CN109053372A - A method of preparing Dibromoducitol - Google Patents
A method of preparing Dibromoducitol Download PDFInfo
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- CN109053372A CN109053372A CN201811106002.3A CN201811106002A CN109053372A CN 109053372 A CN109053372 A CN 109053372A CN 201811106002 A CN201811106002 A CN 201811106002A CN 109053372 A CN109053372 A CN 109053372A
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- Prior art keywords
- dibromoducitol
- propyl
- preparing
- reaction
- melampyrin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0285—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre also containing elements or functional groups covered by B01J31/0201 - B01J31/0274
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of methods for preparing Dibromoducitol, 1- propyl -3-N-morpholinopropanesulfonic acid imidazole bisulfate ionic-liquid catalyst is added in reaction, hydrogen bromide still can smoothly be reacted in low concentration, it is added in the reaction and the substance of bromide ion is provided, the rate of reaction selectivity, catalysis reaction can be improved, it is effectively facilitated reaction to carry out, promotes the yield of mitolactol.Method provided by the invention is at low cost, easy to operate, and safety and environmental protection is easy to industrial applications.
Description
Technical field
The invention belongs to pharmaceutical intermediate fields, and in particular to a method of prepare Dibromoducitol.
Background technique
Mitolactol is also known as dibromo galactitol, outer literary fame: Dibromidulcitol, Mitolactol, D-
Galactitol., foreign language is abridged: DBD；Chemical name: 1,6- bis- bromo- 1,6- dideoxy dulcitol；Molecular formula: C6H12Br2O4.
Structure is as follows:
The carbohydrate derivative of two unrestrained melampyrin (Dibromoeluleitol, abridge DBD) system tool anti-tumor activities, both at home and abroad
Research has shown that zoopery has extensive anti-tumor activity, can interfere the synthesis of DNA, RNA and protein, is that a cell cycle is non-
Specific medicine.Hungary and the U.S. etc. have carried out extensive comprehensive study to the medicine during the last ten years, and some scholars think that DBD may
As new anticancer agent important in Clinical Oncology.China also once had individual areas to be tried with a small amount of preproduction in clinic in recent years
Report.In the research of the antiviral effective component of Oriental Bittersweet Root, discovery Oriental Bittersweet Root centre halfback thatch alcohol content is up to 1 and opens up for we
Left and right (with dry powder juice).In order to make full use of this Chinese herbal medicine resource abundant of Jiangxi, we are with the melampyrin of celastrus orbiculatus extraction
Melampyrin is smelt for Material synthesis anticancer agent two.
It manufactures experimently through Jiangxi Traditional Chinese Medicine Factory into tablet, and in the attached institute's internal medicine of Jiangxi Medical College two to treat the white blood of chronic granulocyte
Patient obtains the synthesis about mitolactol, it has been disclosed that following preparation method:
" synthesis of anticancer agent Dibromoducitol " " Jiangxi Medical College's journal " second phase in 1984 it is disclosed the preparation method comprises the following steps:
It is under normal pressure 90 DEG C (± 1 DEG C) suitable heating time from melampyrin synthesis Dibromoducitol optimum temperature 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.The recrystallization mitolactol highest yield for using this method to obtain 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, it also refers to the preparation method of mitolactol: galactitol 400mg being placed in cold
Freeze glass reaction kettle and be dissolved in dense HBr1.2ml, the closed container, is heated 12 hours in 70 DEG C of water-baths, mixed liquor is poured into
In 3g ice, DBD is crystallized immediately, and after ice all dissolution, filtration, filter residue is dissolved in hot methanol, is recrystallized." the no public affairs of this method
Open the yield of mitolactol.
By current published technical method, resulting mitolactol crystallization purity is low, yield is unstable；Corresponding essence
Means processed also have no any open report.
Summary of the invention
The object of the present invention is to provide a kind of methods for preparing Dibromoducitol.
