CN1304361C - Method for synthesizing N- (2-hydroxyethyl)-glucosamine - Google Patents
Method for synthesizing N- (2-hydroxyethyl)-glucosamine Download PDFInfo
- Publication number
- CN1304361C CN1304361C CNB2003101083198A CN200310108319A CN1304361C CN 1304361 C CN1304361 C CN 1304361C CN B2003101083198 A CNB2003101083198 A CN B2003101083198A CN 200310108319 A CN200310108319 A CN 200310108319A CN 1304361 C CN1304361 C CN 1304361C
- Authority
- CN
- China
- Prior art keywords
- reaction
- glucose
- hydroxyethyl
- glycosamine
- catalyzer
- 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.)
- Expired - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Abstract
The present invention relates to a method for synthesizing the intermediate N-(2-hydroxyethyl)-glucosamine of medicine, namely miglitol, for curing diabetes. The synthetic method of the N-(2-hydroxyethyl)-glucosamine is not recorded on the existing literature. The present invention has the following reaction steps of charge, reaction and preparation of powdery white solids by post treatment, wherein in charge, D-glucose and ethanolamine are added to an autoclave in the mole rate equal to 1:1.05 to 1.10; then, 70 to 95% of alcohol solvent with the weight of 5 to 10 times of that of the glucose is added; after displacement by nitrogen, 5%Pd-CaCO3-1 to 5%Pb catalysts with the weight of 2 to 10% of that of the glucose are added; high-purity hydrogen is blown in; hydrogen pressure is maintained at 2 to 3MPa; the mixture is slowly heated to reaction temperature; in reaction, the reaction temperature is controlled at 35 to 45 DEG C; the hydrogen pressure is from 2 to 4MPa; reaction time is from 20 to 24 hours. The present invention has the advantages of correspondingly mild reaction condition of the glucose and the ethanolamine by the selection of the appropriate catalysts and a reasonable hydrogenation process, easy operation of the reaction, hard generation of by-products and other impurities, high conversion rate and purity more than or equal to 98%.
Description
[technical field]
The present invention relates to the synthetic method of pharmaceutical intermediate, the synthetic method of the important intermediate N-of specifically a kind of synthetic Remedies for diabetes miglitol (Miglitol) (2-hydroxyethyl)-glycosamine.
[background technology]
N-(2-hydroxyethyl)-glycosamine is the important intermediate of synthetic Remedies for diabetes miglitol (Miglitol), English N-(2-hydroxyethyl) glucamine by name, and structural formula is as follows:
At present, this material does not all have ready-made product to sell at home and in the world, and the industrialization production of N-(2-hydroxyethyl)-glycosamine seems extremely important concerning synthetic miglitol.US4266025, US4405714 and US2001/0019837A1 have mentioned N-(2-hydroxyethyl)-glycosamine, but these three parts of patent contents all are that to replace glycosamine with N-be feedstock production 1-S-GI N substitutive derivative, all do not relate to the synthetic method of N-(2-hydroxyethyl)-glycosamine.EP0477160 is a kind of synthetic method of N-(butyl)-glycosamine, and this patent adopts 4%Pd-C to make catalyzer, is raw material with glucose and butylamine, and hydrogenation obtains N-(butyl)-glycosamine in autoclave; This patent has been mentioned homologue N-(2-hydroxyethyl)-glycosamine, but does not mention the synthetic method of N-(2-hydroxyethyl)-glycosamine.Through experimental results demonstrate that the method for preparing N-(butyl)-glycosamine by EP0477160 prepares its homologue N-(2-hydroxyethyl)-glycosamine, can't obtain required product.
[summary of the invention]
The technical assignment of technical problem to be solved by this invention and proposition provides a kind of synthetic method of intermediate N (2-hydroxyethyl)-glycosamine of synthetic Remedies for diabetes miglitol, it selects appropriate catalyst and hydrogenation technique, so that glucose and thanomin are under the relative gentle condition of reaction conditions, be converted into N-(2-hydroxyethyl)-glycosamine with high yield, achieve industrialization production.
