CN105801362A - Application of macroporous type cation exchange resin to improvement of yield in bromination reaction of dulcitol - Google Patents
Application of macroporous type cation exchange resin to improvement of yield in bromination reaction of dulcitol Download PDFInfo
- Publication number
- CN105801362A CN105801362A CN201410839625.7A CN201410839625A CN105801362A CN 105801362 A CN105801362 A CN 105801362A CN 201410839625 A CN201410839625 A CN 201410839625A CN 105801362 A CN105801362 A CN 105801362A
- Authority
- CN
- China
- Prior art keywords
- dulcitol
- organic acid
- hydrobromic acid
- cation exchange
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 title claims abstract description 87
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 239000003729 cation exchange resin Substances 0.000 title claims abstract description 28
- 238000005893 bromination reaction Methods 0.000 title claims abstract description 19
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 claims description 81
- 229950010913 mitolactol Drugs 0.000 claims description 81
- 238000002425 crystallisation Methods 0.000 claims description 64
- 230000008025 crystallization Effects 0.000 claims description 64
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 62
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 238000010438 heat treatment Methods 0.000 claims description 37
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Substances Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 35
- -1 hydrogen bromide organic acid Chemical class 0.000 claims description 35
- 239000007864 aqueous solution Substances 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 29
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 28
- 239000011148 porous material Substances 0.000 claims description 26
- 150000007524 organic acids Chemical class 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 16
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 238000010306 acid treatment Methods 0.000 claims description 11
- 230000031709 bromination Effects 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 239000011347 resin Substances 0.000 abstract description 29
- 229920005989 resin Polymers 0.000 abstract description 29
- 238000002360 preparation method Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 229910052799 carbon Inorganic materials 0.000 description 21
- 229960000583 acetic acid Drugs 0.000 description 19
- 238000001953 recrystallisation Methods 0.000 description 16
- 238000010790 dilution Methods 0.000 description 13
- 239000012895 dilution Substances 0.000 description 13
- 239000012065 filter cake Substances 0.000 description 13
- 239000000376 reactant Substances 0.000 description 13
- 125000002091 cationic group Chemical group 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 230000008569 process Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000005341 cation exchange Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000005342 ion exchange Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940006460 bromide ion Drugs 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 241000238370 Sepia Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000000205 computational method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 210000003746 feather Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000003361 porogen Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to an application of macroporous type cation exchange resin to a bromination reaction of dulcitol. The yield of dibromoducitol is substantially increased by 50% or above by using the resin in the preparation process of dibromoducitol, and the effects are obviously better than the effects in the prior art.
Description
Technical field
The present invention relates to chemical drugs field, be specifically related to large pores cation exchange resin in the purposes promoting dulcitol bromination reaction yield.
Background technology
Mitolactol is also known as dibromo galactitol, and for the isomer of mitobronitol, structure is as follows:
Mitolactol itself has pharmacologically active, is also the precursor of a lot of compound.
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 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.
By current published technical method, the mitolactol crystallization purity of gained is low, yield is unstable；Corresponding refining means also have no any open report.
Dulcitol is practically insoluble in conventional vehicles.Above-mentioned report uses the glacial acetic acid solution of hydrogen bromide to carry out bromo-reaction, and gained crystal grain is only small, and color is partially deep, and not easy cleaning and filtration, yield is not high；When preparing with hydrobromic acid method, hydrobromic acid concentration requirement content, more than 69%, to skilled operator, could obtain a small amount of mitolactol, only when hydrobromic acid concentration is more than 80%, could obtain the yield of about 30%, but product colour is sepia；Meanwhile, the maximum concentration hydrobromic acid being commercially available in the market is 62%, exceedes this concentration, it is necessary to oneself preparation, complex process, is not suitable for the industrialization synthesis of more than feather weight.
Cation exchange resin, a kind of chemical substance, mainly for the manufacture of the purification of refined sugar and senior table syrup.
