CN105801359B - A kind of synthetic method of dianhydrogalactitol intermediate - Google Patents
A kind of synthetic method of dianhydrogalactitol intermediate Download PDFInfo
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Abstract
The present invention relates to a kind of synthetic methods of dianhydrogalactitol intermediate.Water winged euonymus alcohol intermediate mitolactol preparation method provided by the invention, can obtain average yield more than 50%, product of the average purity more than 80%, 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 synthetic method of dianhydrogalactitol intermediate.
Background technology
In dianhydrogalactitol preparation process, the intermediate being typically used for is mitolactol, also known as dibromo galactitol, is
The isomers of dibromannitol, although being typically considered alkylating agent, its effect cannot be explained with alkanisation theory completely,
DNA synthesis is inhibited to inhibit strong compared with RNA synthesis, its main metabolites in vivo is di-epoxide, is that the cell cycle is non-
Specific drug.The LD50 of rat is:Oral 1400mg/kg, is injected intraperitoneally 470mg/kg.Effect is similar to dibromannitol,
After being converted to the dianhydrogalactitol with diethyl epoxy construction in vivo, 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 disclosed in the second phase in 1984 is:
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 recrystallization mitolactol highest yield that this method obtains for 40% (with mole
Meter).
" the stability instruction high pressure liquid chromatography of Dibromoducitol in aqueous solution "《External medicine synthetic drug Biochemical Drugs
Preparation fascicle》The 4th phase of volume 10 in 1989 also refers 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, 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." the no public affairs of this method
Open mitolactol yield.
Due to dulcitol, dissolubility is all very poor in most solvent, can select to make the narrow range of bromating agent, to anti-
Answer condition requirement harsh, and method made above is suitable only for laboratory lab scale, because experimental raw is using analysis rank, sample
All conditions can disregard cost and accomplish most preferably during trial-production, during mass production, in order to reduce production cost, generally use industry
Grade raw material, condition can not possibly be as mitolactol that laboratory lab scale obtains is there are the problem of yield is low, purity is low, 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, the very big ability of usage amount
Fundamental reaction is complete, causes waste of solvent and environmental pollution.When selecting hydrobromic acid as bromating agent, if it is higher to obtain purity
Mitolactol must also select the solvent of high-purity, more than such as a concentration of 69% hydrobromic acid solution, could obtain 70% left side
The mitolactol of right purity, if using low concentration hydrobromic acid solution yield usually below 10%.It can buy in the market
The maximum concentration hydrobromic acid arrived is 62%, more than this concentration, it is necessary to which oneself is prepared, complex process, operating process danger close, and not
One is surely successfully prepared.
Invention content
The object of the present invention is to provide a kind of synthetic methods of dianhydrogalactitol intermediate.
A kind of synthetic method of dianhydrogalactitol intermediate of the present invention includes bromination step, it is characterised in that:Institute
The bromination process reaction process stated carries out under elevated pressure.
Preferably:Described being pressurised into is passed through the pressurization of gas gradient type.
Preferably:The gas is is not involved in reaction and will not cause dysgenic gas to reaction.
Preferably:The gas is inert gas, carbon dioxide or helium.
Preferably:The pressure of the pressurization is not less than 0.1Mpa at the end of reaction.
A kind of synthetic method of dianhydrogalactitol intermediate of the present invention, which is characterized in that the bromination process packet
Include following steps:Dulcitol is taken to put in reaction kettle, adds in hydrobromic acid solution, heating reaction 2-24 hours, heating temperature 30-90
DEG C, in the reaction time of 2-24 hours, pressure is started to step up by 0Mpa, until 2.0Mpa is finally reached, during reaction
It is stirred continuously, reaction terminates up to mitolactol solution.
Preferably:The temperature during reaction is 40-80 DEG C.
Preferably:The temperature during reaction is 70 DEG C.
Preferably:A concentration of 20-80% of hydrobromic acid solution.
Preferably:A concentration of 30-62% of hydrobromic acid solution.
Preferably:The hydrobromic acid solution a concentration of 40%.
Preferably:The amount of the hydrobromic acid solution is 2-15 times of dulcitol weight.