Technical scheme of the present invention is such: the synthetic method of N-(2-hydroxyethyl)-glycosamine, it is characterized in that reactions steps is as follows: A) feed intake: in autoclave, D-glucose in molar ratio: thanomin=1: 1.05～1.10 add D-glucose and thanomins, adding weight again is the 70-95% alcoholic solvent (moisture 5～30%) of 5～10 times of glucose amounts, with adding 5%Pd-CaCO behind the nitrogen replacement
3-1～5%Pb catalyzer, its weight is 2～10% of glucose, blasts high-purity hydrogen, the maintenance hydrogen pressure is 2～3Mpa, slowly is warming up to temperature of reaction; B) reaction: control reaction temperature is 35～45 ℃, and hydrogen pressure is 2～4Mpa, 20～24 hours reaction times, follow the tracks of reaction with TLC point plate, and glucose point disappears and is reaction end; C) obtain the white powder solid through aftertreatment, yield: 82～90%.The present invention has found the special catalyst of a kind of suitable N-(2-hydroxyethyl)-glycosamine reaction, promptly does skeleton with lime carbonate, and 5% palladium catalyst that the lead of adding 1～5% is partly poisoned palladium abbreviates as: 5%Pd-CaCO
3-1～5%Pb catalyzer (Acros company is on sale).5%Pd-CaCO
3-1～5%Pb catalyzer is added rational hydrogenation technique, makes glucose and thanomin under the relative gentle condition of reaction conditions, is converted into N-(2-hydroxyethyl)-glycosamine with high yield, and the purity height, produces by product and other impurity hardly.
The synthetic method of described N-(2-hydroxyethyl)-glycosamine, last handling process is as follows: reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement; With the nitrogen press filtration that displacement obtains, filter residue is useless 5%Pd-CaCO
3-1～5%Pb catalyzer is deposited in the deionized water, focuses on the back recovery set and uses; Faint yellow filtrate is under violent stirring, and slowly adding volume is that 3～5 times of acetone to described alcoholic solvent, acetonitrile or tetrahydrofuran (THF) disperse, and obtains oyster white suspendible system, puts into whizzer and gets rid of material, with acetone, acetonitrile or tetrahydrofuran (THF) washing, dries; Material after drying is put into vacuum drying oven, vacuum tightness for≤-0.09Mpa, temperature are 60～80 ℃ of bakings 4～10 hours down, with the detection of TLC point plate, product point is main point, can't see impure point, obtains the white powder solid.
The synthetic method of described N-(2-hydroxyethyl)-glycosamine, useless 5%Pd-CaCO
3The recovery set of-1～5%Pb catalyzer is as follows with treatment process: the spent catalyst of depositing in the deionized water joins in the reactor, is spent catalyst by weight: deionized water=1: 10～15 add deionized waters; Be warming up to 90～95 ℃ and stirred 2～4 hours down, with the suction of suction filtration rod; Repeat aforesaid operations, till the water of sucking-off is colourless; Filter, drain, the catalyzer that obtains handling, it can directly overlap and be used for reaction, has reduced production cost.
The synthetic method of described N-(2-hydroxyethyl)-glycosamine, alcoholic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol.
The invention has the beneficial effects as follows: the synthetic method that provides a kind of N-of realization (2-hydroxyethyl)-glycosamine industrialization to produce; This method has been selected appropriate catalyst 5%Pd-CaCO
3-1～5%Pb and rational hydrogenation technique make the reaction conditions of glucose and thanomin relative gentle, and reaction is carried out easily, produces by product and other impurity hardly, transformation efficiency height, purity 〉=98%.
Synthetic route involved in the present invention is as follows:
[embodiment]
The present invention is further illustrated below in conjunction with embodiment.
Embodiment 1:
A, feed intake: in the 20L autoclave, add D-glucose 2kg (10.1mol), thanomin 650g (10.7mol) adds the solvent 18L of 90% methyl alcohol (moisture 10%) again.With adding 5%Pd-CaCO behind the nitrogen replacement
3-2%Pb catalyzer 60g blasts high-purity hydrogen, and the maintenance hydrogen pressure is 2～3Mpa, slowly is warming up to 35 ℃ of reactions.
B, reaction: control reaction temperature is 35～45 ℃, and hydrogen pressure is 2～4MPa reaction 24 hours.Follow the tracks of reaction with TLC, glucose point disappears, and finishes reaction.
