CN101870671A - Adamantly pyrrolidine derivative, and preparation and application thereof - Google Patents
Adamantly pyrrolidine derivative, and preparation and application thereof Download PDFInfo
- Publication number
- CN101870671A CN101870671A CN 201010200827 CN201010200827A CN101870671A CN 101870671 A CN101870671 A CN 101870671A CN 201010200827 CN201010200827 CN 201010200827 CN 201010200827 A CN201010200827 A CN 201010200827A CN 101870671 A CN101870671 A CN 101870671A
- Authority
- CN
- China
- Prior art keywords
- adamantly pyrrolidine
- adamantly
- pyrrolidine
- sodium
- double salt
- 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.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an adamantly pyrrolidine derivative, which is obtained by the step of reacting adamantly pyrrolidine with acid, alkali metal elements or ammonium (ammonia) compound or amino acid or amino alcohol sequentially, or with acid salt directly. When the acid or the acid salt is sulfate, adamantly pyrrolidine sulfate double salt is obtained, and when the acid or the acid salt is phosphate, adamantly pyrrolidine phosphate double salt is obtained. The preparation method according to the invention has reasonable design, stable process and good production feasibility. The adamantly pyrrolidine derivative according to the invention has the obvious advantages of good stability, high purity and the like, is lower in bleeding rate than adamantly pyrrolidine, and can lessen side effect. The adamantly pyrrolidine derivative, which can be made into preparation, penetrates into blood by means of adamantly pyrrolidine, both absorption and functioning are fast, thus better therapeutic effect for diabetes is achieved; and the adamantly pyrrolidine derivative has the following structural formula.
Description
Technical field
The invention belongs to compound, relate to Adamantly pyrrolidine derivative and preparation method and application.
Background technology
Adamantly pyrrolidine also is Vildagliptin (vildagliptin, trade(brand)name: Galvus), be oral anti-diabetes B medicine, obtained EU Committee's approval in 2007, in 27 European Union member countries and Norway and Ireland listing.
Vildagliptin is a kind of have selectivity, competitiveness, reversible DPP-4 inhibitor.Glucose-dependent-insulinotropic polypeptide (GIP) and glucagon kind polypeptide-1 (GLP-1) are the important hormone of keeping glucose concn in the body, all have the incretin effect.The promoting insulin secretion of diabetes B patient GIP is impaired, only has GLP-1 can bring into play the insulinotropin secretion, and it promotes secretion of insulin by acting on the acceptor on the B cell film.But also thereby the secretion and the inhibition stomach emptying of glucagon suppression increase satiety (depress appetite) to GLP-1.DPP-4 and protein binding are present in many tissues, and as brush shape edge, ductus pancreaticus, lymphocyte, the endotheliocyte of kidney, liver, little goldbeater's skin, it can hold the 2nd L-Ala to make its inactivation rapidly by the N of hydrolysis GLP-1.
Vildagliptin forms the activity that the DPP-4 mixture suppresses this enzyme by combining with DPP-4, is improving GLP-1 concentration, when impelling B cell to produce Regular Insulin, reduces hyperglycemic-glycogenolytic factor concentration, thus lowering blood glucose.And body weight there is not obvious influence.
The healthy human body pharmacokinetic studies shows that oral this product absorbs rapidly, and bioavailability is about 85%.Peak time is 1～2h after the administration, and be 1.5～4.5h plasma half-life, protein binding rate low (4%～17%).Its physiological disposition has linear characteristics of pharmacokinetics, repeatedly drug accumulation do not occur behind the oral administration, its pharmacokinetic parameters unable to take food thing influence.Vildagliptin stability is not enough, and the risk of cancer is forbidden and may be increased to liver major injury patient.
CN101238099 and WO2007019255A2 disclose the salt form of Vildagliptin, and the whole world is not seen so far has any Vildagliptin acid salt, subsalt raw material and preparation to declare and go on the market.
Summary of the invention
The object of the invention is to provide a kind of good stability, purity height, the little Adamantly pyrrolidine derivative of side effect.
