CN108586477B - A kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrate - Google Patents
A kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrate Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract
The invention belongs to medical synthesis fields, a kind of method for specifically disclosing micro passage reaction synthesis 5- Isosorbide Mononitrate, nitrating agent and isobide liquid are pumped into micro passage reaction respectively and carry out hybrid reaction by the present invention, after the reaction was completed, product is exported from micro passage reaction to flow out, post-treated, isolate and purify to obtain purpose product 5- Isosorbide Mononitrate.Method provided by the present invention, the reaction time is short, relative to traditional handicraft safety, and the yield of 5- Isosorbide Mononitrate is greatly improved.
Description
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a method of synthesis 5- Isosorbide Mononitrate, it is special
It is not related to a kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrate.
Background technique
5- Isosorbide Mononitrate (Isosorbide-5-Nitrae: 3,6- bis- dehydrations-D-glucitol -5- nitrate, compound in structural formula such as Formulas I
It 1) is Isosorbide Nitrate (Isosorbide-5-Nitrae: 3,6- bis- dehydrations-D-glucitol -2,5- dinitrate, compound 2 in structural formula such as Formulas I) In
Intracorporal main metabolites, compared to Isosorbide Nitrate and 2- Isosorbide Mononitrate (Isosorbide-5-Nitrae: 3,6- bis- dehydration-D- sorbs
Alcohol -2- nitrate, 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 Mononitrate has been widely used in clinic at present, becomes the fiest-tire medication of antianginal.
The synthetic route report of 5- Isosorbide Mononitrate 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 specific route of direct nitrification process are as follows: with isobide (Isosorbide-5-Nitrae: in 3,6- bis- dehydrations-D-glucitol, structural formula such as Formulas I
Compound 4) it is after starting material is reacted with 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, glycerol 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), it is target product when 5- hydroxyl nitric acid esterifications that two hydroxyls of isobide, which are asymmetrical, and 2- hydroxyls
Nitric acid esterification products be 2- Isosorbide Mononitrate.So synthesizing 5- Isosorbide Mononitrate difficulty by direct nitrification process
Bigger, yield is lower.Currently, the yield of directly nitrification process synthesis 5- Isosorbide Mononitrate not can exceed that 40%.
Another main problem existing for direct nitrification process synthesis 5- Isosorbide Mononitrate is that process safety risk is big,
Since nitrating agent and nitric acid ester products itself all have explosivity, especially containing there are two the Isosorbides of itrate group
Ester can be generated largely in the synthesis process, need strict 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,
Reduce because mass transfer, heat transfer it is bad caused by side reaction and security risk, and reaction liquid be 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, since uninterrupted flux reaction may be implemented, Nian Tongliang can achieve 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.
Summary of the invention
Low for yield present in above-mentioned nitrification process direct in the prior art, 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 and efficient in micro passage reaction
The method of Isosorbide Nitrate.
Compared with the chemical reaction that popular response container carries out, micro passage reaction is had the advantage that
(1) microchannel width and depth are smaller in reactor, and general tens arrive several hundred microns, make between reactant diffusion away from
From greatly shortening, mass transfer velocity is fast, and reactant can be sufficiently mixed in the short time during flowing.
(2) large specific surface area of microchannel has very big heat exchanger effectiveness, even violent exothermic reaction, moment
Releasing a large amount of reaction heat can also remove in time, and maintaining reaction temperature in safe range, since reaction-ure mixture is few, is conducted heat
Fastly, 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, not only can be reduced 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 mentions
Height, side reaction are less.
(5) it is reacted by the way of continuously flowing in micro passage reaction, chemistry cracking for reaction speed
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 and efficiently is utilized in micro passage reaction
Isobide carries out nitric acid esterification, and then synthesizing 5- Isosorbide Mononitrate is the direction that we study.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 to improve the activity of 5- hydroxyls of isobide in order to obtain, and inventor grinds by further test
Study carefully discovery, reduces reaction temperature and be conducive to improve the activity of isobide 5- hydroxyl, and then improve purpose product 5- single nitric acid
The yield of Soquad.
Inventor also found the addition by-product Isosorbide Nitrate into reaction system, and Isosorbide can be effectively reduced
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 respectively and carry out hybrid reaction by the present invention,
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-
The reaction solution of channel reactor outlet outflow is post-treated, isolates and purifies to obtain 5- Isosorbide Mononitrate.
