CN101492470B - Synthesis of phosphocreatine disodium salt - Google Patents
Synthesis of phosphocreatine disodium salt Download PDFInfo
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- CN101492470B CN101492470B CN2008100328843A CN200810032884A CN101492470B CN 101492470 B CN101492470 B CN 101492470B CN 2008100328843 A CN2008100328843 A CN 2008100328843A CN 200810032884 A CN200810032884 A CN 200810032884A CN 101492470 B CN101492470 B CN 101492470B
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Abstract
The invention relates to a synthetic method of disodium creatine phosphate, which is characterized in that a barium-free salt operation method is adopted. In the method, disodium creatinine phosphate is dissolved in water, activated carbon is used in ice-water bath for decolorizing, the filtering is carried out, ethanol is added to filtering liquid, and after the air pump filtration, refined products of the disodium creatinine phosphate are obtained; the refined products of the disodium creatinine phosphate are dissolved in water, the activated carbon is added, and then the refined products are stirred and filtered in the ice-water bath, sodium hydroxide regulating solution with pH value of 13-14 is added to the filtrate and stirred, hydrochloric acid is used in the ice-water bath to regulate the pH value to 7-10, the activated carbon is used for decolorizing at the room temperature, the filtering is carried out, ethanol is added to the filtrate and stirred continuously, and the disodium creatine phosphate is obtained after the air pump filtration; the obtained disodium creatine phosphate is dissolved in water, activated carbon is added and stirred, the filtering is carried out, ethanol is added to the filtrate and stirred continuously, and the refined products of the disodium creatine phosphate are obtained after the air pump filtration. The synthetic method of the invention has the advantage of removing impurities produced during the preparing process of the disodium creatine phosphate to the utmost extent.
Description
Technical field
The present invention relates to a kind of compound method of disodium creatine phosphate, relate in particular to the myocardial protective agent in the clinical application of the inside and outside section of a kind of clinical medicine heart, belong to the high energy compound technical field.
Background technology
Phosphocreatine (CP) is a kind of high energy compound that contains high-energy phosphate bond; In the animal muscle cell, exist in a large number; The important energy source of short, the big motion of intensity of the time of still not being engaged in, or the human body emergent energy that condition changes rapidly that starts, quickens and conform.Because exogenous phosphocreatine is not classified anti-depressant category as, also is widely used in sports in recent years.Phosphocreatine also has infringement in protection Skelettmuskel and the myocardium cell of avoiding causing under the Stress of intensive training and match; Improve a series of physiology, the biochemical functions such as recovery of training back muscle, so exogenous phosphocreatine is widely used also in medical field.Assign phosphocreatine as a kind of myocardial protective agent in the clinical application of the inside and outside section of heart, be applicable to the assisting therapy of myocardial ischemia, plumpness, myocardial infarction and heart failure, also can be used as various heart operatioies.
Phosphocreatine is many to be used with sodium-salt form.The preparation method of exogenous phosphocreatine sodium has synthesis method, biological extraction method and enzyme process at present.The patent documentation of biosynthetic enzyme process such as IT1044765 report, characteristics such as this method has the reaction conditions gentleness, speed of reaction is fast and specificity is strong.But the optimum condition of enzyme reaction is wayward, and reaction finishes to remove relatively difficulty of zymoprotein.The biological extraction method mainly is raw material with muscle tissue, because of phosphocreatine relative content in the muscle tissue on the low side, so cost is high.
Preparing Disodium phosphocreatine with synthesis method is a main path that obtains exogenous phosphocreatine at present.Comprise barium salt technology and no barium salt technology in the compound method.Barium salt technology is many to be the synthetic phosphocreatine of raw material with the creatine, and like Harbin University of Science and Technology's journal (2004,94 phases of volume, 124 pages-126 pages) reported method, this method yield is lower, and raw material can not reclaim, and wastes bigger.No barium salt technology such as US3036087 are that raw material is through the synthetic Disodium phosphocreatine of polystep reaction with dibenzyl phosphite and methyl-isothiourea; This method synthetic route is oversize; And used toxic agent such as red precipitate in the reaction, so safety precaution requires height in actual production, and cost is also corresponding higher.
If used barium salt, purifying is bad then might be brought in the product, influence Product Safety in Disodium phosphocreatine synthetic, so not have barium salt technology should be that the Disodium phosphocreatine synthetic is mainly developed direction.The patent documentation of US3632603 has been reported by creatinine and has been prepared chloro phosphinylidyne creatinine with phosphorus oxychloride reaction earlier; The latter obtains the Phosphorylcreatinine disodium with sodium hydroxide hydrolysis, neutralization, and this provides an important midbody for the synthetic phosphocreatine disodium of no barium salt mode.