Adamantly pyrrolidine derivative of the present invention has formula (I) general structure:
Wherein:
M is a kind of in basic metal, ammonia (or ammonium), amino acid, the amino alcohol; Described basic metal is Na
+, K
+Or Cs
+Described amino acid is a kind of in arginine, ornithine, citrulline or the Methionin; Described amino alcohol is a kind of in tromethane, amino-propanediol, monoethanolamine or the glucosamine.
Y is SO4
2-(sulfate radical) or HPO4
2-(phosphoric acid one hydrogen root).
Another object of the present invention provides two kinds of preparation methods of described Adamantly pyrrolidine derivative:
First kind of preparation method realizes by following steps: Adamantly pyrrolidine and equimolar H
2After Y mixes in polar solvent, make Adamantly pyrrolidine acid salt, after adding and the equimolar alkali metal compound of Adamantly pyrrolidine or ammonium compound or amino acid or amino alcohol react completely again, concentrate, add the weak polar solvent crystallization, filter,, promptly get Adamantly pyrrolidine derivative solid drying.
Reaction formula is
Wherein M, Y in the compound (I) definition.
The alkali metal compound comprises in the method for making: a kind of in sodium methylate, potassium methylate, methyl alcohol caesium, sodium ethylate, potassium ethylate, ethanol caesium, sodium propylate, potassium propylate, propyl alcohol caesium, sodium butylate, butanols potassium, butanols caesium, sodium isopropylate, potassium isopropoxide, Virahol caesium, butyl alcohol-tert sodium, butyl alcohol-tert potassium, butyl alcohol-tert caesium, sodium-acetate, Potassium ethanoate, cesium acetate, Sodium Propionate, potassium propionate, propionic acid caesium, Sodium propanecarboxylate, potassium butyrate, butyric acid caesium, sodium hydroxide, potassium hydroxide or the cesium hydroxide.Ammonium compound is selected a kind of in ammonia, ammoniacal liquor, ammonium acetate, propionic acid ammonium or the butyric acid ammonium for use.Amino acid or amino alcohol in the compound (I) definition.
R is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3CH
2CH
2CH
2-, (CH
3)
2CH-, (CH
3)
3C-, CH
3CO-, CH
3CH
2CO-, CH
3CH
2CH
2A kind of among CO-or the H.
Second kind of preparation method realizes by following steps: with Adamantly pyrrolidine with after acid salt MHY mixes in polar solvent, reacts completely with 1: 1 mol ratio, concentrate, add the weak polar solvent crystallization, filter, with solid drying, promptly get Adamantly pyrrolidine derivative.
Reaction formula is
Wherein M, Y in the compound (I) definition.
Acid salt described in the preparation method (MHY) is selected a kind of in sodium pyrosulfate, sal enixum, monoammonium sulfate, cesium hydrogen sulfate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, primary ammonium phosphate or the cesium dihydrogen phosphate for use.
Described polar solvent is selected a kind of among water, ethanol, methyl alcohol, Virahol, acetone, DMF (N, dinethylformamide) or the DMSO (dimethyl sulfoxide (DMSO)) for use.
The weak polar solvent that described its crystallization is used is a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
Adamantly pyrrolidine derivative of the present invention comprises Adamantly pyrrolidine hydrogen sulfate double salt and Adamantly pyrrolidine biphosphate double salt.
2 kinds of concrete method for makings of Adamantly pyrrolidine hydrogen sulfate double salt of the present invention are:
1. Adamantly pyrrolidine is with after equimolar sulfuric acid mixes in polar solvent, add and the equimolar alkali metal compound of Adamantly pyrrolidine or ammonium compound or amino acid or amino alcohol again, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter,, promptly get Adamantly pyrrolidine hydrogen sulfate double salt solid drying;
2. Adamantly pyrrolidine and equimolar sodium pyrosulfate or sal enixum or cesium dihydrogen phosphate or monoammonium sulfate are mixed in polar solvent, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter,, promptly get Adamantly pyrrolidine hydrogen sulfate double salt solid drying.
2 kinds of concrete method for makings of Adamantly pyrrolidine biphosphate double salt of the present invention are:
1. Adamantly pyrrolidine is with after equimolar phosphoric acid mixes in polarity, add and the equimolar alkali metal compound of Adamantly pyrrolidine or ammonium compound or amino acid or amino alcohol again, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter,, promptly get Adamantly pyrrolidine biphosphate double salt solid drying;
2. Adamantly pyrrolidine and equimolar SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate or cesium dihydrogen phosphate or primary ammonium phosphate mix in polar solvent, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, separate out solid filtering, with solid drying, promptly get Adamantly pyrrolidine biphosphate double salt.
