CN105801370B - A method of improving two substitution dulcitol reaction product yields - Google Patents
A method of improving two substitution dulcitol reaction product yields Download PDFInfo
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Abstract
The present invention relates to a kind of methods improving two substitution dulcitol reaction product yields.The method provided by the invention for improving two substitution dulcitol reaction product yields 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 method of improving two substitution dulcitol reaction product yields.
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 water-baths, mixed liquor is poured into
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 two
The yield of bromine dulcitol 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 methods improving two substitution dulcitol reaction product yields.
The method of the present invention for improving two substitution dulcitol reaction product yields includes bromination step, it is characterised in that
Include the following steps：
1) take dulcitol to set in reaction vessel, be added 1-10 times of dulcitol weight, a concentration of 20-60% hydrobromic acid acetic acid
Solution stirs 0.5-5 hours at room temperature；
2) oxidant is added in the 1-15% for pressing dulcitol quality, is heated to 30-55 DEG C, is persistently stirred to react 5-30 hours.
Preferably, the oxidant is perchloric acid, potassium hyperchlorate, potassium permanganate, sodium hypochlorite, hydrogen peroxide.
Preferably, it is 10-28 hours that the step 2), which is stirred to react,.
Preferably, it is 20-25 hours that the step 2), which is stirred to react,.
Preferably, temperature when step 2) reaction is 40-50 DEG C.
Preferably, primary every sampling in 0.5-3 hours during the reaction after oxidant is added in the step 2), it measures
The concentration of hydrogen bromide in reaction solution, if be less than 30%, hydrobromic acid acetic acid solution is added, until in reaction solution hydrogen bromide it is dense
Degree is 50% or more.
Preferably, a concentration of 40-60% of hydrobromic acid acetic acid solution.
Preferably, the hydrobromic acid acetic acid solution concentration being added after the step 2) sampling is higher than 40%.
Preferably, the hydrobromic acid acetic acid solution is prepared as follows and obtains：At a temperature of less than -5 DEG C, hydrogen bromide
Gas is passed through in the acetic acid of a concentration of 60-100%, obtains the hydrobromic acid acetic acid solution of a concentration of 40-60%.
The method of the present invention for improving two substitution dulcitol reaction product yields, includes the following steps：
1) take dulcitol to set in reaction vessel, be added 1-10 times of dulcitol weight, a concentration of 20-60% hydrobromic acid acetic acid
Solution stirs 1-5 hours at room temperature；
2) oxidant is added in the 1-15% for pressing dulcitol quality, is heated to 30-55 DEG C, is persistently stirred to react 5-30 hours,
It is primary every sampling in 0.5-3 hours during the reaction, the concentration of hydrogen bromide in reaction solution is measured, if it is less than 30%, plus
Enter hydrobromic acid acetic acid solution, until the concentration of hydrogen bromide is 50% or more in reaction solution；
3) purified water that 1-10 times of dulcitol weight is added stirs 2-3 hour, and supernatant is pumped after standing at least 12 hours
Liquid adds 0.1-2 times of dulcitol weight, a concentration of 70-95% ethyl alcohol, stirs evenly, filtering, filter residue with purified water rinse to
After neutrality, washed with 1-5 times of dulcitol weight, a concentration of 70-95% ethyl alcohol, the solid being collected into is dry at 25-35 DEG C
24-48 hours, obtain mitolactol.
During dulcitol and hydrobromic acid acetic acidreaction, key reaction substance is dulcitol and hydrogen bromide, hydrogen bromide dissolving
In acetic acid solution, when solution concentration drops to certain proportion, hydrogen bromide be precipitated it is extremely difficult, cause reaction slowly or cannot
It is further continued for carrying out.Oxidant is added in reaction solution, bromine can be promoted slowly to be analysed from the hydrobromic acid acetic acid solution of low concentration
Go out, be oxidized to simple substance bromine, while increasing the yield of mitolactol, reduces the addition of hydrobromic acid acetic acid solution, save
Cost mitigates environmental pollution.
The concentration for monitoring hydrogen bromide in reaction solution by sampling during the reaction, it is molten to be replenished in time hydrobromic acid acetic acid
Liquid, makes the concentration of hydrogen bromide maintain sufficient concentration, and reaction can keep saturation state, improve reaction rate and dibromo be defended
The yield of lance alcohol.
A kind of method improving two substitution dulcitol reaction product yields 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 reacted using cryogenic conditions, not only not high to equipment requirement and easily controllable, can be adjusted at any time, although when reaction
Between be 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 acetic acid solution
At a temperature of -5 DEG C, bromination hydrogen is passed through in a concentration of 60% acetic acid, obtains a concentration of 60% hydrobromic acid
Acetic acid solution.
Embodiment 2：Prepare hydrobromic acid acetic acid solution
At a temperature of less than -10 DEG C, bromination hydrogen is passed through in a concentration of 100% acetic acid, obtains a concentration of 40%
Hydrobromic acid acetic acid solution.