Summary of the invention
The purpose of this invention is to provide and a kind ofly can remove the compound method that the Phosphorylcreatinine disodium prepares the disodium creatine phosphate of the impurity that produces in the process to greatest extent.
For realizing above purpose, technical scheme of the present invention provides a kind of compound method of disodium creatine phosphate, it is characterized in that, adopts no barium salt working method, and its method is:
The first step. the Phosphorylcreatinine disodium is dissolved in the water of 2-8 times of weight, with the decolorizing with activated carbon of 5%-20% times of weight, filters in the ice-water bath, in filtrating, add 4-80 times of weight ethanol, suction filtration gets Phosphorylcreatinine disodium highly finished product;
Second step. the Phosphorylcreatinine disodium highly finished product with the first step makes, be dissolved in the water of 2-10 times of weight, add the activated carbon of 5%-20% times of weight; Stirred 1 hour in the ice-water bath, filter, in filtrating, add sodium hydrate regulator solution pH13-14; 20-80 ℃ was stirred 0.1-36 hour, and in ice-water bath, transferred pH7-10 with hydrochloric acid again, the decolorizing with activated carbon of room temperature 5%-20% times of weight; Filter; In filtrating, add 6-100 times of weight ethanol, room temperature continues to stir 12 hours, and suction filtration must be suc as formula the phosphocreatine disodium shown in the I:
The 3rd step. the phosphocreatine disodium that second step was made is dissolved in the water of 2-10 times of weight; Add 5%-20% times of weight activated carbon; 20-80 ℃ was stirred 0.5-2 hour, filtered, and in filtrating, added 4-80 times of weight ethanol under the room temperature; Room temperature continues to stir 12 hours, and suction filtration gets phosphocreatine disodium highly finished product;
The 4th step. repeating step three to phosphocreatine disodium reaches the pharmaceutical quality requirement.
The employed Phosphorylcreatinine disodium of technology of the present invention is with reference to american documentation literature US3632603 preparation, and the quality product of phosphocreatine disodium is with HPLC method and ultraviolet absorption spectroscopy control.The phosphocreatine disodium the specification of quality that will reach comprise:
1. assay: measure phosphocreatine disodium (C according to HPLC (two appendix VD of Chinese Pharmacopoeia version in 2005)
4H
8N
3Na
2O
5P) content (calculating by anhydride) is no less than 97%;
2. related substance: creatinine≤1%; Creatine≤1%; Total impurities≤3%;
3. transmittance: transmittance >=98% of 25% phosphocreatine, two sodium water solutions under the 430nm wavelength.
The solvent that uses is general commercially available rank in the process step, need not special processing.
Positively effect of the present invention is: earlier the Phosphorylcreatinine disodium is made with extra care in the technical scheme, can be removed the impurity that the Phosphorylcreatinine disodium prepares in the process to be produced to greatest extent, this impurity is if bring in next step reaction, with the purifying number of times that increases product.The present invention proves through controlled trial: if the Phosphorylcreatinine disodium do not separate purifying, direct hydrolysis, then purifying products often, cost increases.
Embodiment
Through embodiment the present invention is done further explain below.
Embodiment 1
A kind of compound method of disodium creatine phosphate is:
The first step. the Phosphorylcreatinine disodium is dissolved in the water of 2 times of weight, with the decolorizing with activated carbon of 5% times of weight, filters in the ice-water bath, in filtrating, add 4 times of weight ethanol, suction filtration gets Phosphorylcreatinine disodium highly finished product;
Second step. the Phosphorylcreatinine disodium highly finished product with the first step makes, be dissolved in the water of 2 times of weight, add the activated carbon of 10% times of weight, stirred 1 hour in the ice-water bath; Filter, in filtrating, add sodium hydrate regulator solution pH13,80 ℃ were stirred 0.1 hour; In ice-water bath, transfer pH7 with hydrochloric acid again, the decolorizing with activated carbon of 20% times of weight of room temperature filters; In filtrating, add 6 times of weight ethanol, room temperature continues to stir 12 hours, and suction filtration must be suc as formula the phosphocreatine disodium shown in the I:
The 3rd step. the phosphocreatine disodium that second step was made is dissolved in the water of 2 times of weight, adds 5% times of weight activated carbon, and 80 ℃ were stirred 0.5 hour; Filter; In filtrating, add 4 times of weight ethanol under the room temperature, room temperature continues to stir 12 hours, and suction filtration gets phosphocreatine disodium highly finished product;
The 4th step. repeating step three once promptly gets and arrives the phosphocreatine disodium that pharmaceutical quality requires.Assay: 97.1%; Related substance: creatinine≤1%; Creatine≤1%; Total impurities≤3%; Transmittance: 98.2%.
