CN101497582A - N-substituted-1-deoxynojirimycin compound and preparation thereof - Google Patents
N-substituted-1-deoxynojirimycin compound and preparation thereof Download PDFInfo
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- CN101497582A CN101497582A CNA200810045328XA CN200810045328A CN101497582A CN 101497582 A CN101497582 A CN 101497582A CN A200810045328X A CNA200810045328X A CN A200810045328XA CN 200810045328 A CN200810045328 A CN 200810045328A CN 101497582 A CN101497582 A CN 101497582A
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- methanol solution
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Abstract
The invention belongs to the technical field of organic chemistry and pharmaceutical chemistry, and particularly relates to an N-substitution-1-deoxynojirimycin compound and a method for preparing the same. Derivatives of 5-substitution amino ribose furanoside, under the actions of alkali triethylamine or/and a methanol solution of sodium methoxide, or/and methanol solution of potassium carbonate, or/and methanol solution of sodium hydroxide, or/and methanol solution of potassium hydroxide, are stirred at the room temperature, and the obtained product reacts with Ac2O to obtain the N-substitution-1-deoxynojirimycin compound. The compound and the method have the characteristics of easy obtaining of the reagents, low cost, simple operation and easy industrialization.
Description
Invention field
The invention belongs to organic chemistry and pharmaceutical chemistry technical field, be specifically related to N-substituted-1-deoxynojirimycin compound and preparation method thereof.
Background technology
The iminosugar compounds is a small molecule, and is simple in structure, and stable in properties can be oral, can be used as immunomodulator, antineoplastic agent and antiviral agent.Since it is found that natural iminosugar compounds 1-S-GI has fine inhibition effect to people's visceral enzym alpha-glycosidase, the scientist of countries in the world has carried out extensive studies to the N-substituted-1-deoxynojirimycin compound.Is that the basis conducts a research as German Bayer company with the 1-S-GI, successfully hydroxyethyl-the 1-S-GI (is a miglitol to screening acquisition N-, miglitol), and make it to become first imino-carbohydrate medicine, be used for non-insulin-depending type (II type) treatment of diabetes.Regius professor and affiliate thereof have also successfully made N-butyl-1-S-GI by chemically modified on the basis of 1-S-GI (be the Beagle spy, miglustat trade(brand)name: Zavesca), it is a kind of glycosyl transferase inhibitor, be used for the glycolipid storage diseases, light to moderate I type familial splenic anemia, N-butyl-1-S-GI can be regulated by the blocking virus envelope glycoprotein, propagate effective etc. to suppressing HIV, in addition, the imino sugar compounds by chemically modified is used for the treatment of tumour as immunomodulator and virus infection also demonstrates good prospect.Therefore, the design of N-substituted-1-deoxynojirimycin compound is with synthetic significant.
At present, the preparation method of the N-substituted-1-deoxynojirimycin compound reported of patent and document.As: Olivier R.Martin etc. at Organic Letters, 2000,2, introduced among the 2971-2974 with 2,3; 4,6-two-O-isopropylidene-α-L-sorb furanose is raw material through ten steps the imido grpup sugar derivatives has been synthesized in reaction.
And for example: Dilip D.Dhavale etc. are at Bioorganic ﹠amp; Medicine Chemistry, 2003,11,3295-3305 has reported and has used D-glucose to be the synthetic N-hydroxyethyl of raw material-1-deoxidization nojirimycin derivative.
For another example: patent US5602013 has also introduced N-and has replaced glucosamine and reduce under the oxidisability action of microorganisms and obtain N-replacement-1-S-GI.
Several synthetic methods of above-mentioned bibliographical information can both obtain required product, but have different shortcomings such as step is long, overall yield is low, microbiological oxidation is not easy to operate.
Summary of the invention
Having the object of the present invention is to provide a kind of is raw material with 5-substituted-amino ribose furanoside derivative, prepares the method for N-substituted-1-deoxynojirimycin compound under the alkaline condition effect.
The process of preparation N-substituted-1-deoxynojirimycin compound (II) is as follows:
In reactor, add 5-substituted-amino ribose furanoside derivative (I), and then add sodium methylate methanol solution or/and triethylamine or/and the methanol solution of salt of wormwood or/and the methanol solution of sodium hydroxide or/and the methanol solution of potassium hydroxide, after reacting completely under the room temperature, the product that obtains of reaction again with Ac
2The O reaction makes N-substituted-1-deoxynojirimycin compound (II).
The catalyzer that adopts alkali to reset among the present invention as open loop, wherein alkali be triethylamine or/and the methanol solution of sodium methylate or/and the methanol solution of salt of wormwood or/and the methanol solution of sodium hydroxide or/and the methanol solution of potassium hydroxide.