Macroporous ion-exchange resin is the addition porogen when polyreaction, forms the skeleton of mandruka columnar structure, and there is a large amount of permanent micropore inside, then imports cation exchange groups and make.It also has minute aperture and big mesh (macro-pore), and the aperture of wetting resin reaches 100～500nm, and its size and number can control during fabrication.The surface area in duct can increase above 1000m2/g.Jiangsu Se Kesai think resin company limited arrange this be not only ion exchange provide good contact conditions, shorten the distance of ion diffusion, also add many chain link active center, Molecular Adsorption effect is produced by intermolecular Van der Waals force (vandeWaalsforce), various nonionic material can be adsorbed as activated carbon, expand its function.Some also are able to absorption, separate multiple substances without the macroporous ion-exchange resin of function of exchange group, for instance the phenolic material in chemical plant wastewater.
Hole within macroporous resin is not only many but also big, and surface area is very big, and active center is many, and ion diffusion velocity is fast, and ion-exchange speed is also fast a lot, about than gel type resin fast about ten times.Effect during use is fast, efficiency is high, and the required process time shortens.Macroporous resin also has multiple advantage: swelling resistance, not easily broken, and resistance to oxidation is wear-resistant, heat-resisting and resistance to variations in temperature, and organic macromolecule material is easier to absorption and exchange, thus antipollution power is strong, and is easier to regeneration.The current application there are no large pores cation exchange resin in dulcitol bromination process.
Summary of the invention
It is an object of the invention to provide large pores cation exchange resin and promote the purposes of dulcitol bromination reaction yield.
Preferably, large pores cation exchange resin is: D001 type, D002 type, D751 type or D113 type.
Preferably, the 0.1-20% that described large pores cation exchange resin makes consumption be dulcitol weight.
Preferably, described large pores cation exchange resin acid treatment adds in reaction solution after being 2-4 to pH.
Preferably, described large pores cation exchange resin using method is:
Being put into after in reaction vessel by dulcitol, together add reaction vessel by large pores cation exchange resin with mixing hydrobromic acid solution, heating is also constantly reacted, and making dulcitol bromination is mitolactol；
Or put in reaction vessel at dulcitol, add mixing hydrobromic acid solution reaction to after crystallization occurs, add large pores cation exchange resin, organic acid or hydrogen bromide organic acid soln, keep heating and be stirred continuously, continue reaction 1～10 hour, letting cool to room temperature, stand more than 10 hours, making dulcitol bromination is mitolactol；
Described mixing hydrobromic acid solution is hydrobromic acid aqueous solution and organic acid mixed liquor, or the mixed liquor of hydrobromic acid aqueous solution and hydrogen bromide organic acid soln.
Preferably, described dulcitol bromination reaction comprises the steps:
A dulcitol is put in reaction vessel by (), add mixing hydrobromic acid solution and large pores cation exchange resin；Described mixing hydrobromic acid solution is hydrobromic acid aqueous solution and organic acid mixed liquor, or the mixed liquor of hydrobromic acid aqueous solution and hydrogen bromide organic acid soln；
B () heats and is stirred continuously, make dulcitol dissolve, and continues heating and stirs to crystallization occur；
C () adds organic acid or hydrogen bromide organic acid soln, keep the temperature of step b) and be stirred continuously, and continues reaction 1～10 hour, lets cool to room temperature, stand more than 10 hours；
D () is filtered and is cleaned, dry, obtains mitolactol coarse crystallization.
Preferably, described dulcitol bromination reaction comprises the steps:
A dulcitol is put in reaction vessel by (), add mixing hydrobromic acid solution；Described mixing hydrobromic acid solution is hydrobromic acid aqueous solution and organic acid mixed liquor, or the mixed liquor of hydrobromic acid aqueous solution and hydrogen bromide organic acid soln；
B () heats and is stirred continuously, make dulcitol dissolve, and continues heating and stirs to crystallization occur；
C () adds large pores cation exchange resin, organic acid or hydrogen bromide organic acid soln, keep the temperature of step b) and be stirred continuously, continuing reaction 1～10 hour, let cool to room temperature, stand more than 10 hours；
D () is filtered and is cleaned, dry, obtains mitolactol coarse crystallization.
Preferably, in described step (a), dulcitol is 1:0.1-40 with the mass ratio mixing hydrobromic acid solution.
Preferably, in described step (a), the concentration of hydrobromic acid aqueous solution is 40-60%.
Preferably, the mixed liquor of hydrobromic acid aqueous solution and organic acid or hydrogen bromide organic acid soln in described step (a), mass ratio is 1:0.1～10.
