CN105801375A - Method for improving yield and purity of dianhydrodulcitol intermediate - Google Patents
Method for improving yield and purity of dianhydrodulcitol intermediate Download PDFInfo
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- CN105801375A CN105801375A CN201410841471.5A CN201410841471A CN105801375A CN 105801375 A CN105801375 A CN 105801375A CN 201410841471 A CN201410841471 A CN 201410841471A CN 105801375 A CN105801375 A CN 105801375A
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Abstract
The invention relates to a method for improving the yield and purity of a dianhydrodulcitol intermediate. With the method provided by the invention, the dianhydrodulcitol intermediate with average yield of 50% or above and average purity of 80% or above can be obtained; and the effect of the method is obviously better than effect in the prior art.
Description
Technical field
The present invention relates to chemical drugs field, be specifically related to a kind of method improving dianhydrodulcitol intermediate yield and purity.
Background technology
Dianhydrodulcitol intermediate is mitolactol, 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, and 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 DEG C of 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
It is an object of the invention to provide a kind of method improving dianhydrodulcitol intermediate yield and purity.
A kind of method improving dianhydrodulcitol intermediate yield and purity of the present invention includes bromination step, it is characterised in that comprise the steps:
Taking dulcitol and put in reaction vessel, addition dulcitol weight 1-10 times, concentration are the hydrobromic acid glacial acetic acid solution of 5-45%, closed reaction vessel, pass into hydrogen bromide gas, pressure remains between 0.1-1.0Mpa, maintains the temperature at 30-55 DEG C, continuously stirred reaction 10-30 hour.
Preferably, described stirring reaction is 10-28 hour.
Preferably, described stirring reaction is 20-25 hour.
Preferably, temperature during described reaction is 40-50 DEG C.
Preferably, described hydrobromic acid glacial acetic acid solution concentration is 33-45%.
Preferably, described hydrobromic acid glacial acetic acid solution is prepared by the following method and is obtained: lower than, at-5 DEG C of temperature, hydrogen bromide gas being passed in glacial acetic acid, obtaining the hydrobromic acid glacial acetic acid solution that concentration is 33-45%.
A kind of method improving dianhydrodulcitol intermediate yield and purity of the present invention, comprises the steps:
1) taking dulcitol and put in reaction vessel, addition dulcitol weight 1-10 times, concentration are the hydrobromic acid glacial acetic acid solution of 5-45%, closed reaction vessel, pass into hydrogen bromide gas, pressure remains between 0.1-1.0Mpa, maintains the temperature at 30-55 DEG C, continuously stirred reaction 10-30 hour；
2) purified water adding dulcitol weight 1-10 times stirs 2-3 hour, supernatant is pumped after standing at least 12 hours, add dulcitol weight 0.1-2 times, concentration is 70-95% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 70-95% washing with alcohol by dulcitol weight 1-5 times, concentration, the solid collected is dried 24-48 hour at 25-35 DEG C, obtains mitolactol
In dulcitol and hydrobromic acid glacial acetic acid course of reaction, dominant response material is dulcitol and hydrogen bromide, and hydrogen bromide second is dissolved in be recalled in acid solution, and when solution concentration drops to certain proportion, hydrogen bromide precipitates out extremely difficult, causes that sluggish maybe can not be further continued for carrying out.Pass into HBr gas in reaction whole process, keep bromine to maintain saturation in the reaction always, while increasing the yield of mitolactol, improve reaction rate, and reduce the addition of hydrobromic acid glacial acetic acid solution, save cost, alleviate environmental pollution.
A kind of method improving dianhydrodulcitol intermediate yield and purity 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 reaches 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, large-scale production mitolactol yield below 40% (in mol), present invention process safe and reasonable, prepared mitolactol average yield is more than 50%.
3, mitolactol preparation method disclosed in prior art all have employed high concentration of hydrogen bromic acid, high temperature, in the short time reaction and obtain.Because the reagent operation of high concentration is dangerous big, and high-temperature operation is difficult to control to the precise procedural of reaction.The present invention adopts relatively low temperature conditioned response, not only that equipment requirements is not high, and easily controllable, it is possible to adjust at any time, although the response time is longer than prior art, but the yield of gained reactant of the present invention and purity are above prior art products obtained therefrom.