Reaction reagent is easy to get among the present invention, and cost is lower, and is easy to operate simple, provide a kind of simple and effective be the method for feedstock production N-substituted-1-deoxynojirimycin compound with 5-substituted-amino ribose furanoside derivative.
Embodiment
In order further to understand summary of the invention, characteristics and effect of the present invention, exemplify following example now:
Example 1: in the round-bottomed flask of 50mL, add 1-C-acetylmethyl-2,3-two-O-benzyl-5-fourth amino-α-D-ribose furanoside (I:R=C
4H
9) 0.5g, the methanol solution 5mL that adds 1% sodium methylate again, reaction is 2 hours under the stirring at room, after reaction finishes, add a little ammonium chloride, the pH value of regulator solution is used the 15mL dichloromethane extraction 3 times again to neutral, merges organic phase, again with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, 15mL saturated sodium-chloride water solution washing 2 times, wash again 2 times, use anhydrous magnesium sulfate drying, filter, separate through silica gel column chromatography again after concentrating, use earlier sherwood oil: ethyl acetate=1:1 wash-out, use sherwood oil again: ethyl acetate=1:10 wash-out gets α, beta isomer mix products 0.44g, productive rate are 88%.
This product is joined in the round-bottomed flask of 25mL, add acetic anhydride 120 μ L and pyridine 2mL respectively, reaction is 12 hours under the room temperature, the hydrochloric acid 20mL that adds 1M again uses the 15mL dichloromethane extraction 3 times again, and the hydrochloric acid 15mL with 1M washs 2 times again, again with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, 15mL saturated sodium-chloride water solution washing 2 times washes with water 2 times again, uses anhydrous magnesium sulfate drying.Filter, separate through silica gel column chromatography again after concentrating, use earlier sherwood oil: ethyl acetate=5:1 wash-out, use sherwood oil again: ethyl acetate=3:2 wash-out, get product 0.42g (α, beta isomer), productive rate is 87%.
Example 2: the round-bottomed flask at 50mL adds 1-C-acetylmethyl-2,3-two-O-benzyl-5-third amino-α-D-ribose furanoside (I:R=C
3H
7) 0.3g, the methanol solution that adds 10mL 4% sodium methylate again, reaction is 5 hours under the stirring at room, after reaction finishes, add a little ammonium chloride, the pH value of regulator solution is used the 15mL dichloromethane extraction 3 times again to neutral, merges organic phase, again with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, 15mL saturated sodium-chloride water solution washing 2 times is washed 2 times again, uses anhydrous magnesium sulfate drying.Filter, concentrate crude product.
This crude product is joined in the round-bottomed flask of 25mL, add acetic anhydride 100 μ L, pyridine 2mL respectively, reaction is 12 hours under the room temperature.The hydrochloric acid 20mL that adds 1M again uses 15mL dichloromethane extraction 3 times, and the hydrochloric acid 15mL with 1M washs 2 times again, and with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, the 15mL saturated sodium-chloride water solution washs 2 times, washes 2 times again, uses anhydrous magnesium sulfate drying.Filter, separate through silica gel column chromatography again after concentrating, use earlier sherwood oil: ethyl acetate=4:1 wash-out, use sherwood oil again: ethyl acetate=2:1 wash-out, get product 0.23g (α, beta isomer), the productive rate of two-step reaction is 70%.
Example 3: the round-bottomed flask at 50mL adds 1-C-acetylmethyl-2,3-two-O-benzyl-5-ethylamino-α-D-ribose furanoside (I:R=C
2H
5) 0.18g, adding the methanol solution 10mL of 8% sodium methylate again, reaction is 3 hours under the stirring at room.Reaction adds a little ammonium chloride after finishing, and the pH value of regulator solution is to neutral, use the 15mL dichloromethane extraction again 3 times, merge organic phase, again with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, 15mL saturated sodium-chloride water solution washing 2 times is washed 2 times again, uses anhydrous magnesium sulfate drying.Filter, concentrate crude product.
This crude product is joined in the round-bottomed flask of 25mL, add acetic anhydride 100 μ L, pyridine 2mL respectively, reaction is 12 hours under the room temperature.The hydrochloric acid 20mL that adds 1M again, with methylene dichloride 15mL extraction 3 times, the hydrochloric acid 15mL with 1M washs 2 times again, and with saturated sodium bicarbonate aqueous solution 15mL washing 2 times, saturated sodium-chloride water solution 15mL washing 2 times is washed 2 times again, uses anhydrous magnesium sulfate drying.Filter, separate through silica gel column chromatography again after concentrating, use earlier sherwood oil: ethyl acetate=2:1 wash-out, use sherwood oil again: ethyl acetate=1:1 wash-out, get product 0.12g (α, beta isomer), the productive rate of two-step reaction is 60%.