The synthetic method of a kind of dianhydrogalactitol intermediate of the present invention, it is characterised in that include the following steps:
1) dulcitol is taken to put in reaction kettle, add in 2-15 times of dulcitol weight, a concentration of 20-80% hydrobromic acid solution,
Heating reaction 2-24 hours, heating temperature is 30-90 DEG C, 30-90 DEG C is heated to, the reaction time of 2-24 hours, in 2-24
In the reaction time of hour, pressure is started to step up by 0Mpa, until finally reaching 2.0Mpa, is stirred continuously during reaction,
Reaction terminates up to mitolactol solution;
2) mitolactol solution stands 12 hours or more at room temperature, and filtering obtains mitolactol coarse crystallization;
3) mitolactol coarse crystallization recrystallizing methanol is to get mitolactol.
Existing literature document announcement can prepare the mitolactol of more than 70% yield in a short time, and propose using more
The hydrobromic acid of high concentration is reacted (more than 62%), and the prior art requires hydrobromic acid concentration more than 69%, to skilled behaviour
Make personnel, a small amount of mitolactol could be obtained, only when hydrobromic acid concentration is more than 80%, 30% or so could be obtained
Yield.Actually these technical solutions are not suitable for large-scale production, and reason is:
1st, currently without the high concentration of hydrogen bromic acid of commercialization, large-scale production maximum concentration is 62%, through transporting, storing,
To often concentration has been reduced to 60% in actual use.The maximum concentration hydrobromic acid being commercially available currently on the market is 62%, is surpassed
Cross this concentration, it is necessary to which oneself is prepared, complex process, operating process danger close, and is differed and be surely successfully prepared, and be not suitable for public affairs
Industry more than jin grade is combined to.Therefore it is unrealistic using high concentration hydrobromic acid solution large-scale production.
2nd, for material quality without guarantee, and under conditions of high concentration, reaction is excessively violent, and not only production environment is dangerous, and
Excessive impurity is included in mitolactol crystallization and can not be purified.
Since the reaction of dulcitol and hydrobromic acid reaction generation mitolactol is reversible reaction, when reaction just starts, by
Bromine content is high in reaction mass, overreact, easily generates terbromide, tetrabromo compound;With the progress of reaction, raw material
Concentration reduces, and the generation of mitolactol is increasingly difficult to, and can generate monobromo compound because when substitution reaction adds bromine insufficient;
Factors above is the main reason for causing mitolactol yield too low.
After the present invention have passed through a large amount of experimental study and grope, find in mitolactol preparation process, pressure is one
A very crucial factor by controlling the pressure of reaction process, enables to dulcitol bromination reaction to have higher dibromo
Selectivity, overcomes the problems, such as that dulcitol bromination reaction side reaction is too many, can be obviously improved mitolactol yield, and final
The higher crystallization of purity can be obtained.
The present invention in bromination process by pressure influence reaction process, it is not strong to hydrobromic acid solution concentration selectivity, it is not necessary to
It is required that using the hydrobromic acid solution of high concentration, between a concentration of 20-80% of hydrobromic acid solution, it can enable reaction smoothly and good
Ground carries out, and the yield of mitolactol and purity can be made to be significantly improved.
The present invention also provides the preferred preparation method of mitolactol, and detailed process and technological parameter are given, led to
Cross this preferred process control so that coordinate the bromating agent and reaction temperature of debita spissitudo during bromination reaction, by difference
The response situation of period, steps up reaction pressure, and control pressure in a certain range, can make dulcitol in bromination process
It is selectively brominated agent and replaces two primary hydroxyl generation mitolactols, can further reduce the generation of by-product,
So as to preferably improve the yield and purity of industrialization dibromo hexitol.
A kind of synthetic method of dianhydrogalactitol intermediate provided by the invention has the following advantages:
1st, mitolactol purity is high:The prior art obtain mitolactol product purity 70% hereinafter, using
The mitolactol that the present invention is prepared, purity is more than 80%.
High income during the 2nd, using the present invention applied to industrialization production mitolactol:The prior art is appropriate only for laboratory
Lab scale, during for mass producing mitolactol yield below 40% (in mol), technical solution of the present invention technique peace
Complete reasonable, mitolactol average yield obtained is more than 50%.
Specific embodiment
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 rather than limitation of the present 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 represents solution
Volume ratio.
