CN103408591A - Pterostilbene phosphate disodium salt synthesis method - Google Patents
Pterostilbene phosphate disodium salt synthesis method Download PDFInfo
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- CN103408591A CN103408591A CN2013102989860A CN201310298986A CN103408591A CN 103408591 A CN103408591 A CN 103408591A CN 2013102989860 A CN2013102989860 A CN 2013102989860A CN 201310298986 A CN201310298986 A CN 201310298986A CN 103408591 A CN103408591 A CN 103408591A
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- pterostilene
- disodium salt
- phosphate disodium
- oxyl
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Abstract
The present invention provides a pterostilbene phosphate disodium salt synthesis method, wherein an aprotic solvent is adopted to dissolve pterostilbene, a dialkoxyl phosphoryl halide is adopted as a phosphorylation regent, acylation is performed under catalysis effects of an acid removing agent and 4-dimethylaminopyridine to obtain pterostilbene-alkoxyl-phosphate ester, and hydrolysis, salt formation and crystallization are performed to obtain the pterostilbene phosphate disodium salt. The method has characteristics of mild reaction conditions, short reaction time, no requirement of purification of the phosphorylation intermediate, simple process, high yield, good product quality and low energy consumption, and is suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic method of water-soluble Pterostilene derivative Pterostilene organic phosphate disodium salt, belong to chemical medical preparing technical field.
Background technology
Pterostilene (Pterostilbene), have another name called Pterostilene, chemical name 3, and the 5-dimethoxy-4 ' '-hydroxy stibene, CAS NO.537-42-8, molecular formula is C
16H
16O
3, molecular weight is 256.30.Off-white color crystalloid powder, water insoluble, be dissolved in ethanol, to air-sensitive, fusing point is 89-92 ℃.Pterostilene is the homologue of resveratrol, has the trans stilbene skeleton structure, it is the important activity composition in grape, blueberry, dragon's blood goods and India's anti-diabetic herbal medicine " Bijasar ", existence is also arranged in Chinese Dracaena cochinchinensis, its pharmacological action has part similar to resveratrol, be good antioxidant, have many-sided activity such as anti-inflammatory, antithrombotic, anti-cancer, anticancer, lipidemia disease.Pterostilene also has that stronger anti-mycotic activity, cancer chemoprevention are active, to induce MDR apoptosis activity, PPAR α agonist activity etc., its hypolipidemic activity to be better than Win-35833, anti-diabetic activity and diformazan pair flesh suitable in addition.These efficacy effects of Pterostilene have demonstrated its important researching value and good application prospect.
At present, Pterostilene does not also have pharmaceutical prod listing, and the character such as this is low with the poorly water-soluble of Pterostilene own, bioavailability, poor stability are relevant.
Along with the effect of Pterostilene is day by day well known, let us has been seen the market outlook that it is wide.Given this, some drugmakers, address the water-soluble of Pterostilene and bioavailability problem from prodrug exploitation angle one after another both at home and abroad.
Pterostilene organic phosphate disodium salt after deliberation, water-soluble better, bioavailability improves greatly.
At present, by Pterostilene, prepare Pterostilene organic phosphate disodium salt bibliographical information following several method arranged:
1. with dibenzyl phosphite, react with Pterostilene, under trimethylchlorosilane and sodium iodide existence, slough benzyl subsequently.The method will be used the high and environmentally hazardous tetracol phenixin of toxicity as solvent, while sloughing benzyl simultaneously, will use silane reagent and sodium iodide that price is more expensive, is unfavorable for industrialized production.
2. with two-(2,2,2-, tri-chloroethyls) phosphoryl compounds, react with Pterostilene, then reduce with zinc/acetic acid.In the method, use two-(2,2,2-, tri-chloroethyls) phosphoryl compound is expensive, and severe reaction conditions, unsuitable industrialized production.
3. with Phosphorus Oxychloride or phosphorus oxybromide, react with Pterostilene, then basic hydrolysis obtains the Pterostilene phosphoric acid ester.Although the method is simple to operate, Phosphorus Oxychloride or oxygen sea phosphorus activity are high, so byproduct of reaction is more, and the lower and difficult quality of product yield is controlled.
Summary of the invention
The object of the present invention is to provide that a kind of technique is simple, the preparation method of the Pterostilene organic phosphate disodium salt of mild condition, yield is high, quality good, energy consumption is low applicable suitability for industrialized production.
