CN105801364B - A kind of preparation method of bromo hexitol - Google Patents
A kind of preparation method of bromo hexitol Download PDFInfo
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- CN105801364B CN105801364B CN201410839711.8A CN201410839711A CN105801364B CN 105801364 B CN105801364 B CN 105801364B CN 201410839711 A CN201410839711 A CN 201410839711A CN 105801364 B CN105801364 B CN 105801364B
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Abstract
The present invention relates to a kind of preparation methods of bromo hexitol.The preparation method of bromo hexitol provided by the invention can obtain average yield 50% or more, and reaction product of the average purity 80% or more is with obvious effects to be better than the prior art.
Description
Technical field
The present invention relates to chemical drugs fields, and in particular to a kind of preparation method of bromo hexitol.
Background technology
Mitolactol is also known as dibromo galactitol, is the isomers of dibromannitol, although being typically considered alkanisation
Agent, but its effect cannot be explained with alkanisation theory completely inhibits DNA synthesis to inhibit strong compared with RNA synthesis, it is in vivo
Main metabolites are di-epoxide, are cell cycle nonspecific agent (CCNSA).The LD50 of rat is：Oral 1400mg/kg, abdomen
Chamber injects 470mg/kg.Effect is similar to dibromannitol, is converted to the dianhydrogalactitol with diethyl epoxy construction in vivo
Afterwards, alkanisation is played.
Synthesis about mitolactol, it has been disclosed that following preparation method：
" synthesis of anticancer agent Dibromoducitol "《Jiangxi Medical College's journal》Preparation method is disclosed in the second phase in 1984：
Be under normal pressure 90 DEG C (± 1 DEG C) suitable heating time from melampyrin synthesis Dibromoducitol optimum temperature it is 9 hours；Hydrobromic acid
Concentration should be not less than 69-70%, and otherwise yield substantially reduces；Recrystallization solution boiling point cannot be too high, and heating time cannot be too long,
Otherwise yield can all be significantly reduced.Use the recrystallization mitolactol highest yield that this method obtains be 40% (with mole
Meter).
" stability of Dibromoducitol indicates high pressure liquid chromatography in aqueous solution "《External medicine synthetic drug Biochemical Drugs
Preparation fascicle》The 4th phase of volume 10 in 1989, also refer to the preparation method of mitolactol：Galactitol 400mg is placed in cold
Freeze glass reaction kettle and be dissolved in dense HBr 1.2ml, the closed container, is heated 12 hours in 70 DEG C of water-baths, mixed liquor is fallen
Enter in 3g ice, DBD is crystallized immediately, and after ice all dissolving, filtration, filter residue is dissolved in hot methanol, is recrystallized." this method gained
The yield of mitolactol is not open, and dense HBr refers to the acetum of HBr.
Since dissolubility is all very poor in most solvent for dulcitol, the narrow range for making bromating agent can be selected, to anti-
Condition is answered to require harsh, and method made above is suitable only for laboratory lab scale, because experimental raw is all made of analysis rank, sample
All conditions can disregard cost and accomplish most preferably when trial-production, when mass production, in order to reduce production cost, generally use industry
Grade raw material, condition can not possibly have that yield is low, purity is low such as the mitolactol that laboratory lab scale obtains, and uncomfortable
It is combined to for industry more than feather weight.
Mitolactol technology is prepared by existing, in addition to hydrobromic acid, if using remaining bromating agent, usage amount is mostly winged euonymus
10 times or more of alcohol weight could react completely, cause waste of solvent and environmental pollution.When selection hydrobromic acid is bromating agent, if
Obtain the higher mitolactol of purity, must also select the solvent of high-purity, such as a concentration of 69% hydrobromic acid solution with
On, the mitolactol of 70% or so purity could be obtained, if use low concentration hydrobromic acid solution yield usually 10% with
Under.The maximum concentration hydrobromic acid being commercially available in the market is 62%, is more than this concentration, it is necessary to which oneself is prepared, complex process, behaviour
Make process danger close, and differs and be surely successfully prepared.