Embodiment 2
A kind of compound method of disodium creatine phosphate is:
The first step. the Phosphorylcreatinine disodium is dissolved in the water of 5 times of weight, with the decolorizing with activated carbon of 20% times of weight, filters in the ice-water bath, in filtrating, add 40 times of weight ethanol, suction filtration gets Phosphorylcreatinine disodium highly finished product;
Second step. the Phosphorylcreatinine disodium highly finished product with the first step makes, be dissolved in the water of 6 times of weight, add the activated carbon of 20% times of weight, stirred 1 hour in the ice-water bath; Filter, in filtrating, add sodium hydrate regulator solution pH13,50 ℃ were stirred 18 hours; In ice-water bath, transfer pH8.5 with hydrochloric acid again, the decolorizing with activated carbon of 10% times of weight of room temperature filters; In filtrating, add 46 times of weight ethanol, room temperature continues to stir 12 hours, and suction filtration must be suc as formula the phosphocreatine disodium shown in the I:
The 3rd step. the phosphocreatine disodium that second step was made is dissolved in the water of 6 times of weight, adds 10% times of weight activated carbon, and 40 ℃ were stirred 1 hour; Filter; In filtrating, add 40 times of weight ethanol under the room temperature, room temperature continues to stir 12 hours, and suction filtration gets phosphocreatine disodium highly finished product;
The 4th step. repeating step three once promptly gets and arrives the phosphocreatine disodium that pharmaceutical quality requires.Assay: 97.4%; Related substance: creatinine≤1%; Creatine≤1%; Total impurities≤3%; Transmittance: 98.3%.
Embodiment 3
A kind of compound method of disodium creatine phosphate is:
The first step. the Phosphorylcreatinine disodium is dissolved in the water of 8 times of weight, with the decolorizing with activated carbon of 10% times of weight, filters in the ice-water bath, in filtrating, add 80 times of weight ethanol, suction filtration gets Phosphorylcreatinine disodium highly finished product;
Second step. the Phosphorylcreatinine disodium highly finished product with the first step makes, be dissolved in the water of 10 times of weight, add the activated carbon of 5% times of weight, stirred 1 hour in the ice-water bath; Filter, in filtrating, add sodium hydrate regulator solution pH14,20 ℃ were stirred 36 hours; In ice-water bath, transfer pH10 with hydrochloric acid again, the decolorizing with activated carbon of 5% times of weight of room temperature filters; In filtrating, add 100 times of weight ethanol, room temperature continues to stir 12 hours, and suction filtration must be suc as formula the phosphocreatine disodium shown in the I:
The 3rd step. the phosphocreatine disodium that second step was made is dissolved in the water of 10 times of weight, adds 20% times of weight activated carbon, and 20 ℃ were stirred 2 hours; Filter; In filtrating, add 80 times of weight ethanol under the room temperature, room temperature continues to stir 12 hours, and suction filtration gets phosphocreatine disodium highly finished product;
The 4th step. repeating step three once promptly gets and arrives the phosphocreatine disodium that pharmaceutical quality requires.Assay: 97.9%; Related substance: creatinine≤1%; Creatine≤1%; Total impurities≤3%; Transmittance: 98.7%.
Control Example
The first step. with reference to the patent documentation of US3632603, in the ice-water bath chloro phosphinylidyne creatinine for preparing is joined in 10% aqueous solution of sodium hydroxide of four times of amount of substances, be stirred to the dissolving back and transfer pH13 with sodium hydroxide, room temperature hydrolysis 36 hours.Hydrochloric acid is transferred pH9.0, adds 5 times of volume of ethanol of reaction solution, and room temperature continues to stir 12 hours.Suction filtration, the dry phosphocreatine disodium bullion that gets.
Second step. the phosphocreatine disodium that the first step is made is dissolved in the water of 10 times of weight, adds 20% times of weight activated carbon, and 50 ℃ were stirred 1 hour; Filter; In filtrating, add 60 times of weight ethanol under the room temperature, room temperature continues to stir 12 hours, and suction filtration gets phosphocreatine disodium highly finished product;
The 3rd step. repeating step must arrive the phosphocreatine disodium that pharmaceutical quality requires for two or four times.Assay: 97.2%; Related substance: creatinine≤1%; Creatine≤1%; Total impurities≤3%; Transmittance: 98.1%.