A further object of the present invention provides the application of described Adamantly pyrrolidine derivative in preparation treatment type ii diabetes medicine.
Adamantly pyrrolidine derivative provided by the invention has reduction HbA
1c, on an empty stomach and level of postprandial blood sugar, glucagon secretion and the effect that improves the β cell function after the meal, for type ii diabetes patient's treatment provides new selection.
Adamantly pyrrolidine derivative provided by the invention is not seen any report, and not seeing has overlapping with the patent of having announced.Preparation method of the present invention is reasonable, and technology is simple, good production feasibility.
Adamantly pyrrolidine derivative by the inventive method preparation has purity height, good stability, the little characteristics of side effect.Is converted into Adamantly pyrrolidine in the body of the oral back of described Adamantly pyrrolidine derivative, and goes into blood with Adamantly pyrrolidine, absorbs fast, rapid-action, thereby bring into play better antidiabetic curative effect.
Embodiment
The present invention is further described in conjunction with the embodiments.Can not limit the invention with its any form.
Embodiment 1
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, with the dissolving of 50ml anhydrous methanol, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Adamantly pyrrolidine vitriol 397mg, and Adamantly pyrrolidine acid salt is mixing in acetone again, add 54mg sodium methylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether, separate out solid, filtration, with ether washing, drying, obtain white solid Adamantly pyrrolidine sodium pyrosulfate double salt 415mg, yield 92%.
Embodiment 2
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, use the 50ml anhydrous alcohol solution, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Adamantly pyrrolidine vitriol 397mg, and Adamantly pyrrolidine acid salt is mixing in DMF again, add 84mg potassium ethylate reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil, separate out solid, filtration, with petroleum ether, drying, obtain white solid Adamantly pyrrolidine sal enixum double salt 375mg, yield 78%.
Embodiment 3
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, with the dissolving of 50ml dry DMF, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Adamantly pyrrolidine vitriol 397mg, and Adamantly pyrrolidine acid salt is mixing in ethanol again, add 92mg propionic acid ammonium reaction 3 hours, concentrating under reduced pressure adds an amount of normal hexane, separate out solid, filtration, with normal hexane washing, drying, obtain white solid Adamantly pyrrolidine monoammonium sulfate double salt 308mg, yield 63%.
Embodiment 4
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, with the anhydrous DMSO dissolving of 50ml, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Adamantly pyrrolidine vitriol 397mg, and Adamantly pyrrolidine acid salt is mixing in methyl alcohol again, add 164mg methyl alcohol caesium reaction 3 hours, concentrating under reduced pressure adds an amount of hexanaphthene, separate out solid, filtration, with hexanaphthene washing, drying, obtain white solid Adamantly pyrrolidine cesium hydrogen sulfate double salt 196mg, yield 35%.
Embodiment 5
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, use the 50ml anhydrous alcohol solution, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Adamantly pyrrolidine phosphoric acid salt 396mg, and Adamantly pyrrolidine acid salt is mixing in methyl alcohol again, add 82mg sodium propylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether, separate out solid, filtration, with ether washing, drying, obtain white solid Adamantly pyrrolidine SODIUM PHOSPHATE, MONOBASIC double salt 430mg, yield 90%.
Embodiment 6
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, dissolve with the 50ml anhydrous methanol, stir, add phosphatase 79 8mg, after reaction was finished, recovery concentrated, and obtains Adamantly pyrrolidine phosphoric acid salt 396mg, Adamantly pyrrolidine acid salt is mixing in acetone again, add 98mg potassium propylate reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil, separate out solid, filtration, with petroleum ether, drying, obtain white solid Adamantly pyrrolidine potassium primary phosphate double salt 365mg, yield 74%.
Embodiment 7
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, with the dissolving of 50ml dry DMF, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Adamantly pyrrolidine phosphoric acid salt 396mg, and Adamantly pyrrolidine acid salt is mixing in acetone again, add 77mg ammonium acetate reaction 1 hour, concentrating under reduced pressure adds an amount of normal hexane, separate out solid, filtration, with normal hexane washing, drying, obtain white solid Adamantly pyrrolidine primary ammonium phosphate double salt 303mg, yield 64%.
