embodiment, in step (2), the volume ratio of acetic acid and secondary solvent is 1: 0.5~2, isobide with
The mass volume ratio of acetic acid is 1: 1~2, and wherein quality is in terms of g, and volume is in terms of mL.
In one embodiment, the molar ratio of isobide and fuming nitric aicd is 1: 1~3；Preferably implement at another
In example, the molar ratio of isobide and fuming nitric aicd is 1: 1.2~1.5.
In one embodiment, the reaction time of step (3) micro passage reaction is 15~300s, reaction temperature
It is -15~20 DEG C；In a preferred embodiment, the reaction time of step (3) micro passage reaction is 15~60s,
Reaction temperature is -15~0 DEG C.
The molar ratio of fuming nitric aicd and isobide of the present invention can enter microchannel by nitrating agent and isobide liquid pump
The feed liquor flow control of reactor；The molar ratio of isobide and fuming nitric aicd is 1: 1~3, preferably 1: 1.2~1.5.
The reaction temperature of micro passage reaction of the present invention is controlled by being coupling in the temperature control medium of micro passage reaction, cold
But mediation cycle flows through the interlayer of micro passage reaction.Reaction temperature selects -15~20 DEG C, preferably -15~0 DEG C；Work as reaction
When temperature is -15~0 DEG C, the activity of 5- hydroxyls of isobide is higher than 5- hydroxyls of isobide when reaction temperature is 0~20 DEG C
Base activity.
Reaction solution of the present invention residence time in microchannel is (every by the liquid inlet volume of feed liquid and the inner capacities of micro passage reaction
The liquid holdup of block microchannel plate is multiplied by the plate number of connection) it controls.The feed liquor of feed liquid is controlled by separate metering pump, flow
Range can be adjusted in 1~100mL/min.The plate of microchannel can be increased or decreased by being connected in series with according to experiment.Control
Nitration reaction liquid processed stops 15~300s, preferably 15~60s in micro passage reaction.
In step (4), the post processing mode is after efflux obtained by step (3) is concentrated under reduced pressure, in concentrate
Purified water is added, after stirring and crystallizing, is filtered to remove Isosorbide Nitrate, filtrate GC is taken to detect, sodium hydroxide solution is added in filtrate
It reacts into salt and 5- Isosorbide Mononitrate sodium salt crude products is made, 5- Isosorbide Mononitrate sodium salt crude products are acidified again, are refining to obtain
To target product 5- Isosorbide Mononitrates.
The present invention does not limit the model of micro passage reaction, material etc..It is any to can be used for implementing technical solution of the present invention
Micro passage reaction.
The present invention obtains the synthetic method of 5- Isosorbide Mononitrates using micro passage reaction through direct nitrification process, have with
Lower advantage：
1, in the reaction system, by-product Isosorbide Nitrate is added, is not required to that a large amount of nitrating agent is added so that different mountain
Pears alcohol single nitric acid reduces the progress to Isosorbide Nitrate side reaction, may make that isobide is anti-to Isosorbide Mononitrate
It answers, improves the utilization rate of isobide.In addition, reaction material liquid continues flow forward, liquid holdup is substantially reduced with respect to still reaction,
The security risk brought by nitrification very exothermic and material itself is greatly lowered.
2, in micro passage reaction, the efficiently quick hybrid reaction of reaction material liquid accurately controls reaction temperature, different mountain in addition
The selectivity of positions 5- of pears alcohol/2- can be improved by the 3: 1 of autoclave to 5.2: 1；It is more importantly added containing the molten of furan nucleus
The activity of its 5- hydroxyl can also be greatly improved while dilution agent isobide liquid, and then it is different to improve target product 5- single nitric acids
The yield of sorb ester, reduces the generation of by-product 2- Isosorbide Mononitrates, furan nucleus solvent can make the positions 5- of isobide/
2- selectivity are improved by 5.2: 1 to 8.0: 1 or more.The yield of 5- Isosorbide Mononitrates of the present invention can be carried by 44.5%
Up to 68.6% or more, total recovery can be improved by 34.8% to 56.2% or more.
3, the reaction time is shortened to by a few hours of autoclave within more than ten seconds to a few minutes, substantially reduces the process time,
It can realize that the safety of production capacity expands by serialization, equipment scaleization.