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 Mononitrate is improved, reduce the generation of by-product 2- Isosorbide Mononitrate.
Goal of the invention of the invention is achieved in that
A kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrate, 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 reaction was completed, product goes out from micro passage reaction
Mouthful outflow, it is post-treated, isolate and purify to obtain target product 5- Isosorbide Mononitrate.
Specifically, a kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrate, includes the following steps:
(1) preparation of nitrating agent: at 0~10 DEG C, fuming nitric aicd being slowly dropped in acetic anhydride, is kept the temperature spare.
(2) preparation of isobide liquid: isobide and Isosorbide Nitrate are dissolved into acetic acid and secondary solvent, stirred
It mixes to dissolution 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 reaction was completed, obtains efflux.
(4) efflux obtained by step (3) is post-treated, isolate and purify to obtain target product 5- Isosorbide Mononitrate.
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, methylene chloride, tetrahydrofuran and 2- methyltetrahydrofuran.Implement at one
In example, secondary solvent described in step (2) is the mixed solution of tetrahydrofuran and acetone, ethyl acetate or methylene chloride；Another
In one embodiment, secondary solvent described in step (2) is 2- methyltetrahydrofuran and acetone, ethyl acetate or methylene chloride
Mixed solution；In a preferred embodiment, secondary solvent described in step (2) is tetrahydrofuran or 2- methyl tetrahydro furan
It mutters；In an optimal embodiment, secondary solvent described in step (2) is 2- methyltetrahydrofuran, is contained in secondary solvent
When tetrahydrofuran or 2- methyltetrahydrofuran, the activity of 5- hydroxyls of isobide is significantly higher than in secondary solvent without containing 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 coupled 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 multiplied by connection plate number) control.The feed liquor of feed liquid is controlled by metering pump independent, flow
Range can be adjusted in 1~100mL/min.The plate of microchannel can be increased or decreased by being connected in series 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 product is made, 5- Isosorbide Mononitrate sodium salt crude product is acidified again, is refining to obtain
To target product 5- Isosorbide Mononitrate.
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 Mononitrate through direct nitrification process using micro passage reaction, have with
Lower advantage:
1, by-product Isosorbide Nitrate in the reaction system, 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,
It is greatly lowered because nitrifying very exothermic and material itself bring security risk.
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 the position 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 acid
The yield of sorb ester, reduces the generation of by-product 2- Isosorbide Mononitrate, furan nucleus solvent can make the position 5- of isobide/
2- selectivity are improved by 5.2: 1 to 8.0: 1 or more.The yield of 5- Isosorbide Mononitrate of the present invention can be mentioned 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 within more than ten seconds to a few minutes by a few hours of autoclave, substantially reduces the process time,
It can realize that the safety of production capacity expands by serialization, equipment scaleization.
Specific embodiment
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 through commercial channels.
Embodiment 1
(1) it the preparation of nitrating agent: in 500mL dry there-necked flask, is added acetic anhydride (260.0g, 2.5mol), control
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), after being added dropwise, keeps the temperature spare.
(2) in 2L dry there-necked flask, isobide (250.0g, 1.7mol), nitre the preparation of isobide liquid: is added
750mL acetic acid/ethyl acetate (v/v=2: 1) mixed solvent is added in sour Soquad (12.5g, 0.053mol), stirs molten
It is spare after solution.
(3) nitrating agent and isobide liquid are fed in micro passage reaction by respective metering pump and mix instead
It answers, sets nitrating agent flow as 15mL/min, the flow of isobide liquid is 45mL/min, and control 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 water is added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 59.4% is made, HPLC detects purity 99.10%.
Embodiment 2
(1) it the preparation of nitrating agent: in 1L dry there-necked flask, is added acetic anhydride (347.0g, 3.4mol), temperature control 0
~10 DEG C, fuming nitric aicd (108.0g, 1.7mol) is slowly added dropwise, after being added dropwise, keeps the temperature spare.
(2) in 2L dry there-necked flask, isobide (250.0g, 1.7mol), nitre the preparation of isobide liquid: is added
750mL acetic acid/methylene chloride (v/v=1: 2) mixed solvent is added in sour Soquad (37.5g, 0.159mol), stirs molten
It is spare after solution.
