CN101696223B - Synthesis method of citric acid phosphoric acid ester - Google Patents
Synthesis method of citric acid phosphoric acid ester Download PDFInfo
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- CN101696223B CN101696223B CN2009101863322A CN200910186332A CN101696223B CN 101696223 B CN101696223 B CN 101696223B CN 2009101863322 A CN2009101863322 A CN 2009101863322A CN 200910186332 A CN200910186332 A CN 200910186332A CN 101696223 B CN101696223 B CN 101696223B
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Abstract
The invention discloses a synthesis method of citric acid phosphoric acid ester, which is characterized by comprising the following steps of stirring citric acid with benzoic alcohol to react at 145 DEG C-190 DEG C for 5-12 hours, distilling unreacted benzoic alcohol by pressure reduction at 175 DEG C-185 DEG C after reaction, and re-crystallizing by anhydrous alcohol; under the protection of N2,dissolving the products in benzene or cyclohexane solvent, placing mixture into an ice-bath at 3 DEG C-5 DEGC, slowly dripping benzene solution dissolved with PC15 into the solution, keeping the reaction temperature at 2 DEG C-8 DEG C, dripping for 1-4.5 hours, continuously stirring to react for 0.5-1 hour, slowly adding water to the solution, keeping the temperature constant, stirring for to react for 0.5 h after white solid is separated out, carrying out suction filtration and drying; and catalyzing above products by 10%Pd/C with weight ratio of 2-5% at normal temperature and pressure in the distilled water for 5-10 hours, carrying out suction filtration, washing by the distilled water, and adjusting the PH value to be 7. The invention has the advantages of cheap raw materials, gentle reaction conditions and high yield.
Description
Technical field
The invention belongs to the synthetic field of natural organic-compound.
Background technology
Citric acid phosphoric acid ester (Phosphocitrate is called for short PC) is (W.P.Tew, the C.Mahle et al.Biochemistry that from the plastosome of human urine and rats'liver, extracts the earliest; 1980,19 (9): 1983-1988), find that it has the good restraining effect to the deposition and the crystallization of calcium phosphate; Can prevent effectively that the calcic crystallization from precipitating in osteoarthrosis and osseous tissue; Be used to treat osteo-arthritis, the disease that rheumatic arthritis is relevant with some, as: the calcification of prosthetic heart valve; Soft tissue neoplasm, lithangiuria etc.And citric acid phosphoric acid ester reaches 150umol/kg/day to rat and mouse dosage any pronounced side effects does not take place yet; Show that after deliberation citric acid phosphoric acid ester can not influence the normal function of cell yet when concentration reaches 1.5mM (4.5mg/mL) in vivo; Function (P.A.Turhanen like DNA and protein synthesis; K.D.Demadis et al.J.Org.Chem, 2007,72:1468-1471).Because PC has so significant curative effect, expectation will have good market outlook.
The present synthetic route of citric acid phosphoric acid ester mainly contains following several kinds:
1, J.Meyer, R.J.Bolen et al.J.Am.Chem.Soc, 1959; 81 (9): disclose a kind of compound method among the 2094-2096.; In this compound method, the first step reaction has 30% unreacted triethyl citrate, is difficult to separate; Even the change temperature, the prolongation reaction times etc. all can not be improved productive rate.Second and third step aftertreatment difficulty, productive rate is low, and uses noble metal platinum, Dowex-50-H
+Price is also expensive.
2, W.P.Tew, C.Mahle et al.Biochemistry, 1980; 19 (9): disclose a kind of compound method among the 1983-1988, its synthetic raw materials used price is high, is not suitable for suitability for industrialized production; And catalytic hydrogenation has been used noble metal platinum; Catalytic process can only hydrogenolysis be removed two ethyls, makes the final step aftertreatment difficult, and also handy column chromatography is separated just can obtain PC.
3, G.Williams and J.D.Sallis.Analytical Biochemistry, 1980, a kind of compound method is disclosed among the 102:365-373, its complex synthetic route, operational difficulty, long reaction time.The first step productive rate has only 30～35%, and agents useful for same is more, and the ion exchange resin consumption is big, and price is also expensive.