Embodiment 3：
1) 5.0kg dulcitols is taken to set in reaction kettle, be added 1 times of dulcitol weight, a concentration of 60% hydrobromic acid acetic acid, room
The lower stirring of temperature 0.5 hour；
2) perchloric acid is added in press dulcitol quality 1%, is heated to 30 DEG C, persistently stirring 5 hours, during the reaction often
It is primary every sampling in 1 hour, the concentration of hydrogen bromide in reaction solution is measured, if being less than 30%, hydrobromic acid acetic acid solution is added, until
The concentration of hydrogen bromide is 50% or more in reaction solution；
3) 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 50.6%, average purity 81.3%.
Embodiment 4：
1) 5.0kg dulcitols is taken to set in reaction kettle, be added 2 times of dulcitol weight, a concentration of 34% hydrobromic acid acetic acid, room
The lower stirring of temperature 1 hour；
2) potassium hyperchlorate is added in press dulcitol quality 3%, is heated to 35 DEG C, persistently stirs 10 hours, in reaction process
In it is primary every sampling in 0.5 hour, measure the concentration of hydrogen bromide in reaction solution, if being less than 30%, hydrobromic acid acetic acid be added
Solution, until the concentration of hydrogen bromide is 50% or more in reaction solution；
3) 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 52.8%, average purity 82.9%.
Embodiment 5：
1) 5.0kg dulcitols is taken to set in reaction kettle, be added 4 times of dulcitol weight, a concentration of 40% hydrobromic acid acetic acid, room
The lower stirring of temperature 2 hours；
2) 40 DEG C are heated to by 7% addition potassium permanganate of dulcitol quality, persistently stirring 28 hours, during the reaction
It is primary every sampling in 2 hours, the concentration of hydrogen bromide in reaction solution is measured, if being less than 30%, hydrobromic acid acetic acid solution is added,
To hydrogen bromide in reaction solution concentration 50% or more；
3) 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 55.7%, average purity 86.5%.
Embodiment 6：
1) 5.0kg dulcitols is taken to set in reaction kettle, be added 5 times of dulcitol weight, a concentration of 45% hydrobromic acid acetic acid, room
The lower stirring of temperature 3 hours；
2) 45 DEG C are heated to by 12% addition hydrogen peroxide of dulcitol quality, persistently stirred 20 hours, in reaction process
In it is primary every sampling in 1.5 hours, measure the concentration of hydrogen bromide in reaction solution, if being less than 30%, hydrobromic acid acetic acid be added
Solution, until the concentration of hydrogen bromide is 50% or more in reaction solution；
3) 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 52.5%, average purity 83.4%.
Embodiment 7：
1) 5.0kg dulcitols is taken to set in reaction kettle, be added 8 times of dulcitol weight, a concentration of 50% hydrobromic acid acetic acid, room
The lower stirring of temperature 4 hours；
2) sodium hypochlorite is added in press dulcitol quality 5%, is heated to 50 DEG C, persistently stirs 25 hours, in reaction process
In it is primary every sampling in 2.5 hours, measure the concentration of hydrogen bromide in reaction solution, if being less than 30%, hydrobromic acid acetic acid be added
Solution, until the concentration of hydrogen bromide is 50% or more in reaction solution；
3) 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 35 DEG C, obtain mitolactol.
Experimental result：Mitolactol average yield 51.9%, average purity 82.2%.
Embodiment 8：
1) 5.0kg dulcitols is taken to set in reaction kettle, be added 10 times of dulcitol weight, a concentration of 55% hydrobromic acid acetic acid,
It stirs 5 hours at room temperature；
2) 55 DEG C are heated to by 15% addition hydrogen peroxide of dulcitol quality, persistently stirred 30 hours, in reaction process
In it is primary every sampling in 3.0 hours, measure the concentration of hydrogen bromide in reaction solution, if being less than 30%, hydrobromic acid acetic acid be added
Solution, until the concentration of hydrogen bromide is 50% or more in reaction solution；
3) 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 95% 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 95% 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 53.4%, average purity 83.0%.
Comparative example 1：With reference to the embodiment of the present invention 3, anaerobic agent is added without hydrobromic acid acetic acid halfway
1) 5.0kg dulcitols is taken to set in reaction kettle, be added 1 times of dulcitol weight, a concentration of 60% hydrobromic acid acetic acid, room
The lower stirring of temperature 0.5 hour；30 DEG C are again heated to, 5 hours are persistently stirred to react
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 31.6%, average purity 63.3%.
Comparative example 2：With reference to the embodiment of the present invention 3, anaerobic agent
1) 5.0kg dulcitols is taken to set in reaction kettle, be added 1 times of dulcitol weight, a concentration of 60% hydrobromic acid acetic acid, room
The lower stirring of temperature 0.5 hour, is again heated to 30 DEG C, persistently stirs 5 hours, primary every sampling in 1 hour during the reaction, measures
The concentration of hydrogen bromide in reaction solution, if be less than 30%, hydrobromic acid acetic acid solution is added, until in reaction solution hydrogen bromide it is dense
Degree is 50% or more；
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 32.5%, average purity 64.4%.
