CN105801358A - Preparation method for bromination reaction of dulcitol - Google Patents
Preparation method for bromination reaction of dulcitol Download PDFInfo
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- CN105801358A CN105801358A CN201410837993.8A CN201410837993A CN105801358A CN 105801358 A CN105801358 A CN 105801358A CN 201410837993 A CN201410837993 A CN 201410837993A CN 105801358 A CN105801358 A CN 105801358A
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- mitolactol
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Abstract
The invention relates to a preparation method for a bromination reaction of dulcitol. The preparation method for the bromination reaction of dulcitol is used, and the product whose average yield is 50% or above and average purity is 80% or above is obtained; and compared with the prior art, the effect is obviously better.
Description
Technical field
The present invention relates to chemical drugs field, the preparation method being specifically related to a kind of dulcitol bromo-reaction.
Background technology
Mitolactol is also known as dibromo galactitol, isomer for mitobronitol, although being typically considered alkylating agent, but its effect can not be explained by alkanisation theory completely, DNA synthesis is suppressed relatively RNA synthesis to suppress strong by it, its main metabolites in vivo is di-epoxide, for cell cycle nonspecific agent (CCNSA).The LD50 of rat is: oral 1400mg/kg, lumbar injection 470mg/kg.Act on similar to mitobronitol, after changing into the dianhydrodulcitol with diethyl epoxy construction in vivo, play alkanisation.
Synthesis about mitolactol, it has been disclosed that following preparation method:
Preparation method disclosed in " synthesis of anticarcinogen Dibromoducitol " " Jiangxi Medical College's journal " second phase in 1984 is: synthesizing Dibromoducitol optimum temperature from melampyrin at ambient pressure be 90 DEG C (± 1 DEG C) suitable heat time heating time is 9 hours；Hydrobromic acid concentration should be not less than 69-70%, and otherwise yield is substantially reduced；Recrystallization solution boiling point can not be too high, and heat time heating time can not be oversize, otherwise all can significantly reduce productivity.Adopting the recrystallization the highest yield of mitolactol that the method obtains was 40% (in mol).
" in aqueous solution the stability instruction high pressure liquid chromatography of Dibromoducitol " " medicine abroad. synthetic drug. Biochemical Drugs. preparation fascicle " the 10th volume the 4th phase in 1989, also the preparation method that refer to mitolactol: galactitol 400mg is placed in refrigeration glass reactor and is dissolved in dense HBr1.2ml, this container airtight, heating 12 hours in 70 water-baths, poured into by mixed liquor in 3g ice, DBD is crystallization immediately, after ice all dissolves, filtering, filtering residue is dissolved in hot methanol, recrystallization." yield of the method gained mitolactol is open, and dense HBr refers to the acetum of HBr.
Owing to dulcitol dissolubility in most solvent is all very poor, can select that the narrow range making bromating agent, reaction condition is required harshness, and method made above is suitable only for laboratory lab scale, because experimental raw all adopts analysis rank, during sample trial-production, all conditions can be disregarded cost and accomplishes the best, during production in enormous quantities, in order to reduce production cost, generally adopt industrial raw material, can not all there is the problem that yield is low, purity is low by mitolactol as laboratory lab scale obtains in condition, and be not suitable for the industrialization synthesis of more than feather weight.
By existing mitolactol technology of preparing, outside dehydrogenation bromic acid, if using remaining bromating agent, making consumption mostly be more than 10 times ability complete reactions of dulcitol weight, causing waste of solvent and environmental pollution.When selection hydrobromic acid is bromating agent, if obtaining the mitolactol that purity is higher, also must select highly purified solvent, as more than hydrobromic acid solution that concentration is 69%, the mitolactol of about 70% purity could be obtained, if adopting low concentration hydrobromic acid solution yield generally below 10%.The maximum concentration hydrobromic acid being commercially available on market is 62%, exceedes this concentration, it is necessary to oneself preparation, complex process, operating process danger close, and differs and be successfully prepared surely.
Summary of the invention
The preparation method that it is an object of the invention to provide a kind of dulcitol bromo-reaction.
The preparation method of a kind of dulcitol bromo-reaction of the present invention includes bromination step, it is characterised in that: described bromination process course of reaction carries out under elevated pressure；The pressure limit of described pressurization is 0.1-0.9Mpa.
Preferably: the pressure limit of described pressurization is 0.3-0.7Mpa；
Preferably: the pressure limit of described pressurization is 0.5Mpa.
Preferably: described being pressurised into passes into gas pressurized；
Preferably: described gas is be not involved in reaction and the gas that will not reaction be had undesirable effect；
Preferably: described gas is noble gas, carbon dioxide or helium.