Claims (1)
1. the compound method of a disodium creatine phosphate is characterized in that, adopts no barium salt working method, and its method is:
The first step. the Phosphorylcreatinine disodium is dissolved in the water of 2-8 times of weight, with the decolorizing with activated carbon of 5%-20% times of weight, filters in the ice-water bath, in filtrating, add 4-80 times of weight ethanol, suction filtration gets Phosphorylcreatinine disodium highly finished product;
Second step. the Phosphorylcreatinine disodium highly finished product with the first step makes, be dissolved in the water of 2-10 times of weight, add the activated carbon of 5%-20% times of weight; Stirred 1-2 hour in the ice-water bath, filter, in filtrating, add sodium hydrate regulator solution pH13-14; 20-80 ℃ was stirred 0.1-36 hour, and in ice-water bath, transferred pH7-10 with hydrochloric acid again, the decolorizing with activated carbon of room temperature 5%-20% times of weight; Filter; In filtrating, add 6-100 times of weight ethanol, room temperature continues to stir 12 hours, and suction filtration must be suc as formula the phosphocreatine disodium shown in the I:
The 3rd step. the phosphocreatine disodium that second step was made is dissolved in the water of 2-10 times of weight; Add 5%-20% times of weight activated carbon; 20-80 ℃ was stirred 0.5-2 hour, filtered, and in filtrating, added 4-80 times of weight ethanol under the room temperature; Room temperature continues to stir 8-16 hour, and suction filtration gets phosphocreatine disodium highly finished product;
The 4th step. repeating step three to phosphocreatine disodium reaches pharmaceutical quality and requires:
1. assay: according to the high effective liquid chromatography for measuring of two appendix VD of Chinese Pharmacopoeia version in 2005, phosphocreatine two sodium contents calculate by anhydride and are no less than 97%;
2. related substance: creatinine≤1%; Creatine≤1%; Total impurities≤3%;
3. transmittance: transmittance >=98% of 25% phosphocreatine, two sodium water solutions under the 430nm wavelength.
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| CN2008100328843A CN101492470B (en) | 2008-01-22 | 2008-01-22 | Synthesis of phosphocreatine disodium salt |
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| CN2008100328843A CN101492470B (en) | 2008-01-22 | 2008-01-22 | Synthesis of phosphocreatine disodium salt |
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| CN101492470B true CN101492470B (en) | 2012-01-11 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101812088B (en) * | 2010-03-19 | 2012-09-26 | 海南美大制药有限公司 | High-purity creatine phosphate sodium compound |
| CN103012472B (en) * | 2012-12-10 | 2015-05-20 | 天津大学 | Crystal preparation method of creatine phosphate sodium |
| CN106279267B (en) * | 2015-05-20 | 2018-03-13 | 重庆圣华曦药业股份有限公司 | A kind of purification process of Creatine Phosphate Sodium and its preparation of aseptic powder |
| CN105294768B (en) * | 2015-10-26 | 2017-06-16 | 上海华拓医药科技发展有限公司 | Phosphocreatine class compound and its application |
| CN110294775B (en) * | 2018-03-23 | 2021-11-26 | 安徽古特生物科技有限公司 | Purification method of creatine phosphate sodium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3632603A (en) * | 1967-07-06 | 1972-01-04 | Ugine Kuhlmann | Process for the preparation of n2-di-chlorophosphoryl-creatinine |
| CN101033237A (en) * | 2007-03-30 | 2007-09-12 | 上海华拓医药科技发展股份有限公司 | Medicinal disodium creatine phosphate hexahydrate and preparing method thereof |
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2008
- 2008-01-22 CN CN2008100328843A patent/CN101492470B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3632603A (en) * | 1967-07-06 | 1972-01-04 | Ugine Kuhlmann | Process for the preparation of n2-di-chlorophosphoryl-creatinine |
| CN101033237A (en) * | 2007-03-30 | 2007-09-12 | 上海华拓医药科技发展股份有限公司 | Medicinal disodium creatine phosphate hexahydrate and preparing method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 赵春山.磷酸肌酸钠的合成研究.《哈尔滨理工大学学报》.2004,第9卷(第4期),124-126. * |
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Address after: 200240 Shanghai city Minhang District Jianchuan Road No. 951 Patentee after: Shanghai pharmaceutical Polytron Technologies Inc Address before: 200240 Shanghai city Minhang District Jianchuan Road No. 951 Patentee before: Shanghai Cirui Pharmaceutical Sci. & Tech. Co., Ltd. |
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Granted publication date: 20120111 Termination date: 20210122 |