CN107501102A - A kind of preparation method of high-purity validamine - Google Patents
A kind of preparation method of high-purity validamine Download PDFInfo
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- CN107501102A CN107501102A CN201710609243.9A CN201710609243A CN107501102A CN 107501102 A CN107501102 A CN 107501102A CN 201710609243 A CN201710609243 A CN 201710609243A CN 107501102 A CN107501102 A CN 107501102A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
Validamine and valienamine are important industrial chemicals, but both separation costs are higher, complex process.The present invention develops a kind of preparation method of validamine, it is characterised in that Validoxylamine is first is first passed through the hydrolysis of NBS chemical methods by methods described, and using water as solvent, Validoxylamine and NBS certain mol ratio of pressing add, and react 4h at 25 DEG C.Reactant concentrates through weak-acid cation-exchange resin adsorbing separation, obtains the mixture of valienamine and validamine.The mixture carries out hydrogenation reaction under the catalysis of heavy metal catalyst.Reactant concentrates, vacuum drying through weak-acid cation-exchange resin adsorbing separation, obtains the validamine sample of high-quality.
Description
Technical field
The present invention relates to a kind of new preparation process of high-quality validamine.
Background technology
Jinggangmeisu is China's independent development and the aminoglycoside farm antibiotics produced, is become by streptomyces hygroscopicus Jing Gang
Kind (Streptomyces hygroscopicus var.jinggangensis yen) metabolism produces, and can effectively suppress rice line
Rot bacterium, as China's yield is maximum, one of fermentation unit highest antibiotic, be biological pesticide main kind it
One.
Jinggangmeisu has formd a higher biotechnology industry of economic benefit in China.If can be with jinggangmeisu
For raw material, high value-added product is developed, can undoubtedly bring higher economic benefit and social benefit.Jinggangmycin A sloughs D-
Validoxylamine (Validoxylamine A) is obtained after glucose, Validoxylamine breaks in different C-N key positions
Split to obtain valienamine (Valienamine) or validamine (Validamine).Valienamine and validamine are to sugar
Glycosides enzyme has stronger inhibitory action.Therefore, valienamine and validamine can be used as glycosidase inhibitor class antidiabetic drug (such as
Voglibose, Voglibose) intermediate and bulk drug.
All the time, people compare the production of concern valienamine and validamine, such as use chemical method (N- bromo ambers
Acid imide (NBS), solid catalyst) or microbial method degrade Validoxylamine or jinggangmycin A to obtain the mould alkene in well ridge
The mixture of amine and validamine, then prepare valienamine by further separation.But because of valienamine and Jing Gang
Mould amine only differs 1 carbon-carbon double bond in chemical constitution, very nearly the same in chemical property, so as to cause valienamine or Jing Gang
The separation costs of mould amine are quite huge, can not large-scale production.Therefore, how single, high-purity Jing Gang is efficiently prepared
Mildew enamine or validamine have great economic implications to the production cost for reducing voglibose.
The content of the invention
The present invention provides a kind of new preparation process of high-quality validamine.
The present invention adopts the technical scheme that：
A kind of preparation method of validamine product, methods described are：Validoxylamine and NBS are added to solvent
Hydrolysis occurs in water, reaction solution is post-treated to obtain the mixture of valienamine and validamine, then will be described mixed
Compound carries out catalytic hydrogenation reaction, obtains the purified processing of reaction product and obtains high-purity validamine product.
Further, the amount ratio of the material of Validoxylamine and NBS of the present invention is 0.33-1.0：1.
Further, catalytic hydrogenation reaction of the present invention is using water as solvent, and Hydrogen Vapor Pressure is controlled in 5-15MPa, in a huge sum of money
The lower reaction 3-8h of metal catalyst effect, 50-80 DEG C of reaction temperature；The quality dosage of the mixture is calculated as with the volume of water
0.045~0.2g/mL.
Further, heavy metal catalyst of the present invention be support type or non-loading type Pd, Pt, Ru, Ni, Mn, Cr or
One kind in Pd, Pt, Ni or binary Au catalyst of one kind in binary Au catalyst, preferably support type or non-loading type.
Further, the quality dosage of heavy metal catalyst of the present invention is the 11%-17% of the mixture quality.
