CN1736978B - (+)-(1S,2S,3S,4R,5R)-1-amido-5-hydorxymethyl-N-2-(1,3-dihydroxypropyl)-2,3,4-cyclohexanetriol preparation method - Google Patents
(+)-(1S,2S,3S,4R,5R)-1-amido-5-hydorxymethyl-N-2-(1,3-dihydroxypropyl)-2,3,4-cyclohexanetriol preparation method Download PDFInfo
- Publication number
- CN1736978B CN1736978B CN200410058505A CN200410058505A CN1736978B CN 1736978 B CN1736978 B CN 1736978B CN 200410058505 A CN200410058505 A CN 200410058505A CN 200410058505 A CN200410058505 A CN 200410058505A CN 1736978 B CN1736978 B CN 1736978B
- Authority
- CN
- China
- Prior art keywords
- reaction
- amino
- resin
- phloroglucite
- methylol
- 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
Images
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a process for preparing compound (+)-(1S,2S,3S,4R,5R)-1-amido-5-hydroxymethyl-N-2-(1, 3-dihydroxypropyl)-2,3,4-cyclohexanol by using glacial acetic acid as accelerating agent, absolute methanol as solvent and reacting (+)-(1S,2S,3S,4R,5R)-1-amino-5-hydroxymethyl-2,3,4-cyclohexanol with dihydroxypropanone and sodium cyanohydridoborate.
Description
Technical field
The present invention relates to compound (+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3, the preparation method of 4-phloroglucite.
Background technology
Compound ((+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3,4-phloroglucite (claiming Valibose (valibose) again) is a kind of alpha-glucosidase inhibitor, can compete antagonism ground after oral and suppress disaccharide class lytic enzyme (alpha-glucosidase) in the enteron aisle, thereby the digestion and the absorption of carbohydrate have been delayed, to improve postprandial hyperglycemia.Postprandial hyperglycemia can make the effect of secretion of insulin and Regular Insulin obstacle occur, and carbohydrate metabolism is further worsened, and therefore correcting postprandial hyperglycemia is very important for the development that prevents diabetes and complication.Simultaneously, alpha-glucosidase inhibitor is the best class medicine of tolerance in the oral antidiabetic drug, has characteristics such as blood sugar reducing function gentleness, difficult generation hypoglycemic reaction and toxic side effect are few, relatively is fit to the elderly and takes.The relevant information announcing of its preparation method has: U.S. Pat 4,701,559; US 4,777, and 294; US 4,803, and 303.
In U.S. Pat 4,803, be specifically related to the preparation method of above-claimed cpd in 303, this method employing Validamine and otan, sodium cyanoborohydride are done promotor with hydrochloric acid, react in dimethyl sulfoxide (DMSO), the product lyophilize obtains ((+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3,4-phloroglucite powder, yield 17%.Concrete method is for adding 2.0gValidamine, 3.4g otan, 1.5ml 2N hydrochloric acid and 2.6g sodium cyanoborohydride in the 50ml methyl-sulphoxide, stirred 16 hours at 60～65 ℃, remove methyl-sulphoxide under reduced pressure, resistates is dissolved in 100ml water, with solution process Amberlite H
+Type CG-50 post, water and 0.5N ammoniacal liquor wash-out are with the elutriant concentrating under reduced pressure, then with enriched material process Dowex 1 * 2OH
-Type ion exchange resin post, washing, the elutriant concentrating under reduced pressure, freeze-drying gets the 0.5g white powder.
Formula (I) and formula (II) are respectively the structural formula of Validamine and Valibose:
Because the yield of above-mentioned preparation method's product is lower, makes production cost higher, and separation and purification is relatively more difficult, is unsuitable for the needs of large-scale commercial production.
Summary of the invention
The object of the present invention is to provide a kind of synthetic (+) that is easy to large-scale industrial production, high yield-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3, the method for 4-phloroglucite.