Example 4: in the round-bottomed flask of 50mL, add 1-C-acetylmethyl-2,3-two-O-benzyl-5-fourth amino-α-D-ribose furanoside (I:R=C
4H
9) 100mg and 5mL triethylamine, reaction is 10 hours under the stirring at room.Reaction finishes to remove the back adding 15mL water that desolvates, and uses the 15mL dichloromethane extraction again 3 times, merges organic phase, and with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, 15mL saturated sodium-chloride water solution washing 2 times is washed 2 times again, uses anhydrous magnesium sulfate drying.Filter, separate through silica gel column chromatography again after concentrating, use earlier sherwood oil: ethyl acetate=1:1 wash-out, use sherwood oil again: ethyl acetate=1:10 wash-out, get product 70mg (α, beta isomer), productive rate is 70%.
Example 5: in the round-bottomed flask of 50mL, add 1-C-acetylmethyl-2,3-two-O-benzyl-5-fourth amino-α-D-ribose furanoside (I:R=C
4H
9) 100mg and 5mL methyl alcohol, add 300mgK again
2CO
3, reaction is 10 hours under the stirring at room.Reaction finishes to remove the back adding 15mL water that desolvates, and uses the 15mL dichloromethane extraction again 3 times, merges organic phase, and with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, 15mL saturated nacl aqueous solution washing 2 times is washed 2 times again, uses anhydrous magnesium sulfate drying again.Filter, separate through column chromatography silica gel again after concentrating, use earlier sherwood oil: ethyl acetate=1:1 wash-out, use sherwood oil again: ethyl acetate=1:10 wash-out, get product 75mg (α, beta isomer), productive rate is 75%.
Example 6: in the round-bottomed flask of 50mL, add 1-C-acetylmethyl-2,3-two-O-benzyl-5-fourth amino-α-D-ribose furanoside (I:R=C
4H
9) the methanol solution 5mL of 100mg and 10% sodium hydroxide, reaction is 8 hours under the stirring at room.Reaction finishes to remove the back adding 15mL water that desolvates, and uses the 15mL dichloromethane extraction again 3 times, merges organic phase, and with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, 15mL saturated sodium-chloride water solution washing 2 times is washed 2 times again, uses anhydrous magnesium sulfate drying again.Filter, separate through column chromatography silica gel again after concentrating, use earlier sherwood oil: ethyl acetate=1:1 wash-out, use sherwood oil again: ethyl acetate=1:10 wash-out, get product 55mg (α, beta isomer), productive rate is 55%.
Example 7: the round-bottomed flask at 50mL adds 1-C-acetylmethyl-2, the own amino-α of 3-two-O-benzyl-5--D-ribose furans glycosides (I:R=C
6H
13) the methanol solution 5mL of 100mg and 4% sodium methylate, reaction is 5 hours under the stirring at room.Reaction finishes to add 15mL water again except that after desolvating, and uses 15mL dichloromethane extraction 3 times, merges organic phase, and with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, the 15mL saturated sodium-chloride water solution washs 2 times, washes 2 times again, uses anhydrous magnesium sulfate drying again.Filter, separate through column chromatography silica gel again after concentrating, use earlier sherwood oil: ethyl acetate=1:1 wash-out, use sherwood oil again: ethyl acetate=1:10 wash-out, get product 72mg (α, beta isomer), productive rate is 72%.
Example 8: the round-bottomed flask at 50mL adds 1-C-acetylmethyl-2,3-two-O-benzyl-5-phenylamino-α-D-ribose furans glycosides (I:R=C
6H
5) the methanol solution 3mL of 100mg and 4% sodium methylate, reaction is 3 hours under the stirring at room.Reaction finishes to add 15mL water again except that after desolvating, and uses 15mL dichloromethane extraction 3 times, merges organic phase, and with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, the 15mL saturated sodium-chloride water solution washs 2 times, washes 2 times again, uses anhydrous magnesium sulfate drying again.Filter, separate through column chromatography silica gel again after concentrating, use earlier sherwood oil: ethyl acetate=3:2 wash-out, use sherwood oil again: ethyl acetate=1:1 wash-out, get product 85mg (α, beta isomer), productive rate is 85%.