(3) nitrating agent and isobide liquid are fed in micro passage reaction by respective metering pump and mix instead
It answers, sets nitrating agent flow as 5mL/min, the flow of isobide liquid is 15mL/min, and control 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 water is added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 56.2% is made, HPLC detects purity 99.08%.
Embodiment 3
(1) it the preparation of nitrating agent: in 1L dry there-necked flask, is added acetic anhydride (347.0g, 3.4mol), temperature control 0
~10 DEG C, fuming nitric aicd (108.0g, 1.7mol) is slowly added dropwise, after being added dropwise, keeps the temperature spare.
(2) in 2L dry there-necked flask, isobide (250.0g, 1.7mol), nitre the preparation of isobide liquid: is added
It is mixed that 950mL acetic acid/methylene chloride/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 in micro passage reaction by respective metering pump and mix instead
It answers, sets nitrating agent flow as 20mL/min, the flow of isobide liquid is 50mL/min, and control reaction temperature is 10 DEG C,
It connects 5 pieces of templates, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction is 43s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified water is added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 62.8% is made, HPLC detects purity 99.14%.
Embodiment 4
(1) it the preparation of nitrating agent: in 500mL dry there-necked flask, is added acetic anhydride (208.0g, 2.0mol), control
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), after being added dropwise, keeps the temperature spare.
(2) in 2L dry there-necked flask, isobide (250.0g, 1.7mol), nitre the preparation of isobide liquid: is added
Sour Soquad (50.0g, 0.212mol), addition 800mL acetic acid/ethyl acetate/2- methyltetrahydrofuran (v/v/v=2: 1:
1) mixed solvent, it is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed in micro passage reaction by respective metering pump and mix instead
It answers, sets nitrating agent flow as 40mL/min, the flow of isobide liquid is 80mL/min, and control 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 water is added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 65.5% is made, HPLC detects purity 99.08%.
Embodiment 5
(1) it the preparation of nitrating agent: in 1L dry there-necked flask, is added acetic anhydride (208.0g, 2.0mol), temperature control 0
~10 DEG C, fuming nitric aicd (108.0g, 1.7mol) is slowly added dropwise, after being added dropwise, keeps the temperature spare.
(2) in 2L dry there-necked flask, isobide (250.0g, 1.7mol), nitre the preparation of isobide liquid: is added
It is molten that the mixing of 800mL acetic acid/acetone/tetrahydrofuran (v/v/v=2: 1: 1) is added in sour Soquad (50.0g, 0.212mol)
Agent, it is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed in micro passage reaction by respective metering pump and mix instead
It answers, sets nitrating agent flow as 30mL/min, the flow of isobide liquid is 30mL/min, and control reaction temperature is -15 DEG C,
It connects 5 pieces of templates, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction is 60s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified water is added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 68.8% is made, HPLC detects purity 99.18%.
Embodiment 6
(1) it the preparation of nitrating agent: in 500mL dry there-necked flask, is added acetic anhydride (260.0g, 2.5mol), control
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), after being added dropwise, keeps the temperature spare.
(2) in 2L dry there-necked flask, isobide (250.0g, 1.7mol), nitre the preparation of isobide liquid: is added
750mL acetic acid/2- methyltetrahydrofuran (v/v=2: 1) mixed solvent is added in sour Soquad (50.0g, 0.212mol),
It is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed in micro passage reaction by respective metering pump and mix instead
It answers, sets nitrating agent flow as 20mL/min, the flow of isobide liquid is 60mL/min, and control reaction temperature is -10 DEG C,
It connects 5 pieces of templates, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction is 38s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified water is added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 69.2% is made, HPLC detects purity 99.16%.
Embodiment 7
(1) it the preparation of nitrating agent: in 500mL dry there-necked flask, is added acetic anhydride (260.0g, 2.5mol), control
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), after being added dropwise, keeps the temperature spare.
(2) in 2L dry there-necked flask, isobide (250.0g, 1.7mol), nitre the preparation of isobide liquid: is added
750mL acetone/tetrahydrofuran (v/v=2: 1) mixed solvent is added in sour Soquad (25.0g, 0.106mol), stirs molten
It is spare after solution.