Among the preparation method of the present invention, as promotor, anhydrous methanol is a solvent with Glacial acetic acid, with validamine (chemical name (+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-2,3, the 4-phloroglucite) obtains (+)-(1S, 2S, 3S with otan and sodium cyanoborohydride reaction, 4R, 5R)-1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3,4-phloroglucite (Valibose (formula II)), reaction formula is as follows:
In the methods of the invention, the preparation of raw material Validamine is by obtaining validoxylamine A by jinggangmeisu A through hydrolysis, by validoxylamineA and N-bromo-succinimide (NBS) reaction, obtains validamine again, and reaction formula is as follows:
The product of above-mentioned reaction gained is obtained pure Validamine (formula I compound) and Valienamine. respectively through separating
Because the reaction of above-mentioned preparation Valibose is a dehydration reaction, should under anhydrous condition, carry out, so adopt Glacial acetic acid to replace hydrochloric acid to do promotor in the inventive method, replace dimethyl sulfoxide (DMSO) as solvent with anhydrous methanol, significantly improved the yield of product.
In the methods of the invention, the preferred Glacial acetic acid amount of using is 8～25% (Glacial acetic acid volumes/raw material Validamine weight, down together), and more preferably the consumption of Glacial acetic acid is 20%.Product long-time heating and the product that causes decomposes, yield reduces and separation difficulty under the high heat has been avoided in the use of anhydrous methanol on the one hand, has simplified post-processing operation on the other hand, make concentrate simple.
Proportioning raw materials can adopt mol ratio Validamine among the present invention: otan: sodium cyanoborohydride=1: (1.1～4.0): (0.6～4.0), and preferred Validamine: otan: sodium cyanoborohydride=1: 1.2: 1.5.
In the method for the invention, reinforced can carrying out at normal temperatures, but more preferably reinforced under the reaction conditions that heats up, preferred temperature range is 40～60 ℃, most preferred charge temperature is 50 ℃.
In the inventive method, preferred order of addition(of ingredients) is in the reaction, in anhydrous methanol, adds (+)-1S-[1,2; 4/3,5]-and 1-amino-5-methylol-2,3, the 4-phloroglucite; after being warmed up to 50 ℃, under nitrogen protection, behind the adding otan, add Glacial acetic acid, sodium cyanoborohydride immediately.The temperature of temperature of reaction in methyl alcohol, refluxing.
The present invention further provides the method for the above-mentioned Valibose for preparing according to the inventive method of separation and purification, comprise the steps: that the Valibose that will obtain removes out solvent after, with water dissolution and acidifying, be neutralized to pH6.0 with alkali again; Can adopt following separation method to carry out purifying successively:
(1) H
+Type strong acidic ion resin post, water and 0.5N ammoniacal liquor wash-out;
(2) NH
4 +Type acidulous cation resin post, 0.1N ammoniacal liquor wash-out;
(3) OH
-Type strongly basic anionic resin post, H
2The O wash-out;
And with TLC tracking detection, can make the higher Valibose of purity, and can be further used for crystallization, the Valibose of preparation crystal habit.
Wherein said H
+Type strong acidic ion resin post for example can select 001 * 7 (732) or PUROLITE C100E; Described NH
4 +Type acidulous cation resin post for example can be selected, YDCG-50, HD-2, Amberlite CG-50; Described OH
-Type strongly basic anionic resin post for example can be selected, Dowex1 * 2, PUROLITE A 400, HZ-202; Consider the factor of resin property and production cost aspect, preferably use PUROLITE C100E, HD-2 and HZ-202 to carry out separation and purification.
Preparation method of the present invention is suitable for large-scale commercial production, and the yield of product improves greatly, brings up to 80～85% than the yield (17%) of preparation method in the prior art.Adopt the low boiling point solvent of easy handling to substitute methyl-sulphoxide (189 ℃ of boiling points) in the inventive method, will help the industrialization operation greatly.And separation method good separation of the present invention, cost is low, is suitable for scale operation.
Below in conjunction with accompanying drawing,, describe the present invention in detail by description to the preferable embodiment of the present invention.
The accompanying drawing summary
Fig. 1 is the Valibose of the inventive method preparation
1The H-NMR nuclear magnetic resonance map;
Fig. 2 is the Valibose of the inventive method preparation
13The C-NMR nuclear magnetic resonance map.