Preferably, described organic acid is formic acid, acetic acid, propanoic acid or butanoic acid；Described hydrogen bromide organic acid soln is containing the formic acid solution that bromination hydrogen concentration is 0.1%～70%, acetic acid solution, propionic acid solution or butanoic acid solution.
It is reversible reaction owing to dulcitol generates the reaction of mitolactol, when reaction just starts, owing in reaction mass, bromine content is high, overresponse, easily generate terbromide, tetrabormated compound, many bromines substituent and other product；Along with the carrying out of reaction, material concentration reduces, and the generation of mitolactol is increasingly difficult to, and because adding bromine deficiency during substitution reaction, can generate monobromo compound；Factors above is the main cause causing mitolactol yield too low.
For making technique simplify, and obtaining the mitolactol of high yield, the present inventor finds a kind of simple, safe solution, by adding large pores cation exchange resin in course of reaction, makes the yield of mitolactol be greatly improved.By resin absorption on surface after the heated dissolving of dulcitol, in being stirred continuously process, bromide ion exchanges with cation generation ion, enter the active center of resin, now, the dulcitol being adsorbed on resin surface reacts with the bromide ion entering resin activity center, thus generating mitolactol.Carrier function is played in cation exchange in course of reaction, improves the selectivity that mitolactol generates, therefore improve yield after adding resin cation exchange.Use different bromating agent, variable concentrations, different temperatures reaction condition under, add resin reaction gained mitolactol compared with not adding resin gained mitolactol, yield improves more than 50%.
Large pores cation exchange resin provided by the invention promotes the purposes of dulcitol bromination reaction yield and has the advantage that
1, use different bromating agent, variable concentrations, different temperatures reaction condition under, add large pores cation exchange resin resin reaction gained mitolactol compared with not adding resin gained mitolactol, yield improves more than 50%.
2, large pores cation exchange resin is readily available, and reduces to obtain high yield, uses hazardous agents to the injury of operator ' s health and to reduce environmental pollution.
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:
A 10kg dulcitol is put in reactor by (), add 100g acid treatment to the macroporous type cationic resin D001 that PH is 4, being simultaneously introduced 55% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:3 (weight ratio), addition is 2 times of dulcitol weight；
B () heating in water bath is to 45 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds the acetic acid of dulcitol weight 3 times, keep 45 DEG C and be stirred continuously, and continues reaction 5 hours, lets cool to room temperature, stand 10 hours；
D () reactant liquor adds 1 times amount water dilution, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 0.1 hour that 0.5 times of concentration of volume percent is 60%, drains, and 25 DEG C are decompressed to-0.01MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 100 times of coarse crystallization weight, recrystallization at 4 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 53%, average purity is 92%.
Embodiment 2:
A 10kg dulcitol is put in reactor by (), add 60% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:2 (weight ratio), and addition is 5 times of dulcitol weight；
B () heating in water bath is to 80 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds 500g acid treatment to the macroporous type cationic resin D751 that pH value is 2, be simultaneously introduced the formic acid containing 0.1% hydrogen bromide of dulcitol weight 1 times, keep 80 DEG C and be stirred continuously, and continues reaction 8 hours, lets cool to room temperature, stand 12 hours；
D () reactant liquor adds 2 times amount water dilutions, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 0.2 hour that 1 times of concentration of volume percent is 50%, drains, and 30 DEG C are decompressed to-0.02MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 70 times of coarse crystallization weight, recrystallization at 6 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 54%, average purity is 91%.
Embodiment 3:
A 10kg dulcitol is put in reactor by (), add 10g acid treatment to the macroporous type cationic resin D113 that PH is 3, being simultaneously introduced 40% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:5 (weight ratio), addition is 1 times of dulcitol weight；
B () heating in water bath is to 50 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds dulcitol weight 0.1 again containing the acetic acid of 70% hydrogen bromide, keep 50 DEG C and be stirred continuously, and continues reaction 10 hours, lets cool to room temperature, stand 15 hours；
D () reactant liquor adds 3 times amount water dilutions, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 0.5 hour that 5 times of concentration of volume percent are 65%, drains, and 50 DEG C are decompressed to-0.05MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 80 times of coarse crystallization weight, recrystallization at 2 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 50%, average purity is 93%.
