CN101274943B - Synthetic method for disodium creatine phosphate - Google Patents
Synthetic method for disodium creatine phosphate Download PDFInfo
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- CN101274943B CN101274943B CN2007100384410A CN200710038441A CN101274943B CN 101274943 B CN101274943 B CN 101274943B CN 2007100384410 A CN2007100384410 A CN 2007100384410A CN 200710038441 A CN200710038441 A CN 200710038441A CN 101274943 B CN101274943 B CN 101274943B
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- creatine
- benzyloxy
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Abstract
The invention relates to a synthetic method of disodium creatine phosphate, which is characterized in that the method comprises the following steps: reacting creatine with C1-4 alkyl alcohol to produce corresponding creatine ester, or reacting the creatine with quaternary ammonium base to produce corresponding creatine ammonium salt, then reacting with dibenzyl phosphite to produce corresponding N-(dibenzyloxyphosphoryl) creatine ester or N-(dibenzyloxyphosphoryl) creatine to be hydrolyzed or neutralized by base for obtaining N-(dibenzyloxyphosphoryl) creatine sodium which goes through hydrogenolysis, removing benzyl for obtaining disodium creatine phosphate. The preparation method has the advantages: first, the creatine is prepared into the creatine ester or creatine ammonium salt, which increases the solubility of the creatine in a solvent of subsequent reaction, overcomes the problem that reaction temperature has to be raised, leading to increased by-products due to the poor solubility of the creatine in a reaction solvent existing in a former technique; the dibenzyl phosphite serves as an phosphorylating reagent, which avoids using phosphorus oxychloride with relatively high toxicity and irritation; toxic reagents such as mercuric oxide, etc., are not used in the reaction, thus reducing pollution to environment; the method has simple reaction process, low cost and high production rate.
Description
Technical field
The present invention relates to a kind of synthetic method of disodium creatine phosphate.
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.Simultaneously it also has infringement in the cell that protection skeletal muscle and cardiac muscle avoid causing under the Stress of intensive training and match, improves a series of physiology, the biochemical functions such as recovery of training back muscle.Exogenous phosphocreatine also is widely used 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.Because exogenous phosphocreatine is not classified anti-depressant category as, also is widely used in sports in recent years.
The preparation method of exogenous phosphocreatine has synthesis method, biological extraction method and enzyme process at present.Characteristics such as the patent report of biosynthetic enzyme process such as IT1044765, this method have 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 the cost height.
Preparing phosphocreatine with synthesis method is a main path that obtains exogenous phosphocreatine at present.The synthetic method of reporting among the US3632603 is the synthetic phosphocreatine of raw material with the creatinine, but needs with a large amount of phosphorus oxychloride reagent.Phosphorus oxychloride contaminate environment and required equipment are had relatively high expectations, and are unfavorable for scale operation.US3036087 is a raw material through the synthetic phosphocreatine of polystep reaction with dibenzyl phosphite and methyl-isothiourea, but this method synthetic route is oversize, and has used toxic agent such as red precipitate in the reaction, so safety precaution requires height in actual production.Also having method in addition is the synthetic phosphocreatine [Harbin University of Science and Technology's journal, 2004,9 (4), 124] of raw material with the creatine, but this method yield is low, and has used barium salt in synthetic, brings certain difficulty for the purifying of product.
Summary of the invention
The purpose of this invention is to provide that a kind of product yield height, working condition are realized easily, cost is low, workable and environment is polluted the synthetic method of few disodium creatine phosphate.
The present invention is achieved in that
(1) creatine and the reaction of C1-4 alkyl alcohol are generated corresponding creatine ester, or the level Four ammonium alkali reaction of creatine and equimolar amount is generated the creatine quarternary ammonium salt;
(2) dibenzyl phosphite and the carbon tetrachloride reaction of the creatine ester that step (1) is made or creatine quarternary ammonium salt and 1-5 times of molar weight generate corresponding N-(two benzyloxy phosphoryls) creatine ester or N-(two benzyloxy phosphoryls) creatine;
(3) N-that step (2) is made (two benzyloxy phosphoryls) creatine ester or N-(two benzyloxy phosphoryls) creatine are with basic hydrolysis or neutralize suc as formula the N-shown in the I (two benzyloxy phosphoryls) creatine sodium;
(4) N-that step (3) is made (two benzyloxy phosphoryls) creatine sodium carry out hydrogenolysis remove benzyl must be suc as formula the phosphocreatine sodium salt shown in the II;
Technical scheme provided by the present invention can realize with following more detailed processing step:
(1) with creatine and C
1-4Alkyl alcohol condensation in the presence of acidic substance generates corresponding creatine ester, and described acidic substance can be Lewis acid, hydrochloric acid, sulfuric acid or tosic acid; Or creatine and equimolar amount level Four ammonium alkali reacted in water, boil off behind the water the creatine quarternary ammonium salt;
(2) creatine ester or the creatine quarternary ammonium salt that step (1) is made; make action solvent with methylene dichloride, trichloromethane, ethylene dichloride or ethyl acetate; tetracol phenixin and dibenzyl phosphite with 1～5 times of molar weight in the presence of phase-transfer catalyst and alkaline matter react, and generate corresponding N-(two benzyloxy phosphoryls) creatine ester or the basic creatine of N-(two benzyloxy phosphinylidynes).