Specific implementation mode
The invention will now be further described with reference to specific embodiments, but following embodiment is used only as the purpose of illustration, no
For limiting the scope of the invention.
Micro passage reaction used in following embodiment is Hastelloy micro passage reaction.The present invention does not limit microchannel
Reactor, any micro passage reaction that can be used for implementing technical solution of the present invention.Solvent used in following embodiment is such as
Without specified otherwise, can be obtained by commercial sources.
Embodiment 1
(1) preparation of nitrating agent：In the there-necked flask of 500mL dryings, acetic anhydride (260.0g, 2.5mol), control is added
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), and after being added dropwise, heat preservation is spare.
(2) preparation of isobide liquid：In the there-necked flask of 2L dryings, isobide (250.0g, 1.7mol), nitre is added
Sour Soquad (12.5g, 0.053mol), is added the mixed solvent of 750mL acetic acid/ethyl acetate (v/v=2: 1), and stirring is molten
It is spare after solution.
(3) nitrating agent and isobide liquid are fed to by respective metering pump in micro passage reaction and mix instead
It answers, sets nitrating agent flow as 15mL/min, the flow of isobide liquid is 45mL/min, and controlling reaction temperature is 0 DEG C, string
Join 5 pieces of templates, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction is 50s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified waters are added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detections, and the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 1.
Table 1
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 59.4% is made, HPLC detects purity 99.10%.
Embodiment 2
(1) preparation of nitrating agent：In the there-necked flask of 1L dryings, acetic anhydride (347.0g, 3.4mol), temperature control 0 is added
~10 DEG C, fuming nitric aicd (108.0g, 1.7mol) is slowly added dropwise, after being added dropwise, heat preservation is spare.
(2) preparation of isobide liquid：In the there-necked flask of 2L dryings, isobide (250.0g, 1.7mol), nitre is added
Sour Soquad (37.5g, 0.159mol), is added the mixed solvent of 750mL acetic acid/dichloromethane (v/v=1: 2), and stirring is molten
It is spare after solution.
(3) nitrating agent and isobide liquid are fed to by respective metering pump in micro passage reaction and mix instead
It answers, sets nitrating agent flow as 5mL/min, the flow of isobide liquid is 15mL/min, and controlling reaction temperature is 20 DEG C, string
Join 10 pieces of templates, liquid holdup 100mL, reaction time of the reaction solution in micro passage reaction is 300s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified waters are added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detections, and the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 2.
Table 2
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 56.2% is made, HPLC detects purity 99.08%.
Embodiment 3
(1) preparation of nitrating agent：In the there-necked flask of 1L dryings, acetic anhydride (347.0g, 3.4mol), temperature control 0 is added
~10 DEG C, fuming nitric aicd (108.0g, 1.7mol) is slowly added dropwise, after being added dropwise, heat preservation is spare.
(2) preparation of isobide liquid：In the there-necked flask of 2L dryings, isobide (250.0g, 1.7mol), nitre is added
The mixed of 950mL acetic acid/dichloromethane/tetrahydrofuran (v/v/v=3: 1: 1) is added in sour Soquad (75.0g, 0.318mol)
Bonding solvent, it is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed to by respective metering pump in micro passage reaction and mix instead
It answers, sets nitrating agent flow as 20mL/min, the flow of isobide liquid is 50mL/min, and controlling reaction temperature is 10 DEG C,
5 pieces of templates of series connection, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction are 43s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified waters are added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detections, and the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 3.
Table 3
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 62.8% is made, HPLC detects purity 99.14%.
Embodiment 4
(1) preparation of nitrating agent：In the there-necked flask of 500mL dryings, acetic anhydride (208.0g, 2.0mol), control is added
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), and after being added dropwise, heat preservation is spare.
(2) preparation of isobide liquid：In the there-necked flask of 2L dryings, isobide (250.0g, 1.7mol), nitre is added
Sour Soquad (50.0g, 0.212mol), addition 800mL acetic acid/ethyl acetate/2- methyltetrahydrofurans (v/v/v=2: 1:
1) mixed solvent, it is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed to by respective metering pump in micro passage reaction and mix instead
It answers, sets nitrating agent flow as 40mL/min, the flow of isobide liquid is 80mL/min, and controlling reaction temperature is 0 DEG C, string
Join 3 pieces of templates, liquid holdup 30mL, reaction time of the reaction solution in micro passage reaction is 15s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified waters are added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detections, and the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 4.