Invention content
The object of the present invention is to provide a kind of preparation methods of bromo hexitol.
The preparation method of bromo hexitol of the present invention includes bromination step, it is characterised in that is included the following steps：
Take dulcitol to set in reaction vessel, be added 1-10 times of dulcitol weight, a concentration of 5-60% hydrobromic acid organic acid
Solution, meanwhile, oxidant is added by the 1-15% of dulcitol quality, closed reaction vessel is passed through bromination hydrogen, and pressure is kept
Between 0.1-1.0Mpa, it is heated to 30-55 DEG C, is persistently stirred to react 10-30 hours.
Preferably, the oxidant is perchloric acid, potassium hyperchlorate, potassium permanganate, sodium hypochlorite, hydrogen peroxide.
Preferably, described be stirred to react is 10-28 hours.
Preferably, described be stirred to react is 20-25 hours.
Preferably, the temperature when reaction is 40-50 DEG C.
Preferably, the hydrobromic acid organic acid soln is hydrobromic acid glacial acetic acid solution or hydrobromic acid formic acid solution or hydrogen bromine
Sour propionic acid solution or hydrobromic acid butyric acid solution.
Preferably, a concentration of 30-60% of hydrobromic acid organic acid soln.
Preferably, the hydrobromic acid organic acid soln is prepared as follows and obtains：At a temperature of less than -5 DEG C, bromination
Hydrogen is passed through in organic acid, obtains the hydrobromic acid organic acid soln of a concentration of 30-60%.
Preferably, the organic acid is glacial acetic acid, formic acid, propionic acid or butyric acid.
The preparation method of bromo hexitol of the present invention, includes the following steps：
1) it takes dulcitol to set in reaction vessel, it is organic that 1-10 times of dulcitol weight, the hydrobromic acid of a concentration of 5-60% is added
Acid solution, meanwhile, oxidant is added by the 1-15% of dulcitol quality, closed reaction vessel is passed through bromination hydrogen, and pressure is protected
It holds between 0.1-1.0Mpa, keeps temperature to 30-55 DEG C, be persistently stirred to react 10-30 hours；
2) purified water that 1-10 times of dulcitol weight is added stirs 2-3 hours, and supernatant is pumped after standing at least 12 hours,
0.1-2 times of dulcitol weight, a concentration of 70-95% ethyl alcohol are added, is stirred evenly, is filtered, filter residue is rinsed with purified water into
Property after, washed with 1-5 times of dulcitol weight, a concentration of 70-95% ethyl alcohol, by the solid being collected at 25-35 DEG C dry 24-
48 hours, obtain mitolactol.
During dulcitol and hydrobromic acid organic acid reaction, key reaction substance is dulcitol and hydrogen bromide, and hydrogen bromide is molten
Solution is in organic acid soln, when solution concentration drops to certain proportion, hydrogen bromide be precipitated it is extremely difficult, cause reaction slowly or
It cannot be further continued for carrying out.Oxidant is added in reaction solution, can promote bromine from the hydrobromic acid organic acid soln of low concentration
It is slowly precipitated, is oxidized to simple substance bromine, while increasing the yield of mitolactol, reduce the addition of hydrobromic acid organic acid soln
Amount, it is cost-effective, mitigate environmental pollution.
HBr gases are passed through in reaction whole process, keeps bromine to maintain saturation state always in the reaction, reaction rate can be improved
And the yield of mitolactol.
A kind of preparation method of bromo hexitol provided by the invention has the following advantages：
1, mitolactol purity is high：The obtained mitolactol product purity of the prior art 70% hereinafter, using
The mitolactol that the present invention is prepared, purity reach 80% or more.
High income when 2, using the present invention applied to industrialization production mitolactol：The prior art is appropriate only for laboratory
Lab scale, large-scale production mitolactol yield below 40% (in mol), present invention process safe and reasonable, obtained two
Bromine dulcitol average yield is 50% or more.