(3) nitrating agent and isobide liquid are fed in micro passage reaction by respective metering pump and mix instead
It answers, sets nitrating agent flow as 20mL/min, the flow of isobide liquid is 60mL/min, and control reaction temperature is -10 DEG C,
It connects 5 pieces of templates, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction is 38s.
(4) reaction efflux is concentrated under reduced pressure, addition 2L purified water, after stirring and crystallizing, filters and removes Isosorbide Nitrate, filter
Liquid samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 66.5% is made, HPLC detects purity 99.13%.
Comparative example 1
It in 100mL dry there-necked flask, is added acetic anhydride (23.0g, 0.22mol), 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, keeps the temperature spare.
In 500mL dry there-necked flask, it is added isobide (25.0g, 0.17mol), acetic acid (50mL), stirring and dissolving
Afterwards, temperature control is not higher than 10 DEG C, and above-mentioned nitrating agent reaction is slowly added dropwise, and end of reaction adds after reaction efflux is concentrated under reduced pressure
Enter 2L purified water, after stirring and crystallizing, filter and remove Isosorbide Nitrate, filtrate samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 34.8% is made, HPLC detects purity 98.82%.
Comparative example 2
It in 100mL dry there-necked flask, is added acetic anhydride (23.0g, 0.22mol), 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, keeps the temperature spare.
In 500mL dry there-necked flask, 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 water will be added, after stirring and crystallizing, filter and remove Isosorbide Nitrate, filtrate after reaction efflux is concentrated under reduced pressure
GC detection is 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 product.It is acidified, smart
Target product, total recovery 36.1% is made, HPLC detects purity 98.91%.
Comparative example 3
It in 100mL dry there-necked flask, is added acetic anhydride (23.0g, 0.22mol), 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, keeps the temperature spare.
In 500mL dry there-necked flask, it is added isobide (25.0g, 0.17mol), acetic acid (50mL), 2- methyl four
Hydrogen furans (25mL), after stirring and dissolving, temperature control is not higher than 0 DEG C, above-mentioned nitrating agent reaction is slowly added dropwise, end of reaction will be anti-
After answering efflux to be concentrated under reduced pressure, 2L purified water is added, after stirring and crystallizing, filters and removes Isosorbide Nitrate, filtrate samples GC inspection
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 product.It is acidified, smart
Target product, total recovery 39.8% is made, HPLC detects purity 98.97%.
Comparative example 4
It in 100mL dry there-necked flask, is added acetic anhydride (23.0g, 0.22mol), 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, keeps the temperature spare.
In 500mL dry there-necked flask, it is added 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
State nitrating agent reaction, 2L purified water will be added, after stirring and crystallizing, suction filtration is removed after reaction efflux is concentrated under reduced pressure in end of reaction
Isosorbide Nitrate is gone, filtrate samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 42.6% is made, HPLC detects purity 99.00%.
Comparative example 5
(1) it the preparation of nitrating agent: in 500mL dry there-necked flask, is added acetic anhydride (260.0g, 2.5mol), control
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), after being added dropwise, keeps the temperature spare.
(2) in 2L dry there-necked flask, isobide (250.0g, 1.7mol), nitre the preparation of isobide liquid: is added
750mL acetic acid/2- methyltetrahydrofuran (v/v=2: 1) mixed solvent is added in sour Soquad (50.0g, 0.212mol),
It is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed in micro passage reaction by respective metering pump and mix instead
It answers, sets nitrating agent flow as 40mL/min, the flow of isobide liquid is 20mL/min, and control reaction temperature is -10 DEG C,
It connects 5 pieces of templates, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction is 38s.
(4) 2L purified water will be added, after stirring and crystallizing, filter and remove Isosorbide after reaction efflux is concentrated under reduced pressure
Ester, filtrate sample GC detection, 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 product.It is acidified, smart
Target product, total recovery 49.4% is made, HPLC detects purity 99.03%.
Comparative example 6
(1) it the preparation of nitrating agent: in 500mL dry there-necked flask, is added acetic anhydride (260.0g, 2.5mol), control
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), after being added dropwise, keeps the temperature spare.
