CN103980330A - Preparation method of isothiourea dihydrobromide - Google Patents
Preparation method of isothiourea dihydrobromide Download PDFInfo
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- CN103980330A CN103980330A CN201410133407.1A CN201410133407A CN103980330A CN 103980330 A CN103980330 A CN 103980330A CN 201410133407 A CN201410133407 A CN 201410133407A CN 103980330 A CN103980330 A CN 103980330A
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Abstract
The invention relates to the sugar compound field, and concretely relates to a synthesis method of isothiourea dihydrobromide. The method comprises the following steps: adding acetic anhydride and a catalyst at room temperature, adding D-galactose, adding an acetic acid solution of hydrogen bromide after a reaction, adding the obtained reaction solution to thiourea and an acetonitrile solution with the temperature of 60-65DEG C in a dropwise manner, carrying out a temperature control reaction, post-processing to obtain 2-S-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranose)-2-isothiourea dihydrobromide with the purity of above 99%. The above compound is synthesized through the one-step reaction method, and the method has the advantages of simple operation, easily available raw materials, and operation cost and material saving.
Description
technical field
The present invention relates to sugar compounds synthesis technical field, be specifically related to a kind of preparation method of isothiourea hydrobromate.
background technology
2-S-(2,3,4,6-, tetra--O-ethanoyl-β-D-galactopyranose base)-2-isothiourea hydrobromate, English name: 2-S-(2,3,4,6-Tetra-O-Acetyl-β-D-galactopyranosyl)-2-isothiuranium
Hydrobromide, molecular formula C
15h
23brN
2o
9s, structural formula is as follows:
Saccharide compound is the organic compound that distributed in nature is the most extensive, quantity is maximum, has monose, oligosaccharides, starch, hemicellulose, Mierocrystalline cellulose, complex polysaccharide, and the derivative of sugar; Saccharide compound is the sustain life main source of activity institute energy requirement of all living things body, and it is not only nutritive substance, and some also has special physiologically active.Therefore, glucosides class material medically all has very large use value with industrial.2-(β-D-pyrans acetyl galactosyl)-2-isothiourea hydrobromate is the synthetic very important a kind of intermediate of thio glycoside, so the economy of this compound is synthetic has great importance.
In the prior art, there is document (" 2, 3, 4, synthesizing of 6-tetra--O-ethanoyl-1 sulfydryl-Glucopyranose. chemical and bonding, 2007, 29 (3): 189-192 Jia Yonglin, Li Bin, Bing Baichun. ") report 2-S-(2, 3, 4, the synthetic method of 6-tetra--O-ethanoyl-β-D-glucopyranosyl)-2-isothiourea hydrobromate is, take D-Glucose as raw material, first synthesize penta-acetyl glucose, again and bromine, Glacial acetic acid synthesizes acetylbromoglycose, and then reaction makes 2-S-(2 with thiocarbamide, 3, 4, 6-tetra--O-ethanoyl-β-D-glucopyranosyl)-2-isothiourea hydrobromate.China Patent Publication No. is that CN102627674A discloses a kind of " a kind of preparation method of thio glycoside compound ", and this invention is also first by acetyl sugar, to prepare halo acetyl sugar, then S-glycosyl isothiourea halides is prepared in reaction with thiocarbamide.This route need first be prepared five acetyl sugar and halogeno-sugars, needs three-step reaction, and halogeno-sugar is perishable, causes yield lower.
Summary of the invention
In order to solve the perishable bromo sugar of use existing in the preparation of S-glycosyl isothiourea halides in above prior art, intermediate process steps is many, the present situation of trivial operations, the application uses for reference forefathers' experience, by changing feed way and system temperature, a kind of single stage method, economy simple to operate of adopting is provided, and yield is high and be suitable for the preparation method of the isothiourea hydrobromate of suitability for industrialized production.
The technical problem to be solved in the present invention is achieved through the following technical solutions:
A preparation method for isothiourea hydrobromate, comprises the following steps:
A) under room temperature by aceticanhydride and catalyst mix, under stirring, add D-semi-lactosi, temperature control reaction obtains penta-acetyl galactose solution;
B) hydrogen halide acetum is joined in penta-acetyl galactose solution, temperature control reaction obtains halo tetrem acyl galactose solution;
C) halo tetrem acyl galactose solution is added dropwise in hot thiourea solution, temperature control reaction, after having reacted, cooling crystallization, centrifugal drying obtains product.
Described method, preferred described aceticanhydride: catalyzer: D-semi-lactosi: hydrogen halide acetic acid: the mol ratio of thiocarbamide is 5.5-6: 0.03-0.05: 1:1.5-1.6:1.1-1.3.
Described method, in preferred steps a, catalyzer is perchloric acid.
Described method, in preferred steps a, temperature of reaction is 20-25 ℃, the reaction times is 1-1.5 hour.
Described method, in preferred steps b, temperature of reaction is 15-20 ℃, the reaction times is 0.5-1 hour.