Embodiment 8
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, use the 50ml anhydrous alcohol solution, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Adamantly pyrrolidine phosphoric acid salt 396mg, and Adamantly pyrrolidine acid salt is mixing in acetone again, add 192mg propyl alcohol caesium reaction 2 hours, concentrating under reduced pressure adds an amount of ether, separate out solid, filtration, with ether washing, drying, obtain white solid Adamantly pyrrolidine cesium dihydrogen phosphate double salt 206mg, yield 35%.
Embodiment 9
In the 100ml reaction flask, add 50ml water, sodium pyrosulfate 120mg stirs, and adds Adamantly pyrrolidine 303.4mg again, and after reaction was finished, recovery concentrated, and obtains white solid Adamantly pyrrolidine sodium pyrosulfate double salt 417mg, yield 98.5%.
Embodiment 10
In the 100ml reaction flask, add 50ml water, sal enixum 136mg stirs, and adds Adamantly pyrrolidine 303.4mg again, and after reaction was finished, recovery concentrated, and obtains white solid Adamantly pyrrolidine sal enixum double salt 431mg, yield 98%.
Embodiment 11
In the 100ml reaction flask, add 50ml water, monoammonium sulfate 115mg stirs, and adds Adamantly pyrrolidine 303.4mg again, and after reaction was finished, recovery concentrated, and obtains white solid Adamantly pyrrolidine monoammonium sulfate double salt 408mg, yield 97.6%.
Embodiment 12
In the 100ml reaction flask, add 50ml water, cesium hydrogen sulfate 230mg stirs, and adds Adamantly pyrrolidine 303.4mg again, and after reaction was finished, recovery concentrated, and obtains white solid Adamantly pyrrolidine cesium hydrogen sulfate double salt 512mg, yield 96%.
Embodiment 13
In the 100ml reaction flask, add 50ml water, SODIUM PHOSPHATE, MONOBASIC 120mg stirs, and adds Adamantly pyrrolidine 303.4mg again, and after reaction was finished, recovery concentrated, and obtains white solid Adamantly pyrrolidine SODIUM PHOSPHATE, MONOBASIC double salt 416mg, yield 98.2%.
Embodiment 14
In the 100ml reaction flask, add 50ml water, potassium primary phosphate 136mg stirs, and adds Adamantly pyrrolidine 303.4mg again, and after reaction was finished, recovery concentrated, and obtains white solid Adamantly pyrrolidine potassium primary phosphate double salt 428mg, yield 97.5%.
Embodiment 15
In the 100ml reaction flask, add 50ml water, primary ammonium phosphate 115mg stirs, and adds Adamantly pyrrolidine 303.4mg again, and after reaction was finished, recovery concentrated, and obtains white solid Adamantly pyrrolidine primary ammonium phosphate double salt 405mg, yield 96.7%.
Embodiment 16
In the 100ml reaction flask, add 50ml water, cesium dihydrogen phosphate 230mg stirs, and adds Adamantly pyrrolidine 303.4mg again, and after reaction was finished, recovery concentrated, and obtains white solid Adamantly pyrrolidine cesium dihydrogen phosphate double salt 511mg, yield 95.8%.
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, use the 50ml anhydrous alcohol solution, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Adamantly pyrrolidine vitriol 397mg, Adamantly pyrrolidine vitriol is mixing in acetone again, add 121.14mg tromethane reaction 2 hours, concentrating under reduced pressure adds an amount of ether, separate out solid, filtration, with ether washing, drying, obtain Adamantly pyrrolidine hydrogen sulfate tromethane double salt 482mg, yield 93%.
Embodiment 18
Stir, add sulfuric acid 98mg, after reaction is finished, reclaim and concentrate, obtain Adamantly pyrrolidine vitriol 397mg, Adamantly pyrrolidine vitriol is mixing in DMF again, adds 91.11mg amino-propanediol reaction 2 hours, concentrating under reduced pressure, add an amount of sherwood oil, separate out solid, filtration, with petroleum ether, drying, obtain Adamantly pyrrolidine hydrogen sulfate amino-propanediol double salt 400mg, yield 82%.
