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Synthesis method of citric acid phosphoric acid ester

A synthesis method and technology of citric acid, applied in the direction of phosphorus organic compounds, etc., can solve the problems of difficulty in separation, many steps, and inability to improve yield, etc., and achieve the effects of ensuring that the temperature does not rise, the reaction conditions are mild, and the drop rate is convenient.

Inactive Publication Date: 2012-06-20
JIANGXI WANLI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 1. J.Meyer, R.J.Bolen et al.J.Am.Chem.Soc, 1959, 81 (9): 2094-2096. disclose a kind of synthetic method, in this synthetic method, the first step reaction will have 30 % unreacted triethyl citrate, difficult to separate, even changing the temperature, prolonging the reaction time, etc. can not improve the yield
The second and third steps are difficult to deal with, the yield is low, and the precious metal platinum, Dowex-50-H is used + the price is also expensive
[0005] 2. W.P.Tew, C.Mahle et al.Biochemistry, 1980, 19(9): 1983-1988 discloses a synthetic method, the price of raw materials used in the synthesis is high, it is not suitable for industrial production, and catalytic hydrogenation uses precious metals Platinum, the catalytic process can only remove two ethyl groups by hydrogenolysis, which makes the last step of post-processing difficult, and it must be separated by column chromatography to obtain PC
[0006] 3. G.Williams and J.D.Sallis.Analytical Biochemistry, 1980, 102: 365-373 discloses a synthetic method, the synthetic route is complicated, the operation is difficult, and the reaction time is long
The yield of the first step is only 30-35%, the reagents used are more, the amount of ion exchange resin is large, and the price is also expensive
[0007] 4, A.H.Pankowski, J.D.Meehan et al.Tetrahedron Letters.1994,35 (6): 927-930 discloses a kind of synthetic method, the tribenzyl citrate raw material used in this synthetic method does not sell in our country's market, its No. The one-step reaction directly adds phosphorus pentachloride solid, which makes the feeding uneven, easy to hydrolyze in the air, and the yield is low, only 61%, and the reaction catalyzed by palladium carbon is not specified.
[0008] 5. P.A.Turhanen, K.D.Demadis et al.J.Org.Chem.2007, 72:1468-1471 disclose a synthetic method, which has many steps, inconvenient operation and low yield
It is difficult to hydrolyze the three ethyl groups completely, and in the end, Dowex-50w ion exchange column has to be used, which is expensive and not suitable for industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] The preparation of embodiment 1 tribenzyl citrate

[0021] Weigh 28g of citric acid with a crystal water, put it in a 100ml three-necked bottle equipped with a water separator, a reflux device and a stirrer, then weigh 70g of benzyl alcohol into the three-necked bottle, and stir in an oil bath at 165°C React for 8 hours, then distill off excess benzyl alcohol under reduced pressure in an oil bath at 185°C, and finally dissolve the oily substance in absolute ethanol while standing still for several hours to precipitate tribenzyl citrate, then suction filter and dry Promptly obtain pure tribenzyl citrate, weighing 61.3g, the yield is 91%. The technical index of gained tribenzyl citrate is as follows:

[0022] White solid, m.p.50~51℃.

[0023] 1 H 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).

[0024] ESI-MS m / z (%): 461 ([M-H] - , 100).

Embodiment 2

[0025] The preparation of embodiment 2 tribenzyl citrate

[0026] Weigh 28g of citric acid with one crystal water, put it in a 100ml three-necked bottle equipped with a water separator, a reflux device and a stirrer, then weigh 70g of benzyl alcohol into the three-necked bottle, and stir in an oil bath at 180°C React for 8 hours, then distill off excess benzyl alcohol under reduced pressure in an oil bath at 185°C, and finally dissolve the oily substance in absolute ethanol while standing still for several hours to precipitate tribenzyl citrate, then suction filter and dry Promptly obtain pure tribenzyl citrate, weighing 62.7g, the yield is 93%.

example 3

[0027] The preparation of example 3 dibenzyl phosphate citrate

[0028] Add 30 g of tribenzyl citrate obtained in Example 1 and 25 ml of refined benzene in a 100 ml three-necked bottle equipped with a thermometer and a stirrer, stir and cool to 4 ° C under ice bath, and then dissolve the 13.6g PCl 5 100ml of benzene solution was slowly added dropwise to the solution, the temperature was maintained at 4°C, and the dropwise addition was performed for 2h. After the dropwise completion, the reaction was stirred for 0.5h, and then 4.9ml of distilled water was slowly added dropwise to ensure that the temperature did not rise (maintained at 4°C). After most of the water is added dropwise, there will be a white precipitate formed as dibenzyl phosphate citrate, continue to stir for 1 hour, and finally filter with suction, wash with benzene for 3 times, then dry it with KOH\NaOH drier, weigh 25.2 g, yield 86.3%.

[0029] The technical index of gained dibenzyl phosphate citrate is:

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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 [0001] The invention belongs to the field of synthesis of natural organic compounds. Background technique [0002] Phosphocitrate (PC) was first extracted from the mitochondria of human urine and rat liver (W.P.Tew, C.Mahle et al.Biochemistry, 1980, 19(9): 1983-1988), It is found that it has a good inhibitory effect on the precipitation and crystallization of calcium phosphate, and can effectively prevent the precipitation of calcium-containing crystals in bone joints and bone tissues, and is used for the treatment of osteoarthritis, rheumatoid arthritis and some related diseases, such as : Calcification of artificial heart valve, soft tissue tumor, urinary calculi, etc. Moreover, citrate phosphate does not have any significant side effects on rats and mice at a dose of 150umol / kg / day. Studies have shown that citrate phosphate will not affect the body when the concentration in the body reaches 1.5mM (4.5mg / mL). Normal functions of the cell, such as those of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/09
Inventor 陆豫余勃洪挺唐楚颖
Owner JIANGXI WANLI PHARMA CO LTD