Table 4
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 65.5% is made, HPLC detects purity 99.08%.
Embodiment 5
(1) preparation of nitrating agent：In the there-necked flask of 1L dryings, acetic anhydride (208.0g, 2.0mol), temperature control 0 is added
~10 DEG C, fuming nitric aicd (108.0g, 1.7mol) is slowly added dropwise, after being added dropwise, heat preservation is spare.
(2) preparation of isobide liquid：In the there-necked flask of 2L dryings, isobide (250.0g, 1.7mol), nitre is added
Sour Soquad (50.0g, 0.212mol), the mixing that 800mL acetic acid/acetone/tetrahydrofuran (v/v/v=2: 1: 1) is added are molten
Agent, it is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed to by respective metering pump in micro passage reaction and mix instead
It answers, sets nitrating agent flow as 30mL/min, the flow of isobide liquid is 30mL/min, and controlling reaction temperature is -15 DEG C,
5 pieces of templates of series connection, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction are 60s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified waters are added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detections, and the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 5.
Table 5
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 68.8% is made, HPLC detects purity 99.18%.
Embodiment 6
(1) preparation of nitrating agent：In the there-necked flask of 500mL dryings, acetic anhydride (260.0g, 2.5mol), control is added
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), and after being added dropwise, heat preservation is spare.
(2) preparation of isobide liquid：In the there-necked flask of 2L dryings, isobide (250.0g, 1.7mol), nitre is added
The mixed solvent of 750mL acetic acid/2- methyltetrahydrofurans (v/v=2: 1) is added in sour Soquad (50.0g, 0.212mol),
It is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed to by respective metering pump in micro passage reaction and mix instead
It answers, sets nitrating agent flow as 20mL/min, the flow of isobide liquid is 60mL/min, and controlling reaction temperature is -10 DEG C,
5 pieces of templates of series connection, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction are 38s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified waters are added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detections, and the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 6.
Table 6
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 69.2% is made, HPLC detects purity 99.16%.
Embodiment 7
(1) preparation of nitrating agent：In the there-necked flask of 500mL dryings, acetic anhydride (260.0g, 2.5mol), control is added
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), and after being added dropwise, heat preservation is spare.
(2) preparation of isobide liquid：In the there-necked flask of 2L dryings, isobide (250.0g, 1.7mol), nitre is added
Sour Soquad (25.0g, 0.106mol), is added the mixed solvent of 750mL acetone/tetrahydrofuran (v/v=2: 1), and stirring is molten
It is spare after solution.
(3) nitrating agent and isobide liquid are fed to by respective metering pump in micro passage reaction and mix instead
It answers, sets nitrating agent flow as 20mL/min, the flow of isobide liquid is 60mL/min, and controlling reaction temperature is -10 DEG C,
5 pieces of templates of series connection, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction are 38s.
(4) reaction efflux is concentrated under reduced pressure, addition 2L purified waters, after stirring and crystallizing, filters and removes Isosorbide Nitrate, filter
Liquid samples GC detections, and the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 7.
Table 7
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 66.5% is made, HPLC detects purity 99.13%.
Comparative example 1
In the there-necked flask of 100mL dryings, acetic anhydride (23.0g, 0.22mol) is added, control system temperature is not higher than 10
DEG C, fuming nitric aicd (10.8g, 0.17mol) is slowly added dropwise and prepares nitrating agent, heat preservation is spare.
In the there-necked flask of 500mL dryings, isobide (25.0g, 0.17mol), acetic acid (50mL), stirring and dissolving is added
Afterwards, temperature control is not higher than 10 DEG C, and above-mentioned nitrating agent reaction is slowly added dropwise, and reaction finishes, and after reaction efflux is concentrated under reduced pressure, adds
Enter 2L purified waters, after stirring and crystallizing, filters and remove Isosorbide Nitrate, filtrate samples GC detections, and it is surplus that isobide is calculated
The yield of surplus and each product.Concrete outcome is shown in Table 8.
Table 8
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 34.8% is made, HPLC detects purity 98.82%.
Comparative example 2
In the there-necked flask of 100mL dryings, acetic anhydride (23.0g, 0.22mol) is added, control system temperature is not higher than 10
DEG C, fuming nitric aicd (10.8g, 0.17mol) is slowly added dropwise and prepares nitrating agent, heat preservation is spare.