Example 9: the round-bottomed flask at 50mL adds 1-C-acetylmethyl-2, and 3-two-O-benzyl-5-is to toluino-α-D-ribose furans glycosides (I:R=p-CH
3-C
6H
5) the methanol solution 5mL of 100mg and 4% sodium methylate, reaction is 6 hours under the stirring at room.Reaction finishes to add 15mL water again except that after desolvating, and uses 15mL dichloromethane extraction 3 times, merges organic phase, and with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, the 15mL saturated sodium-chloride water solution washs 2 times, washes 2 times again, uses anhydrous magnesium sulfate drying again.Filter, separate through column chromatography silica gel again after concentrating, use earlier sherwood oil: ethyl acetate=3:2 wash-out, use sherwood oil again: ethyl acetate=1:1 wash-out, get product 82mg (α, beta isomer), productive rate is 82%.
Example 10: the round-bottomed flask at 50mL adds 1-C-acetylmethyl-2,3-two-O-benzyl-5-p-nitrophenyl amino-α-D-ribose furans glycosides (I:R=p-NO
2-C
6H
5) the methanol solution 3mL of 100mg and 4% sodium methylate, reaction is 6 hours under the stirring at room.Reaction finishes to add 15mL water again except that after desolvating, and uses 15mL dichloromethane extraction 3 times, merges organic phase, and with 15mL saturated sodium bicarbonate aqueous solution washing 2 times, the 15mL saturated sodium-chloride water solution washs 2 times, washes 2 times again, uses anhydrous magnesium sulfate drying again.Filter, separate through column chromatography silica gel again after concentrating, use earlier sherwood oil: ethyl acetate=3:2 wash-out, use sherwood oil again: ethyl acetate=1:1 wash-out, get product 80mg (α, beta isomer), productive rate is 80%.
Claims (4)
1. N-substituted-1-deoxynojirimycin compound has following structural formula:
R＝C
4H
9，C
3H
7，C
2H
5，C
6H
13，p-CH
3C
6H
5，p-NO
2C
6H
5，p-CH
3OC
6H
5，
p-HOC
6H
5，p-ClC
6H
5，m-CH
3OC
6H
5，m-CH
3C
6H
5，o-CH
3OC
6H
5
2. the preparation method of N-substituted-1-deoxynojirimycin compound according to claim 1 is: with 5-substituted-amino ribose furanoside derivative at alkali triethylamine or/and the methanol solution of sodium methylate or/and the methanol solution of salt of wormwood or/and the methanol solution of sodium hydroxide or/and under the effect of the methanol solution of potassium hydroxide, stirring at room reaction, resulting product again with Ac
2The O reaction obtains the N-substituted-1-deoxynojirimycin compound.
3, the preparation method of N-substituted-1-deoxynojirimycin compound according to claim 2 is characterized in that: the mass volume ratio of the methanol solution mL of 5-substituted-amino ribose furanoside derivative g, 4% sodium methylate is 1:10～60; The mass volume ratio of 5-substituted-amino ribose furanoside derivative g, triethylamine mL is 1:20～50; The mass volume ratio of the methyl alcohol saturated solution mL of 5-substituted-amino ribose furanoside derivative g, salt of wormwood is 1:20～60; The mass volume ratio of the methanol solution mL of 5-substituted-amino ribose furanoside derivative g, 10% sodium hydroxide or potassium hydroxide is 1:10～50,2～10 hours reaction times.
4, the preparation method of N-substituted-1-deoxynojirimycin compound according to claim 2, it is characterized in that: the weight percent concentration of used alkali is respectively: the methanol solution of sodium methylate is 1%～8%, the methyl alcohol saturated solution of salt of wormwood, the methanol solution of sodium hydroxide is 8%～12%, and the methanol solution of potassium hydroxide is 6%～10%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748970A (en) * | 2016-12-01 | 2017-05-31 | 陕西师范大学 | The deoxidization nojirimycin derivative of N aryl 1 and its application in treatment diabetes medicament is prepared |
| CN110448558A (en) * | 2019-09-26 | 2019-11-15 | 深圳市罗湖区人民医院 | It is a kind of inhibit bladder cancer progress drug and its medicinal application |
-
2008
- 2008-02-01 CN CNA200810045328XA patent/CN101497582A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748970A (en) * | 2016-12-01 | 2017-05-31 | 陕西师范大学 | The deoxidization nojirimycin derivative of N aryl 1 and its application in treatment diabetes medicament is prepared |
| CN106748970B (en) * | 2016-12-01 | 2019-05-14 | 陕西师范大学 | N- aryl -1-DNJ derivative and its application in preparation treatment diabetes medicament |
| CN110448558A (en) * | 2019-09-26 | 2019-11-15 | 深圳市罗湖区人民医院 | It is a kind of inhibit bladder cancer progress drug and its medicinal application |
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Open date: 20090805 |