Preferably, the Hydrogen Vapor Pressure of catalytic hydrogenation reaction of the present invention is controlled in 5-10MPa, is made in heavy metal catalyst
With lower reaction 3-4h, 50-80 DEG C of reaction temperature；The quality dosage of the mixture is calculated as 0.09-0.2g/mL with the volume of water.
Further, through weak-acid cation-exchange resin absorption point after post processing of the present invention is diluted with water for reaction solution
From collecting the part containing valienamine and validamine, be concentrated under reduced pressure into and dry obtain the mixed of valienamine and validamine
Compound.
Further, purification process of the present invention is handed over for reaction product is filtered after being diluted with water through Subacidity cation
Resin adsorption separation is changed, the part reduced pressure concentration containing validamine is collected, is spray-dried, obtains the validamine sample of high-quality
Product.
The main efficacy results of the present invention are embodied in：The mould alkene in well ridge is prepared using the C-N keys of NBS methods hydrolysis Validoxylamine
The mixture of amine and validamine, then the double-bond hydrogenation of valienamine is prepared by validamine by hydrogenation reaction, so as to obtain
Obtain the validamine product of high-purity.The technique can solve the problem that valienamine and validamine isolate and purify, can scale
Change and prepare high-purity validamine product, for industry and medical material.
Brief description of the drawings
Fig. 1 is the chromatogram of validamine and valienamine standard items
Fig. 2 is the validamine product chromatogram of embodiment 1
Embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This.
Embodiment 1：
(1) 100g Validoxylamines, 80g NBS and 500mL deionized waters are added in 1000mL flasks, at 25 DEG C
Lower stirring reaction 4h.After reactant is diluted with water 10 times, upper ion exchange column (D113, Zhengguang Resin Co., Ltd.,
1500mL, NH4 +Type), washed with 5000mL deionized waters, then eluted with 4500mL 0.5mol/L ammoniacal liquor, collect the mould alkene in well ridge
The mixture part of amine and validamine, it is concentrated under reduced pressure into dry, acquisition 45.2g samples.
(2) add the dissolving of 500mL water rearmounted in 1000-mL hydrogenation reaction kettles in mixture, while put into 5g loading type Pds
Catalyst (Kangna Novel Material (Hangzhou) Co., Ltd.), hydrogenation to pressure 5MPa, 4h is reacted at 50 DEG C.After reaction terminates,
Solid is filtered off, 10 times of upper ion exchange columns (being same as above) is diluted with deionized water, is washed with 5000mL deionized waters, then use 4500mL
0.5mol/L ammoniacal liquor elution, collects the mixture part of validamine, is concentrated under reduced pressure, is dried in vacuo (45 DEG C), obtain Jing Gang
Mould amine sample 41.1g, is detected through HPLC, purity 96.4%.
Embodiment 2
(1) different amounts of Validoxylamine, 80g NBS and 500mL deionized waters are added in 1000mL flasks,
Stirring reaction 4h at 25 DEG C.After reactant is diluted with water 10 times, upper ion exchange column (D113, Zhengguang Resin Co., Ltd.,
1500mL, NH4+ type), washed with 5000mL deionized waters, then eluted with 4500mL 0.5mol/L ammoniacal liquor, it is mould to collect well ridge
The mixture part of enamine and validamine, it is concentrated under reduced pressure into dry, acquisition 45.2g samples.(2) add 500mL water-soluble in mixture
It is placed in after solution in 1000-mL hydrogenation reaction kettles, while puts into 5g Supported Pd-Catalysts (Kang Na new materials (Hangzhou) limited public affairs
Department), hydrogenation to pressure 5MPa, 4h is reacted at 50 DEG C.Reaction terminate after, filter off solid, with deionized water dilute 10 times on from
Sub- exchange column (being same as above), is washed with 5000mL deionized waters, then is eluted with 4500mL 0.5mol/L ammoniacal liquor, and it is mould to collect well ridge
The mixture part of enamine and validamine, it is concentrated under reduced pressure, is spray-dried vacuum drying (45 DEG C), obtain validamine sample,
Detected through HPLC, it is as a result as follows：
| Validoxylamine (g) | Example weight (g) | Purity (%) |
| 50 | 42.5 | 96.5 |
| 75 | 42.7 | 97.1 |
| 100 | 41.6 | 96.2 |
| 150 | 41.4 | 96.1 |
| 200 | 41.9 | 89.7 |
It can be seen that the dosage increase of Validoxylamine, hydrogenation effect reduce, mol ratio is in 0.33-1.0:Between 1, effect
Preferably.