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: prepare hydrobromic acid glacial acetic acid solution
Lower than, at-5 DEG C of temperature, hydrogen bromide gas being passed in glacial acetic acid, obtaining the hydrobromic acid glacial acetic acid solution that concentration is 33%.
Embodiment 2: prepare hydrobromic acid glacial acetic acid solution
Lower than, at-15 DEG C of temperature, hydrogen bromide gas being passed in glacial acetic acid, obtaining the hydrobromic acid glacial acetic acid solution that concentration is 45%.
Embodiment 3:
1) taking 5.0kg dulcitol and put in reactor, addition dulcitol weight 8 times, concentration are the hydrobromic acid glacial acetic acid solution of 5%, and closed reaction vessel passes into hydrogen bromide gas, and pressure remains 0.1Mpa, and temperature is maintained at 30 DEG C, continuously stirred 15 hours.
2) purified water adding dulcitol weight 10 times stirs 2 hours, supernatant is pumped after standing 12 hours, add dulcitol weight 0.1 times, concentration is 70% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 70 washing with alcohol by dulcitol weight 1 times, concentration, the solid collected is dried 36 hours at 27 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 51.2%, average purity 80.7%.
Embodiment 4:
1) taking 5.0kg dulcitol and put in reactor, addition dulcitol weight 10 times, concentration are the hydrobromic acid glacial acetic acid solution of 10%, and closed reaction vessel passes into hydrogen bromide gas, and pressure keeps 0.2Mpa, and temperature is maintained at 35 DEG C, continuously stirred 12 hours.
2) purified water adding dulcitol weight 8 times stirs 2 hours, supernatant is pumped after standing 15 hours, add dulcitol weight 0.5 times, concentration is 75% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 75% washing with alcohol by dulcitol weight 2 times, concentration, the solid collected is dried 48 hours at 25 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 52.0%, average purity 82.6%.
Embodiment 5:
1) taking 5.0kg dulcitol and put in reactor, addition dulcitol weight 4 times, concentration are the hydrobromic acid glacial acetic acid solution of 40%, and closed reaction vessel passes into hydrogen bromide gas, and pressure keeps 0.5Mpa, and temperature is maintained at 45 DEG C, continuously stirred 24 hours.
2) purified water adding dulcitol weight 6 times stirs 3 hours, supernatant is pumped after standing 18 hours, add dulcitol weight 1 times, concentration is 95% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 95% washing with alcohol by dulcitol weight 3 times, concentration, the solid collected is dried 48 hours at 28 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 54.5%, average purity 85.3%.
Embodiment 6:
1) taking 5.0kg dulcitol and put in reactor, addition dulcitol weight 6 times, concentration are the hydrobromic acid glacial acetic acid solution of 30%, and closed reaction vessel passes into hydrogen bromide gas, and pressure keeps 0.8Mpa, and temperature is maintained at 40 DEG C, continuously stirred 18 hours.
2) purified water adding dulcitol weight 5 times stirs 2.5 hours, supernatant is pumped after standing 16 hours, add dulcitol weight 1 times, concentration is 80% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 80% washing with alcohol by dulcitol weight 5 times, concentration, the solid collected is dried 24 hours at 32 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 53.7%, average purity 82.8%.
Embodiment 7:
1) taking 5.0kg dulcitol and put in reactor, addition dulcitol weight 2 times, concentration are the hydrobromic acid glacial acetic acid solution of 45%, and closed reaction vessel passes into hydrogen bromide gas, and pressure keeps 0.6Mpa, and temperature is maintained at 38 DEG C, continuously stirred 28 hours.
2) purified water adding dulcitol weight 4 times stirs 3 hours, supernatant is pumped after standing 20 hours, add dulcitol weight 1.5 times, concentration is 90% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 90% washing with alcohol by dulcitol weight 3 times, concentration, the solid collected is dried 36 hours at 34 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 51.4%, average purity 83.5%.