500mL drying there-necked flask in, be added isobide (25.0g, 0.17mol), Isosorbide Nitrate (5.0g,
0.021mol), acetic acid (50mL), after stirring and dissolving, temperature control is not higher than 10 DEG C, and above-mentioned nitrating agent reaction, reaction is slowly added dropwise
It finishes, 2L purified waters will be added, after stirring and crystallizing, filter and remove Isosorbide Nitrate, filtrate after reaction efflux is concentrated under reduced pressure
GC detections are sampled, the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 9.
Table 9
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 36.1% is made, HPLC detects purity 98.91%.
Comparative example 3
In the there-necked flask of 100mL dryings, acetic anhydride (23.0g, 0.22mol) is added, control system temperature is not higher than 10
DEG C, fuming nitric aicd (10.8g, 0.17mol) is slowly added dropwise and prepares nitrating agent, heat preservation is spare.
In the there-necked flask of 500mL dryings, isobide (25.0g, 0.17mol), acetic acid (50mL), 2- methyl four is added
Hydrogen furans (25mL), after stirring and dissolving, temperature control is not higher than 0 DEG C, and above-mentioned nitrating agent reaction is slowly added dropwise, and reaction finishes, will be anti-
After answering efflux to be concentrated under reduced pressure, 2L purified waters are added, after stirring and crystallizing, filters and removes Isosorbide Nitrate, filtrate samples GC inspections
It surveys, the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 10.
Table 10
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 39.8% is made, HPLC detects purity 98.97%.
Comparative example 4
In the there-necked flask of 100mL dryings, acetic anhydride (23.0g, 0.22mol) is added, control system temperature is not higher than 10
DEG C, fuming nitric aicd (10.8g, 0.17mol) is slowly added dropwise and prepares nitrating agent, heat preservation is spare.
In the there-necked flask of 500mL dryings, addition isobide (25.0g, 0.17mol), Isosorbide Nitrate (5.0g,
0.21mol), acetic acid (50mL), 2- methyltetrahydrofuran (25mL), after stirring and dissolving, temperature control is not higher than 0 DEG C, is slowly added dropwise
Nitrating agent reaction is stated, reaction finishes, and will be added 2L purified waters after reaction efflux is concentrated under reduced pressure, after stirring and crystallizing, suction filtration removes
Isosorbide Nitrate, filtrate is gone to sample GC detections, the yield of isobide surplus and each product is calculated.Concrete outcome is shown in
Table 11.
Table 11
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 42.6% is made, HPLC detects purity 99.00%.
Comparative example 5
(1) preparation of nitrating agent：In the there-necked flask of 500mL dryings, acetic anhydride (260.0g, 2.5mol), control is added
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), and after being added dropwise, heat preservation is spare.
(2) preparation of isobide liquid：In the there-necked flask of 2L dryings, isobide (250.0g, 1.7mol), nitre is added
The mixed solvent of 750mL acetic acid/2- methyltetrahydrofurans (v/v=2: 1) is added in sour Soquad (50.0g, 0.212mol),
It is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed to by respective metering pump in micro passage reaction and mix instead
It answers, sets nitrating agent flow as 40mL/min, the flow of isobide liquid is 20mL/min, and controlling reaction temperature is -10 DEG C,
5 pieces of templates of series connection, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction are 38s.
(4) 2L purified waters will be added, after stirring and crystallizing, filter and remove Isosorbide after reaction efflux are concentrated under reduced pressure
Ester, filtrate sample GC detections, the yield of isobide surplus and each product are calculated.Concrete outcome is shown in Table 12.
Table 12
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 49.4% is made, HPLC detects purity 99.03%.
Comparative example 6
(1) preparation of nitrating agent：In the there-necked flask of 500mL dryings, acetic anhydride (260.0g, 2.5mol), control is added
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), and after being added dropwise, heat preservation is spare.
(2) preparation of isobide liquid：In the there-necked flask of 2L dryings, isobide (250.0g, 1.7mol), nitre is added
Sour Soquad (50.0g, 0.212mol), is added the mixed solvent of 750mL acetic acid/methanol (v/v=2: 1), after stirring and dissolving
It is spare.