Embodiment 3：
By the step of embodiment 1 (1) method, the mixture of acquisition valienamine and validamine, and it is molten to hydrogenation reaction
Agent dosage optimizes.By 45g said mixtures add different amounts of water 100,250,500,1000,1500) dissolve after be placed in plus
In hydrogen reactor, while put into 5g Supported Pd-Catalysts (Kangna Novel Material (Hangzhou) Co., Ltd.), hydrogenation to pressure
5MPa, 4h is reacted at 50 DEG C.After reaction terminates, solid is filtered off, 10 times of upper ion exchange columns (being same as above) is diluted with deionized water, uses
The washing of 5000mL deionized waters, then the ammoniacal liquor elution with 4500mL 0.5mol/L, collection valienamine and validamine mix
Polymer portion, it is concentrated under reduced pressure, is dried in vacuo (45 DEG C), obtains validamine sample, and detected with HPLC, concrete outcome such as following table
It is shown：
| Solvent load (mL) | Example weight (g) | Purity (%) |
| 100 | 41.2 | 81.6 |
| 225 | 42.1 | 96.7 |
| 500 | 41.1 | 96.4 |
| 1000 | 42.4 | 97.1 |
| 1500 | 42.3 | 91.1 |
Visible from the above, solvent load is optimal between 225mL-1000mL, when the concentration is excessively high or excessively low, goes out
Now it is hydrogenated with incomplete phenomenon.
Embodiment 4：
By the upper step of embodiment 1 (1) method, the mixture of acquisition valienamine and validamine, and to catalyst kind
Class optimizes.Add the dissolving of 500mL water rearmounted in 2-L hydrogenation reaction kettles in 45g mixtures, put into 5g supported catalysts respectively
Agent (Pd, Pt, Ru, Ni, Mn, Cr, Kangna Novel Material (Hangzhou) Co., Ltd.), hydrogenation to pressure 5MPa, react at 50 DEG C
4h.After reaction terminates, solid is filtered off, 10 times of upper ion exchange columns (being same as above) are diluted with deionized water, with 5000mL deionized waters
Washing, then eluted with 4500mL 0.5mol/L ammoniacal liquor, collect the mixture part of valienamine and validamine, decompression
Concentration, vacuum drying (45 DEG C), obtain validamine sample and detected with HPLC, concrete outcome is as shown in the table：
| Catalyst type | Example weight (g) | Purity (%) |
| Pd | 41.1 | 96.4 |
| Pt | 42.6 | 98.1 |
| Ru | 41.3 | 78.4 |
| Ni | 42.1 | 96.2 |
| Mn | 41.4 | 71.1 |
| Cr | 41.3 | 71.5 |
From upper table, the catalyst of Pd, Pt, Ni support type is respectively provided with preferable catalytic effect；In addition, these three are urged
Agent is combined use, the results showed that, it still has good catalytic effect, and product purity is higher than 96%.
Embodiment 5：
The mixture of validamine and valienamine is prepared by the step of embodiment 1 (1) method, and catalyst dosage is entered
Row investigates (Pd loaded catalysts) and adds the dissolving of 500mL water rearmounted in 1000mL hydrogenation reaction kettles in 45g mixtures, throws simultaneously
Enter the Supported Pd-Catalyst (Kangna Novel Material (Hangzhou) Co., Ltd.) of not same amount (3,4,5,6,8), hydrogenation to pressure
5MPa, 4h is reacted at 50 DEG C.After reaction terminates, solid is filtered off, 10 times of upper ion exchange columns (being same as above) is diluted with deionized water, uses
The washing of 5000mL deionized waters, then the ammoniacal liquor elution with 4500mL 0.5mol/L, collection valienamine and validamine mix
Polymer portion, it is concentrated under reduced pressure, is dried in vacuo (45 DEG C), obtains validamine sample and detect concrete outcome such as following table institute through HPLC
Show：
| Catalyst dosage (g) | Example weight (g) | Purity (%) |
| 3 | 42.3 | 86.5 |
| 4 | 42.1 | 91.8 |
| 5 | 41.1 | 96.4 |
| 6 | 42.2 | 97.3 |
| 8 | 41.9 | 97.7 |
It is visible from the above, when catalyst dosage is less than 5g, the suitable validamine product of purity can not be obtained, with
Catalyst amount increases, and its purity further improves, but cost relative increase.
