CN103980330B

CN103980330B - Preparation method of isothiourea dihydrobromide

Info

Publication number: CN103980330B
Application number: CN201410133407.1A
Authority: CN
Inventors: 孟庆文; 张雷; 孔令华; 索晨苏; 赵海峰
Original assignee: Ji'nan Healtang Biotechnology Co Ltd
Current assignee: Ji'nan Healtang Biotechnology Co Ltd
Priority date: 2014-04-04
Filing date: 2014-04-04
Publication date: 2017-02-01
Anticipated expiration: 2034-04-04
Also published as: CN103980330A

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

A kind of preparation method of isothiourea hydrobromide

Technical field

The present invention relates to sugar compounds synthesis technical field is and in particular to a kind of preparation method of isothiourea hydrobromide.

Background technology

2-s- (2,3,4,6- tetra--o- acetyl group-β-d- galactopyranosyl glycosyl) -2- isothiourea hydrobromide, English name: 2-s-(2,3,4,6-tetra-o-acetyl-β-d-galactopyranosyl)-2-isothiuranium

Hydrobromide, molecular formula c₁₅h₂₃brn₂o₉S, structural formula is as follows:

Saccharide compound be distributed in nature the most extensively, the most organic compound of quantity, have monosaccharide, oligosaccharide, starch, half Cellulose, cellulose, complex polysaccharide, and the derivant of sugar；Saccharide compound is that all living things body sustains life needed for activity The main source of energy, it is not only nutrient substance, and some also have special physiologically active.Therefore, glucosides class material Medically with industrial, all there is very big use value.2- (β-d- pyrans acetyl galactose base) -2- isothiourea hydrobromic acid Salt is a kind of critically important intermediate of synthesis thio glycoside, and the economic synthesis of therefore this compound has great importance.

In the prior art, have document (" synthesis of 2,3,4,6- tetra--o- acetyl group -1 sulfydryls-Glucopyranose.. chemistry With bonding, 2007,29 (3): 189-192 Jia Yonglin, Li Bin, Bing Baichun. ") report 2-s- (2,3,4,6- tetra--o- acetyl group- β-d- glucopyranosyl) synthetic method of -2- isothiourea hydrobromide is, with d- glucose as raw material, first to synthesize five acetyl Base glucose, then synthesize acetylbromoglycose with bromine, glacial acetic acid, then 2-s- (2,3,4,6- tetra--o-s are obtained with thiourea reaction again Acetyl group-β-d- glucopyranosyl) -2- isothiourea hydrobromide.China Patent Publication No. discloses for cn102627674a A kind of " a kind of preparation method of thio glycoside compound ", this invention is also first to prepare haloacetyl sugar by acetyl sugar, then and sulfur Urea reaction preparation s- glycosyl isothiourea halides.This route need to first prepare five acetyl sugar and halogeno-sugar, needs three-step reaction, and Halogeno-sugar is perishable, leads to yield relatively low.

Content of the invention

In order to solve present in s- glycosyl isothiourea halides preparation in above prior art using perishable bromo Sugar, intermediate process steps are many, the present situation of trivial operations, and the application uses for reference the experience of forefathers, by changing feed way and system Temperature, there is provided a kind of employing one-step method, simple to operate economic, high income and be suitable to the isothiourea hydrobromic acid of industrialized production The preparation method of salt.

The technical problem to be solved in the present invention is achieved through the following technical solutions:

A kind of preparation method of isothiourea hydrobromide, comprises the following steps:

A) under room temperature, acetic anhydride and catalyst are mixed, stirring is lower to add d- galactose, and temperature control reaction obtains penta-acetyl half Lactose solution；

B) hydrogen halides acetum is added in penta-acetyl galactose solution, temperature control reaction obtains halo four acetyl Galactose solution；

C) halo four acetyl galactose solution is added dropwise in the thiourea solution of heat, temperature control reacts, after the completion of reaction, cooling Crystallize, centrifugal drying obtains final product product.

Described method, preferably described acetic anhydride: catalyst: d- galactose: halogenation acetate hydrogen: the mol ratio of thiourea is 5.5- 6 : 0.03-0.05 : 1: 1.5-1.6: 1.1-1.3.

Described method, in preferred steps a, catalyst is perchloric acid.

Described method, in preferred steps a, reaction temperature is 20-25 DEG C, and the response time is 1-1.5 hour.

Described method, in preferred steps b, reaction temperature is 15-20 DEG C, and the response time is 0.5-1 hour.

Described method, in preferred steps c, reaction temperature is 60-70 DEG C, and the response time is 0.5-1 hour.

Described method, in preferred steps c, the thiourea solution temperature of heat is 60-65 DEG C.

Described method, in preferred steps c, dry run temperature is 65-75 DEG C, and recrystallization temperature is 0-5 DEG C.