Embodiment 1:
10kg dulcitols is taken to put in reaction kettle, add in 15 times of dulcitol weight, a concentration of 40% hydrobromic acid solution, water-bath
70 DEG C are heated to, keep the temperature and is constantly stirred to react 15 hours, nitrogen pressurization is passed through during reaction, with reaction time pressurization range
For:0-1 hours, pressure gradually added to 0.1MPa by 0MPa;1-5 hours, pressure gradually added to 0.5MPa by 0.1MPa;5-9 is small
When, pressure gradually adds to 0.9MPa by 0.5MPa;9-15 hours, pressure gradually added to 1.4MPa by 0.9MPa;Reaction terminates
Mitolactol solution;Mitolactol solution stands 24 hours at room temperature, and filtering obtains mitolactol coarse crystallization;Dibromo is defended
Lance alcohol coarse crystallization adds the methanol of 100 times of coarse crystallization weight, is recrystallized at 2 DEG C, obtains mitolactol.
Experimental result:Mitolactol average yield 56%, average purity 86%.
Embodiment 2:
10kg dulcitols is taken to put in reaction kettle, add in 2 times of dulcitol weight, a concentration of 20% hydrobromic acid solution, water-bath
30 DEG C are heated to, keep the temperature and is constantly stirred to react 2 hours, argon pressurization is passed through during reaction, with reaction time pressurization ranging from:
0-1 hours, pressure gradually added to 0.05MPa by 0MPa;1-2 hours, pressure gradually added to 0.1MPa by 0.05MPa;Reaction knot
Beam obtains mitolactol solution;Mitolactol solution stands 12 hours at room temperature, and filtering obtains mitolactol coarse crystallization;Two
Bromine dulcitol coarse crystallization adds the methanol of 80 times of coarse crystallization weight, is recrystallized at 6 DEG C, obtains mitolactol.
Experimental result:Mitolactol average yield 50%, average purity 80%.
Embodiment 3:
10kg dulcitols is taken to put in reaction kettle, add in 6 times of dulcitol weight, a concentration of 30% hydrobromic acid solution, water-bath
90 DEG C are heated to, keep the temperature and is constantly stirred to react 8 hours, helium pressurization is passed through during reaction, with reaction time pressurization ranging from:
0-1 hours, pressure gradually added to 0.1MPa by 0MPa;1-4 hours, pressure gradually added to 0.3MPa by 0.1MPa;4-8 hours,
Pressure gradually adds to 0.5MPa by 0.3MPa;Reaction terminates to obtain mitolactol solution;Mitolactol solution is stood at room temperature
30 hours, filtering obtained mitolactol coarse crystallization;Mitolactol coarse crystallization adds the methanol of 70 times of coarse crystallization weight, at 8 DEG C
Recrystallization, obtains mitolactol.
Experimental result:Mitolactol average yield 53%, average purity 84%.
Embodiment 4:
10kg dulcitols is taken to put in reaction kettle, add in 4 times of dulcitol weight, a concentration of 62% hydrobromic acid solution, water-bath
40 DEG C are heated to, keep the temperature and is constantly stirred to react 24 hours, carbon dioxide pressurization is passed through during reaction, with reaction time pressurization model
Enclose for:0-1 hours, pressure gradually added to 0.1MPa by 0MPa;1-6 hours, pressure gradually added to 0.5MPa by 0.1MPa;6-12
Hour, pressure gradually adds to 1.0MPa by 0.5MPa;12-18 hours, pressure gradually added to 1.5MPa by 1.0MPa;18-24 is small
When, pressure gradually adds to 2.0MPa by 1.5MPa;Reaction terminates to obtain mitolactol solution;Mitolactol solution is quiet at room temperature
It puts 48 hours, filters, obtain mitolactol coarse crystallization;Mitolactol coarse crystallization adds the methanol of 60 times of coarse crystallization weight, at 4 DEG C
Lower recrystallization, obtains mitolactol.
Experimental result:Mitolactol average yield 56%, average purity 86%.
Embodiment 5:
10kg dulcitols is taken to put in reaction kettle, add in 7 times of dulcitol weight, a concentration of 50% hydrobromic acid solution, water-bath
80 DEG C are heated to, keep the temperature and is constantly stirred to react 16 hours, carbon dioxide pressurization is passed through during reaction, with reaction time pressurization model
Enclose for:0-1 hours, pressure gradually added to 0.1MPa by 0MPa;1-5 hours, pressure gradually added to 0.4MPa by 0.1MPa;6-12
Hour, pressure gradually adds to 1.9MPa by 0.4MPa;12-16 hours, pressure gradually added to 1.2MPa by 0.9MPa;Reaction terminates
Obtain mitolactol solution;Mitolactol solution stands 18 hours at room temperature, and filtering obtains mitolactol coarse crystallization;Dibromo
Dulcitol coarse crystallization adds the methanol of 50 times of coarse crystallization weight, is recrystallized at 3 DEG C, obtains mitolactol.