Embodiment 4:
A 10kg dulcitol is put in reactor by (), add 50% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:0.1 (weight ratio), and addition is 10 times of dulcitol weight；
B () heating in water bath is to 60 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds 2000g acid treatment to the macroporous type cationic resin D002 that pH value is 2.5, be simultaneously introduced the propanoic acid of dulcitol weight 0.01 times, keep 60 DEG C and be stirred continuously, and continues reaction 15 hours, lets cool to room temperature, stand 14 hours；
D () reactant liquor adds 2 times amount water dilutions, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 1 hour that 100 times of concentration of volume percent are 70%, drains, and 65 DEG C are decompressed to-0.1MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 150 times of coarse crystallization weight, recrystallization at 5 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 52%, average purity is 95%.
Embodiment 5:
A 10kg dulcitol is put in reactor by (), add 1000g acid treatment to the macroporous type cationic resin D001 that PH is 3.5, being simultaneously introduced 45% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:1 (weight ratio), addition is 3 times of dulcitol weight；
B () heating in water bath is to 75 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds the acetic acid containing 33% hydrogen bromide of dulcitol weight 5 times, keep 75 DEG C and be stirred continuously, and continues reaction 18 hours, lets cool to room temperature, stand 16 hours；
D () reactant liquor adds 1 times amount water dilution, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 2 hours that 50 times of concentration of volume percent are 55%, drains, and 40 DEG C are decompressed to-0.5MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 90 times of coarse crystallization weight, recrystallization at 3 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 51%, average purity is 96%.
Embodiment 6:
A 10kg dulcitol is put in reactor by (), add 45% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:0.5 (weight ratio), and addition is 6 times of dulcitol weight；
B () heating in water bath is to 70 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds 50g acid treatment to the macroporous type cationic resin D751 that pH value is 4, be simultaneously introduced the butanoic acid of dulcitol weight 0.5 times, keep 70 DEG C and be stirred continuously, and continues reaction 24 hours, lets cool to room temperature, stand 18 hours；
D () reactant liquor adds 3 times amount water dilutions, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 0.5 hour that 10 times of concentration of volume percent are 60%, drains, and 50 DEG C are decompressed to-0.03MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 100 times of coarse crystallization weight, recrystallization at 4 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 51%, average purity is 92%.
Embodiment 7:
A 10kg dulcitol is put in reactor by (), add 1500g acid treatment to the macroporous type cationic resin D113 that PH is 2, being simultaneously introduced 55% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:2 (weight ratio), addition is 8 times of dulcitol weight；
B () heating in water bath is to 65 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds dulcitol weight 2 again containing the butanoic acid of 1% hydrogen bromide, keep 65 DEG C and be stirred continuously, and continues reaction 20 hours, lets cool to room temperature, stand 20 hours；
D () reactant liquor adds 2 times amount water dilutions, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 1 hour that 0.5 times of concentration of volume percent is 70%, drains, and 25 DEG C are decompressed to-0.1MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 90 times of coarse crystallization weight, recrystallization at 3 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 53%, average purity is 94%.
Embodiment 8:
A 10kg dulcitol is put in reactor by (), add 60% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:6 (weight ratio), and addition is 7 times of dulcitol weight；
B () heating in water bath is to 55 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds 200g acid treatment to the macroporous type cationic resin D002 that pH value is 3.3, be simultaneously introduced the bromic acid aqueous solution of dulcitol weight 1 times: the mixed liquor of acetic acid=1:3 (weight ratio), and addition is 2 times of dulcitol weight；
B () heating in water bath is to 45 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () keeps 45 DEG C and is stirred continuously, continue reaction 5 hours, let cool to room temperature, stand 10 hours；
D () reactant liquor adds 1 times amount water dilution, filter, and filter cake is washed with water to neutrality, formic acid, keeps 55 DEG C and is stirred continuously, and continues reaction 12 hours, lets cool to room temperature, stand 10 hours；
D () reactant liquor adds 5 times amount water dilutions, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 0.1 hour that 100 times of concentration of volume percent are 55%, drains, and 25 DEG C are decompressed to-1MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 150 times of coarse crystallization weight, recrystallization at 5 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 56%, average purity is 94%.
