CN105801365A - Method for improving yield of brominated alkylating agent reaction product - Google Patents
Method for improving yield of brominated alkylating agent reaction product Download PDFInfo
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Abstract
The invention relates to a method for improving yield of a brominated alkylating agent reaction product. The method for improving yield of the brominated alkylating agent reaction product is used, and the reaction 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, be specifically related to a kind of method improving bromoalkane agent product yield.
Background technology
Mitolactol generally uses dulcitol bromo-reaction to obtain, 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 bromoalkane agent product yield.
The method of raising bromoalkane agent product yield of the present invention includes bromination step, 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 20-50%, heat to 30-55 DEG C, continuously stirred reaction 5-30 hour；
2) in course of reaction every sampling in 0.5-3 hour once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%.
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 34-40%.
Preferably, described step 2) the hydrobromic acid glacial acetic acid solution concentration that adds after sampling is higher than 40%.
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 20-50%.
Preferably, a kind of method improving bromoalkane agent product yield 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 20-50%, continuously stirred 5-30 hour；
2) in course of reaction every sampling in 0.5-3 hour once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%；
3) 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 is dissolved in acetic 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.By the concentration of hydrogen bromide in monitoring reaction solution of sampling in course of reaction, supplement hydrobromic acid glacial acetic acid solution in time, the concentration making hydrogen bromide maintains the concentration of abundance, reaction can keep saturation, 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 bromoalkane agent product yield 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
At-5 DEG C of temperature, hydrogen bromide gas is passed in glacial acetic acid, obtain the hydrobromic acid glacial acetic acid solution that concentration is 20%.
Embodiment 2: prepare hydrobromic acid glacial acetic acid solution
Lower than, at-10 DEG C of temperature, hydrogen bromide gas being passed in glacial acetic acid, obtaining the hydrobromic acid glacial acetic acid solution that concentration is 50%.
Embodiment 3:
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 1 times, concentration is the hydrobromic acid glacial acetic acid of 50%, heats to 30 DEG C, continuously stirred reaction 5 hours；
2) in course of reaction every sampling in 2.5 hours once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%；
3) 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 50.4%, average purity is 80.5%.
Embodiment 4:
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 2 times, concentration is the hydrobromic acid glacial acetic acid of 45%, heats to 35 DEG C, continuously stirred reaction 10 hours；
2) in course of reaction every sampling in 1.0 hours once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%；
3) 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 51.7%, average purity is 80.9%.
Embodiment 5:
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 4 times, concentration is the hydrobromic acid glacial acetic acid of 40%, heats to 40 DEG C, continuously stirred reaction 18 hours；
2) in course of reaction every sampling in 1.5 hours once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%；
3) purified water adding dulcitol weight 6 times stirs 3 hours, supernatant is pumped after standing 18 hours, add dulcitol weight 1.0 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 52.3%, average purity is 81.8%.
Embodiment 6:
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 5 times, concentration is the hydrobromic acid glacial acetic acid of 34%, heats to 45 DEG C, continuously stirred reaction 28 hours；
2) in course of reaction every sampling in 0.5 hour once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%；
3) purified water adding dulcitol weight 5 times stirs 2.5 hours, supernatant is pumped after standing 16 hours, add dulcitol weight 1.0 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 53.3%, average purity is 83.5%.
Embodiment 7:
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 6 times, concentration is the hydrobromic acid glacial acetic acid of 25%, heats to 43 DEG C, continuously stirred reaction 30 hours；
2) in course of reaction every sampling in 2 hours once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%；
3) 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 51.6%, average purity is 80.7%.
Embodiment 8:
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 8 times, concentration is the hydrobromic acid glacial acetic acid of 30%, heats to 50 DEG C, continuously stirred reaction 20 hours；
2) in course of reaction every sampling in 1 hour once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%；
3) 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 average yield 50.2%, average purity is 81.6%.