3, low concentration hydrobromic acid solution is easy to get, and reduce the injury in big production to operator's health and
It reduces environmental pollution.
4, mitolactol preparation method disclosed in the prior art has been all made of high concentration of hydrogen bromic acid, in high temperature, short time
It is interior reaction and obtain.Because the reagent operation of high concentration is dangerous big, and high-temperature operation is difficult to control the precise procedural of reaction.This
Invention is not only high to equipment requirement and easily controllable using compared with low temperature conditioned response, can adjust at any time, although reaction
Time is longer than the prior art, but the yield of gained reactant of the present invention and purity are above prior art products obtained therefrom.
Specific implementation mode
It is further illustrated the present invention below by embodiment.It should be understood that the embodiment of the present invention is for illustrating
The present invention is rather than limiting the invention.The simple modifications that essence according to the present invention carries out the present invention belong to the present invention
Claimed range.Unless otherwise indicated, the percentage of the amount of alcohol in the present invention is percentage by volume, and v/v indicates solution
Volume ratio.
Embodiment 1：Prepare hydrobromic acid ice organic acid soln
At a temperature of -5 DEG C, bromination hydrogen is passed through in organic acid, obtains a concentration of 30% hydrobromic acid organic acid soln.
Embodiment 2：Prepare hydrobromic acid organic acid soln
At a temperature of -10 DEG C, bromination hydrogen is passed through in organic acid, obtain a concentration of 60% hydrobromic acid organic acid it is molten
Liquid.
Embodiment 3：
1) it takes 5.0kg dulcitols to set in reaction kettle, it is molten that 4 times of dulcitol weight, a concentration of 45% hydrobromic acid glacial acetic acid is added
Liquid, meanwhile, hydrogen peroxide is added by the 7% of dulcitol quality, closed reaction vessel is passed through bromination hydrogen, and pressure remains
It between 0.6Mpa, keeps temperature to 45 DEG C, persistently stirs 20 hours.
2) purified water that 10 times of dulcitol weight is added stirs 2 hours, pumps supernatant after standing 12 hours, adds and defend
0.1 times of lance alcohol weight, a concentration of 70% ethyl alcohol, stir evenly, and filtering, filter residue is rinsed with purified water to neutrality, uses dulcitol
1 times of weight, the washing of a concentration of 70% ethyl alcohol, the solid being collected into is 36 hours dry at a temperature of 27 DEG C, obtain mitolactol.
Experimental result：Mitolactol average yield 60.5%, average purity 89.8%
Embodiment 4：
1) it takes 5.0kg dulcitols to set in reaction kettle, 2 times of dulcitol weight, a concentration of 50% hydrobromic acid butyric acid solution is added,
Meanwhile potassium hyperchlorate is added by the 5% of dulcitol quality, closed reaction vessel is passed through bromination hydrogen, and pressure remains
It between 0.4Mpa, keeps temperature to 35 DEG C, persistently stirs 10 hours.
2) purified water that 8 times of dulcitol weight is added stirs 2 hours, pumps supernatant after standing 15 hours, adds and defend
0.5 times of lance alcohol weight, a concentration of 75% ethyl alcohol, stir evenly, and filtering, filter residue is rinsed with purified water to neutrality, uses dulcitol
2 times of weight, the washing of a concentration of 75% ethyl alcohol, the solid being collected into is 48 hours dry at a temperature of 25 DEG C, obtain mitolactol.
Experimental result：Mitolactol average yield 56.2%, average purity 88.4%
Embodiment 5：
1) it takes 5.0kg dulcitols to set in reaction kettle, 6 times of dulcitol weight, a concentration of 30% hydrobromic acid propionic acid solution is added,
Meanwhile potassium permanganate is added by the 1% of dulcitol quality, closed reaction vessel is passed through bromination hydrogen, and pressure remains
It between 0.2Mpa, keeps temperature to 40 DEG C, persistently stirs 25 hours.