Embodiment 6：
The mixture of validamine and valienamine is prepared by the step of embodiment 1 (1) method, hydrogenation pressure is carried out excellent
Change.Add the dissolving of 500mL water rearmounted in 1000mL hydrogenation reaction kettles in 45g mixtures, while put into 5g Supported Pd-Catalysts
(Kangna Novel Material (Hangzhou) Co., Ltd.), hydrogenation to pressure is respectively set to 1,3,5,10,15MPa, react at 50 DEG C
4h.After reaction terminates, solid is filtered off, 10 times of upper ion exchange columns (being same as above) are diluted with deionized water, with 5000mL deionized waters
Washing, then eluted with 4500mL 0.5mol/L ammoniacal liquor, collect the mixture part of valienamine and validamine, decompression
Concentration, vacuum drying (45 DEG C), obtain validamine sample and detected through HPLC, it is as a result as shown in the table：
| Hydrogen Vapor Pressure (MPa) | Example weight (g) | Purity (%) |
| 1 | 42.5 | 76.5 |
| 3 | 41.8 | 88.8 |
| 5 | 41.1 | 96.4 |
| 10 | 42.3 | 97.1 |
| 15 | 41.9 | 97.2 |
It is visible from the above, when Hydrogen Vapor Pressure is higher than 5Mpa, more satisfactory hydrogenation effect, pressure liter can be obtained
Height, product purity are slightly increased.
Embodiment 7：
The mixture of validamine and valienamine is prepared by the step of embodiment 1 (1) method, hydrogenation temperature is carried out excellent
Change.Add the dissolving of 500mL water rearmounted in 1000mL hydrogenation reaction kettles in 45g mixtures, while put into 5g Supported Pd-Catalysts
(Kangna Novel Material (Hangzhou) Co., Ltd.), hydrogenation to pressure 5MPa are anti-under different temperatures (25,35,50,80,110 DEG C)
Answer 4h.After reaction terminates, solid is filtered off, 10 times of upper ion exchange columns (being same as above) are diluted with deionized water, with 5000mL deionizations
Water washing, then eluted with 4500mL 0.5mol/L ammoniacal liquor, the mixture part of valienamine and validamine is collected, is subtracted
Pressure concentration, vacuum drying (45 DEG C), acquisition validamine sample are simultaneously as shown in the table through HPLC testing results：
From upper table, for reaction temperature when between 50-80 DEG C, hydrogenation effect is preferable, and temperature is too high, when reaching 110 DEG C,
Impurity is produced, causes product content to reduce.
Embodiment 8：
The mixture of validamine and valienamine is prepared by the step of embodiment 1 (1) method, the hydrogenation reaction time is entered
Row optimization.Add the dissolving of 500mL water rearmounted in 1000mL hydrogenation reaction kettles in 45g mixtures, while put into 5g loading type Pds and urge
Agent (Kangna Novel Material (Hangzhou) Co., Ltd.), hydrogenation to pressure 5MPa, react at 50 and 80 DEG C, different time takes
Sample, it is as a result as shown in the table with normalization method measure wherein validamine purity：
| Reaction time (DEG C) | 50 DEG C of reactions | 80 DEG C of reactions |
| 0 | 67.5% | 67.5% |
| 1 | 72.3% | 91.2% |
| 2 | 88.4% | 96.1% |
| 3 | 96.1% | 96.3% |
| 4 | 96.4% | 96.8% |
| 6 | 96.9% | 97.1% |
| 8 | 97.1% | 97.2% |
Visible from the above, as the reaction time extends, product purity further raises, and when temperature is higher, hydrogenation is anti-
Answer speed.
Embodiment 9：
100g Validoxylamines, 80g NBS and 500mL deionized waters are added in 1000mL flasks, is stirred at 25 DEG C
Mix reaction 4h.After reactant is diluted with water 10 times, upper ion exchange column (D113, Zhengguang Resin Co., Ltd., 1500mL,
NH4 +Type), washed with 5000mL deionized waters, then eluted with 4500mL 0.5mol/L ammoniacal liquor, collect valienamine and well
The mixture part of the mould amine in ridge, it is concentrated under reduced pressure into dry, acquisition 45.8g samples.Mixture plus the dissolving of 500mL water is rearmounted in 1-L
In hydrogenation reaction kettle, while 5g supported Pt catalysts (Kangna Novel Material (Hangzhou) Co., Ltd.) are put into, hydrogenation to pressure
Power 15MPa, 4h is reacted at 50 DEG C.After reaction terminates, solid is filtered off, it is (same to dilute 10 times of upper ion exchange columns with deionized water
On), washed with 5000mL deionized waters, then eluted with 4500mL 0.5mol/L ammoniacal liquor, collect valienamine and well ridge is mould
The mixture part of amine, it is concentrated under reduced pressure, is dried in vacuo (45 DEG C), obtains validamine sample 43.1g, detected through HPLC, purity
For 98.6%.