Fig. 3 is the Valibose mass spectrum of the inventive method preparation;
Fig. 4 is the Valibose infrared absorption spectrum of the inventive method preparation.
The embodiment of invention
The preparation of [embodiment 1] raw material Validamine
Raw material Validamine can be by disclosed method preparation in the prior art document, for example: J.Antibiotics 24:57-58,1971 and Chem.Lctt., 1989,725-728 (Harii, s.j.T.Iwasa﹠amp; Y.Kameda) method of describing in, among the preparation technology of the present invention, the preparation of raw material Validamine be by by jinggangmeisu A (available from Zhejiang Qian Jiang biochemistry corporation,Ltd., content 60%) obtain validoxylamine A through hydrolysis, again by validoxylamineA and N-bromo-succinimide (NBS) (5-linked chemical plant, Shanghai, chemical pure) reaction obtains validamine.Reaction formula is as follows:
With reaction product CG-50NH
4 +The acidulous cation resin post, the separation of 0.1N ammoniacal liquor wash-out obtains pure Validamine and Valienamine.
The preparation of [embodiment 2] Valibose
Prepare Valibose according to following reaction formula
In 290 milliliters of dimethyl sulfoxide (DMSO), add Validamine 11 grams (62.1 mmole), 1, (FRUKA 97% for 3 otans, 19.55 grams, 210.5 mmole, CAS:96-25-4), (ACROS 95% for 1.10 milliliters in Glacial acetic acid, sodium cyanoborohydride 15.4 grams, 232.8 mmole, CAS:25895-60-7), in 60-65 ℃ of reaction 16 hours.Behind the evaporate to dryness reaction solution of trying one's best in the oil bath, add 500 milliliters in water, be acidified to pH1.5 with 2N HCl, be neutralized to pH6.0 with NaOH again.Respectively through 001 * 7 (732) H
+Type strong acidic ion resin post (water and 0.5N ammoniacal liquor), YD CG-50NH
4 +Acidulous cation resin post (0.1N ammoniacal liquor), Dowex1 * 2OH
-Strongly basic anionic resin post (H
2O), TLC follows the tracks of and detects (developping agent: propyl carbinol: methyl alcohol: chloroform: ammoniacal liquor=5: 4: 2: 5; Developer: 0.2% ethanol solution of ninhydrin; Rf=0.46 (validamine); Rf=0.52 (valibose)).Merge that triketohydrindene hydrate is positive and with the identical component of Valibose reference substance Rf value, be evaporated to driedly, weighing 6.2 restrains yield: 39.70%.Yield calculates:
In the formula: W---charging capacity maybe must be measured
M---molecular weight
The preparation of [embodiment 3] Valibose
In 60 milliliters of dimethyl sulfoxide (DMSO), add Validamine2.25 gram (12.7 mmole), 1, (FRUKA 97% for 3 otans, 3.83 grams, 0.412 mmole), Glacial acetic acid is 0.3 milliliter, (ACROS 95% to add sodium cyanoborohydride 2.93 grams after 1 hour in 60-65 ℃ of reaction, 44.3 mmole), continue reaction 15 hours.After finishing reaction, the evaporate to dryness reaction solution of trying one's best in oil bath adds 100 milliliters in water, is acidified to pH1.5 with 2N HCl solution, is neutralized to pH6.0 with NaOH again.Pass through PUROLITEC100E H respectively
+Type strong acidic ion resin post (water and 0.5N ammoniacal liquor), YD CG-50NH
4 +Acidulous cation resin post (0.1N ammoniacal liquor), Dowex1 * 2OH
-Strongly basic anionic resin post (H
2O), TLC follows the tracks of and detects (developping agent: propyl carbinol: methyl alcohol: chloroform: ammoniacal liquor=5: 4: 2: 5; Developer: 0.2% ethanol solution of ninhydrin; Rf=0.46 (validamine); Rf=0.52 (valibose)).Merge that triketohydrindene hydrate is positive and with the identical component of Valibose reference substance Rf value, merge and be concentrated into driedly, weighing 0.65 restrains.Yield: 20.38%.