Described method, in thiourea solution in preferred steps c, solvent is acetonitrile, and thiourea and acetonitrile mol ratio are 1:30- 35.

Beneficial effect: the inventive method is only reacted by one-step method, changes feed way and system temperature, prepares purity More than 99% product, without three-step reaction, is effectively improved production safety coefficient；Simple to operate, raw material is easy to get, and saves Running cost and material, the product yield obtaining is high, purity is high.

Brief description

The hplc spectrogram of the product that Fig. 1 obtains for embodiment 1,

The hydrogen nuclear magnetic resonance spectrogram of the product that Fig. 2 obtains for embodiment 1.

Specific embodiment

In order to further understand the present invention, with reference to specific embodiment, the process of this programme is described, but It should be appreciated that these descriptions are intended merely to further instruction the features and advantages of the present invention, rather than will to right of the present invention The restriction asked.

Embodiment 1 5.5:0.03:1:1.5:1.1

A) 5.5mol acetic anhydride and 0.03mol perchloric acid are added in room temperature reaction device, temperature control adds 1mold- at 20-25 DEG C Galactose, reacts 1 hour, detects reaction end by tlc,

B) hydrogen bromide acetic acid solution of hydrogen bromide mole for 1.5mol 33%, controlling reaction temperature are added in reactor At 15 DEG C, react 0.5 hour, reaction end detected by tlc point plate,

C) mole that above-mentioned reactant liquor is added dropwise to 65 DEG C is in the thiourea of 1.1mol and the acetonitrile of 30mol, controls anti- Answer temperature at 70 DEG C, react 0.5 hour, reaction end is detected by tlc point plate.

Cooling controls temperature crystallize 2 hours at 0 DEG C, obtains solid 0.752mol, product yield after 65 DEG C of dryings of centrifugation For 75.2%, purity is 99.37%, sees Fig. 1, hydrogen nuclear magnetic resonance spectrogram is shown in Fig. 2, result shows, the product that the present invention obtains For 2-s- (2,3,4,6- tetra--o- acetyl group-β-d- galactopyranosyl glycosyl) -2- isothiourea hydrobromide.

Embodiment 2 5.5: 0.04: 1:1.5:1.2

A) 5.5mol acetic anhydride and 0.04mol perchloric acid are added in room temperature reaction device, temperature control adds 1mold- at 20-25 DEG C Galactose, reacts 1 hour, detects reaction end by tlc,

B) hydrogen bromide acetic acid solution of hydrogen bromide mole for 1.5mol 33%, controlling reaction temperature are added in reactor At 20 DEG C, react 0.5 hour, reaction end detected by tlc point plate,

C) mole that above-mentioned reactant liquor is added dropwise to 60 DEG C is in the thiourea of 1.2mol and the acetonitrile of 30mol, controls anti- Answer temperature at 60 DEG C, react 0.5 hour, reaction end is detected by tlc point plate.

Cooling controls temperature crystallize 2 hours at 0 DEG C, obtains solid 0.744mol, product yield after 65 DEG C of dryings of centrifugation For 74.4%, purity is 99.39%.

Embodiment 36: 0.03: 1:1.5:1.2

A) 6mol acetic anhydride and 0.03mol perchloric acid are added in room temperature reaction device, temperature control adds 1mold- half at 20-25 DEG C Lactose, reacts 1.5 hours, detects reaction end by tlc,

B) hydrogen bromide acetic acid solution of hydrogen bromide mole for 1.5mol 33%, controlling reaction temperature are added in reactor At 15 DEG C, react 1 hour, reaction end detected by tlc point plate,

C) mole that above-mentioned reactant liquor is added dropwise to 65 DEG C is the thiourea of 1.2mol and the acetonitrile of 32mol, controls reaction Temperature, at 65 DEG C, is reacted 0.5 hour, detects reaction end by tlc point plate.

Cooling controls temperature crystallize 2 hours at 0 DEG C, obtains solid 0.739mol, product yield after 65 DEG C of dryings of centrifugation For 73.9%, purity is 99.38%.

Embodiment 46: 0.05: 1:1.6:1.3

C) above-mentioned reactant liquor is added dropwise in the thiourea that 60 DEG C of moles are 1.2mol and the acetonitrile of 32mol, controls reaction Temperature, at 70 DEG C, is reacted 0.5 hour, detects reaction end by tlc point plate.

Cooling controls temperature crystallize 3 hours at 0 DEG C, obtains solid 0.760mol, product yield after 75 DEG C of dryings of centrifugation For 76.0%, purity is 99.42%.