Embodiment 9:
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 10 times, concentration is the hydrobromic acid glacial acetic acid of 20%, heats to 55 DEG C, continuously stirred reaction 25 hours；
2) in course of reaction every sampling in 3 hours once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%；
3) 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 51.5%, average purity is 81.2%.
Comparative example 1: with reference to the embodiment of the present invention 3, midway is added without hydrobromic acid glacial acetic acid
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 1 times, concentration is the hydrobromic acid glacial acetic acid of 50%, heats to 30 DEG C, continuously stirred reaction 5 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 30.4%, average purity is 61.4%.
Comparative example 2: with reference to the embodiment of the present invention 4, midway is added without hydrobromic acid glacial acetic acid
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 2 times, concentration is the hydrobromic acid glacial acetic acid of 45%, heats to 35 DEG C, continuously stirred reaction 10 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 28 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 31.3%, average purity is 62.1%.
Comparative example 3: with reference to the embodiment of the present invention 5, midway is added without hydrobromic acid glacial acetic acid
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 4 times, concentration is the hydrobromic acid glacial acetic acid of 40%, heats to 40 DEG C, continuously stirred reaction 18 hours；
2) purified water adding dulcitol weight 6 times stirs 3 hours, supernatant is pumped after standing 18 hours, add dulcitol weight 19.0 times, concentration is 75% 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 25 DEG C of temperature, obtains mitolactol.
Experimental result: mitolactol average yield 32.8%, average purity is 64.0%.
Comparative example 4: with reference to the embodiment of the present invention 3, midway is added without hydrobromic acid glacial acetic acid, improves the addition started when reacting.
1) taking 5.0kg dulcitol and put in reactor, add dulcitol weight 3 times, concentration is the hydrobromic acid glacial acetic acid of 50%, heats to 30 DEG C, continuously stirred reaction 5 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 33.3%, average purity is 64.6%.
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 midway and add the reaction condition of hydrobromic acid glacial acetic acid, prepare comparative example 1-4 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: the hydrobromic acid glacial acetic acid amount added when comparative example is monitoring halfway, is added to when starting to react and is simultaneously introduced, but reaction result shows that the yield of so operation acquisition mitolactol reactant and purity are unsatisfactory.Midway adds together with adding in time starting, and its result has 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 (8)
1. the method improving bromoalkane agent product yield, including bromination step, 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 20-50%, heat to 30-55 DEG C, continuously stirred reaction 5-30 hour；
2) in course of reaction every sampling in 0.5-3 hour once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%.
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 34-40%.
6. the method for claim 1, it is characterised in that described step 2) the hydrobromic acid glacial acetic acid solution concentration that adds after sampling is higher than 40%.
7. the method for claim 1, 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 20-50%.
8. 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 20-50%, continuously stirred 5-30 hour；
2) in course of reaction every sampling in 0.5-3 hour once, the concentration of hydrogen bromide in assaying reaction solution, if lower than 20%, then add hydrobromic acid glacial acetic acid solution, to reaction solution, the concentration of hydrogen bromide is more than 30%；
3) 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 (4)
| 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 |
| WO2012024368A2 (en) * | 2010-08-18 | 2012-02-23 | Del Mar Pharmaceuticals | Method of synthesis of substituted hexitols such as dianhydrogalactitol |
| CN103923039A (en) * | 2014-01-30 | 2014-07-16 | 天津中津药业股份有限公司 | Method for preparing dianhydrogalactitol |
-
2014
- 2014-12-30 CN CN201410839713.7A patent/CN105801365A/en active Pending
Patent Citations (4)
| 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 |
| WO2012024368A2 (en) * | 2010-08-18 | 2012-02-23 | Del Mar Pharmaceuticals | Method of synthesis of substituted hexitols such as dianhydrogalactitol |
| 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 (1)
| Title |
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| 刘铭勋等: "抗癌剂二溴卫茅醇的合成", 《江西医学院学报》 * |
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