4, A.H.Pankowski, J.D.Meehan et al.Tetrahedron Letters.1994,35 (6): disclose a kind of compound method among the 927-930; Tribenzyl citrate raw material China market used in this compound method is not sold, and its first step reaction directly adds the phosphorus pentachloride solid, makes reinforced inhomogeneous like this; Hydrolysis easily in air; Productive rate is low, has only 61%, does not also write used reaction conditions exactly with the catalytic reaction of palladium carbon.
5, P.A.Turhanen, K.D.Demadis et al.J.Org.Chem.2007 discloses a kind of compound method among the 72:1468-1471, and this compound method step is many, operation inconvenience, productive rate is low.Three very difficult hydrolysis of ethyl are thorough, also handy at last Dowex-50w ion exchange column, and expense is high, is not suitable for suitability for industrialized production.
Summary of the invention
The objective of the invention is to overcome the shortcoming of prior art, provide a kind of raw material cheap, production cost is low, and technology is simple, and is easy to operate, the compound method of the citric acid phosphoric acid ester that transformation efficiency and purity are high.
Compound method of the present invention may further comprise the steps:
1, Hydrocerol A and benzylalcohol at 145～190 ℃, stirring reaction 5～12h, the reaction back goes out unreacted benzylalcohol 175～185 ℃ of underpressure distillation, oily liquids, get purified tribenzyl citrate with the absolute ethyl alcohol recrystallization then;
Preferable reaction temperature is 160～180 ℃, and the reaction times is 6～8h.
2, at N
2Protection is dissolved in tribenzyl citrate in benzene or the cyclohexane solvent down, and to 3～5 ℃ of ice baths, slowly dropping is dissolved with PCl in this solution
5Benzole soln, maintain is at 2～8 ℃, drips 1～4.5h, drips and finishes; Continue stirring reaction 0.5～1h, slowly in solution, add water again, the maintenance temperature does not rise, and treats that the adularescent solid separates out; Restir reaction 0.5h, last suction filtration, oven dry promptly gets phosphoric acid Hydrocerol A dibenzyl ester;
Preferable reaction temperature is 3-5 ℃, and the dropping time is 2-3h.
3, in zero(ppm) water, add 10% the Pd/C that phosphoric acid Hydrocerol A dibenzyl ester and weight ratio are 2-5%, catalysis 5～10h under the normal temperature and pressure, and then suction filtration use distilled water wash, transfer PH to 7 again, and evaporate to dryness promptly gets citric acid phosphoric acid ester salt at last.
The preferred catalytic time is 6～8h.
Compared with prior art, the invention has the beneficial effects as follows:
The raw material that uses among the present invention is cheap, and the first step esterification productive rate reaches 93%; The solid PCl of the second step usefulness
5Be dissolved in earlier before the reaction in the benzene, better avoided it to separate in water in air, reaction process is used N
2Protection makes whole process all effectively prevent PCl
5Hydrolysis, and be convenient to control drop rate, guarantee that it is the key of reaction that temperature does not rise, make the second step productive rate bring up to 86.3% like this by 61% of report; The final step catalytic hydrogenation is made solvent with zero(ppm) water, and reaction conditions is gentle, and productive rate can reach 100%.If it is then very difficult complete two benzyl hydrogenolysis to make solvent with ETHYLE ACETATE, if use ETHYLE ACETATE: the volume ratio of water=10: 0.5～0.7 is made solvent, then can introduce an ethyl, makes that reaction is impure, is difficult to separate.
Embodiment
The present invention will be described further through following examples.
The preparation of embodiment 1 tribenzyl citrate
Take by weighing Hydrocerol A 28g, be put in the water trap that is equipped with of 100ml, in the three-necked bottle of reflux and whisking appliance with a crystal water; Claim that again benzylalcohol 70g pours this three-necked bottle into,, go out excessive benzylalcohol in 185 ℃ of following underpressure distillation of oil bath then at 165 ℃ of oil bath stirring reaction 8h; Take advantage of heat to be dissolved in absolute ethyl alcohol to this oily matter at last, leave standstill and promptly separated out tribenzyl citrate, suction filtration again in several hours; The oven dry promptly obtain purified tribenzyl citrate, claim 61.3g, yield is 91%.The technical indicator of gained tribenzyl citrate is following:
White solid, m.p.50～51 ℃.