The preparation of [embodiment 4] Valibose
In 150 milliliters of anhydrous methanols (chromatographically pure), add Validamine6.08 gram (34.3 mmole), 1, (FRUKA 97% for 3 otans, 6.37 grams, 68.6 mmole), (ACROS 95% for 0.6 milliliter in Glacial acetic acid, sodium cyanoborohydride 8.40 grams, 127 mmoles), back flow reaction is 6 hours.Steam and remove methyl alcohol, add 100 milliliters in water, be acidified to 1.5, be neutralized to pH6.0 with NaOH again with 2N HCl.Pass through PUROLITE C100H respectively
+Type strong acidic ion resin post (water and 0.5N ammoniacal liquor), YDCG-50NH
4 +Acidulous cation resin post (0.1N ammoniacal liquor), HZ-202OH
-Strongly basic anionic resin post (H
2O), TLC follows the tracks of and detects (developping agent: propyl carbinol: methyl alcohol: chloroform: ammoniacal liquor=5: 4: 2: 5; Developer: 0.2% ethanol solution of ninhydrin; Rf=0.46 (validamine); Rf=0.52 (valibose)).Merge that triketohydrindene hydrate is positive and with the identical component of Valibose reference substance Rf value, merge be concentrated into dried, 6.8 restrain.Yield: 78.9%.
The preparation of [embodiment 5] crystal habit Valibose
In 2500 milliliters of anhydrous methanols (analytical pure); under nitrogen protection, add Validamine100 gram (564 mmole); be warming up to 50 ℃ and add 1; (FRUKA 97% for 3 otans, 63 grams; 678 milliliters of moles), (chemical industry company limited 97% is levied in Yingkou three to 20 milliliters in Glacial acetic acid, sodium cyanoborohydride 56 grams; 865 mmoles), back flow reaction is 6 hours.After finishing reaction, steam and remove methyl alcohol, add 500 milliliters in water, be acidified to PH1.5, be neutralized to pH6.0 with NaOH again, pass through (PUROLITE C100E) H respectively with 2N HCl
+Type strong acidic ion resin post (water and 0.5N ammoniacal liquor), HD-2NH
4 +Acidulous cation resin post (0.1N ammoniacal liquor), HZ-202OH
-Strongly basic anionic resin post (H
2O), TLC follows the tracks of and detects (developping agent: propyl carbinol: methyl alcohol: chloroform: ammoniacal liquor=5: 4: 2: 5; Developer: 0.2% ethanol solution of ninhydrin; Rf=0.46 (validamine); Rf=0.52 (valibose)). merge that triketohydrindene hydrate is positive and with the identical component of Valibose reference substance Rf value, be evaporated to driedly, use dissolve with ethanol, add the crystal seed crystallization, must 120 restrain. yield: 84.6%, mp:88-89 ℃, content: 99.40%.
[embodiment 6] Valibose determination of physical appearance
The compound of preparation according to the method described above that obtains has been carried out nuclear magnetic resonance spectroscopy and ultimate analysis, determined that the compound that the present invention obtains is (+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3,4-phloroglucite.