Embodiment 8:
1) taking 5.0kg dulcitol and put in reactor, addition dulcitol weight 1 times, concentration are the hydrobromic acid glacial acetic acid solution of 20%, and closed reaction vessel passes into hydrogen bromide gas, and pressure keeps 0.7Mpa, and temperature is maintained at 50 DEG C, continuously stirred 20 hours.
2) purified water adding dulcitol weight 2 times stirs 2.5 hours, supernatant is pumped after standing 24 hours, add dulcitol weight 2 times, concentration is 95% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 95% washing with alcohol by dulcitol weight 1 times, concentration, the solid collected is dried 48 hours at 30 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol weight average yield 50.9%, average purity 81.4%.
Embodiment 9:
1) taking 5.0kg dulcitol and put in reactor, addition dulcitol weight 5 times, concentration are the hydrobromic acid glacial acetic acid solution of 33%, and closed reaction vessel passes into hydrogen bromide gas, and pressure keeps 1.0Mpa, and temperature is maintained at 55 DEG C, continuously stirred 30 hours.
2) purified water adding dulcitol weight 1 times stirs 3 hours, supernatant is pumped after standing 30 hours, add dulcitol weight 2 times, concentration is 85% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 85% washing with alcohol by dulcitol weight 3 times, concentration, the solid collected is dried 24 hours at 35 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 52.4%, average purity 83.0%.
Comparative example 1: with reference to the embodiment of the present invention 3, do not pass into hydrogen bromide gas
1) taking 5.0kg dulcitol and put in reactor, addition dulcitol weight 8 times, concentration are the hydrobromic acid glacial acetic acid solution of 5%, heat to 30 DEG C, continuously stirred 15 hours.
2) purified water adding dulcitol weight 10 times stirs 2 hours, supernatant is pumped after standing 12 hours, add dulcitol weight 0.1 times, concentration is 70% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 70 washing with alcohol by dulcitol weight 1 times, concentration, the solid collected is dried 36 hours at 27 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 31.9%, average purity 62.3%.
Comparative example 2: with reference to the embodiment of the present invention 4, do not pass into hydrogen bromide gas
1) taking 5.0kg dulcitol and put in reactor, addition dulcitol weight 10 times, concentration are the hydrobromic acid glacial acetic acid solution of 10%, heat to 35 DEG C, continuously stirred 12 hours.
2) purified water adding dulcitol weight 8 times stirs 2 hours, supernatant is pumped after standing 15 hours, add dulcitol weight 0.5 times, concentration is 75% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 75% washing with alcohol by dulcitol weight 2 times, concentration, the solid collected is dried 48 hours at 25 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 33.3%, average purity 64.2%.
Comparative example 3: with reference to the embodiment of the present invention 5, do not pass into hydrogen bromide gas
1) taking 5.0kg dulcitol and put in reactor, addition dulcitol weight 4 times, concentration are the hydrobromic acid glacial acetic acid solution of 40%, heat to 45 DEG C, continuously stirred 24 hours.
2) purified water adding dulcitol weight 6 times stirs 3 hours, supernatant is pumped after standing 18 hours, add dulcitol weight 1 times, concentration is 95% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 95% washing with alcohol by dulcitol weight 3 times, concentration, the solid collected is dried 48 hours at 28 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 34.7%, average purity 64.5%.
Process ration is tested:
Experimental technique: according to reaction pressure disclosed by the invention, reaction temperature and hydrobromic acid solution concentration, prepares embodiment 1-9 sample；On embodiment preparation method basis, deduct whole process and pass into the reaction condition of hydrogen bromide gas, prepare comparative example 1-3 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: dulcitol bromination reaction experimental result
Table 1 result shows: comparative example has deducted the omnidistance step passing into hydrogen bromide gas, and reaction result shows that the yield of so operation acquisition mitolactol reactant and purity are unsatisfactory, and its result and embodiment have significant difference.