The purpose of the present invention is what is realized by following measures: this method is the substance and polar solvent to offer bromide ion
The in the mixed solvent of composition adds ionic-liquid catalyst, hydrobromic acid solution and melampyrin then is added dropwise simultaneously, in 1- propyl -3- third
Under the action of sulfonic acid imidazole bisulfate ionic-liquid catalyst, bromination reaction occurs for hydrobromic acid and melampyrin, and obtained dibromo is defended
Thatch alcoholic solution, reaction solution stratification separate 1- propyl -3- propyl imidazole hexafluorophosphate ionic liquid layer and product layer, produce
Nitride layer is washed with water to neutrality, drains, and obtains mitolactol crude product, 0.5~100 times of overstriking product weight, concentration of volume percent
It ethyl alcohol immersion 0.1 hour or more not less than 50%, drains, low-temperature reduced-pressure is dry, obtains mitolactol coarse crystallization.
The hydrobromic acid solution is that concentration is 40~62%, it is preferable that the concentration of aqueous solution is 48~62%.It is described
Hydrobromic acid solution additional amount be 1~20 times of melampyrin weight, preferably 3~15 times, most preferably 5~10 times.
The dosage of the ionic-liquid catalyst accounts for 10~20wt% of hydrobromic acid and melampyrin raw material total amount.
The ionic-liquid catalyst is 1- propyl -3-N-morpholinopropanesulfonic acid imidazole bisulfate ionic-liquid catalyst, described
The dosage of catalyst accounts for 10~20wt% of hydrogen bromide and melampyrin raw material total amount.
The ionic-liquid catalyst 1- propyl -3-N-morpholinopropanesulfonic acid imidazole bisulfate is prepared by the following method: with 1,3- third
Sultones and N- propyl imidazole are raw material, in the presence of ethyl acetate, are reacted in 60-80 DEG C to generation white precipitate,
It filters out sediment and is washed, dried with ethyl acetate, obtain 1- (3- sulfonic group) propyl -3- propyl imidazole salt；By the 1- (3-
Sulfonic group) propyl -3- propyl imidazole salt is dissolved in water, and the concentrated sulfuric acid is added and is reacted in 80-90 DEG C, and it then removes moisture content and obtains
Faint yellow sticky shape product liquid, as 1- propyl -3-N-morpholinopropanesulfonic acid imidazole bisulfate ionic-liquid catalyst.
Ionic liquid (IonicLiquids abbreviation ILs) is also known as ionic liquid at room temperature, is at room temperature in ionic condition
Salts substances, have it is non-volatile, do not aoxidize, be highly polar, having the characteristics such as good dissolubility to inorganic and organic compound, it is wide
The general environment-friendly type solvent for the volatile chemical solvent of replacement.1- propyl -3-N-morpholinopropanesulfonic acid base imidazole bisulfate is existing skill
A kind of known ionic-liquid catalyst, is used in chemical reaction in art, for overcoming the catalyst such as conventional solid acid to deposit
Corrosivity it is strong, equipment investment is high, side reaction is more, pollution environment, be difficult to recycle, product with reaction system is difficult to separate
The defects of.
Wherein polar solvent is methanol, ethyl alcohol, propyl alcohol, ethylene glycol, propylene glycol, butanediol, tetrahydrofuran, ether, dioxy
Six rings etc..
The substance of bromide ion is wherein provided selected from one of the salt of bromine or brominated acid or a variety of, these offer bromide ions
Substance be preferably NaBr, KBr, LiBr, IBr, BrCl.
The dosage for wherein providing the polar solvent of the substance of bromide ion and the in the mixed solvent of polar solvent composition presses quality
Percentages are the 61~99% of mixed solvent dosage, and the substance dosage for providing bromide ion is mixed solvent by mass percentage
The 1~39% of dosage.
Wherein the time for adding of hydrobromic acid and melampyrin is generally 1~10 hour, preferably at 3~8 hours.Wherein bromination is anti-
Three phases control should be divided, first stage temperature is 1~50 DEG C, is reacted 2~14 hours, and second stage temperature is 50~70 DEG C,
Reaction 4~8 hours, phase III temperature are 70~90 DEG C, are reacted 2~6 hours.