(3) nitrating agent and isobide liquid are fed to by respective metering pump in micro passage reaction and mix instead
It answers, sets nitrating agent flow as 20mL/min, the flow of isobide liquid is 60mL/min, and controlling reaction temperature is -10 DEG C,
5 pieces of templates of series connection, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction are 38s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified waters are added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detections, and the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 13.
Table 13
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 35.4% is made, HPLC detects purity 99.02%.
Comparative example 7
(1) preparation of nitrating agent：In the there-necked flask of 500mL dryings, acetic anhydride (260.0g, 2.5mol), control is added
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), and after being added dropwise, heat preservation is spare.
(2) preparation of isobide liquid：In the there-necked flask of 2L dryings, isobide (250.0g, 1.7mol) is added, adds
Enter the mixed solvent of 750mL acetic acid/2- methyltetrahydrofurans (v/v=2: 1), it is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed to by respective metering pump in micro passage reaction and mix instead
It answers, sets nitrating agent flow as 20mL/min, the flow of isobide liquid is 60mL/min, and controlling reaction temperature is -10 DEG C,
5 pieces of templates of series connection, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction are 38s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified waters are added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detections, and the yield of isobide surplus and each product is calculated.Concrete outcome is shown in Table 14.
Table 14
Above-mentioned filtrate is reacted through 30% sodium hydroxide solution is made 5- Isosorbide Mononitrate sodium salt wet products.It is acidified, smart
Target product, total recovery 64.8% is made, HPLC detects purity 99.06%.
Claims (10)
1. a kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrates, which is characterized in that the specific steps are：
(1) preparation of nitrating agent：At 0~10 DEG C, fuming nitric aicd is slowly dropped in acetic anhydride, heat preservation is spare；
(2) preparation of isobide liquid：Isobide and Isosorbide Nitrate are dissolved into acetic acid and secondary solvent, stirring is extremely
Dissolving is complete, spare；
(3) reaction temperature is set, above-mentioned nitrating agent and isobide liquid are pumped into micro passage reaction mix respectively
Reaction, product is flowed out from reactor outlet after the completion of reaction, obtains efflux；
(4) by efflux is post-treated obtained by step (3), isolates and purifies to obtain purpose product 5- Isosorbide Mononitrates.
2. according to the method described in claim 1, it is characterized in that, in step (1), the molar ratio of fuming nitric aicd and acetic anhydride is
1: 1~2；Preferably 1: 1~1.5.
3. according to the method described in claim 1, it is characterized in that, in step (2), the matter of isobide and Isosorbide Nitrate
Amount is than being 1: 0.05~0.3.
4. according to the method described in claim 1, it is characterized in that, in step (2), the secondary solvent is selected from acetone, second
One or more of acetoacetic ester, dichloromethane, tetrahydrofuran and 2- methyltetrahydrofurans.
5. according to the method described in claim 1, it is characterized in that, in step (2), the secondary solvent be tetrahydrofuran or
2- methyltetrahydrofurans.
6. according to the method described in claim 1, it is characterized in that, in step (2), the volume ratio of acetic acid and secondary solvent is 1:
0.5~2.
7. according to the method described in claim 1, it is characterized in that, the mass volume ratio of isobide and acetic acid be 1: 1~2,
Wherein quality is in terms of g, and volume is in terms of mL.
8. according to the method described in claim 1, it is characterized in that, nitrating agent and isobide liquid are distinguished in step (3)
It is pumped into micro passage reaction, the molar ratio of isobide and fuming nitric aicd is 1: 1~3, preferably 1: 1.2~1.5.
9. according to the method described in claim 1, it is characterized in that, in step (3) reaction temperature be -15~20 DEG C, preferably -
15~0 DEG C.
10. according to the method described in claim 1, it is characterized in that, in step (3), nitrating agent and isobide liquid are micro-
The residence time of channel reactor is 15~300s, preferably 15~60s.
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| WO2021109099A1 (en) * | 2019-12-06 | 2021-06-10 | 鲁南贝特制药有限公司 | Method for preparing isosorbide 5-mononitrate by using micro-channel continuous flow reactor |
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| WO2021109099A1 (en) * | 2019-12-06 | 2021-06-10 | 鲁南贝特制药有限公司 | Method for preparing isosorbide 5-mononitrate by using micro-channel continuous flow reactor |
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