Comparative example 1: with reference to the embodiment of the present invention 1, without resin, step C is without organic acid or hydrogen bromide organic acid soln
A 10kg dulcitol is put in reactor by (), add 55% hydrogen and drain, and adds the soak with ethanol 0.1 hour that 0.5 times of concentration of volume percent is 60%, drains, and 25 DEG C are decompressed to-0.01MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 100 times of coarse crystallization weight, recrystallization at 4 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 35%, average purity is 71%.
Comparative example 2: with reference to the embodiment of the present invention 2, without resin, step C is without organic acid or hydrogen bromide organic acid soln
A 10kg dulcitol is put in reactor by (), add 60% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:2 (weight ratio), and addition is 5 times of dulcitol weight；
B () heating in water bath is to 80 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () keeps 80 DEG C and is stirred continuously, continue reaction 8 hours, let cool to room temperature, stand 12 hours；
D () reactant liquor adds 2 times amount water dilutions, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 0.2 hour that 1 times of concentration of volume percent is 50%, drains, and 30 DEG C are decompressed to-0.02MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 70 times of coarse crystallization weight, recrystallization at 6 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 33%, average purity is 66%.
Comparative example 3: with reference to the embodiment of the present invention 3, without resin, step C is without organic acid or hydrogen bromide organic acid soln
A 10kg dulcitol is put in reactor by (), add 40% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:5 (weight ratio), and addition is 1 times of dulcitol weight；
B () heating in water bath is to 50 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () keeps 50 DEG C and is stirred continuously, continue reaction 10 hours, let cool to room temperature, stand 15 hours；
D () reactant liquor adds 3 times amount water dilutions, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 0.5 hour that 5 times of concentration of volume percent are 65%, drains, and 50 DEG C are decompressed to-0.05MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 80 times of coarse crystallization weight, recrystallization at 2 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 32%, average purity is 69%.
Comparative example 4: with reference to the embodiment of the present invention 4, without resin
A 10kg dulcitol is put in reactor by (), add 50% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:0.1 (weight ratio), and addition is 10 times of dulcitol weight；
B () heating in water bath is to 60 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () keeps 60 DEG C and is stirred continuously, continue reaction 15 hours, let cool to room temperature, stand 14 hours；
D () reactant liquor adds 2 times amount water dilutions, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 1 hour that 100 times of concentration of volume percent are 70%, drains, and 65 DEG C are decompressed to-0.1MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 150 times of coarse crystallization weight, recrystallization at 5 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 39%, average purity is 73%.
Comparative example 5: with reference to the embodiment of the present invention 6, step c organic acid or hydrogen bromide organic acid soln are added in step a
A 10kg dulcitol is put in reactor by (), add 45% hydrobromic acid aqueous solution: the mixed liquor of acetic acid=1:0.5 (weight ratio), and addition is 6 times of dulcitol weight, is simultaneously introduced the butanoic acid of dulcitol weight 0.5 times；
B () heating in water bath is to 70 DEG C and be stirred continuously, and makes dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds 50g acid treatment to the macroporous type cationic resin D751 that pH value is 4, keep 70 DEG C and be stirred continuously, and continues reaction 24 hours, lets cool to room temperature, stand 18 hours；
D () reactant liquor adds 3 times amount water dilutions, filter, and filter cake is washed with water to neutrality, drains, and adds the soak with ethanol 0.5 hour that 10 times of concentration of volume percent are 60%, drains, and 50 DEG C are decompressed to-0.03MPa and dry, obtain mitolactol coarse crystallization；Mitolactol coarse crystallization adds the methanol of 100 times of coarse crystallization weight, recrystallization at 4 DEG C, obtains mitolactol.
Experimental result: mitolactol average yield 43%, average purity is 82%.
Process ration is tested:
Experimental technique: according to reaction pressure disclosed by the invention, reaction temperature and hydrobromic acid solution concentration, prepares embodiment 1-8 sample；Want, on the preparation method basis of embodiment 1-3, to deduct the reaction condition of pressurization, prepare comparative example 1-3 sample respectively；Adopt the not response parameter in reaction temperature disclosed by the invention and hydrobromic acid concentration range, prepare comparative example 4,5.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:
1, the operating procedure of comparative example 1,2,3 corresponding embodiment 1,2,3 respectively, deducts resin, and step C is without organic acid or hydrogen bromide organic acid soln condition, and the yield of its mitolactol has pole significant difference (P < 0.01) with purity compared with embodiment.