The invention has the advantages that:
1) due to hydrogen bromide, different solubility, the hydrobromic acid solution containing hydrogen bromide are usual in aqueous solution and organic acid soln
Preparation gained maximum concentration is 62%, and hydrobromic acid glacial acetic acid solution maximum concentration is 33%, is more than that concentrations above is being produced and transported
It is abnormally dangerous in defeated, use process.During the reaction, when the concentration of hydrogen bromide in the solution reaches certain lower limit, because
For insufficient raw material, reaction is difficult to occur, and reaction is almost stagnated.But ionic-liquid catalyst is added in reaction, not due to certain
The reaction mechanism known, hydrogen bromide still can smoothly be reacted in low concentration, make dulcitol bromination mitolactol.
2) inventor has found the progress with reaction, and bromination hydrogen concentration reduces in raw material, and the generation of mitolactol is more next
It is more difficult to, because bromine is insufficient when bromination reaction, will cause the generation of more monobromo substituents, to reduce the receipts of mitolactol
Rate, and will increase the impurity in crystallization.At this moment, the substance of bromide ion is provided if be added in the reaction, reaction choosing can be improved
Selecting property, the rate of catalysis reaction, are effectively facilitated reaction and carry out, promote the yield of mitolactol.
Specific embodiment
The following is a clear and complete description of the technical scheme in the embodiments of the invention, it is clear that described embodiment
Only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, the common skill in this field
Art personnel every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
[embodiment 1]
Weigh 184g1,3-N-morpholinopropanesulfonic acid lactone, and measure 1L ethyl acetate be added reactor in, load onto constant pressure funnel,
Magnetic stirring apparatus and reflux condensing tube are slowly added to 123gN- propyl imidazole, wait drip when being heated to 60 DEG C in water-bath
After the completion of adding, make architecture heat preservation in 80 DEG C of reaction 2h, until generating white precipitate；Decompression suction filtration carried out to system, and with acetic acid second
Ester washs filter cake, is put into 100 DEG C of drying in baking oven, and products obtained therefrom is 1- (3- sulfonic group) propyl -3- propyl imidazole salt；It will be described
1- (3- sulfonic group) propyl -3- propyl imidazole salt is dissolved in water, and the concentrated sulfuric acid is added and is reacted in 85 DEG C, then removes moisture content and obtains
To faint yellow sticky shape product liquid, as 1- propyl -3-N-morpholinopropanesulfonic acid imidazole bisulfate ionic liquid.
[embodiment 2]
Blender is being housed, in the four-hole bottle of thermometer and constant pressure funnel, 95g tetrahydrofuran, 30g bromination is added
Sodium, 12g 1- propyl -3-N-morpholinopropanesulfonic acid imidazole bisulfate ionic liquid start agitating device, are added dropwise simultaneously under the conditions of 50 DEG C
The hydrobromic acid solution and 23g melampyrin that 80g concentration is 50% control rate of addition, make the two in 5 hours while dripping off, and protect
Temperature reaction was warming up to 60 DEG C after about 4 hours, kept the temperature 5 hours, then be warming up to 90 DEG C, kept the temperature 3 hours, and it is molten that Dibromoducitol is made
Liquid, reaction solution stratification separate 1- methyl -3- propyl imidazole hexafluorophosphate ionic liquid layer and product layer, and product layer is used
Water washing is drained to neutrality, obtains mitolactol crude product, 3 times of overstriking product weight, the ethyl alcohol that concentration of volume percent is 62% soak
It bubble 0.1 hour or more, drains, low-temperature reduced-pressure is dry, obtains mitolactol coarse crystallization.
Experimental result: mitolactol average yield 80%, average purity 93%.