1, nuclear magnetic resonance spectroscopy
Instrument: Varian 500
Result: see Fig. 1 and Fig. 2
1H-NMR(D
2O，500MHZ)δ
1.32(1H，ddt，J＝3，1.5，15)，1.80-1.87(1H，m)，1.92(1H，dt，J＝3，15)，2.78(1H，m，J＝5.5)，3.15(1H，dd，J＝3.5)，3.25(1H，dd，J＝10.5).3.50-3.55(2H，m)，3.57(2H，t，J＝4.5)，3.62(2H，t，J＝5.5)，3.65(1H，dd，J＝5，11.5)，3.72(1H，dd，J＝3.5，11)；
13C-NMR(D
2O，75MHZ)δ
28.61，38.97，55.63，59.28，61.31，62.70，63.19，73.91，74.21，75.34
2, mass spectrum
Instrument model: the Britain ZAB-HS of VG company double focusing magnetic mass spectrometer
Condition determination: fast atom bombardment(FAB) ionization (FAB)
Spectrum data: see the following form and Fig. 3
| Mass-to-charge ratio (m/z) | Relative abundance (%) | |
| 252 220 154 136 107 89 77 57 | 100 26 72 62 26 29 33 22 | M ++1 M-CH 2OH |
3, infrared absorption spectrum
Instrument: German Bruker Fourier transform infrared spectroscopy-infrared microscope combined instrument
Spectrum analysis: see the following form and Fig. 4
| Absorption peak (CM -1) | Oscillatory type | Group | Absorption peak strength | Remarks |
| 3378 2929 2884 1649 1452 1413 1077 1038 854 594 | V O-H，V N-H V asC-H V sC-H N-H N-H N-H V C-O V C-O γ N-H C-H | OH，NH CH 2 CH NH NH NH C-O C-O NH CH | s s s w m m s s w m | Broad peak, V O-HWith V N-HOverlapping spike spike broad peak |
4, ultimate analysis (C
10H
21NO
6)
Instrument: the German ELEMENTAR vario EL of company elemental analyser
Calculated value: (%) C, 47.80; H, 8.42; N, 5.57
Measured value (twice): (%) C, 47.90/47.84; H, 8.56/8.57; N, 5.41/5.45
5, specific optical rotation
Instrument: Polartronic HHW5 polarimeter
Probe temperature: 25 ± 0.5 ℃
Sample pipe range: 100mm
Lambda1-wavelength: 589.3nm
Test solvent: water (C=1)
Measurement result: [α]
D 25+ (77-79) °
The preparation interpretation of result:
A) reaction among the preparation method of the present invention is a dehydration condensation, under anhydrous condition, help reaction and carry out, so, among the present invention hydrochloric acid is changed into Glacial acetic acid, yield reaches 39.70%.(embodiment 2)
B) reaction among the preparation method of the present invention is to be condensed into Schiff alkali earlier.And then reduction.For making its condensation complete, add reductive agent after one hour at Validamine and otan reaction.From reacting phenomenon, this Schiff alkali instability has side reaction to generate, and yield reduces (embodiment 3).So should after otan is reinforced, add sodium cyanoborohydride immediately, to improve yield.
C) dimethyl sulfoxide (DMSO) is changed into anhydrous methanol (chromatographically pure) after, yield is significantly increased. on the one hand avoided product long-time heating under high heat, made that product decomposes, yield reduces, separation difficulty; On the other hand, simplified post-processing operation, make concentrated, separate simple. (embodiment 4)
D) when testing, there is side reaction to generate with analytical reagent.In the method for the present invention the Glacial acetic acid amount is increased to 20%, impels reaction to carry out, obtain good result.Simultaneously, feed way also has a significant effect to reaction: reinforced the carrying out that is unfavorable for condensation reaction of room temperature.(embodiment 5, embodiment 6)
E) use H in the method for prior art
+Type acidulous cation resin Amberlite CG-50 absorption is found its adsorptive capacity little (be about highly acidic resin 0.3 times), the big (NH of resin rate of expansion in the test
4 +The type volume is H
+1.5 times of type volume), be unfavorable for the industrialization operation, and resin is shortened work-ing life.In addition, the adsorptive capacity of home-made 001 * 7 (732) strong acidic ion resin (Guangzhou product) is than PUROLITE C100E low (being about 0.5 times), the performance of YD CG-50 resin and HD-2 resin is the same substantially, but YD CG-50 resin price height, so the preferred PUROLITE C100E of the present invention resin, HD-2 resin, HZ-202 resin.The selected separation method good separation of the present invention, material cost is low, is suitable for scale operation.
F) decompose because of the easy moisture absorption of sodium cyanoborohydride, should suitably strengthen charge ratio.
More than the description of better embodiment of the present invention is not limited the present invention, those skilled in the art can make various changes or distortion according to the present invention, only otherwise break away from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (13)
1. (+)-(1S, 2S, 3S, 4R, 5R)-and 1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3, the preparation method of 4-phloroglucite comprises:
As promotor, anhydrous methanol is a solvent, with (+)-(1S with Glacial acetic acid, 2S, 3S, 4R, 5R)-and 1-amino-5-methylol-2,3,4-phloroglucite and otan and sodium cyanoborohydride reaction obtain (+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3,4-phloroglucite.