Test result indicate that: by response parameter provided by the invention, it is possible to obtain being substantially better than prior art 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 (7)
1. the method improving dianhydrodulcitol intermediate yield and purity, including bromination step, it is characterised in that: comprise the steps:
Taking dulcitol and put in reaction vessel, addition dulcitol weight 1-10 times, concentration are the hydrobromic acid glacial acetic acid solution of 5-45%, closed reaction vessel, pass into hydrogen bromide gas, pressure remains between 0.1-1.0Mpa, maintains the temperature at 30-55 DEG C, continuously stirred reaction 10-30 hour.
2. the method for claim 1, it is characterised in that described stirring reaction is 10-28 hour.
3. method as claimed in claim 2, it is characterised in that described stirring reaction is 20-25 hour.
4. the method for claim 1, it is characterised in that temperature during described reaction is 40-50 DEG C.
5. the method for claim 1, it is characterised in that described hydrobromic acid glacial acetic acid solution concentration is 33-45%.
6. method as claimed in claim 5, it is characterised in that described hydrobromic acid glacial acetic acid solution is prepared by the following method and obtained: lower than, at-5 DEG C of temperature, hydrogen bromide gas being passed in glacial acetic acid, obtaining the hydrobromic acid glacial acetic acid solution that concentration is 33-45%.
7. the method for claim 1, it is characterised in that comprise the steps:
1) taking dulcitol and put in reaction vessel, addition dulcitol weight 1-10 times, concentration are the hydrobromic acid glacial acetic acid solution of 5-45%, closed reaction vessel, pass into hydrogen bromide gas, pressure remains between 0.1-1.0Mpa, maintains the temperature at 30-55 DEG C, continuously stirred reaction 10-30 hour；
2) purified water adding dulcitol weight 1-10 times stirs 2-3 hour, supernatant is pumped after standing at least 12 hours, add dulcitol weight 0.1-2 times, concentration is 70-95% ethanol, stir, filtering, filtering residue purified water is rinsed to neutrality, is 70-95% washing with alcohol by dulcitol weight 1-5 times, concentration, the solid collected is dried 24-48 hour at 25-35 DEG C, obtains mitolactol.
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Citations (5)
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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 |
| CN101016227A (en) * | 2007-02-08 | 2007-08-15 | 宜兴市中正化工有限公司 | Synthetic method and refining for tribromoneoamyl alcohol |
| US20110087050A1 (en) * | 2008-06-05 | 2011-04-14 | Showa Denko K.K. | Acrolein manufacturing method and acrylic acid manufacturing method |
| CN103270035A (en) * | 2010-08-18 | 2013-08-28 | 德玛医药 | Method of synthesis of substituted hexitols such as dianhydrogalactitol |
| US20140155638A1 (en) * | 2010-08-18 | 2014-06-05 | Del Mar Pharmaceuticals | Method of synthesis of substituted hexitols such as dianhydrogalactitol |
-
2014
- 2014-12-30 CN CN201410841471.5A patent/CN105801375A/en active Pending
Patent Citations (5)
| 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 |
| CN101016227A (en) * | 2007-02-08 | 2007-08-15 | 宜兴市中正化工有限公司 | Synthetic method and refining for tribromoneoamyl alcohol |
| US20110087050A1 (en) * | 2008-06-05 | 2011-04-14 | Showa Denko K.K. | Acrolein manufacturing method and acrylic acid manufacturing method |
| CN103270035A (en) * | 2010-08-18 | 2013-08-28 | 德玛医药 | Method of synthesis of substituted hexitols such as dianhydrogalactitol |
| US20140155638A1 (en) * | 2010-08-18 | 2014-06-05 | Del Mar Pharmaceuticals | Method of synthesis of substituted hexitols such as dianhydrogalactitol |
Non-Patent Citations (2)
| Title |
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| NICHOLAS E.MISCHLER等: "Dibromodulcitol", 《CANCER TREATMENT REVIEWS》 * |
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Application publication date: 20160727 |