2) purified water that 6 times of dulcitol weight is added stirs 3 hours, pumps supernatant after standing 18 hours, adds and defend
1 times of lance alcohol weight, a concentration of 95% ethyl alcohol, stir evenly, and filtering, filter residue is rinsed with purified water to neutrality, with dulcitol weight
3 times of amount, the washing of a concentration of 95% ethyl alcohol, the solid being collected into is 48 hours dry at a temperature of 28 DEG C, obtain mitolactol.
Experimental result：Mitolactol average yield 58.1%, average purity 88.6%
Embodiment 6：
1) it takes 5.0kg dulcitols to set in reaction kettle, 1 times of dulcitol weight, a concentration of 60% hydrobromic acid formic acid solution is added,
Meanwhile perchloric acid is added by the 3% of dulcitol quality, closed reaction vessel is passed through bromination hydrogen, and pressure remains 0.1Mpa
Between, it keeps temperature to 30 DEG C, persistently stirs 18 hours.
2) purified water that 5 times of dulcitol weight is added stirs 2.5 hours, pumps supernatant after standing 16 hours, adds
1 times of dulcitol weight, a concentration of 80% ethyl alcohol, stir evenly, and filtering, filter residue is rinsed with purified water to neutrality, uses dulcitol
5 times of weight, the washing of a concentration of 80% ethyl alcohol, the solid being collected into is 24 hours dry at a temperature of 32 DEG C, obtain mitolactol.
Experimental result：Mitolactol average yield 53.7%, average purity 87.2%
Embodiment 7：
1) it takes 5.0kg dulcitols to set in reaction kettle, it is molten that 8 times of dulcitol weight, a concentration of 20% hydrobromic acid glacial acetic acid is added
Liquid, meanwhile, hydrogen peroxide is added by the 12% of dulcitol quality, closed reaction vessel is passed through bromination hydrogen, and pressure remains
It between 0.8Mpa, keeps temperature to 55 DEG C, persistently stirs 28 hours.
2) purified water that 4 times of dulcitol weight is added stirs 3 hours, pumps supernatant after standing 20 hours, adds and defend
1.5 times of lance alcohol weight, a concentration of 90% ethyl alcohol, stir evenly, and filtering, filter residue is rinsed with purified water to neutrality, uses dulcitol
3 times of weight, the washing of a concentration of 90% ethyl alcohol, the solid being collected into is 36 hours dry at a temperature of 34 DEG C, obtain mitolactol.
Experimental result：Mitolactol average yield 57.3%, average purity 86.5%
Embodiment 8：
1) it takes 5.0kg dulcitols to set in reaction kettle, it is molten that 10 times of dulcitol weight, a concentration of 5% hydrobromic acid glacial acetic acid is added
Liquid, meanwhile, hydrogen peroxide is added by the 15% of dulcitol quality, closed reaction vessel is passed through bromination hydrogen, and pressure remains
It between 1.0Mpa, keeps temperature to 50 DEG C, persistently stirs 30 hours.
2) purified water that 2 times of dulcitol weight is added stirs 2.5 hours, pumps supernatant after standing 24 hours, adds
2 times of dulcitol weight, a concentration of 85% ethyl alcohol, stir evenly, and filtering, filter residue is rinsed with purified water to neutrality, uses dulcitol
1 times of weight, the washing of a concentration of 85% ethyl alcohol, the solid being collected into is 48 hours dry at a temperature of 30 DEG C, obtain mitolactol.
Experimental result：Mitolactol average yield 54.0%, average purity 85.3%
Comparative example 1：With reference to the embodiment of the present invention 3, anaerobic agent is not passed through hydrogen bromide gas
1) it takes 5.0kg dulcitols to set in reaction kettle, it is molten that 4 times of dulcitol weight, a concentration of 45% hydrobromic acid glacial acetic acid is added
Liquid keeps temperature to 45 DEG C, is persistently stirred to react 20 hours.