C, aftertreatment: reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is useless 5%Pd-CaCO
3-1～5%Pb catalyzer is deposited in the deionized water, focuses on the back recovery set and uses.Faint yellow filtrate enters 300L and wards off the glass reactor, slowly adds the 100L acetonitrile and disperse under violent stirring, obtains oyster white suspendible system.Put into whizzer and get rid of material,, dry with the washing of 10L acetonitrile.Material is put into vacuum drying oven, is 0.09MPa in vacuum tightness, and temperature is to dry by the fire 10 hours under 60～80 ℃ of conditions, obtains 2.2kg (9.1mol) white powder solid, and fusing point is 185～188 ℃, yield: 90.0%.Detect with TLC point plate, product point is main point, can't see impure point.Analyze through HPLC, purity is 98.4%.
The recovery set of D, spent catalyst is used: with filtered and recycled and deposit in useless 5%Pd-CaCO in the deionized water
3-1～5%Pb catalyzer, the conversion dry weight is 30kg, joins 500L and wards off in the glass reactor, adds deionization 300 water; Be warming up to 90 ℃, stirred 4 hours at 90～95 ℃, sop up most of water with the suction filtration rod, add deionized water 300L according to above operation again, 90～95 ℃ of heated and stirred are washed, repetitive operation to the water of sucking-off be colourless till; Filter, drain.The 5%Pd-CaCO that obtains handling
3-1～5%Pb catalyzer 29.5kg, the 5%Pd-CaCO that this was handled
3-1～5%Pb catalyzer can directly overlap and be used for reaction next time.
Embodiment 2:
A, feed intake: in the 50L autoclave, add D-glucose 5kg (25.2mol), thanomin 1.6kg (26.7mol) adds the solvent 35L of 85% Virahol (moisture 15%) again.Add 5%Pd-CaCO behind the nitrogen replacement
3-4%Pb catalyzer 200g blasts high-purity hydrogen, and the maintenance hydrogen pressure is 2～3Mpa, slowly is warming up to 35 ℃ of reactions.
B, reaction: control reaction temperature is 35～45 ℃, and hydrogen pressure is 2～4MPa reaction 22 hours.Follow the tracks of reaction with TLC, glucose point disappears, and finishes reaction.
C, aftertreatment: reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is useless 5%Pd-CaCO
3-1～5%Pb catalyzer is deposited in the deionized water, focuses on the back recovery set and uses.Faint yellow filtrate enters 300L and wards off the glass reactor, slowly adds the 200L tetrahydrofuran (THF) and disperse under violent stirring, obtains oyster white suspendible system.Put into whizzer and get rid of material,, dry with the washing of 20L tetrahydrofuran (THF).Material is put into vacuum drying oven, in vacuum tightness be-0.10MPa, temperature is to dry by the fire 10 hours under 60～80 ℃ of conditions, obtains 5.3kg (124.5mol) white powder solid, and fusing point is 185～188 ℃, yield: 87.3%.Detect with TLC point plate, product point is main point, can't see impure point.Analyze through HPLC, purity is 98.1%.
The recovery set of D, spent catalyst is used: treatment process is identical with embodiment 1.
Embodiment 3:
A, feed intake: in the 400L autoclave, add D-glucose 30kg (151.5mol), thanomin 10kg (166.2mol) adds the solvent 250L of 80% propyl carbinol (moisture 20%) again.Add 5%Pd-CaCO behind the nitrogen replacement
3-3%Pb catalyzer 1.2kg.Blast high-purity hydrogen, the maintenance hydrogen pressure is 2～3Mpa, slowly is warming up to 35 ℃ of reactions.
B, reaction: control reaction temperature is 35～45 ℃, and hydrogen pressure is 2～4MPa reaction 20 hours.Follow the tracks of reaction with TLC, glucose point disappears, and finishes reaction.
C, aftertreatment: reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is useless 5%Pd-CaCO
3-1～5%Pb catalyzer is deposited in the deionized water, focuses on the back recovery set and uses.Faint yellow filtrate enters 2000L and wards off the glass reactor, slowly adds 1000L acetone and disperse under violent stirring, obtains oyster white suspendible system.Put into whizzer and get rid of material, use the 50L washing with acetone, dry.Material is put into vacuum drying oven, in vacuum tightness be-0.09MPa, temperature is to dry by the fire 10 hours under 60～80 ℃ of conditions, obtains 31.5kg (130.7mol) white powder solid, and fusing point is 185～188 ℃, yield: 86.3%.Detect with TLC point plate, product point is main point, can't see impure point.Analyze through HPLC, purity is 98.0%.
The recovery set of D, spent catalyst is used: treatment process is identical with embodiment 1.