Experimental result:Mitolactol average yield 54%, average purity 84%.
Embodiment 6:
8kg dulcitols is taken to put in reaction kettle, add in 10 times of dulcitol weight, a concentration of 80% hydrobromic acid solution, water-bath
50 DEG C are heated to, keep the temperature and is constantly stirred to react 18 hours, nitrogen pressurization is passed through during reaction, with reaction time pressurization range
For:0-1 hours, pressure gradually added to 0.1MPa by 0MPa;1-6 hours, pressure gradually added to 0.4MPa by 0.1MPa;6-12 is small
When, pressure gradually adds to 0.7MPa by 0.4MPa;12-18 hours, pressure gradually added to 1.0MPa by 0.7MPa;Reaction terminates
Mitolactol solution;Mitolactol solution stands 20 hours at room temperature, and filtering obtains mitolactol coarse crystallization;Dibromo is defended
Lance alcohol coarse crystallization adds the methanol of 100 times of coarse crystallization weight, is recrystallized at 7 DEG C, obtains mitolactol.
Experimental result:Mitolactol average yield 55%, average purity 85%.
Comparative example 1:With reference to the embodiment of the present invention 1, no pressure
10kg dulcitols is taken to put in reaction kettle, add in 15 times of dulcitol weight, a concentration of 40% hydrobromic acid solution, water-bath
70 DEG C are heated to, keep the temperature and is constantly stirred to react 15 hours, reaction terminates to obtain mitolactol solution;Mitolactol solution room
Temperature is lower to stand 24 hours, and filtering obtains mitolactol coarse crystallization;Mitolactol coarse crystallization adds the first of 100 times of coarse crystallization weight
Alcohol recrystallizes at 2 DEG C, obtains mitolactol.
Experimental result:Mitolactol average yield 37%, average purity 65%.
Comparative example 2:With reference to the embodiment of the present invention 2, no pressure
10kg dulcitols is taken to put in reaction kettle, add in 2 times of dulcitol weight, a concentration of 20% hydrobromic acid solution, water-bath
30 DEG C are heated to, keep the temperature and is constantly stirred to react 2 hours, reaction terminates to obtain mitolactol solution;Mitolactol solution room
Temperature is lower to stand 12 hours, and filtering obtains mitolactol coarse crystallization;Mitolactol coarse crystallization adds the first of 80 times of coarse crystallization weight
Alcohol recrystallizes at 6 DEG C, obtains mitolactol.
Experimental result:Mitolactol average yield 35%, average purity 64%.
Comparative example 3:With reference to the embodiment of the present invention 3, no pressure
10kg dulcitols is taken to put in reaction kettle, add in 6 times of dulcitol weight, a concentration of 30% hydrobromic acid solution, water-bath
90 DEG C are heated to, keep the temperature and is constantly stirred to react 8 hours, reaction terminates to obtain mitolactol solution;Mitolactol solution room
Temperature is lower to stand 30 hours, and filtering obtains mitolactol coarse crystallization;Mitolactol coarse crystallization adds the first of 70 times of coarse crystallization weight
Alcohol recrystallizes at 8 DEG C, obtains mitolactol.
Experimental result:Mitolactol average yield 37%, average purity 63%.
Comparative example 4:With reference to the embodiment of the present invention 4, no pressure
10kg dulcitols is taken to put in reaction kettle, add in 4 times of dulcitol weight, a concentration of 62% hydrobromic acid solution, water-bath
40 DEG C are heated to, keep the temperature and is constantly stirred to react 24 hours;Reaction terminates to obtain mitolactol solution;Mitolactol solution room
Temperature is lower to stand 48 hours, and filtering obtains mitolactol coarse crystallization;Mitolactol coarse crystallization adds the first of 60 times of coarse crystallization weight
Alcohol recrystallizes at 4 DEG C, obtains mitolactol.
Experimental result:Mitolactol average yield 34%, average purity 63%.