The present invention adopts following technical scheme:
This Pterostilene organic phosphate disodium salt synthesis route carries out according to accompanying drawing, and synthetic method comprises the following steps:
(1) Pterostilene is dissolved in aprotic solvent, at acid scavenger and N, under the N-Dimethylamino pyridine exists, drip the solution of two-oxyl phosphoryl halogen II, dropping temperature is: 20-40 ℃ dropwises, in uniform temp reaction 0.5～2 hour, after adding the water termination reaction, extract product with non-polar organic solvent, after evaporate to dryness, obtain the phosphoric acid ester III of Pterostilene;
(2) the phosphoric acid ester III of Pterostilene is dissolved in organic solvent, removes R
1And R
2, then in methyl alcohol with the NaOH salify, add the acetone crystallization, after filtration drying, obtain Pterostilene organic phosphate disodium salt I.
Wherein in the described two-oxyl phosphoryl halogen II of (1) step, X is chlorine or bromine, and chlorine is better than bromine; R
1With R
2For the tertiary butyl, trityl group, 2-cyano ethyl, benzyl, phenyl, R
1With R
2For identical or different substituting group.For the tertiary butyl or benzyl optimum.
Wherein, (1) the described non-polar organic solvent of step is methylene dichloride, 1,1-ethylene dichloride, 1,2-ethylene dichloride, trichloromethane, toluene, normal hexane, hexanaphthene, ethyl formate, ethyl acetate, butylacetate, trimethyl phosphite 99, triethyl phosphate, ether, isopropyl ether, sherwood oil.Described non-polar organic solvent does not dissolve each other with water, but can lysate.
Wherein, (1) the described aprotic solvent of step is acetone, tetrahydrofuran (THF), second eyeball, methylene dichloride, 1,1-ethylene dichloride, 1,2-ethylene dichloride, trichloromethane, toluene, normal hexane, hexanaphthene, ethyl formate, ethyl acetate, butylacetate, trimethyl phosphite 99, triethyl phosphate, ether, isopropyl ether or sherwood oil.
Wherein, the described acid scavenger of (1) step is heterocyclic amine, trialkylamine or mineral alkali.
Wherein, the described organic solvent of (2) step is methyl alcohol, ethanol, Virahol, methylene dichloride, trichloromethane, diisopropyl ether, t-butyl methyl ether, ethyl acetate or butylacetate.
Described (2) step removes R
1And R
2The method of blocking group is: R
1With R
2During for the tertiary butyl, trityl group, remove with acid-hydrolysis method; R
1With R
2During for 2-cyano ethyl substituted alkyl, remove with alkali hydrolysis method; R
1With R
2During for phenyl, remove with metallic reducing or catalytic hydrogenation.
Wherein, described (1), (2) step operate in nitrogen or rare gas element.
The method be take the dialkoxy phosphoryl halogen and is phosphorus esterification reagent; phosphorus esterification reagent used is cheap and easy to get; in reaction, add simultaneously catalyst n; the N-Dimethylamino pyridine, make the reaction conditions gentleness, and the reaction times is short; simple to operate; the phosphorylated intermediate does not need purifying, and product yield is high, quality good, is easy to suitability for industrialized production.
The accompanying drawing explanation
Accompanying drawing is Pterostilene organic phosphate disodium salt synthesis route.
Embodiment
The invention will be further described by the following examples, it should be noted that reaction conditions and raw material purpose that following examples are related are the present invention is done to better explanation, rather than limitation of the present invention.
Embodiment 1
Under nitrogen protection; by Pterostilene 2.56g (0.01mol); 4-dimethylamino pyrrole 0.06g (0.0005mol) and diisopropylethylamine 1.42g (0.011mol) are dissolved in the 20ml methylene dichloride; in 20 ℃, drip the solution of two-(tert.-butoxy)-phosphoryl chloride 2.51g (0.011mol) and 10ml methylene dichloride.After dropwising, keep this temperature stirring reaction, with thin-layer chromatography, monitor reaction process, disappear to raw material point, reaction times is 0.5 hour, by in reaction solution impouring 50ml frozen water, separate organic layer, water layer is used the 20ml dichloromethane extraction once again, merge organic layer, washing, dry, it is 94% oily matter Pterostilene-bis--(tert.-butoxy)-phosphoric acid ester 4.07g that evaporate to dryness obtains yield, and its input 50ml is led to dry hydrogen chloride in advance to saturated methyl alcohol, stirring at room reaction 24 hours, the evaporated under reduced pressure solvent, resistates is dissolved in the 50ml methylene dichloride, be washed to neutrality, anhydrous sodium sulfate drying, evaporate to dryness, resistates is dissolved in 25ml methyl alcohol, stir the lower NaOH-of dropping methanol solution to PH8～10, stirred 1 hour, slowly drip acetone 200ml, filter, the washing with acetone solid, drying under reduced pressure, obtain white powder product 2.95g, yield 82.7%.