2. the described preparation method of claim 1, the amount that it is characterized in that Glacial acetic acid in the described reaction with Glacial acetic acid volume/raw material (+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-2,3,4-phloroglucite weight meter is 8～25%.
3. the described preparation method of claim 2, the amount that it is characterized in that Glacial acetic acid in the described reaction with Glacial acetic acid volume/raw material (+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-2,3,4-phloroglucite weight meter is 20%.
4. the described preparation method of claim 1 is characterized in that the mol ratio of raw material in the described reaction is: (+)-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-2,3,4-phloroglucite: otan: sodium cyanoborohydride=1: 1.1～4.0: 0.6～4.0.
5. the described preparation method of claim 5 is characterized in that the mol ratio of raw material in the described reaction is: (+)-(1S, 2S, 3S, 4R, 5R)-and 1-amino-5-methylol-2,3,4-phloroglucite: otan: sodium cyanoborohydride=1: 1.2: 1.5.
6. the described preparation method of claim 1, the reaction times that it is characterized in that described reaction is 1～8 hour.
7. the described preparation method of claim 1 is characterized in that the charge temperature of adding reaction raw materials in the described reaction is 40～60 ℃.
8. the described method of claim 7 is characterized in that the charge temperature of adding reaction raw materials in the described reaction is 50 ℃.
9. the described method of claim 8 is characterized in that order of addition(of ingredients) is in the described reaction, in anhydrous methanol; add (+)-(1S, 2S, 3S; 4R; 5R)-and 1-amino-5-methylol-2,3, the 4-phloroglucite; after being warmed up to 50 ℃; under nitrogen protection, behind the adding otan, add Glacial acetic acid, sodium cyanoborohydride immediately.
10. the described method of claim 9 is characterized in that the temperature of temperature of reaction for refluxing in the described reaction in methyl alcohol.
11. the described method of claim 1 is characterized in that further comprising the steps:
With (+) that obtain-(1S, 2S, 3S, 4R, 5R)-1-amino-5-methylol-N-2-(1, the 3-dihydroxypropyl)-2,3, the 4-phloroglucite with water dissolution and acidifying, is neutralized to pH6.0 with alkali after removing solvent again;
Separate with following resin column successively, and follow the tracks of detection with TLC:
Strong acidic ion resin;
Acidulous cation resin;
Strongly basic anionic resin;
Merge product and be concentrated into dried.
12. the described method of claim 11 is characterized in that described strong acidic ion resin is 001 * 7 or the H of PUROLITE C100E
+The type strong acidic ion resin; Described acidulous cation resin is the NH of YD CG-50, HD-2 or Amberlite CG-50
4 +The type acidulous cation resin; Described strongly basic anionic resin is the OH of Dowexl * 2, PUROLITE A 400 or HZ-202
-The type strongly basic anionic resin.
13. claim 11 or 12 described methods is characterized in that, described resin column separating step comprises:
PUROLITE C100E H
+Type strong acidic ion resin post, water and 0.5N ammoniacal liquor wash-out;
HD-2NH
4 +Type acidulous cation resin post, 0.1N ammoniacal liquor wash-out;
HZ-202OH
-The strongly basic anionic resin post, water elution.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200410058505A CN1736978B (en) | 2004-08-16 | 2004-08-16 | (+)-(1S,2S,3S,4R,5R)-1-amido-5-hydorxymethyl-N-2-(1,3-dihydroxypropyl)-2,3,4-cyclohexanetriol preparation method |
| PCT/CN2005/001168 WO2006017975A1 (en) | 2004-08-16 | 2005-08-01 | Preparation method of (+)-(1s, 2s, 3s, 4r, 5r)-1-amino-5-hydroxymethyl-n-2-(1, 3-dihydroxypropyl)-2, 3, 4-cyclohexanetriol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200410058505A CN1736978B (en) | 2004-08-16 | 2004-08-16 | (+)-(1S,2S,3S,4R,5R)-1-amido-5-hydorxymethyl-N-2-(1,3-dihydroxypropyl)-2,3,4-cyclohexanetriol preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1736978A CN1736978A (en) | 2006-02-22 |