Comparative example 3：With reference to the embodiment of the present invention 3, it is added without hydrobromic acid acetic acid halfway
1) 5.0kg dulcitols is taken to set in reaction kettle, be added 1 times of dulcitol weight, a concentration of 60% hydrobromic acid acetic acid, room
The lower stirring of temperature 0.5 hour, is added perchloric acid by the 1% of dulcitol quality, is heated to 30 DEG C, persistently stirs 5 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 35.3%, average purity 64.0%.
Comparative example 4：With reference to the embodiment of the present invention 3, it is added without hydrobromic acid acetic acid halfway, improves addition when starting reaction
Amount.
1) 5.0kg dulcitols is taken to set in reaction kettle, be added 2 times of dulcitol weight, a concentration of 60% hydrobromic acid acetic acid, room
The lower stirring of temperature 0.5 hour；Perchloric acid is added by the 1% of dulcitol quality, is heated to 30 DEG C, persistently stirs 5 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 36.6%, average purity 65.2%.
Process ration is tested：
Experimental method：Disclosed reaction pressure, reaction temperature and hydrobromic acid solution concentration according to the present invention prepare embodiment
1-8 samples；On the basis of embodiment preparation method, not oxidizer, subtract midway be added hydrobromic acid glacial acetic acid reaction item
Part prepares 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：The hydrobromic acid glacial acetic acid amount that comparative example has subtracted oxidant or has been added when midway is monitored, adds
To start reaction when simultaneously be added, reaction result show in this way operate acquisition mitolactol reactant yield and purity not
It is ideal.Midway addition is added together with when starting, as a result, 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 (8)
1. a kind of method improving two substitution dulcitol reaction product yields, including bromination step, it is characterised in that：Including such as
Lower step：
1) take dulcitol to set in reaction vessel, be added 1-10 times of dulcitol weight, a concentration of 20-60% hydrobromic acid acetic acid
Solution stirs 0.5-5 hours at room temperature；
2) oxidant is added in the 1-15% for pressing dulcitol quality, is heated to 30-55 DEG C, is persistently stirred to react 5-30 hours；
It is primary every sampling in 0.5-3 hours during the reaction after oxidant is added in the step 2), measure reaction solution
If being less than 30% hydrobromic acid acetic acid solution is added, until the concentration of hydrogen bromide exists in reaction solution in the concentration of middle hydrogen bromide
50% or more；The oxidant is perchloric acid, potassium hyperchlorate, potassium permanganate, sodium hypochlorite, hydrogen peroxide.
2. the method as described in claim 1, which is characterized in that it is 10-28 hours that the step 2), which is stirred to react,.
3. the method as described in claim 2, which is characterized in that it is 20-25 hours that the step 2), which is stirred to react,.
4. the method as described in claim 1, which is characterized in that temperature when step 2) reaction is 40-50 DEG C.
5. the method as described in claim 1, which is characterized in that a concentration of 40-60% of hydrobromic acid acetic acid solution.
6. the method as described in claim 1, which is characterized in that the hydrobromic acid acetic acid being added after the step 2) sampling is molten
Liquid concentration is higher than 40%.
7. the method as described in claim 5, which is characterized in that the hydrobromic acid acetic acid solution is prepared as follows and obtains
：At a temperature of less than -5 DEG C, bromination hydrogen is passed through in the acetic acid of a concentration of 60-100%, obtains a concentration of 40-60%'s
Hydrobromic acid acetic acid solution.
8. the method as described in claim 1, which is characterized in that include the following steps：
1) take dulcitol to set in reaction vessel, be added 1-10 times of dulcitol weight, a concentration of 20-60% hydrobromic acid acetic acid
Solution stirs 1-5 hours at room temperature；
2) oxidant is added in the 1-15% for pressing dulcitol quality, is heated to 30-55 DEG C, is persistently stirred to react 5-30 hours,
It is primary every sampling in 0.5-3 hours during the reaction, the concentration of hydrogen bromide in reaction solution is measured, if being less than 30%,
Hydrobromic acid acetic acid solution is added, until the concentration of hydrogen bromide is 50% or more in reaction solution；
3) purified water that 1-10 times of dulcitol weight is added stirs 2-3 hour, is pumped after standing at least 12 hours
Clear liquid adds 0.1-2 times of dulcitol weight, a concentration of 70-95% ethyl alcohol, stirs evenly, filtering, filter residue purified water
It rinses to neutrality, is washed with 1-5 times of dulcitol weight, a concentration of 70-95% ethyl alcohol, by the solid being collected into 25-
It is 24-48 hours dry at 35 DEG C, obtain mitolactol.
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