The preparation method of a kind of dulcitol bromo-reaction of the present invention, it is characterized in that, described bromination process comprises the steps: that taking dulcitol puts in reactor, add hydrobromic acid solution, it is heated and pressurized to 0.1-0.9Mpa, react 16-24 hour under 50-80 DEG C of condition, obtain mitolactol solution.
Preferably: temperature during described reaction is 60-70 DEG C；
Preferably: temperature during described reaction is 62 DEG C；
Preferably: described hydrobromic acid solution concentration is 50-75%；
Preferably: described hydrobromic acid solution concentration is 60-70%；
Preferably: described hydrobromic acid solution concentration is 62%；
Preferably: 2-15 times that amount is dulcitol weight of described hydrobromic acid solution.
The preparation method of a kind of dulcitol bromo-reaction of the present invention, it is characterised in that comprise the steps:
1) take dulcitol and put in reactor, add dulcitol weight 2-15 times, concentration is the hydrobromic acid solution of 50-75%, is heated and pressurized to 0.1-0.9Mpa, reacts 16-24 hour under 50-80 DEG C of condition, being stirred continuously during reaction, reaction terminates and obtains mitolactol solution；
2) mitolactol solution left at room temperature 12-48 hour, filters, obtains mitolactol coarse crystallization；
3) mitolactol coarse crystallization recrystallizing methanol, obtains mitolactol.
Existing documents and materials report can prepare the mitolactol of yield more than 70% at short notice, and propose to adopt the hydrobromic acid of higher concentration to react (more than 62%), prior art requires that hydrobromic acid concentration is more than 69%, to skilled operator, a small amount of mitolactol could be obtained, only when hydrobromic acid concentration is more than 80%, the yield of about 30% could be obtained.Actually these technical schemes are not suitable for large-scale production, and reason is:
1, currently without commercial high concentration of hydrogen bromic acid, large-scale production maximum concentration is 62%, through transport, storage etc., to time actually used often concentration have been reduced to 60%.The maximum concentration hydrobromic acid being commercially available in the market is 62%, exceedes this concentration, it is necessary to oneself preparation, complex process, operating process danger close, and differs and be successfully prepared surely, and is not suitable for the industrialization synthesis of more than feather weight.Therefore use high concentration hydrobromic acid solution large-scale production unrealistic.
2, raw materials quality is without guarantee, and when high concentration, and reaction is excessively violent, and not only production environment is dangerous, and comprises too much impurity and cannot purification in mitolactol crystallization.
It is reversible reaction owing to dulcitol and hydrobromic acid react the reaction generating mitolactol, when reaction just starts, owing in reaction mass, bromine content is high, overresponse, easily generate terbromide, tetrabormated compound；Along with the carrying out of reaction, material concentration reduces, and the generation of mitolactol is increasingly difficult to, and because adding bromine deficiency during substitution reaction, can generate monobromo compound；Factors above is the main cause causing mitolactol yield too low.
After the present invention have passed through substantial amounts of experimentation and gropes, find in mitolactol preparation process, pressure is a very crucial factor, by controlling the pressure of course of reaction, enable to dulcitol bromination reaction and there is higher dibromo selectivity, overcome the problem that dulcitol bromination reaction side reaction is too many, it is possible to be obviously improved mitolactol yield, and finally can obtain the crystallization that purity is higher.
The present invention passes through pressure influence reaction process in bromination process, hydrobromic acid solution concentration selectivity is not strong, without requiring the hydrobromic acid solution using high concentration, hydrobromic acid solution concentration is between 20-80%, reaction all can be made to carry out smoothly and well, and the yield of mitolactol and purity can be made all to be significantly improved.
Present invention also offers the preferred preparation method of mitolactol, and give detailed process and technological parameter, by this preferred process control, make bromination reaction process coordinates bromating agent and the reaction temperature of debita spissitudo, by the response situation of different periods, step up reaction pressure, control pressure within the specific limits, dulcitol can be made optionally to be brominated agent in bromination process and to replace two primary hydroxyls generation mitolactols, can further reduce the generation of by-product, thus better improving yield and the purity of industrialization dibromo hexanhexol.
The preparation method of a kind of dulcitol bromo-reaction provided by the invention has the advantage that
1, mitolactol purity is high: the obtained mitolactol product purity of prior art, all below 70%, adopts the mitolactol that the present invention is prepared from, and purity is more than 80%.