2) purified water that 10 times of dulcitol weight is added stirs 2 hours, pumps supernatant after standing 12 hours, adds and defend
0.1 times of lance alcohol weight, a concentration of 70% ethyl alcohol, stir evenly, and filtering, filter residue is rinsed with purified water to neutrality, uses dulcitol
1 times of weight, the washing of a concentration of 70% ethyl alcohol, the solid being collected into is 36 hours dry at a temperature of 27 DEG C, obtain mitolactol.
Experimental result：Mitolactol average yield 34.0%, average purity 64.5%
Comparative example 2：With reference to the embodiment of the present invention 3, anaerobic agent
1) it takes 5.0kg dulcitols to set in reaction kettle, it is molten that 4 times of dulcitol weight, a concentration of 45% hydrobromic acid glacial acetic acid is added
Liquid, after all reaction raw materials are added, closed reaction vessel between pressure remains 0.6Mpa, keeps temperature by bromination hydrogen
Degree persistently stirs 20 hours to 45 DEG C.
2) purified water that 10 times of dulcitol weight is added stirs 2 hours, pumps supernatant after standing 12 hours, adds and defend
0.1 times of lance alcohol weight, a concentration of 70% ethyl alcohol, stir evenly, and filtering, filter residue is rinsed with purified water to neutrality, uses dulcitol
1 times of weight, the washing of a concentration of 70% ethyl alcohol, the solid being collected into is 36 hours dry at a temperature of 27 DEG C, obtain mitolactol.
Experimental result：Mitolactol average yield 35.8%, average purity 66.7%
Comparative example 3：With reference to the embodiment of the present invention 3, it is not passed through hydrogen bromide gas
1) it takes 5.0kg dulcitols to set in reaction kettle, it is molten that 4 times of dulcitol weight, a concentration of 45% hydrobromic acid glacial acetic acid is added
Liquid, meanwhile, hydrogen peroxide is added by the 7% of dulcitol quality, keeps temperature to 45 DEG C, persistently stirs 20 hours.
2) purified water that 10 times of dulcitol weight is added stirs 2 hours, pumps supernatant after standing 12 hours, adds and defend
0.1 times of lance alcohol weight, a concentration of 70% ethyl alcohol, stir evenly, and filtering, filter residue is rinsed with purified water to neutrality, uses dulcitol
1 times of weight, the washing of a concentration of 70% ethyl alcohol, the solid being collected into is 36 hours dry at a temperature of 27 DEG C, obtain mitolactol.
Experimental result：Mitolactol average yield 38.1%, average purity 68.3%
Process ration is tested：
Experimental method：The reaction conditions such as disclosed reaction pressure, reaction temperature according to the present invention prepare embodiment 1-8 samples
Product；On the basis of embodiment preparation method, not oxidizer, be not passed through hydrogen bromide gas, prepare comparative example 1-4 samples respectively；
It the results are shown 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 the final product.Reference substance is made by oneself for laboratory, purity 98.57%.
Table 1：Dulcitol bromination reaction experimental result
1 result of table is shown：Comparative example has subtracted oxidant, has not been passed through hydrogen bromide gas, and reaction result shows such operation
Yield and the purity for obtaining mitolactol reactant are unsatisfactory.Midway addition is added together with when starting, as a result, having
Significant difference.
The experimental results showed that：By response parameter provided by the invention, it may be significantly and prepared better than prior art
The effect of gained mitolactol.
Although above having used general explanation, specific implementation mode and experiment, the present invention is made to retouch in detail
It states, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Range.
Claims (10)
1. a kind of preparation method of bromo hexitol, including bromination step, it is characterised in that：Include the following steps：
Take dulcitol to set in reaction vessel, be added 1-10 times of dulcitol weight, a concentration of 5-60% hydrobromic acid organic acid soln,
Meanwhile oxidant is added by the 1-15% of dulcitol quality, closed reaction vessel is passed through bromination hydrogen, and pressure remains
Between 0.1-1.0Mpa, keeps temperature to 30-55 DEG C, be persistently stirred to react 10-30 hours.
2. the method as described in claim 1, which is characterized in that the oxidant be perchloric acid, potassium hyperchlorate, potassium permanganate,
Sodium hypochlorite, hydrogen peroxide.