[embodiment 3]
Blender is being housed, in the four-hole bottle of thermometer and constant pressure funnel, 1kg ethyl acetate, 100g bromination is added
Lithium, 0.15kg 1- propyl -3-N-morpholinopropanesulfonic acid imidazole bisulfate ionic liquid start agitating device, drip simultaneously under the conditions of 50 DEG C
Adding 0.6kg concentration is 50% hydrobromic acid solution and 0.3kg melampyrin, controls rate of addition, makes the two in 5 hours while dripping
Complete, insulation reaction is warming up to 60 DEG C after about 4 hours, keeps the temperature 5 hours, then be warming up to 90 DEG C, keeps the temperature 3 hours, obtained dibromo defends thatch
Alcoholic solution, reaction solution stratification separate 1- methyl -3- propyl imidazole hexafluorophosphate ionic liquid layer and product layer, product
Layer is washed with water to neutrality, drains, and obtains mitolactol crude product, 3 times of overstriking product weight, the second that concentration of volume percent is 62%
It alcohol immersion 0.1 hour or more, drains, low-temperature reduced-pressure is dry, obtains mitolactol coarse crystallization.
Experimental result: mitolactol average yield 81%, average purity 92%.
[comparative example 1]
Blender is being housed, in the four-hole bottle of thermometer and constant pressure funnel, 95g tetrahydrofuran, 30g bromination is added
Sodium starts agitating device, and the hydrobromic acid solution and 23g melampyrin that 80g concentration is 50%, control is added dropwise simultaneously under the conditions of 50 DEG C
Rate of addition makes the two in 5 hours while dripping off, and insulation reaction is warming up to 60 DEG C after about 4 hours, keeps the temperature 5 hours, then heat up
To 90 DEG C, 3 hours are kept the temperature, Dibromoducitol solution is made, reaction solution stratification separates 1- methyl -3- propyl imidazole hexafluoro
Phosphate ion liquid level and product layer, product layer are washed with water to neutrality, drain, and obtain mitolactol crude product, overstriking product weight
3 times of amount, the ethyl alcohol that concentration of volume percent is 62% impregnate 0.1 hour or more, drain, and low-temperature reduced-pressure is dry, obtains dibromo winged euonymus
Alcohol coarse crystallization.
Experimental result: mitolactol average yield 32%, average purity 80%.
[comparative example 2]
Blender is being housed, in the four-hole bottle of thermometer and constant pressure funnel, 95g tetrahydrofuran, 13g 1- first is added
Base -3- propyl imidazole hexafluorophosphate starts agitating device, and the hydrogen bromine that 80g concentration is 50% is added dropwise simultaneously under the conditions of 50 DEG C
Acid solution and 23g melampyrin control rate of addition, make the two in 5 hours while dripping off, insulation reaction heats up after about 4 hours
To 60 DEG C, 5 hours are kept the temperature, then be warming up to 90 DEG C, keep the temperature 3 hours, Dibromoducitol solution is made, reaction solution stratification divides
It is washed with water to neutrality from 1- methyl -3- propyl imidazole hexafluorophosphate ionic liquid layer and product layer, product layer, drains, obtains
Mitolactol crude product, 3 times of overstriking product weight, the ethyl alcohol that concentration of volume percent is 62% are impregnated 0.1 hour or more, are drained,
Low-temperature reduced-pressure is dry, obtains mitolactol coarse crystallization.
Experimental result: mitolactol average yield 38%, average purity 81%.
Above description sufficiently discloses a specific embodiment of the invention.It should be pointed out that being familiar with the field
Range of any change that technical staff does a specific embodiment of the invention all without departing from claims of the present invention.
Correspondingly, the scope of the claims of the invention is also not limited only to previous embodiment.
Claims (10)
1. a kind of method for preparing Dibromoducitol, it is characterised in that: formed to the substance and polar solvent for providing bromide ion
In the mixed solvent adds ionic-liquid catalyst, hydrobromic acid solution and melampyrin then is added dropwise simultaneously, in 1- propyl -3-N-morpholinopropanesulfonic acid miaow
Under the action of azoles hydrogen sulphate ionic liquid catalyst, bromination reaction occurs for hydrobromic acid and melampyrin, and it is molten that Dibromoducitol is made
Liquid, reaction solution stratification separate 1- propyl -3- propyl imidazole hexafluorophosphate ionic liquid layer and product layer, and product layer is used
Water washing is drained to neutrality, obtains mitolactol crude product, 0.5~100 times of overstriking product weight, concentration of volume percent are not less than
Ethyl alcohol immersion 0.1 hour or more of 50%, is drained, low-temperature reduced-pressure is dry, obtains mitolactol coarse crystallization.