2, adopt the present invention to be applied to industrialization and produce yield height during mitolactol: prior art is appropriate only for laboratory lab scale, during for large-scale production mitolactol yield below 40% (in mol), technical solution of the present invention process safety is reasonable, and the mitolactol average yield prepared is more than 50%.
Detailed description of the invention
Further illustrate the present invention by the examples below.It should be understood that embodiments of the invention are an illustration for the present invention rather than limitation of the present invention.The simple modifications that the present invention is carried out by the essence according to the present invention broadly falls into the scope of protection of present invention.Except as otherwise noted, the percent of the amount of alcohol in the present invention is percentage by volume, and v/v represents the volume ratio of solution.
Embodiment 1:
Taking 10kg dulcitol and put in reactor, addition dulcitol weight 15 times, concentration are the hydrobromic acid solution of 62%, and heating in water bath, to 62 DEG C, passes into nitrogen pressurization, and pressure is 0.5Mpa, and insulated and stirred is reacted 20 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 24 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 100 times of coarse crystallization weight, recrystallization at 2 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 57%, average purity is 87%.
Embodiment 2:
Taking 10kg dulcitol and put in reactor, addition dulcitol weight 2 times, concentration are the hydrobromic acid solution of 50%, and heating in water bath, to 50 DEG C, passes into argon pressurization, and pressure is 0.1Mpa, and insulated and stirred is reacted 16 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 12 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 80 times of coarse crystallization weight, recrystallization at 6 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 50%, average purity is 80%.
Embodiment 3:
Taking 10kg dulcitol and put in reactor, addition dulcitol weight 6 times, concentration are the hydrobromic acid solution of 75%, and heating in water bath, to 50 DEG C, passes into helium pressurization, and pressure is 0.9Mpa, and insulated and stirred is reacted 16 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 18 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 70 times of coarse crystallization weight, recrystallization at 8 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 53%, average purity is 84%.
Embodiment 4:
Taking 10kg dulcitol and put in reactor, addition dulcitol weight 4 times, concentration are the hydrobromic acid solution of 60%, and heating in water bath, to 70 DEG C, passes into carbon dioxide pressurization, and pressure is 0.3Mpa, and insulated and stirred is reacted 18 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 24 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 60 times of coarse crystallization weight, recrystallization at 4 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 57%, average purity is 87%.
Embodiment 5:
Taking 10kg dulcitol and put in reactor, addition dulcitol weight 8 times, concentration are the hydrobromic acid solution of 70%, and heating in water bath, to 60 DEG C, passes into carbon dioxide pressurization, and pressure is 0.7Mpa, and insulated and stirred is reacted 20 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 48 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 50 times of coarse crystallization weight, recrystallization at 3 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 54%, average purity is 83%.
Embodiment 6:
Taking 8kg dulcitol and put in reactor, addition dulcitol weight 10 times, concentration are the hydrobromic acid solution of 50%, and heating in water bath, to 80 DEG C, passes into nitrogen pressurization, and pressure is to 0.2Mpa, under these conditions stirring reaction 20 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 30 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 100 times of coarse crystallization weight, recrystallization at 7 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 56%, average purity is 86%.
Comparative example 1: with reference to the embodiment of the present invention 1, no pressure
Taking 10kg dulcitol and put in reactor, addition dulcitol weight 15 times, concentration are the hydrobromic acid solution of 62%, and heating in water bath is to 62 DEG C, and insulated and stirred is reacted 20 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 24 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 100 times of coarse crystallization weight, recrystallization at 2 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 37%, average purity is 64%.
Comparative example 2: with reference to the embodiment of the present invention 2, no pressure
Taking 10kg dulcitol and put in reactor, addition dulcitol weight 2 times, concentration are the hydrobromic acid solution of 50%, and heating in water bath is to 50 DEG C, and insulated and stirred is reacted 16 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 12 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 80 times of coarse crystallization weight, recrystallization at 6 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 35%, average purity is 64%.
Comparative example 3: with reference to the embodiment of the present invention 3, no pressure
Taking 10kg dulcitol and put in reactor, addition dulcitol weight 6 times, concentration are the hydrobromic acid solution of 75%, and heating in water bath is to 50 DEG C, and insulated and stirred is reacted 16 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 18 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 70 times of coarse crystallization weight, recrystallization at 8 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 35%, average purity is 63%.
Comparative example 4: with reference to the embodiment of the present invention 4, no pressure
Taking 10kg dulcitol and put in reactor, addition dulcitol weight 4 times, concentration are the hydrobromic acid solution of 60%, and heating in water bath is to 70 DEG C, and insulated and stirred is reacted 18 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 24 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 60 times of coarse crystallization weight, recrystallization at 4 DEG C, obtains mitolactol.