Embodiment 4:
A, feed intake: in the 400L autoclave, add D-glucose 30kg (151.5mol), thanomin 10kg (166.2mol) adds the solvent 300L of 75% trimethyl carbinol (moisture 25%) again.Add behind the nitrogen replacement by embodiment 1 and reclaim the 5%Pd-CaCO that obtains
3-1～5%Pb catalyzer 2kg blasts high-purity hydrogen, and the maintenance hydrogen pressure is 2～3Mpa, slowly is warming up to 35 ℃ of reactions.
B, reaction: control reaction temperature is 35～45 ℃, and hydrogen pressure is 2～4MPa reaction 24 hours.Follow the tracks of reaction with TLC, glucose point disappears, and finishes reaction.
C, aftertreatment: reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement.The nitrogen press filtration, filter residue is useless 5%Pd-CaCO
3-1～5%Pb catalyzer is deposited in the deionized water, focuses on the back recovery set and uses.Faint yellow filtrate enters 2000L and wards off the glass reactor, slowly adds the 1000L tetrahydrofuran (THF) and disperse under violent stirring, obtains oyster white suspendible system.Put into whizzer and get rid of material,, dry with the washing of 50L tetrahydrofuran (THF).Material is put into vacuum drying oven, in vacuum tightness be-the 0.09MPa. temperature is to dry by the fire 10 hours under 60～80 ℃ of conditions, obtains 30kg (124.5mol) white powder solid, fusing point is 185～188 ℃, yield: 82.2%.Detect with TLC point plate, product point is main point, can't see impure point.Analyze through HPLC, purity is 98.3%.
The recovery set of D, spent catalyst is used: treatment process is identical with embodiment 1.
The invention is not restricted to the foregoing description, the foregoing description is the embodiment that optimizes.
Claims (4)
1, the synthetic method of N-(2-hydroxyethyl)-glycosamine, it is characterized in that reactions steps is as follows: A) feed intake: in autoclave, D-glucose in molar ratio: thanomin=1: 1.05～1.10 add D-glucose and thanomins, adding weight again is the 70-95% alcoholic solvent of 5～10 times of glucose amounts, with adding 5%Pd-CaCO behind the nitrogen replacement
3-1～5%Pb catalyzer, its weight is 2～10% of glucose, blasts high-purity hydrogen, the maintenance hydrogen pressure is 2～3Mpa, slowly is warming up to temperature of reaction; B) reaction: control reaction temperature is 35～45 ℃, and hydrogen pressure is 2～4Mpa, 20～24 hours reaction times; C) obtain the white powder solid through aftertreatment.
2, the synthetic method of N-according to claim 1 (2-hydroxyethyl)-glycosamine is characterized in that last handling process is as follows: reaction is unloaded hydrogen pressure after finishing, and uses nitrogen replacement; With the nitrogen press filtration that displacement obtains, filter residue is useless 5%Pd-CaCO
3-1～5%Pb catalyzer is deposited in the deionized water, focuses on the back recovery set and uses; Faint yellow filtrate is under violent stirring, and slowly adding volume is that 3～5 times of acetone to described alcoholic solvent, acetonitrile or tetrahydrofuran (THF) disperse, and obtains oyster white suspendible system, puts into whizzer and gets rid of material, with acetone, acetonitrile or tetrahydrofuran (THF) washing, dries; Material after drying is put into vacuum drying oven, vacuum tightness for≤-0.09Mpa, temperature are 60～80 ℃ of bakings 4～10 hours down, obtain the white powder solid.
3, the synthetic method of N-according to claim 2 (2-hydroxyethyl)-glycosamine is characterized in that useless 5%Pd-CaCO
3The recovery set of-1～5%Pb catalyzer is as follows with treatment process: the spent catalyst of depositing in the deionized water joins in the reactor, is spent catalyst by weight: deionized water=1: 10～15 add deionized waters; Be warming up to 90～95 ℃ and stirred 2～4 hours down, with the suction of suction filtration rod; Repeat aforesaid operations, till the water of sucking-off is colourless; Filter, drain, the catalyzer that obtains handling, it can directly overlap and be used for reaction.