Embodiment 5 comparative examples

A) add 6mol acetic anhydride and 0.04mol perchloric acid in room temperature reaction device, control and at temperature 20-25 DEG C, add 1mold- Galactose, after the completion of reaction, adds the deionized water of 10mol, separates out yellow solid, obtains through the acetone recrystallization of 6mol Five acetyl galactose of 0.87mol；

B) hydrogen bromide acetic acid solution of hydrogen bromide mole for 0.87mol 33%, controlling reaction temperature are added in reactor At 15 DEG C, react 1 hour, after the completion of reaction, the deionized water of 0-5 DEG C of Deca 10mol stirs 2 hours, with the dichloromethane of 4mol Alkane aqueous layer extracted, organic faciess 8mol deionized water wash organic faciess three times, separate organic faciess and concentrate, add the 0.8mol tert-butyl group The isohexane mixed liquor crystallization of methyl ether and 1.2mol, processes the bromoacetyl galactose obtaining 0.78mol；

C) above-mentioned reactant liquor adds in the thiourea of 1.2mol and the acetonitrile of 32mol, and controlling reaction temperature, at 70 DEG C, is reacted 0.5 hour, reaction end is detected by tlc point plate.Cooling controls temperature crystallize 3 hours at 0 DEG C, after 75 DEG C of dryings of centrifugation To solid 0.65mol, product yield is 65.0%, and purity is 99.04%.

Claims

1. a kind of preparation method of isothiourea hydrobromide is it is characterised in that comprise the following steps:

A) 5.5mol acetic anhydride and 0.03mol perchloric acid are added in room temperature reaction device, temperature control adds 1mold- gala at 20-25 DEG C Sugar, reacts 1 hour, detects reaction end by tlc,

B) hydrogen bromide acetic acid solution of add that hydrogen bromide mole is 1.5mol in reactor 33%, controlling reaction temperature is 15 DEG C, react 0.5 hour, reaction end detected by tlc point plate,

C) mole that the reactant liquor that step b) obtains is added dropwise to 65 DEG C is control in the thiourea of 1.1mol and the acetonitrile of 30mol Reaction temperature processed, at 70 DEG C, is reacted 0.5 hour, detects reaction end by tlc point plate,

Cooling controls temperature crystallize 2 hours at 0 DEG C, obtains solid 0.752mol, product yield is after 65 DEG C of dryings of centrifugation 75.2%, purity is 99.37%.

2. a kind of preparation method of isothiourea hydrobromide is it is characterised in that comprise the following steps:

A) 5.5mol acetic anhydride and 0.04mol perchloric acid are added in room temperature reaction device, temperature control adds 1mold- gala at 20-25 DEG C Sugar, reacts 1 hour, detects reaction end by tlc,

B) hydrogen bromide acetic acid solution of add that hydrogen bromide mole is 1.5mol in reactor 33%, controlling reaction temperature is 20 DEG C, react 0.5 hour, reaction end detected by tlc point plate,

C) mole that the reactant liquor that step b) obtains is added dropwise to 60 DEG C is control in the thiourea of 1.2mol and the acetonitrile of 30mol Reaction temperature processed, at 60 DEG C, is reacted 0.5 hour, detects reaction end by tlc point plate,

Cooling controls temperature crystallize 2 hours at 0 DEG C, obtains solid 0.744mol, product yield is after 65 DEG C of dryings of centrifugation 74.4%, purity is 99.39%.

3. a kind of preparation method of isothiourea hydrobromide is it is characterised in that comprise the following steps:

A) 6mol acetic anhydride and 0.03mol perchloric acid are added in room temperature reaction device, temperature control adds 1mold- gala at 20-25 DEG C Sugar, reacts 1.5 hours, detects reaction end by tlc,

B) hydrogen bromide acetic acid solution of add that hydrogen bromide mole is 1.5mol in reactor 33%, controlling reaction temperature is 15 DEG C, react 1 hour, reaction end detected by tlc point plate,

C) mole that the reactant liquor that step b) obtains is added dropwise to 65 DEG C is the thiourea of 1.2mol and the acetonitrile of 32mol, controls Reaction temperature, at 65 DEG C, is reacted 0.5 hour, detects reaction end by tlc point plate,

Cooling controls temperature crystallize 2 hours at 0 DEG C, obtains solid 0.739mol, product yield is after 65 DEG C of dryings of centrifugation 73.9%, purity is 99.38%.

4. a kind of preparation method of isothiourea hydrobromide is it is characterised in that comprise the following steps:

C) reactant liquor that step b) obtains is added dropwise in the thiourea that 60 DEG C of moles are 1.2mol and the acetonitrile of 32mol, controls Reaction temperature, at 70 DEG C, is reacted 0.5 hour, detects reaction end by tlc point plate,

Cooling controls temperature crystallize 3 hours at 0 DEG C, obtains solid 0.760mol, product yield is after 75 DEG C of dryings of centrifugation 76.0%, purity is 99.42%.