Experimental result: mitolactol yield 33%, purity is 63%.
Comparative example 5: with reference to the embodiment of the present invention 5, no pressure
Taking 10kg dulcitol and put in reactor, addition dulcitol weight 8 times, concentration are the hydrobromic acid solution of 70%, and heating in water bath is to 60 DEG C, and insulated and stirred is reacted 20 hours, obtains mitolactol solution；Mitolactol solution left at room temperature 48 hours, filters, obtains mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 50 times of coarse crystallization weight, recrystallization at 3 DEG C, obtains mitolactol.
Experimental result: mitolactol yield 32%, purity is 59%.
Process ration is tested:
Experimental technique: according to reaction pressure disclosed by the invention, reaction temperature and hydrobromic acid solution concentration, prepares embodiment 1-6 sample；Want, on the preparation method basis of embodiment 1-5, to deduct the reaction condition of pressurization, prepare comparative example 1-5 sample respectively.Result is in Table 1.
Yield computational methods:
Method for detecting purity: method for detecting purity: according to high effective liquid chromatography for measuring, by external standard method with calculated by peak area, to obtain final product.Reference substance is laboratory self-control, and purity is 98.57%.
Table 1: mitolactol yield and purity
Table 1 result shows: the operating procedure of comparative example 1-5 corresponding embodiment 1-5 respectively, only deduct compressive reaction condition, the yield of mitolactol has significant difference with purity compared with pressurization, and average yield is between the 59-70% of embodiment, and average purity is between the 68-80% of embodiment.
Test result indicate that: by response parameter provided by the invention, it is possible to obtain being substantially better than existing technical scheme and prepare the effect of gained mitolactol.
Although, above use generality explanation, detailed description of the invention and test, the present invention is described in detail, but on basis of the present invention, it is possible to it is made some modifications or improvements, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to the scope of protection of present invention.
Claims (14)
1. a preparation method for dulcitol bromo-reaction, including bromination step, it is characterised in that: described bromination process course of reaction carries out under elevated pressure；The pressure limit of described pressurization is 0.1-0.9Mpa.
2. the method for claim 1, it is characterised in that: the pressure limit of described pressurization is 0.3-0.7Mpa.
3. the method for claim 1, it is characterised in that the pressure of described pressurization is 0.5Mpa.
4. the method for claim 1, it is characterised in that: described being pressurised into passes into gas pressurized.
5. method as claimed in claim 4, it is characterised in that: described gas is be not involved in reaction and the gas that will not reaction be had undesirable effect.
6. method according to claim 5, it is characterised in that: described gas is noble gas, carbon dioxide or helium.
7. the method for claim 1, it is characterised in that described bromination process comprises the steps:
Take dulcitol and put in reactor, add hydrobromic acid solution, be heated and pressurized to 0.1-0.9Mpa, react 16-24 hour under 50-80 DEG C of condition, obtain mitolactol solution.
8. method as claimed in claim 7, it is characterised in that temperature during described reaction is 60-70 DEG C.
9. method as claimed in claim 7, it is characterised in that temperature during described reaction is 62 DEG C.
10. method as claimed in claim 7, it is characterised in that described hydrobromic acid solution concentration is 50-75%.
11. method as claimed in claim 7, it is characterised in that described hydrobromic acid solution concentration is 60-70%.
12. method as claimed in claim 7, it is characterised in that described hydrobromic acid solution concentration is 62%.
13. the method as described in any one of claim 10-12, it is characterised in that 2-15 times that amount is dulcitol weight of described hydrobromic acid solution.
14. the method for claim 1, it is characterised in that comprise the steps:
1) take dulcitol and put in reactor, add dulcitol weight 2-15 times, concentration is the hydrobromic acid solution of 50-75%, is heated and pressurized to 0.1-0.9Mpa, reacts 16-24 hour under 50-80 DEG C of condition, being stirred continuously during reaction, reaction terminates and obtains mitolactol solution；
2) mitolactol solution left at room temperature more than 12 hours, filter, obtain mitolactol coarse crystallization；
3) mitolactol coarse crystallization recrystallizing methanol, obtains mitolactol.
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| CN109384773A (en) * | 2017-08-02 | 2019-02-26 | 新发药业有限公司 | A kind of synthetic method of inexpensive, high-purity S- glycidol phthalimide |
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| CN109384773A (en) * | 2017-08-02 | 2019-02-26 | 新发药业有限公司 | A kind of synthetic method of inexpensive, high-purity S- glycidol phthalimide |
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