Described method, in preferred steps c, temperature of reaction is 60-70 ℃, the reaction times is 0.5-1 hour.
Described method, in preferred steps c, the thiourea solution temperature of heat is 60-65 ℃.
Described method, in preferred steps c, drying process temperature is 65-75 ℃, recrystallization temperature is 0-5 ℃.
Described method, in preferred steps c, in thiourea solution, solvent is acetonitrile, thiocarbamide and acetonitrile mol ratio are 1:30-35.
Beneficial effect: the inventive method is only reacted by single stage method, changes feed way and system temperature, and more than 99% product of preparation purity, without three-step reaction, has improved production safety coefficient effectively; Simple to operate, raw material is easy to get, and has saved running cost and material, and the product yield that obtains is high, purity is high.
Accompanying drawing explanation
Fig. 1 is the HPLC spectrogram of the product that obtains of embodiment 1,
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the product that obtains of embodiment 1.
Embodiment
In order further to understand the present invention, below in conjunction with specific embodiment, the process of this programme is described, but should be appreciated that these are described is for further instruction the features and advantages of the present invention, rather than limiting to the claimed invention.
embodiment 1 5.5:0.03:1:1.5:1.1
A) in room temperature reaction device, add 5.5mol aceticanhydride and 0.03mol perchloric acid, temperature control adds 1molD-semi-lactosi at 20-25 ℃, react 1 hour, and by TLC detection reaction terminal,
B) in reactor, adding hydrogen bromide molar weight is 33% the hydrogen bromide acetic acid solution of 1.5mol, controls temperature of reaction at 15 ℃, react 0.5 hour, and by TLC point plate detection reaction terminal,
C) above-mentioned reaction solution is added dropwise in the acetonitrile of thiocarbamide that the molar weight of 65 ℃ is 1.1mol and 30mol, controls temperature of reaction at 70 ℃, react 0.5 hour, by TLC point plate detection reaction terminal.
Temperature crystallization 2 hours at 0 ℃ is controlled in cooling; centrifugal 65 ℃ obtain solid 0.752mol after dry; product yield is 75.2%, and purity is 99.37%, sees Fig. 1; hydrogen nuclear magnetic resonance spectrogram is shown in Fig. 2; result shows, the reaction product that the present invention obtains is 2-S-(2,3; 4,6-, tetra--O-ethanoyl-β-D-galactopyranose base)-2-isothiourea hydrobromate.
embodiment 2 5.5: 0.04: 1:1.5:1.2
A) in room temperature reaction device, add 5.5mol aceticanhydride and 0.04mol perchloric acid, temperature control adds 1molD-semi-lactosi at 20-25 ℃, react 1 hour, and by TLC detection reaction terminal,
B) in reactor, adding hydrogen bromide molar weight is 33% the hydrogen bromide acetic acid solution of 1.5mol, controls temperature of reaction at 20 ℃, react 0.5 hour, and by TLC point plate detection reaction terminal,
C) above-mentioned reaction solution is added dropwise in the acetonitrile of thiocarbamide that the molar weight of 60 ℃ is 1.2mol and 30mol, controls temperature of reaction at 60 ℃, react 0.5 hour, by TLC point plate detection reaction terminal.
Temperature crystallization 2 hours at 0 ℃ is controlled in cooling, and centrifugal 65 ℃ obtain solid 0.744mol after dry, and product yield is 74.4%, and purity is 99.39%.
embodiment 36: 0.03: 1:1.5:1.2
A) in room temperature reaction device, add 6mol aceticanhydride and 0.03mol perchloric acid, temperature control adds 1molD-semi-lactosi at 20-25 ℃, react 1.5 hours, and by TLC detection reaction terminal,
B) in reactor, adding hydrogen bromide molar weight is 33% the hydrogen bromide acetic acid solution of 1.5mol, controls temperature of reaction at 15 ℃, react 1 hour, and by TLC point plate detection reaction terminal,
C) above-mentioned reaction solution is added dropwise to thiocarbamide that the molar weight of 65 ℃ is 1.2mol and the acetonitrile of 32mol, controls temperature of reaction at 65 ℃, react 0.5 hour, by TLC point plate detection reaction terminal.
Temperature crystallization 2 hours at 0 ℃ is controlled in cooling, and centrifugal 65 ℃ obtain solid 0.739mol after dry, and product yield is 73.9%, and purity is 99.38%.
embodiment 46: 0.05: 1:1.6:1.3
A) in room temperature reaction device, add 6mol aceticanhydride and 0.03mol perchloric acid, temperature control adds 1molD-semi-lactosi at 20-25 ℃, react 1.5 hours, and by TLC detection reaction terminal,
B) in reactor, adding hydrogen bromide molar weight is 33% the hydrogen bromide acetic acid solution of 1.5mol, controls temperature of reaction at 15 ℃, react 1 hour, and by TLC point plate detection reaction terminal,
C) above-mentioned reaction solution is added dropwise in the acetonitrile of thiocarbamide that 60 ℃ of molar weights are 1.2mol and 32mol, controls temperature of reaction at 70 ℃, react 0.5 hour, by TLC point plate detection reaction terminal.