Embodiment 19
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, dissolve with the 50ml anhydrous isopropyl alcohol, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Adamantly pyrrolidine vitriol 397mg, Adamantly pyrrolidine vitriol is mixing in methyl alcohol again, add 61.08mg monoethanolamine reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane, separate out solid, filtration, with normal hexane washing, drying, obtain Adamantly pyrrolidine hydrogen sulfate monoethanolamine double salt 344mg, yield 75%.
Embodiment 20
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, dissolve with the 50ml dry DMF, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Adamantly pyrrolidine vitriol 397mg, Adamantly pyrrolidine vitriol is mixing in DMSO again, add 179.17mg glucosamine reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene, separate out solid, filtration, with hexanaphthene washing, drying, obtain Adamantly pyrrolidine hydrogen sulfate glucosamine double salt 392mg, yield 68%.
Embodiment 21
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, use the 50ml anhydrous alcohol solution, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Adamantly pyrrolidine phosphoric acid salt 397mg, and Adamantly pyrrolidine phosphoric acid salt is mixing in acetone again, add 174.2mg arginine reaction 2 hours, concentrating under reduced pressure adds an amount of ether, separate out solid, filtration, with ether washing, drying, obtain Adamantly pyrrolidine biphosphate arginine double salt 514mg, yield 90%.
Embodiment 22
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, dissolve with the 50ml anhydrous methanol, stir, add phosphatase 79 8mg, after reaction was finished, recovery concentrated, and obtains Adamantly pyrrolidine phosphoric acid salt 397mg, Adamantly pyrrolidine phosphoric acid salt is mixing in acetone again, add 132.16mg ornithine reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil, separate out solid, filtration, with petroleum ether, drying, obtain Adamantly pyrrolidine biphosphate ornithine double salt 539mg, yield 83%.
Embodiment 23
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, dissolve with the 50ml anhydrous isopropyl alcohol, stir, add phosphatase 79 8mg, after reaction was finished, recovery concentrated, and obtains Adamantly pyrrolidine phosphoric acid salt 397mg, Adamantly pyrrolidine phosphoric acid salt is mixing in DMF again, add 175.19mg citrulline reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane, separate out solid, filtration, with normal hexane washing, drying, obtain Adamantly pyrrolidine biphosphate citrulline double salt 463mg, yield 81%.
Embodiment 24
In the 100ml reaction flask, add Adamantly pyrrolidine 303.4mg, dissolve with the 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Adamantly pyrrolidine vitriol 397mg, Adamantly pyrrolidine vitriol is mixing in Virahol again, add 146.19mg Methionin reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene, separate out solid, filtration, with hexanaphthene washing, drying, obtain Adamantly pyrrolidine hydrogen sulfate Methionin double salt 353mg, yield 65%.
Embodiment 25
Compound of the present invention is measured content with HPLC, and the result is referring to table 1.Compound purity of the present invention is much improved, and total impurities is all below 0.8%.
Table 1
| Sequence number | Medicine | Content | Purity |
| ??1 | Adamantly pyrrolidine sodium pyrosulfate double salt | ??99.35％ | ??99.68％ |
| ??2 | Adamantly pyrrolidine hydrogen sulfate arginine double salt | ??99.26％ | ??99.45％ |
| ??3 | Adamantly pyrrolidine hydrogen sulfate tromethane double salt | ??99.40％ | ??99.65％ |
| ??4 | Adamantly pyrrolidine SODIUM PHOSPHATE, MONOBASIC double salt | ??98.73％ | ??99.36％ |
| ??5 | The amino trihydroxybutane double salt of Adamantly pyrrolidine biphosphate | ??99.15％ | ??99.28％ |
| ??6 | Adamantly pyrrolidine biphosphate arginine double salt | ??99.08％ | ??99.32％ |
Embodiment 26
The beagle dog is adopted in the bioavailability test, and is complete male, body weight 10kg, and fasting 12h can't help water; Control group Adamantly pyrrolidine capsule.Medicine of the present invention is directly overlapped into capsule (being 30mg in Adamantly pyrrolidine) irritate stomach, feed in about 3 hours behind the filling stomach, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h and the about 0.5ml of 10h venous blood collection after irritating stomach respectively, measure the Adamantly pyrrolidine Plasma Concentration, the result is referring to table 2.Illustrate that compound of the present invention is significantly improved than Adamantly pyrrolidine bioavailability.Peak time shifts to an earlier date significantly, and the result is referring to table 3.