2. the method according to claim 1 for preparing Dibromoducitol, it is characterised in that: the hydrobromic acid solution is concentration
It is 40~62%, it is preferable that concentration is 48~62%.
3. the method according to claim 1 for preparing Dibromoducitol, which is characterized in that the hydrobromic acid solution is added
Amount is 1~20 times of melampyrin weight, preferably 3~15 times, most preferably 5~10 times.
4. the method according to claim 1 for preparing Dibromoducitol, which is characterized in that the ionic-liquid catalyst
Dosage accounts for 10~20wt% of hydrobromic acid and melampyrin raw material total amount.
5. the method according to claim 1 for preparing Dibromoducitol, which is characterized in that 1- propyl -3-N-morpholinopropanesulfonic acid imidazoles
Disulfate is prepared by the following method: using 1,3-propane sultone and N- propyl imidazole as raw material, in the presence of ethyl acetate, in
60-80 DEG C is reacted to white precipitate is generated, and is filtered out sediment and is washed, dried with ethyl acetate, obtains 1- (3- sulfonic acid
Base) propyl -3- propyl imidazole salt；The 1- (3- sulfonic group) propyl -3- propyl imidazole salt is dissolved in water, be added the concentrated sulfuric acid in
80-90 DEG C is reacted, and is then removed moisture content and is obtained faint yellow sticky shape product liquid, as 1- propyl -3-N-morpholinopropanesulfonic acid imidazoles
Hydrogen sulphate ionic liquid catalyst.
6. the method according to claim 1 for preparing Dibromoducitol, it is characterised in that: the polar solvent be methanol,
Ethyl alcohol, propyl alcohol, ethylene glycol, propylene glycol, butanediol, tetrahydrofuran, ether, dioxane etc..
7. the method according to claim 1 for preparing Dibromoducitol, it is characterised in that: described to provide the substance of bromide ion
With polar solvent composition in the mixed solvent polar solvent dosage be by mass percentage mixed solvent dosage 61~
99%, the substance dosage for providing bromide ion is the 1~39% of mixed solvent dosage by mass percentage.
8. the method according to claim 1 for preparing Dibromoducitol, it is characterised in that: described to provide the substance of bromide ion
One of salt or brominated acid selected from bromine are a variety of, these provide bromide ions substances be preferably NaBr, KBr, LiBr,
IBr、BrCl。
9. the time for adding one of the method according to claim 1 for preparing Dibromoducitol, the hydrobromic acid and melampyrin
As be 1~10 hour, preferably at 3~8 hours.
10. the method according to claim 1 for preparing Dibromoducitol, the bromination reaction divides three phases control, the
One phase temperature is 1~50 DEG C, is reacted 2~14 hours, and second stage temperature is 50~70 DEG C, is reacted 4~8 hours, third rank
Duan Wendu is 70~90 DEG C, is reacted 2~6 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811106002.3A CN109053372A (en) | 2018-09-21 | 2018-09-21 | A method of preparing Dibromoducitol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811106002.3A CN109053372A (en) | 2018-09-21 | 2018-09-21 | A method of preparing Dibromoducitol |
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| Publication Number | Publication Date |
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| CN109053372A true CN109053372A (en) | 2018-12-21 |
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ID=64763335
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| Application Number | Title | Priority Date | Filing Date |
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| CN201811106002.3A Withdrawn CN109053372A (en) | 2018-09-21 | 2018-09-21 | A method of preparing Dibromoducitol |
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| Country | Link |
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| CN (1) | CN109053372A (en) |
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2018
- 2018-09-21 CN CN201811106002.3A patent/CN109053372A/en not_active Withdrawn
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