2, all comparative example groups are respectively compared with embodiment group, and yield and purity all have pole significance (P < 0.01).
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 (11)
1. large pores cation exchange resin promotes the purposes of dulcitol bromination reaction yield.
2. purposes as claimed in claim 1, it is characterised in that large pores cation exchange resin is: D001 type, D002 type, D751 type or D113 type.
3. purposes as claimed in claim 1 or 2, it is characterised in that: the 0.1-20% that described large pores cation exchange resin makes consumption be dulcitol weight.
4. purposes as claimed in claim 1 or 2, it is characterised in that: described large pores cation exchange resin acid treatment adds in reaction solution when being 2-4 to pH.
5. purposes as claimed in claim 1, it is characterised in that described large pores cation exchange resin using method is:
Being put into after in reaction vessel by dulcitol, together add reaction vessel by large pores cation exchange resin with mixing hydrobromic acid solution, heating is also constantly reacted, and making dulcitol bromination is mitolactol；
Or put in reaction vessel at dulcitol, add mixing hydrobromic acid solution reaction to after crystallization occurs, add large pores cation exchange resin, organic acid or hydrogen bromide organic acid soln, keep heating and be stirred continuously, continue reaction 1～10 hour, letting cool to room temperature, stand more than 10 hours, making dulcitol bromination is mitolactol；
Described mixing hydrobromic acid solution is hydrobromic acid aqueous solution and organic acid mixed liquor, or the mixed liquor of hydrobromic acid aqueous solution and hydrogen bromide organic acid soln.
6. purposes as claimed in claim 5, it is characterised in that described dulcitol bromination reaction comprises the steps:
A dulcitol is put in reaction vessel by (), add mixing hydrobromic acid solution and large pores cation exchange resin；Described mixing hydrobromic acid solution is hydrobromic acid aqueous solution and organic acid mixed liquor, or the mixed liquor of hydrobromic acid aqueous solution and hydrogen bromide organic acid soln；
B () heats and is stirred continuously, make dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds organic acid or hydrogen bromide organic acid soln, keep the temperature of step b) and be stirred continuously, and continues reaction 1～10 hour, lets cool to room temperature, stand more than 10 hours；
D () is filtered and is cleaned, dry, obtains mitolactol coarse crystallization.
7. purposes as claimed in claim 5, it is characterised in that described dulcitol bromination reaction comprises the steps:
A dulcitol is put in reaction vessel by (), add mixing hydrobromic acid solution；Described mixing hydrobromic acid solution is hydrobromic acid aqueous solution and organic acid mixed liquor, or the mixed liquor of hydrobromic acid aqueous solution and hydrogen bromide organic acid soln；
B () heats and is stirred continuously, make dulcitol dissolve, and then proceedes to heating and stirs until there is crystallization；
C () adds large pores cation exchange resin, organic acid or hydrogen bromide organic acid soln, keep the temperature of step b) and be stirred continuously, and continues reaction 1～10 hour, lets cool to room temperature, stand more than 10 hours；
D () is filtered and is cleaned, dry, obtains two bromo dulcitol coarse crystallization.
8. the purposes according to any one of claim 5-7, it is characterised in that dulcitol described in step (a) is 1:0.1-40 with the mass ratio mixing hydrobromic acid solution.
9. the purposes according to any one of claim 5-7, it is characterised in that the concentration of hydrobromic acid aqueous solution described in step (a) is 40-60%.
10. the purposes according to any one of claim 5-7, it is characterised in that the mixed liquor of hydrobromic acid aqueous solution described in step (a) and organic acid or hydrogen bromide organic acid soln, mass ratio is 1:0.1～10.