3. the method as described in claim 1, which is characterized in that described be stirred to react is 10-28 hours.
4. method as claimed in claim 3, which is characterized in that described be stirred to react is 20-25 hours.
5. the method as described in claim 1, which is characterized in that the temperature when reaction is 40-50 DEG C.
6. the method as described in claim 1, which is characterized in that the hydrobromic acid organic acid soln is that hydrobromic acid glacial acetic acid is molten
Liquid or hydrobromic acid formic acid solution or hydrobromic acid propionic acid solution or hydrobromic acid butyric acid solution.
7. the method as described in claim 1, which is characterized in that a concentration of 30-60% of hydrobromic acid organic acid soln.
8. the method for claim 7, which is characterized in that the hydrobromic acid organic acid soln be prepared as follows and
：At a temperature of less than -5 DEG C, bromination hydrogen is passed through in organic acid, the hydrobromic acid organic acid for obtaining a concentration of 30-60% is molten
Liquid.
9. method as claimed in claim 8, which is characterized in that the organic acid is glacial acetic acid, formic acid, propionic acid or butyric acid.
10. the method as described in claim 1, which is characterized in that include the following steps：
1) it takes dulcitol to set in reaction vessel, it is molten that 1-10 times of dulcitol weight, the hydrobromic acid organic acid of a concentration of 5-60% is added
Liquid, meanwhile, oxidant is added by the 1-15% of dulcitol quality, closed reaction vessel is passed through bromination hydrogen, and pressure remains
Between 0.1-1.0Mpa, keeps temperature to 30-55 DEG C, be persistently stirred to react 10-30 hours；
2) purified water that 1-10 times of dulcitol weight is added stirs 2-3 hours, supernatant is pumped after standing at least 12 hours, then add
Entering 0.1-2 times of dulcitol weight, a concentration of 70-95% ethyl alcohol, stir evenly, filters, filter residue is rinsed with purified water to neutrality,
It is washed with 1-5 times of dulcitol weight, a concentration of 70-95% ethyl alcohol, by the solid being collected into, dry 24-48 is small at 25-35 DEG C
When, obtain mitolactol.
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| HU195227B (en) * | 1986-02-28 | 1988-04-28 | Chinoin Gyogyszer Es Vegyeszet | New process for preparing 1,6-dibromo-dideoxy-d-mannitol and 1,6-dibromo-dideoxy-dulcitol |
| CN101070268A (en) * | 2007-06-14 | 2007-11-14 | 大连理工大学 | Process for preparing 2,7-2-bromofluorene |
| CN103923039A (en) * | 2014-01-30 | 2014-07-16 | 天津中津药业股份有限公司 | Method for preparing dianhydrogalactitol |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2013001860A (en) * | 2010-08-18 | 2013-09-02 | Del Mar Pharmaceuticals | Method of synthesis of substituted hexitols such as dianhydrogalactitol. |
-
2014
- 2014-12-30 CN CN201410839711.8A patent/CN105801364B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU195227B (en) * | 1986-02-28 | 1988-04-28 | Chinoin Gyogyszer Es Vegyeszet | New process for preparing 1,6-dibromo-dideoxy-d-mannitol and 1,6-dibromo-dideoxy-dulcitol |
| CN101070268A (en) * | 2007-06-14 | 2007-11-14 | 大连理工大学 | Process for preparing 2,7-2-bromofluorene |
| CN103923039A (en) * | 2014-01-30 | 2014-07-16 | 天津中津药业股份有限公司 | Method for preparing dianhydrogalactitol |
Non-Patent Citations (2)
| Title |
|---|
| 抗癌剂二溴卫茅醇的合成;刘铭勋等;《江西医学院学报》;19841231(第2期);第8-9页 * |
| 氢溴酸/双氧水溴代体系的应用及4-甲基二苯甲酮衍生物的合成;龚年华;《中国优秀硕士学位论文全文数据库 工程科技I辑》;20100515(第5期);第B016-12页 * |
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