| CN1736978B true CN1736978B (en) | 2010-05-12 |
Family
ID=35907219
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200410058505A Expired - Fee Related CN1736978B (en) | 2004-08-16 | 2004-08-16 | (+)-(1S,2S,3S,4R,5R)-1-amido-5-hydorxymethyl-N-2-(1,3-dihydroxypropyl)-2,3,4-cyclohexanetriol preparation method |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1736978B (en) |
| WO (1) | WO2006017975A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4803303A (en) * | 1981-01-05 | 1989-02-07 | Takeda Chemical Industries, Ltd. | N-substituted pseudo-aminosugars, their production and use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4595678A (en) * | 1982-03-19 | 1986-06-17 | Takeda Chemical Industries, Ltd. | N-substituted pseudo-aminosugars and pharmaceutical compositions containing same |
-
2004
- 2004-08-16 CN CN200410058505A patent/CN1736978B/en not_active Expired - Fee Related
-
2005
- 2005-08-01 WO PCT/CN2005/001168 patent/WO2006017975A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4803303A (en) * | 1981-01-05 | 1989-02-07 | Takeda Chemical Industries, Ltd. | N-substituted pseudo-aminosugars, their production and use |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1736978A (en) | 2006-02-22 |
| WO2006017975A1 (en) | 2006-02-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112876454A (en) | Preparation method of artificially synthesized (R, S) -nicotine salt | |
| Sardella et al. | HPLC/ELSD analysis of amidated bile acids: An effective and rapid way to assist continuous flow chemistry processes | |
| CN103073439B (en) | Synthesis method of ambroxol hydrochloride compound | |
| CN1736978B (en) | (+)-(1S,2S,3S,4R,5R)-1-amido-5-hydorxymethyl-N-2-(1,3-dihydroxypropyl)-2,3,4-cyclohexanetriol preparation method | |
| CN105254569B (en) | Ornidazole injection impurity 1（3 Chloroallyls）The preparation method of the nitroimidazole of 2 methyl 5 | |
| CN104650140B (en) | A kind of preparation method of high-purity good fortune department Fluconazole | |
| CN107417692A (en) | A kind of method of purification of chlorinated nitidine | |
| CN115677583A (en) | Phenylhydrazine-based natural product photoaffinity probe reactant, and preparation method and application thereof | |
| CN102234253B (en) | Method for preparing febuxostat intermediate | |
| CN105884625B (en) | Synthetic method of R-salmeterol | |
| Bharathi et al. | Identification, isolation and characterization of impurities of clindamycin palmitate hydrochloride | |
| CN101486702B (en) | Ailamode analogue and separation method thereof | |
| CN112724046A (en) | Peramivir impurity F and preparation method and application thereof | |
| CN1684680A (en) | Imidazole alkaloids from lepidium meyenii and methods of usage | |
| CN1736977B (en) | crystallized (+)-(1S,2S,3S,4R,5R)-1-amido-5-hydroxymethyl-N-2(1,3-dihydroxypropyl)-2,3,4-cyclohexanetriol and its preparation method | |
| CN102050846B (en) | Amino sugar, and preparation method and use thereof | |
| CN108586442A (en) | A kind of compound and the preparation method and application thereof | |
| CN102020602B (en) | Crystal form of lercanidipine hydrochloride and preparation method thereof and crystal form-containing medicinal composition | |
| CN109096273A (en) | The method for separating and preparing of mezlocillin sodium impurity C, D and F | |
| WO2024060271A1 (en) | Characteristic impurity in empagliflozin bulk drug or preparation and use thereof | |
| CN111662186B (en) | Crystal form of salt formed by bromhexine and fumaric acid and preparation method thereof | |
| CN112409338B (en) | Midazolam hydrochloride syrup impurity C and impurity D and application thereof | |
| CN105906559B (en) | A kind of one-step synthesis of pharmaceutical grade metadoxine | |
| CN115876899A (en) | Method for pretreating polyethylene glycol derivative sample and measuring content | |
| CN106117016A (en) | The Industrialized processing technique of high-load hydroxytyrosol is prepared with oleuropein for raw material |
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: 20100512 Termination date: 20180816 |