Table 2 compares with Adamantly pyrrolidine, and the relative bioavailability of The compounds of this invention is:
| Medicine | Relative bioavailability |
| Adamantly pyrrolidine sodium pyrosulfate double salt | ??129％ |
| Adamantly pyrrolidine hydrogen sulfate arginine double salt | ??125％ |
| Adamantly pyrrolidine hydrogen sulfate tromethane double salt | ??126％ |
| Adamantly pyrrolidine SODIUM PHOSPHATE, MONOBASIC double salt | ??123％ |
| The amino trihydroxybutane double salt of Adamantly pyrrolidine biphosphate | ??120％ |
| Adamantly pyrrolidine biphosphate arginine double salt | ??124％ |
The peak time of table 3 The compounds of this invention and Adamantly pyrrolidine relatively
| Medicine | Peak time |
| Adamantly pyrrolidine | 90 minutes |
| Adamantly pyrrolidine sodium pyrosulfate double salt | 50 minutes |
| Adamantly pyrrolidine hydrogen sulfate tromethane double salt | 40 minutes |
Claims (9)
1. a diamondoid-based pyrrolidin derivatives has following general structure:
Wherein:
M is a kind of in basic metal, ammonia or ammonium, amino acid, the amino alcohol, and described basic metal is Na
+, K
+, or Cs
+In a kind of; Described amino acid is arginine, ornithine, a kind of in citrulline or the Methionin; Described amino alcohol is a kind of in tromethane, amino-propanediol, monoethanolamine or the glucosamine;
Y is SO4
2-Or HPO4
2-
2. the preparation method of Adamantly pyrrolidine derivative according to claim 1 is characterized in that, realizes by following steps:
Adamantly pyrrolidine and equimolar H
2After Y mixes in polar solvent, make Adamantly pyrrolidine acid salt, after adding and the equimolar alkali metal compound of Adamantly pyrrolidine or ammonium compound or amino acid or amino alcohol react completely again, concentrate, add the weak polar solvent crystallization, filter, solid drying, promptly get Adamantly pyrrolidine derivative
Reaction formula is:
Wherein the definition of M, Y is with claim 1,
Described alkali metal compound is selected sodium methylate for use, potassium methylate, the methyl alcohol caesium, sodium ethylate, potassium ethylate, the ethanol caesium, sodium propylate, potassium propylate, the propyl alcohol caesium, sodium butylate, butanols potassium, the butanols caesium, sodium isopropylate, potassium isopropoxide, the Virahol caesium, butyl alcohol-tert sodium, butyl alcohol-tert potassium, the butyl alcohol-tert caesium, sodium-acetate, Potassium ethanoate, cesium acetate, Sodium Propionate, potassium propionate, the propionic acid caesium, Sodium propanecarboxylate, potassium butyrate, the butyric acid caesium, sodium hydroxide, a kind of in potassium hydroxide or the cesium hydroxide, described ammonium or ammoniate are selected ammonia for use, ammoniacal liquor, ammonium acetate, a kind of in propionic acid ammonium or the butyric acid ammonium, the definition of described amino acid or amino alcohol is with claim 1;
R is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3CH
2CH
2CH
2-, (CH
3)
2CH-, (CH
3)
3C-, CH
3CO-, CH
3CH
2CO-, CH
3CH
2CH
2A kind of among CO-or the H.
3. the preparation method of Adamantly pyrrolidine derivative according to claim 1 is characterized in that, realizes by following steps:
Adamantly pyrrolidine with after acid salt MHY mixes in polar solvent, reacts completely with 1: 1 mol ratio, is concentrated, adds the weak polar solvent crystallization, filter,, promptly get Adamantly pyrrolidine derivative solid drying,
Reaction formula is
Wherein the definition of M, Y is with claim 1,
Described acid salt is selected a kind of in sodium pyrosulfate, sal enixum, monoammonium sulfate, cesium hydrogen sulfate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, primary ammonium phosphate or the cesium dihydrogen phosphate for use.