Embodiment 2
Under nitrogen protection; by Pterostilene 2.56g (0.01moi); DMAP 0.06g (0.0005mol) and diisopropylethylamine 1.428 (0.011mol) are dissolved in the 20ml methylene dichloride; in 30 ℃, drip the solution of two-(2-cyano group oxyethyl group)-phosphoryl chloride 2.45g (0.011mol) and 10ml methylene dichloride.After dropwising, keep this temperature stirring reaction, with thin-layer chromatography, monitor reaction process, disappear to raw material point, reaction times is 0.8 hour, by in reaction solution impouring 50ml frozen water, separate organic layer, water layer is used the 20ml dichloromethane extraction once again, merge organic layer, washing, dry, it is 93% oily matter Pterostilene-bis--(2-cyano group oxyethyl group)-phosphoric acid ester 4.45g that evaporate to dryness obtains yield, it is dropped in 25ml methyl alcohol, stir the lower NaOH-of dropping methanol solution to PH8～10, stirred 1 hour, slowly drip acetone 200ml, filter, the washing with acetone solid, drying under reduced pressure, obtain white powder product 2.83g, yield 78%.
Embodiment 3
Under nitrogen protection; by Pterostilene 2.56g (0.01mol); DMAP 0.068 (0.0005mol) and diisopropylethylamine 1.42g (0.011mol) are dissolved in the 20ml trichloromethane; in 20 ℃, drip the solution of two-(triphenyl methoxyl group)-phosphoryl chloride 6.61g (0.011mol) and 10ml trichloromethane.After dropwising, keep this temperature stirring reaction, with thin-layer chromatography, monitor reaction process, disappear to raw material point, reaction times is 0.5 hour, by in reaction solution impouring 50ml frozen water, separate organic layer, water layer is used the 20ml chloroform extraction once again, merge organic layer, washing, dry, it is 89% oily matter Pterostilene-bis--(triphenyl methoxyl group)-phosphoric acid ester 7.92g that evaporate to dryness obtains yield, and its input 50ml is led to dry hydrogen chloride in advance to saturated methyl alcohol, stirring at room reaction 24 hours, the evaporated under reduced pressure solvent, resistates is dissolved in the 50ml methylene dichloride, be washed to neutrality, anhydrous sodium sulfate drying, evaporate to dryness, resistates is dissolved in 25ml methyl alcohol, stir the lower NaOH-of dropping methanol solution to PH8～10, stirred 1 hour, slowly drip acetone 200ml, filter, the washing with acetone solid, drying under reduced pressure, obtain white powder product 2.46g, yield 69.5%.
Embodiment 4
Under nitrogen protection; by Pterostilene 2.56g (0.01mol); DMAP 0.06g (0.0005mol) and diisopropylethylamine 1.42g (0.011mol) are dissolved in the 20ml methylene dichloride; in 20 ℃, drip the solution of 21 (benzyloxy) phosphoryl chloride 2.92g (0.011mol) and 10mll methylene dichloride.Keep this temperature stirring reaction, with thin-layer chromatography, monitor reaction process, disappear to raw material point, reaction times is 1 hour, by in reaction solution impouring 50ml frozen water, separate organic layer, . water layer is used the 20ml dichloromethane extraction once again, merge organic layer, washing, dry, it is 96% oily matter Pterostilene-bis--(benzyloxy)-phosphoric acid ester 4.5g that evaporate to dryness obtains yield, it is dropped in 25ml methyl alcohol, add 10%Pd/C0.04g, under room temperature, logical hydrogen normal pressure stirring reaction is 24 hours, remove by filter catalyzer, stir the lower NaOH-of dropping methanol solution to PH8～10, stirred 1 hour, slowly drip acetone 200ml, filter, the washing with acetone solid, drying under reduced pressure, obtain white powder product 2.84g, yield 80.5%.
Claims (9)
1. the synthetic method of a Pterostilene organic phosphate disodium salt, it is characterized in that: dissolve Pterostilene with aprotic solvent, the two-oxyl phosphoryl halogens of take are phosphorus esterification reagent, acidylate under the katalysis of acid scavenger and DMAP, add the water termination reaction, use the non-polar organic solvent extraction product, after evaporate to dryness, obtain Pterostilene--oxyl-phosphoric acid ester; Pterostilene--oxyl-phosphoric acid ester is dissolved in organic solvent, sloughs alkyl with correlation method, then in methyl alcohol with the sodium hydroxide salify, add the acetone crystallization, obtain the Pterostilene organic phosphate disodium salt.