1H?NMR(CDCl
3)，δ：2.86(d，J＝15，2H)，2.94(d，J＝15，2H)，5.07(s，4H)，5.10(s，2H)，7.25～7.35(m，15H)。
ESI-MS?m/z(％)：461([M-H]
-，100)。
The preparation of embodiment 2 tribenzyl citrates
Take by weighing Hydrocerol A 28g, be put in the water trap that is equipped with of 100ml, in the three-necked bottle of reflux and whisking appliance with a crystal water; Claim that again benzylalcohol 70g pours this three-necked bottle into,, go out excessive benzylalcohol in 185 ℃ of following underpressure distillation of oil bath then at 180 ℃ of oil bath stirring reaction 8h; Take advantage of heat to be dissolved in absolute ethyl alcohol to this oily matter at last, leave standstill and promptly separated out tribenzyl citrate, suction filtration again in several hours; Oven dry promptly obtains purified tribenzyl citrate, and weighing gets 62.7g, and yield is 93%.
The preparation of instance 3 phosphoric acid Hydrocerol A dibenzyl esters
Tribenzyl citrate that adding 30g embodiment 1 obtains and 25ml purified benzene are equipped with temperature in 100ml to be taken into account in the three-necked bottle of whisking appliance, under ice bath, stirs and is cooled to 4 ℃, again the 13.6gPCl that is dissolved with in the liquid sampler
5Benzole soln 100ml slowly be added dropwise in this solution, temperature maintenance is at 4 ℃, drips 2h, drips and finishes; 0.5h is stirred in reaction, toward wherein slowly dripping 4.9ml zero(ppm) water, guarantees that temperature does not rise (maintaining 4 ℃) again, wait most of water droplet to add after; Have the white precipitate generation and be phosphoric acid Hydrocerol A dibenzyl ester, continue stirring reaction 1h, last suction filtration is with benzene washing 3 times; Again with NaOH moisture eliminator drain, weighing gets 25.2g, yield is 86.3%.
The technical indicator of gained phosphoric acid Hydrocerol A dibenzyl ester is:
White solid, m.p.121-123 ℃
1H?NMR(CD
3COCD3)，δ：3.58(s，4H)，5.26(s，4H)，7.52(m，10H)，10.74(s，2H)。
ESI-MS?m/z(％)：451([M-H]
-，100)。
The preparation of embodiment 4 phosphoric acid Hydrocerol A dibenzyl esters
Take by weighing 40g tribenzyl citrate and 35ml purified benzene and in 250ml temperature is housed and takes into account in the three-necked bottle of whisking appliance, under ice bath, stir and be cooled to 4 ℃, again the 18gPCl that is dissolved with in the liquid sampler
5Benzole soln 125ml slowly be added dropwise in this solution, temperature maintenance is at 5 ℃, drips 3.5h, drips and finishes; Continue reaction and stir 0.5h, toward wherein slowly dripping 4.9ml zero(ppm) water, guarantee that temperature does not rise (maintaining 5 ℃) again, wait most of water droplet to add after; Have the white precipitate generation and be phosphoric acid Hydrocerol A dibenzyl ester, restir reaction 0.5h, last suction filtration is with benzene washing 2 times; Again NaOH drain in the moisture eliminator, weighing gets 32.54g, yield is 83.12%.
The preparation of embodiment 5 citric acid phosphoric acid ester sodium salts
With the phosphoric acid Hydrocerol A dibenzyl ester 10g that instance 2 obtains, join and temperature is housed takes into account in the 50ml three-necked bottle of whisking appliance, in this three-necked bottle, add 30ml zero(ppm) water and 0.1g 10%Pd/C again; React 7h at normal temperatures and pressures; Suction filtration again with distilled water wash three times, adds the NaOH of equivalent; Concentrate, drying obtains white solid productive rate 100%.
The technical indicator of gained citric acid phosphoric acid ester sodium salt is:
White solid, m.p.＞250 ℃
1H NMR (D
2O), δ: 2.50 (d, J=12,2H), 2.63 (d, J=12,2H).