4. the preparation method of Adamantly pyrrolidine derivative according to claim 2, it is characterized in that: described polar solvent is selected water, ethanol, methyl alcohol, Virahol, acetone, N for use, a kind of in dinethylformamide or the dimethyl sulfoxide (DMSO); Described weak polar solvent is a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
5. Adamantly pyrrolidine derivative according to claim 1 is characterized in that: described Adamantly pyrrolidine derivative is Adamantly pyrrolidine hydrogen sulfate double salt or Adamantly pyrrolidine biphosphate double salt.
6. Adamantly pyrrolidine derivative according to claim 5 is characterized in that: described Adamantly pyrrolidine hydrogen sulfate double salt obtains by following preparation method:
Adamantly pyrrolidine is with after equimolar sulfuric acid mixes in polar solvent, add and the equimolar alkali metal compound of Adamantly pyrrolidine or ammonium compound or amino acid or amino alcohol again, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter,, promptly get Adamantly pyrrolidine hydrogen sulfate double salt solid drying;
7. Adamantly pyrrolidine derivative according to claim 5 is characterized in that: described Adamantly pyrrolidine hydrogen sulfate double salt obtains by following preparation method:
Adamantly pyrrolidine and equimolar sodium pyrosulfate or sal enixum or cesium dihydrogen phosphate or monoammonium sulfate are mixed in polar solvent, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter,, promptly get Adamantly pyrrolidine hydrogen sulfate double salt solid drying.
8. Adamantly pyrrolidine derivative according to claim 5 is characterized in that: described Adamantly pyrrolidine biphosphate double salt obtains by following preparation method:
Adamantly pyrrolidine is with after equimolar phosphoric acid mixes in polar solvent, add and the equimolar alkali metal compound of Adamantly pyrrolidine or ammonium compound or amino acid or amino alcohol again, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter,, promptly get Adamantly pyrrolidine biphosphate double salt solid drying.
9. Adamantly pyrrolidine derivative according to claim 5 is characterized in that: described Adamantly pyrrolidine biphosphate double salt obtains by following preparation method:
Adamantly pyrrolidine and equimolar SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate or cesium dihydrogen phosphate or primary ammonium phosphate mix in polar solvent, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, separate out solid filtering, with solid drying, promptly get Adamantly pyrrolidine biphosphate double salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102008279A CN101870671B (en) | 2010-06-11 | 2010-06-11 | Adamantly pyrrolidine derivative, and preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102008279A CN101870671B (en) | 2010-06-11 | 2010-06-11 | Adamantly pyrrolidine derivative, and preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101870671A true CN101870671A (en) | 2010-10-27 |
| CN101870671B CN101870671B (en) | 2012-06-27 |
Family
ID=42995774
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102008279A Active CN101870671B (en) | 2010-06-11 | 2010-06-11 | Adamantly pyrrolidine derivative, and preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101870671B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724248A (en) * | 2014-01-16 | 2014-04-16 | 江苏万特制药有限公司 | Preparation method of vildagliptin process impurities |
| CN104529857A (en) * | 2015-01-13 | 2015-04-22 | 佛山市赛维斯医药科技有限公司 | Halogen-substituted adamantane amide derivant, and preparing method and application thereof |
| CN106432026A (en) * | 2016-09-12 | 2017-02-22 | 重庆医科大学 | Compound with potential therapeutic activity on diabetes |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329593A (en) * | 1998-12-10 | 2002-01-02 | 诺瓦提斯公司 | N-substituted 2-cyanopyrrolidines |
| CN101238099A (en) * | 2005-08-04 | 2008-08-06 | 诺瓦提斯公司 | Salts of vildagliptin |
-
2010
- 2010-06-11 CN CN2010102008279A patent/CN101870671B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329593A (en) * | 1998-12-10 | 2002-01-02 | 诺瓦提斯公司 | N-substituted 2-cyanopyrrolidines |