11. according to the purposes described in any one of claim 5-7, it is characterised in that described organic acid is formic acid, acetic acid, propanoic acid or butanoic acid；Described hydrogen bromide organic acid soln is containing the formic acid solution that bromination hydrogen concentration is 0.1%～70%, acetic acid solution, propionic acid solution or butanoic acid solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410839625.7A CN105801362A (en) | 2014-12-30 | 2014-12-30 | Application of macroporous type cation exchange resin to improvement of yield in bromination reaction of dulcitol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410839625.7A CN105801362A (en) | 2014-12-30 | 2014-12-30 | Application of macroporous type cation exchange resin to improvement of yield in bromination reaction of dulcitol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105801362A true CN105801362A (en) | 2016-07-27 |
Family
ID=56979991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410839625.7A Pending CN105801362A (en) | 2014-12-30 | 2014-12-30 | Application of macroporous type cation exchange resin to improvement of yield in bromination reaction of dulcitol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105801362A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080107598A1 (en) * | 2006-10-05 | 2008-05-08 | Yang David J | Efficient Synthesis of Chelators for Nuclear Imaging and Radiotherapy: Compositions and Applications |
| CN103270035A (en) * | 2010-08-18 | 2013-08-28 | 德玛医药 | 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 CN201410839625.7A patent/CN105801362A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080107598A1 (en) * | 2006-10-05 | 2008-05-08 | Yang David J | Efficient Synthesis of Chelators for Nuclear Imaging and Radiotherapy: Compositions and Applications |
| CN103270035A (en) * | 2010-08-18 | 2013-08-28 | 德玛医药 | 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 (2)
| Title |
|---|
| ALAIN BOUILLAUD等: "Synthesis of Dibromohydrins from Glycerol by Using an Ion Exchange Resin as Catalyst", 《AUST. J. CHEM.》 * |
| 刘铭勋等: "抗癌剂二溴卫茅醇的合成", 《江西医学院学报》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110563992A (en) | Preparation method of cationic metal organic framework membrane material | |
| CN100491244C (en) | A method for preparing activated carbon from wheat straw | |
| CN115430399B (en) | A sulfur-doped carbon material and its preparation method and application | |
| CN106955718A (en) | A kind of ZnS/Bi2O3Hetero-junctions molecular engram photocatalysis membrana and preparation method and purposes | |
| CN104447279B (en) | The method of the synthetic azelaic acid of a kind of hydrogen peroxide and potassium permanganate co-oxidation | |
| CN105198728B (en) | A kind of method for preparing medicinal potassium acetate | |
| CN105801362A (en) | Application of macroporous type cation exchange resin to improvement of yield in bromination reaction of dulcitol | |
| CN107511134B (en) | Mesoporous Zr-based coordination polymer and preparation and application thereof | |
| CN109734722A (en) | A kind of method for preparing isosorbide by dehydration of sorbitol | |
| CN105440496A (en) | Method for manufacturing photodegradable polyvinyl chloride mulch film and product | |
| CN105801363A (en) | Application of acrylic acid type cation exchange resin to improvement of yield in bromination reaction of dulcitol | |
| CN105801357A (en) | Application of styrene type cation exchange resin to improvement of yield in bromination reaction of dulcitol | |
| CN105801356A (en) | Application of weak acid type cation exchange resin to improvement of yield in bromination reaction of dulcitol | |
| CN105801368A (en) | Application of gel type cation exchange resin to improvement of yield in bromination reaction of dulcitol | |
| BR102016030353A2 (en) | magnetic activated carbon, process for obtaining and applying the same | |
| CN105801373A (en) | Application of strongly acidic cation exchange resin in improvement of bromination reaction yield of dulcitol | |
| CN111170908B (en) | A kind of synthetic method of 2,4-dimethyl-3-methanesulfonyl halide benzene | |
| CN103285816B (en) | Adsorbent for treating dye wastewater in different concentrations and preparation method and application | |
| CN107383418A (en) | A kind of unioresistant plastic additive and preparation method thereof | |
| CN105801351A (en) | Application of cation exchange resin to improvement of yield in bromination reaction of hexanehexol | |
| CN105801374B (en) | A kind of synthetic method for improving bromo hexitol reaction product yield | |
| CN105801371B (en) | Purposes of the oxidant in bromo-reaction | |
| CN101139245A (en) | New production process of hexabromocyclododecane | |
| CN106588562B (en) | A kind of method of purification of iodoformum | |
| CN105801369B (en) | The method for improving mitolactol substitution reaction product yield and purity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160727 |