13C?NMR(D
2O)：δ：45.82，75.31，179.38，182.05。
ESI-MS?m/z(％)：271([M-H]
-，80)。
Claims (4)
1. the compound method of citric acid phosphoric acid ester is characterized in that operating according to the following steps:
(1) Hydrocerol A and benzylalcohol at 145～190 ℃, stirring reaction 5～12h, the reaction back goes out unreacted benzylalcohol 175～185 ℃ of underpressure distillation, gets purified tribenzyl citrate with the absolute ethyl alcohol recrystallization then;
(2) at N
2Protection is dissolved in tribenzyl citrate in benzene or the cyclohexane solvent down, and to 3～5 ℃ of ice baths, slowly dropping is dissolved with PCl in this solution
5Benzole soln, maintain is at 2～8 ℃, drips 1～4.5h, drips and finishes; Continue stirring reaction 0.5～1h, slowly in solution, add water again, the maintenance temperature does not rise, and treats that the adularescent solid separates out; Restir reaction 0.5h, last suction filtration, oven dry gets phosphoric acid Hydrocerol A dibenzyl ester;
(3) in zero(ppm) water, adding phosphoric acid Hydrocerol A dibenzyl ester and weight ratio is 2～5% 10% Pd/C, and catalysis 5～10h under the normal temperature and pressure, and then suction filtration use distilled water wash, transfer pH to 7 again, and evaporate to dryness gets citric acid phosphoric acid ester at last.
2. method according to claim 1 is characterized in that middle Hydrocerol A of step (1) and benzylalcohol at 160～180 ℃, stirring reaction 6～8h.
3. method according to claim 1 is characterized in that in the step (2) at N
2Protection is dissolved in tribenzyl citrate in benzene or the cyclohexane solvent down, and to 3～5 ℃ of ice baths, slowly dropping is dissolved with PCl in this solution
5Benzole soln, maintain is at 3～5 ℃, drips 2～3h, drips and finishes, and continues stirring reaction 0.5～1h, slowly toward solution in, adds water again, keeps temperature not rise, and treats that the adularescent solid separates out, restir reaction 0.5h, suction filtration is dried at last.
4. method according to claim 1 is characterized in that the catalysis time is 6～8h in the step (3).
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| CN2009101863322A CN101696223B (en) | 2009-10-27 | 2009-10-27 | Synthesis method of citric acid phosphoric acid ester |
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| CN101696223B true CN101696223B (en) | 2012-06-20 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784191B (en) * | 2015-03-04 | 2017-11-03 | 南昌大学 | Application of the phosphate citrate acid dibenzyl ester in calcium ion deposition disease is suppressed |
| ITUB20160259A1 (en) * | 2016-01-18 | 2017-07-18 | Univ Degli Studi Roma La Sapienza | COATING COMPOSITION WITH ANTIMICROBIAL AND ANTISALIN ACTIVITY, AND PROCEDURE FOR ITS PREPARATION. |
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Non-Patent Citations (2)
| Title |
|---|
| W. P. Tew et al..Synthesis and Characterization of Phosphocitric Acid, a Potent Inhibitor of Hydroxylapatite Crystal Growth.《Biochemistry》.1980,第19卷(第9期),1983-1988. * |
| W.P.Tewetal..SynthesisandCharacterizationofPhosphocitricAcid a Potent Inhibitor of Hydroxylapatite Crystal Growth.《Biochemistry》.1980 |
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Inventor after: Lu Yu Inventor after: Wang Zikun Inventor after: Yu Bo Inventor after: Wang Jinpeng Inventor after: Hong Ting Inventor after: Tang Chuying Inventor before: Lu Yu Inventor before: Yu Bo Inventor before: Hong Ting Inventor before: Tang Chuying |
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Effective date of registration: 20170120 Address after: 344800 Jiangxi city of Fuzhou province Jinxi County Industrial Park C District Patentee after: JIANGXI WANLI PHARMACEUTICAL Co.,Ltd. Address before: 999 No. 330031 Jiangxi province Nanchang Honggutan University Avenue Patentee before: Nanchang University |
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Granted publication date: 20120620 Termination date: 20211027 |