4, the synthetic method of N-according to claim 1 (2-hydroxyethyl)-glycosamine is characterized in that described alcoholic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101083198A CN1304361C (en) | 2003-10-28 | 2003-10-28 | Method for synthesizing N- (2-hydroxyethyl)-glucosamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101083198A CN1304361C (en) | 2003-10-28 | 2003-10-28 | Method for synthesizing N- (2-hydroxyethyl)-glucosamine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1611485A CN1611485A (en) | 2005-05-04 |
| CN1304361C true CN1304361C (en) | 2007-03-14 |
Family
ID=34758553
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003101083198A Expired - Fee Related CN1304361C (en) | 2003-10-28 | 2003-10-28 | Method for synthesizing N- (2-hydroxyethyl)-glucosamine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1304361C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100402490C (en) * | 2006-11-30 | 2008-07-16 | 四川维奥制药有限公司 | 1- hydroxyethylamine-1-deoxy-D-sorbierite preparation method |
| CN101891777B (en) * | 2010-01-15 | 2013-10-16 | 山东新时代药业有限公司 | Method for preparing miglitol intermediate N-hydroxyethyl glucosamine |
| CN104151175B (en) * | 2014-08-18 | 2016-03-09 | 王秀梅 | A kind of miglitol impurity compound and its production and use |
| CN115010610B (en) * | 2022-06-16 | 2024-07-16 | 常州大学 | Synthesis method of miglitol intermediate N-hydroxyethyl glucosamine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061959A (en) * | 1990-11-09 | 1992-06-17 | 普罗格特-甘布尔公司 | In amine and amine/water solvent, prepare the N-alkyl polyhydroxy amine and prepare the method for fatty acid amide by this N-alkyl polyhydroxy amine |
| US5916748A (en) * | 1996-04-12 | 1999-06-29 | Cedars-Sinai Medical Center | Method of diagnosing a clinical subtype of crohn's disease with features of ulcerative colitis |
-
2003
- 2003-10-28 CN CNB2003101083198A patent/CN1304361C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061959A (en) * | 1990-11-09 | 1992-06-17 | 普罗格特-甘布尔公司 | In amine and amine/water solvent, prepare the N-alkyl polyhydroxy amine and prepare the method for fatty acid amide by this N-alkyl polyhydroxy amine |
| US5916748A (en) * | 1996-04-12 | 1999-06-29 | Cedars-Sinai Medical Center | Method of diagnosing a clinical subtype of crohn's disease with features of ulcerative colitis |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1611485A (en) | 2005-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2014030820A1 (en) | Method for preparing lactide directly from lactic acid, and catalyst used therein | |
| CN1583776A (en) | Preparing method for cytarabine | |
| US11697658B2 (en) | Method for preparing lornoxicam | |
| CN103922931B (en) | A kind of method of a step catalytically synthesizing glycol ether acetate | |
| CN1304361C (en) | Method for synthesizing N- (2-hydroxyethyl)-glucosamine | |
| CN109096122A (en) | The method for preparing spermidine | |
| CN1023864C (en) | Process for preparing phenylacetic acid by chlorobenzyl carbonylation under normal pressure | |
| CN1300098C (en) | Method for synthesizing N-butyl-glucosamine | |
| CN111205216A (en) | Method for preparing saxagliptin | |
| CN111646919A (en) | Method for recovering acidic DMF (dimethyl formamide) in sucralose esterification reaction | |
| CN114874227B (en) | Catalyst for amide synthesis and preparation and application thereof | |
| CN111099975A (en) | Preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone | |
| CN106636241B (en) | Method for preparing esmollin intermediate by enzyme method | |
| CN1524847A (en) | Producing method of of tranexamic acid | |
| CN1488623A (en) | Method for preparing 2,4-toluene diamino menthyl formate | |
| CN100591652C (en) | Method for producing 2-(4-fluoro-benzyl)-phenyl-acetic acid | |
| CN114478216A (en) | Novel synthesis method of 1-acetyl-1-chlorocyclopropane | |
| CN112250615A (en) | Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride | |
| CN1239460C (en) | Synthesis of trans-4-alkyl cyclohexyl formic acid | |
| CN112538055A (en) | Preparation method of benzotriazole ultraviolet absorbent | |
| CN112495439A (en) | Photocatalytic catalyst, preparation method thereof and preparation method of vitamin A palmitate | |
| CN100402490C (en) | 1- hydroxyethylamine-1-deoxy-D-sorbierite preparation method | |
| CN113698355B (en) | Synthesis method of 4, 5-dihydroxypyridazine | |
| CN1256319C (en) | Process for synthesis of L-beta-asparagine | |
| CN113620826B (en) | Preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070314 Termination date: 20171028 |