Temperature crystallization 3 hours at 0 ℃ is controlled in cooling, and centrifugal 75 ℃ obtain solid 0.760mol after dry, and product yield is 76.0%, and purity is 99.42%.
embodiment 5 control Example
A) in room temperature reaction device, add 6mol aceticanhydride and 0.04mol perchloric acid, control at 20-25 ℃ of temperature and add 1molD-semi-lactosi, after having reacted, add the deionized water of 10mol, separate out yellow solid, through the acetone recrystallization of 6mol, obtain the five acetyl semi-lactosis of 0.87mol;
B) in reactor, adding hydrogen bromide molar weight is 33% the hydrogen bromide acetic acid solution of 0.87mol, control temperature of reaction at 15 ℃, react 1 hour, reacted the deionized water and stirring of 0-5 ℃ 2 hours of rear dropping 10mol, with the dichloromethane extraction water layer of 4mol, organic phase 8mol deionized water wash organic phase three times, separate organic phase concentrated, the isohexane mixed solution crystallization that adds 0.8mol t-butyl methyl ether and 1.2mol, processes the bromo acetyl semi-lactosi that obtains 0.78mol;
C) above-mentioned reaction solution adds in the thiocarbamide of 1.2mol and the acetonitrile of 32mol, controls temperature of reaction at 70 ℃, reacts 0.5 hour, by TLC point plate detection reaction terminal.Temperature crystallization 3 hours at 0 ℃ is controlled in cooling, and centrifugal 75 ℃ obtain solid 0.65mol after dry, and product yield is 65.0%, and purity is 99.04%.
Claims (9)
1. a preparation method for isothiourea hydrobromate, is characterized in that comprising the following steps:
A) under room temperature by aceticanhydride and catalyst mix, under stirring, add D-semi-lactosi, temperature control reaction obtains penta-acetyl galactose solution;
B) hydrogen halide acetum is joined in penta-acetyl galactose solution, temperature control reaction obtains halo tetrem acyl galactose solution;
C) halo tetrem acyl galactose solution is added dropwise in hot thiourea solution, temperature control reaction, after having reacted, cooling crystallization, centrifugal drying obtains product.
2. method according to claim 1, is characterized in that described aceticanhydride: catalyzer: D-semi-lactosi: hydrogen halide acetic acid: the mol ratio of thiocarbamide is 5.5-6: 0.03-0.05: 1:1.5-1.6:1.1-1.3.
3. method according to claim 1, is characterized in that in step a, catalyzer is perchloric acid.
4. method according to claim 1, is characterized in that in step a, temperature of reaction is 20-25 ℃, and the reaction times is 1-1.5 hour.
5. method according to claim 1, is characterized in that in step b, temperature of reaction is 15-20 ℃, and the reaction times is 0.5-1 hour.
6. method according to claim 1, is characterized in that in step c, temperature of reaction is 60-70 ℃, and the reaction times is 0.5-1 hour.
7. method according to claim 1, is characterized in that the thiourea solution temperature of heat in step c is 60-65 ℃.
8. method according to claim 1, is characterized in that in step c, drying process temperature is 65-75 ℃, and recrystallization temperature is 0-5 ℃.
9. method according to claim 1, is characterized in that in step c in thiourea solution that solvent is acetonitrile, and thiocarbamide and acetonitrile mol ratio are 1:30-35.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102627674A (en) * | 2012-04-18 | 2012-08-08 | 济南圣泉唐和唐生物科技有限公司 | Preparation method of thioglycoside compound |
| WO2012142615A2 (en) * | 2011-04-14 | 2012-10-18 | Board Of Regents, The University Of Texas System | Auranofin and auranofin analogs useful to treat proliferative disease and disorders |
| CN103087121A (en) * | 2013-01-12 | 2013-05-08 | 江西师范大学 | Synthetic method for isopropyl-beta-D-thiogalactoside |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012142615A2 (en) * | 2011-04-14 | 2012-10-18 | Board Of Regents, The University Of Texas System | Auranofin and auranofin analogs useful to treat proliferative disease and disorders |
| CN102627674A (en) * | 2012-04-18 | 2012-08-08 | 济南圣泉唐和唐生物科技有限公司 | Preparation method of thioglycoside compound |
| CN103087121A (en) * | 2013-01-12 | 2013-05-08 | 江西师范大学 | Synthetic method for isopropyl-beta-D-thiogalactoside |
Non-Patent Citations (2)
| Title |
|---|
| QINGZHI ZHANG，等: "The synthesis of novel hexa-13C-labelled glucosinolates from [13C6]-D-glucose", 《TETRAHEDRON》 * |
| 徐希明，等: "2-亚氨基-2-甲氧基乙基-1-硫代-beta-D-半乳吡喃糖苷的合成及其肝靶向应用研究", 《中国新药杂志》 * |
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