(2) in 2L dry there-necked flask, isobide (250.0g, 1.7mol), nitre the preparation of isobide liquid: is added
750mL acetic acid/methanol (v/v=2: 1) mixed solvent is added, after stirring and dissolving in sour Soquad (50.0g, 0.212mol)
It is spare.
(3) nitrating agent and isobide liquid are fed in micro passage reaction by respective metering pump and mix instead
It answers, sets nitrating agent flow as 20mL/min, the flow of isobide liquid is 60mL/min, and control reaction temperature is -10 DEG C,
It connects 5 pieces of templates, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction is 38s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified water is added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 35.4% is made, HPLC detects purity 99.02%.
Comparative example 7
(1) it the preparation of nitrating agent: in 500mL dry there-necked flask, is added acetic anhydride (260.0g, 2.5mol), control
0~10 DEG C of temperature, is slowly added dropwise fuming nitric aicd (108.0g, 1.7mol), after being added dropwise, keeps the temperature spare.
(2) it the preparation of isobide liquid: in 2L dry there-necked flask, is added isobide (250.0g, 1.7mol), adds
Enter 750mL acetic acid/2- methyltetrahydrofuran (v/v=2: 1) mixed solvent, it is spare after stirring and dissolving.
(3) nitrating agent and isobide liquid are fed in micro passage reaction by respective metering pump and mix instead
It answers, sets nitrating agent flow as 20mL/min, the flow of isobide liquid is 60mL/min, and control reaction temperature is -10 DEG C,
It connects 5 pieces of templates, liquid holdup 50mL, reaction time of the reaction solution in micro passage reaction is 38s.
(4) after reaction efflux is concentrated under reduced pressure, 2L purified water is added, after stirring and crystallizing, filters and removes Isosorbide Nitrate,
Filtrate samples GC detection, 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 product.It is acidified, smart
Target product, total recovery 64.8% is made, HPLC detects purity 99.06%.
Claims (13)
1. a kind of method of micro passage reaction synthesis 5- Isosorbide Mononitrate, which is characterized in that specific steps are as follows:
(1) preparation of nitrating agent: at 0 ~ 10 DEG C, fuming nitric aicd being slowly dropped in acetic anhydride, is kept the temperature spare；
(2) preparation of isobide liquid: isobide and Isosorbide Nitrate are dissolved into acetic acid and secondary solvent, and stirring is extremely
Dissolution is completely, 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 reaction was completed, obtains efflux；
(4) efflux obtained by step (3) is post-treated, isolate and purify to obtain purpose product 5- Isosorbide Mononitrate；
Wherein, in step (2), the secondary solvent is selected from acetone, ethyl acetate, methylene chloride, tetrahydrofuran and 2- methyl
One or more of tetrahydrofuran.
2. the method according to claim 1, wherein in step (1), the molar ratio of fuming nitric aicd and acetic anhydride is
1:1~2。
3. according to the method described in claim 2, it is characterized in that, in step (1), the molar ratio of fuming nitric aicd and acetic anhydride is
1:1~1.5。
4. the method according to claim 1, wherein isobide and the mass ratio of Isosorbide Nitrate are 1:
0.05~0.3。
5. the method according to claim 1, wherein in step (2), the secondary solvent be tetrahydrofuran or
2- methyltetrahydrofuran.
6. the method according to claim 1, wherein the volume ratio of acetic acid and secondary solvent is 1 in step (2):
0.5~2。
7. the method according to claim 1, wherein the mass volume ratio of isobide and acetic acid be 1:1 ~ 2,
Middle quality is in terms of g, and volume is in terms of mL.
8. the method according to claim 1, wherein 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.
9. according to the method described in claim 8, 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 1:1.2 ~ 1.5.
10. the method according to claim 1, wherein reaction temperature is -15 ~ 20 DEG C in step (3).
11. according to the method described in claim 10, it is characterized in that, reaction temperature is -15 ~ 0 DEG C in step (3).
12. the method according to claim 1, wherein nitrating agent and isobide liquid are micro- in step (3)
The residence time of channel reactor is 15 ~ 300 s.
13. according to the method for claim 12, which is characterized in that in step (3), nitrating agent and isobide liquid are micro-
The residence time of channel reactor is 15 ~ 60s.
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