Claims (9)
1. a kind of preparation method of validamine product, it is characterised in that methods described is：Validoxylamine and NBS are added
Enter and hydrolysis occurs into aqueous solvent, reaction solution is post-treated to obtain the mixture of valienamine and validamine, then
The mixture is subjected to catalytic hydrogenation reaction, the purified processing of reaction product is obtained and obtains high-purity validamine product.
2. the preparation method of validamine product as claimed in claim 1, it is characterised in that：The Validoxylamine with
The amount ratio of NBS material is 0.33-1.0：1.
3. the preparation method of validamine product as claimed in claim 1, it is characterised in that：The catalytic hydrogenation reaction is with water
For solvent, Hydrogen Vapor Pressure is controlled in 5-15MPa, reacts 3-8h, 50-80 DEG C of reaction temperature under heavy metal catalyst effect；Institute
The quality dosage for stating mixture is calculated as 0.045-0.2g/mL with the volume of water.
4. the preparation method of validamine product as claimed in claim 3, it is characterised in that：The heavy metal catalyst is negative
One kind in Pd, Pt, Ru, Ni, Mn, Cr or binary Au catalyst of load type or non-loading type.
5. the preparation method of validamine product as claimed in claim 4, it is characterised in that：The heavy metal catalyst is negative
One kind in Pd, Pt, Ni or binary Au catalyst of load type or non-loading type.
6. the preparation method of validamine product as claimed in claim 3, it is characterised in that：The matter of the heavy metal catalyst
Measure the 11%-17% that dosage is the mixture quality.
7. the preparation method of validamine product as claimed in claim 3, it is characterised in that：The Hydrogen Vapor Pressure control is in 5-
10MPa, react 3-4h, 50-80 DEG C of reaction temperature under heavy metal catalyst effect；The quality dosage of the mixture is with water
Volume is calculated as 0.09~0.2g/mL.
8. the preparation method of the validamine product as described in one of claim 1-7, it is characterised in that：The post processing is anti-
Answer liquid be diluted with water after through weak-acid cation-exchange resin adsorbing separation, collect the portion containing valienamine and validamine
Point, it is concentrated under reduced pressure into and dry obtains the mixture of valienamine and validamine.
9. the preparation method of the validamine product as described in one of claim 1-7, it is characterised in that：The purification processes are
Reaction product is filtered, through weak-acid cation-exchange resin adsorbing separation after being diluted with water, collects the part containing validamine
It is concentrated under reduced pressure, is dried in vacuo, obtains the validamine sample of high-quality.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108059603A (en) * | 2017-12-29 | 2018-05-22 | 山东新华制药股份有限公司 | The process for refining of voglibose impurity N- methyl wells hilllock enzyme hydramine |
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| US20100151528A1 (en) * | 2008-09-17 | 2010-06-17 | The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of | Methods of producing validamycin a analogs and uses thereof |
| CN105399638A (en) * | 2014-09-12 | 2016-03-16 | 上海天伟生物制药有限公司 | Amino sugar intermediate preparation method |
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2017
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20100151528A1 (en) * | 2008-09-17 | 2010-06-17 | The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of | Methods of producing validamycin a analogs and uses thereof |
| CN105399638A (en) * | 2014-09-12 | 2016-03-16 | 上海天伟生物制药有限公司 | Amino sugar intermediate preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108059603A (en) * | 2017-12-29 | 2018-05-22 | 山东新华制药股份有限公司 | The process for refining of voglibose impurity N- methyl wells hilllock enzyme hydramine |
| CN108059603B (en) * | 2017-12-29 | 2020-08-14 | 山东新华制药股份有限公司 | Refining process of Voglibose impurity N-methyl Jinggang enzyme alcohol amine |
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