| CN101238099A (en) * | 2005-08-04 | 2008-08-06 | 诺瓦提斯公司 | Salts of vildagliptin |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724248A (en) * | 2014-01-16 | 2014-04-16 | 江苏万特制药有限公司 | Preparation method of vildagliptin process impurities |
| CN103724248B (en) * | 2014-01-16 | 2018-07-27 | 万全万特制药江苏有限公司 | The preparation method of vildagliptin process contaminants |
| CN104529857A (en) * | 2015-01-13 | 2015-04-22 | 佛山市赛维斯医药科技有限公司 | Halogen-substituted adamantane amide derivant, and preparing method and application thereof |
| CN106432026A (en) * | 2016-09-12 | 2017-02-22 | 重庆医科大学 | Compound with potential therapeutic activity on diabetes |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101870671B (en) | 2012-06-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6113660B2 (en) | Bismuth-containing compounds that regulate the properties of bioactive substances | |
| EP2767276B1 (en) | Improving / prophylactic agent for chronic kidney disease | |
| CN101870671B (en) | Adamantly pyrrolidine derivative, and preparation and application thereof | |
| CN109988132B (en) | Preparation method of amiodarone hydrochloride | |
| CN101792444B (en) | Sodium levofolinate and preparation method and drug combination thereof | |
| CN103833593A (en) | Method for preparing N-(9-fluorenylmethoxy carbony)-O-tertiary butyl-L-tyrosine | |
| CN101838213B (en) | Method for preparing laminine and pharmaceutically acceptable salts thereof | |
| JP2010505885A (en) | Calcium L-carnitine fumarate and production method and use thereof | |
| CN105367470A (en) | Method for preparing vildagliptin | |
| CN103159651B (en) | Sulfonylurea guanidine and preparation method and application thereof | |
| CN101955436B (en) | Naphthyloxy benzedrine derivatives and preparation method thereof | |
| CN104355989B (en) | A kind of preparation method of Malic acid magnesium salt (1:1). | |
| CN101863891A (en) | Trifluoromethane triazolidine quinoxaline derivative and preparation method thereof | |
| CN102363599B (en) | A kind of sitagliptin intermediate chiral separation method | |
| CN101978945A (en) | Ibuprofen medicinal composition | |
| CN102875362A (en) | Preparation method of L-threonic acid or salts thereof | |
| CN111072755B (en) | Lipeptide complex, pharmaceutical composition thereof, preparation method and application thereof | |
| CN101366722A (en) | Hydrotalcite doxifluridine slow release formulation and preparation method thereof | |
| CN113461551A (en) | 3-amino-1-adamantanol and preparation method and application thereof | |
| CN101914100B (en) | Benzenesulfonyl lupetazin derivative and preparation method thereof | |
| CN101933939A (en) | Malic acid bicarbonate external hemodialysis agent | |
| CN101798301A (en) | Pyrrolidyl pyrimidine methanesulfonamide derivatives and preparation method thereof | |
| CN101077333A (en) | External applied gel with butenafine hydrochloride as principal ingredient | |
| CN100484520C (en) | 5-aminoketone valerate externally-applied preparation and production thereof | |
| CN101870698A (en) | Sulfonyl-phenyl imidazo triazine derivative and preparation method |
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 | ||
| ASS | Succession or assignment of patent right |
Owner name: HANGZHOU AOMO MEDICAL TECHNOLOGY CO., LTD. Free format text: FORMER OWNER: QI YOUMAO Effective date: 20140305 |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20140305 Address after: 7, No. 310011, 39 Cheung Road, Hangzhou, Zhejiang, Gongshu District Patentee after: Hangzhou Aomo Medical Technology Co., Ltd. Address before: 7, No. 310011, 39 Cheung Road, Hangzhou, Zhejiang, Gongshu District Patentee before: Qi Youmao |
|
| C56 | Change in the name or address of the patentee |
Owner name: HANGZHOU AOMO PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: HANGZHOU AOMO MEDICAL TECHNOLOGY CO., LTD. |
|
| CP03 | Change of name, title or address |
Address after: 5, building 7, building 39, 310011 Cheung Road, Hangzhou, Zhejiang, Gongshu District Patentee after: HANGZHOU ADAMERCK PHARMLABS INC. Address before: 7, No. 310011, 39 Cheung Road, Hangzhou, Zhejiang, Gongshu District Patentee before: Hangzhou Aomo Medical Technology Co., Ltd. |