Comparative example 5:With reference to the embodiment of the present invention 5, no pressure
8kg dulcitols is taken to put in reaction kettle, add in 10 times of dulcitol weight, a concentration of 80% hydrobromic acid solution, water-bath
50 DEG C are heated to, keep the temperature and is constantly stirred to react 18 hours;Reaction terminates to obtain mitolactol solution;Mitolactol solution room
Temperature is lower to stand 20 hours, and filtering obtains mitolactol coarse crystallization;Mitolactol coarse crystallization adds the first of 100 times of coarse crystallization weight
Alcohol recrystallizes at 7 DEG C, obtains mitolactol.
Experimental result:Mitolactol average yield 32%, average purity 59%.
Process ration is tested:
Experimental method:Disclosed reaction pressure, reaction temperature and hydrobromic acid solution concentration according to the present invention prepare embodiment
1-6 samples;On the basis of the preparation method for wanting embodiment 1-5, the reaction condition of pressurization is subtracted, prepares comparative example 1-5 samples respectively
Product.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:Mitolactol yield and purity
1 result of table is shown:The operating procedure of comparative example 1-5 difference corresponding embodiments 1-5, only subtracts compressive reaction item
Part, the yield of the mitolactol significant difference compared with pressurization with purity, average yield the 58-70% of embodiment it
Between, average purity is between the 70-80% of embodiment.
The experimental results showed that:By response parameter provided by the invention, it may be significantly and prepare institute better than existing technical solution
Obtain the effect of mitolactol.
Although above having used general explanation, specific embodiment 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 synthetic method of dianhydrogalactitol intermediate, including bromination step, it is characterised in that:The bromination process is anti-
Process is answered using hydrobromic acid solution as bromating agent, and is carried out under elevated pressure, described being pressurised into is passed through the pressurization of gas gradient type, described
Gas be nitrogen, argon gas, carbon dioxide or helium.
2. the method as described in claim 1, it is characterised in that:The pressure of the pressurization is not less than at the end of reaction
0.1MPa。
3. the method as described in claim 1, which is characterized in that the bromination process includes the following steps:
Dulcitol is taken to put in reaction kettle, adds in hydrobromic acid solution, heating reaction 2-24 hours, heating temperature is 30-90 DEG C, in 2-
In the reaction time of 24 hours, pressure is started to step up by 0MPa, until finally reaching 2.0MPa, is constantly stirred during reaction
It mixes, reaction terminates up to mitolactol solution.
4. method as claimed in claim 3, which is characterized in that the temperature during reaction is 40-80 DEG C.
5. method as claimed in claim 3, which is characterized in that the temperature during reaction is 70 DEG C.
6. method as claimed in claim 3, which is characterized in that a concentration of 20-80% of hydrobromic acid solution.
7. method as claimed in claim 3, which is characterized in that a concentration of 30-62% of hydrobromic acid solution.
8. method as claimed in claim 3, which is characterized in that the hydrobromic acid solution a concentration of 40%.
9. such as claim 6-8 any one of them methods, which is characterized in that the weight of the hydrobromic acid solution is dulcitol weight
2-15 times of amount.
10. the method as described in claim 1, it is characterised in that include the following steps:
1) dulcitol is taken to put in reaction kettle, add in 2-15 times of dulcitol weight, a concentration of 20-80% hydrobromic acid solution, heat
Reaction 2-24 hours, heating temperature are 30-90 DEG C, and in the reaction time of 2-24 hours, pressure is started to step up by 0MPa,
Until finally reaching 2.0MPa, it is stirred continuously during reaction, reaction terminates up to mitolactol solution;
2) mitolactol solution stands 12 hours or more at room temperature, and filtering obtains mitolactol coarse crystallization;
3) mitolactol coarse crystallization recrystallizing methanol is to get mitolactol.
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Non-Patent Citations (4)
Title |
---|
"卫康醇(去水卫矛醇)";---;《中国药学杂志》;19860308;第21卷(第3期);1580159 * |
"抗癌剂二溴卫茅醇的合成";刘铭勋;《江西医学院学报》;1984(第2期);8-9页,全文第2段和实验部分 * |
"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);B016-12 * |
"水溶液中二溴卫茅醇的稳定性指示高压液相色谱";Clark BA et al;《国外医药.合成药.生化药.制剂分册》;1989;第10卷(第4期);229、204 * |
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