2. Pterostilene organic phosphate disodium salt synthetic method according to claim 1, it is characterized in that: described aprotic solvent is acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, 1,1-ethylene dichloride, 1, one or more in 2-ethylene dichloride, trichloromethane, toluene, normal hexane, hexanaphthene, ethyl formate, ethyl acetate, butylacetate, trimethyl phosphite 99, triethyl phosphate, ether or isopropyl ether.
3. Pterostilene organic phosphate disodium salt synthetic method according to claim 1, it is characterized in that: described two-oxyl phosphoryl halogens are two-oxyl phosphoryl chlorides or two-oxyl phosphoryl bromides.
4. described in claim 1,3, in two-oxyl phosphoryl halogens, two-oxyls can be identical or different, and described-oxyl is tert.-butoxy, triphenyl methoxyl group, 2-cyano group oxyethyl group, benzyloxy, phenoxy group.
5. Pterostilene organic phosphate disodium salt synthetic method according to claim 1, it is characterized in that: described deacidification is one or more in heterocyclic amine, trialkylamine or mineral alkali.
6. Pterostilene organic phosphate disodium salt synthetic method according to claim 1; it is characterized in that: described Pterostilene, phosphorus esterification reagent, acid scavenger, DMAP mol ratio are 1: 1.1～2: 1.1～2: 0.05～0.1, and described aprotic solvent consumption is 5～20 times of Pterostilene weight.
7. Pterostilene organic phosphate disodium salt synthetic method according to claim 1, it is characterized in that: described temperature of reaction is 20～40 ℃, the reaction times is 0.5～2h.
8. Pterostilene organic phosphate disodium salt synthetic method according to claim 1, it is characterized in that: described non-polar organic solvent is methylene dichloride, 1,1-ethylene dichloride, 1, one or more in 2-ethylene dichloride, trichloromethane, toluene, normal hexane, hexanaphthene, ethyl formate, ethyl acetate, butylacetate, trimethyl phosphite 99, triethyl phosphate, ether or isopropyl ether.
9. Pterostilene organic phosphate disodium salt synthetic method according to claim 1 is characterized in that: described is one or more of methyl alcohol, ethanol, Virahol, methylene dichloride, trichloromethane, diisopropyl ether, t-butyl methyl ether, ethyl acetate or butylacetate for the organic solvent that dissolves Pterostilene--oxyl-phosphoric acid ester.
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Cited By (3)
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| WO2014147641A2 (en) * | 2013-03-21 | 2014-09-25 | Laurus Labs Private Limited | Sitagliptin pterostilbene phosphate salt, process for the preparation and pharmaceutical composition thereof |
| CN109942630A (en) * | 2019-02-28 | 2019-06-28 | 上海市第十人民医院 | Natural activity molecule coupling labeled compound and application thereof based on Osalmid and pterostilbene |
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Denomination of invention: A synthetic method of disodium pterostilbene phosphate Effective date of registration: 20210930 Granted publication date: 20160420 Pledgee: Agricultural Bank of China Limited Zhangjiagang branch Pledgor: ZHANG JIA GANG VINSCE BIO-PHARM Co.,Ltd. Registration number: Y2021320010400 |
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Address after: No. 2, Nanjing Middle Road, Jiangsu Yangzijiang Chemical Industrial Park, Zhangjiagang Free Trade Zone, Suzhou City, Jiangsu Province, 215634 Patentee after: Wison Biomedical (Suzhou) Co.,Ltd. Address before: 215634 No. 2 Nanjing Middle Road, Yangtze River Chemical Industrial Park, Zhangjiagang Free Trade Zone, Suzhou City, Jiangsu Province Patentee before: Weisheng Biomedical (Suzhou) Co.,Ltd. Address after: 215634 No. 2 Nanjing Middle Road, Yangtze River Chemical Industrial Park, Zhangjiagang Free Trade Zone, Suzhou City, Jiangsu Province Patentee after: Weisheng Biomedical (Suzhou) Co.,Ltd. Address before: 215634 Building D, No. 7, Guangdong Road, Zhangjiagang Free Trade Zone, Jiangsu Province (Weisheng) Patentee before: ZHANG JIA GANG VINSCE BIO-PHARM Co.,Ltd. |
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Date of cancellation: 20221031 Granted publication date: 20160420 Pledgee: Agricultural Bank of China Limited Zhangjiagang branch Pledgor: ZHANG JIA GANG VINSCE BIO-PHARM Co.,Ltd. Registration number: Y2021320010400 |