(3) N-that step (2) is made (two benzyloxy phosphoryls) creatine ester or N-(two benzyloxy phosphoryls) creatine are with sodium hydroxide, yellow soda ash hydrolysis or neutralize suc as formula the N-shown in the I (two benzyloxy phosphoryls) creatine sodium.
(4) N-that step (3) is made (two benzyloxy phosphoryls) creatine sodium is catalyzer with palladium-carbon, carry out under the normal pressure hydrogenolysis remove benzyl must be suc as formula the disodium creatine phosphate shown in the II.
The solvent that uses is general commercially available rank in the processing step, need not special processing.
Positively effect of the present invention is: earlier creatine is prepared into creatine ester or creatine ammonium salt in the technical scheme, increase the solvability of creatine in the solvent of subsequent reactions, overcome in the past in the technology because of creatine poorly soluble temperature of reaction that raises of having in reaction solvent, the problem that by product is increased; The present invention as phosphorus esterification reagent, has avoided the use of the bigger phosphorus oxychloride of toxicity and pungency with dibenzyl phosphite, does not use toxic agent such as red precipitate in the reaction, has reduced pollution on the environment; Reaction process is simple, cost is low, productive rate is high.
Embodiment
Below by embodiment the present invention is described in further detail.
Embodiment 1:
(1) methyl alcohol 400mL is chilled to-10 ℃ in cryosel is bathed, dripping thionyl chloride 37mL, and speed is dripped in control makes interior temperature not be higher than-5 ℃.Drip off the back and add anhydrous creatine (0.381mol), be warming up to 25 ℃, continue to stir treat that it dissolve after, continuation stirring 30 minutes.Slowly add ether 2600mL in reaction solution, suction filtration behind 0 ℃ of restir 1h gets the creatine methyl ester hydrochloride, yield 80.8%.
(2) creatine methyl ester hydrochloride (40.1mmol) is dissolved in the 100mL methylene dichloride, adds triethylamine (40.1mmol), adds phase-transfer catalyst bromination tetrabutylammonium (2mmol), KHCO down more successively in stirring
3(96.3mmol), K
2CO
3(96.3mmol), dibenzyl phosphite (48.1mmol) and CCl
4(51.2mmol), behind the room temperature reaction 24h, boil off solvent, get oily matter.This oily matter is dissolved in the ethyl acetate, respectively gives a baby a bath on the third day after its birth time through 5% citric acid and the saturated NaCl aqueous solution, with anhydrous sodium sulfate drying, the elimination siccative steams and desolventizes to such an extent that N-two benzyloxy phosphoryl creatine methyl esters are oily matter, yield 71.1%.
(3) N-two benzyloxy phosphoryl creatine methyl esters (20mmol) are stirred to raw material reaction and finish (TLC monitoring) in 10mL sodium hydroxide solution (4N) and 16mL alcoholic acid mixing solutions, and the gained reaction solution is directly used in next step reaction.
(4) add 10% palladium carbon catalyst, 1 gram in step (3) the gained reaction solution, stirring down, normal pressure suction H-H reaction stops to inhaling hydrogen, filtration catalizer, filter cake washs with 50% ethanol-water solution 10mL, merging filtrate, stir and slowly add 95% ethanol 250mL down, keep to stir 4-6 hour, and had the off-white color crystallization to separate out, next day suction filtration, it is white solid that vacuum-drying gets disodium creatine phosphate, two step yields 78%.Product is 98.6% through the HPLC purity assay.
Embodiment 2:
(1) butanols 500mL mixes with anhydrous creatine (0.381mol), adds a hydration tosic acid 1 gram, reflux water-dividing reaction 6 hours.Reclaim under reduced pressure butanols, residue are dissolved in ethyl acetate 200mL, with saturated sodium carbonate solution 100mL washing, divide and get ethyl acetate layer, and the saturated common salt washing boils off ethyl acetate and gets the creatine butyl ester, yield 62.1%.
(2) creatine butyl ester (40.1mmol) is dissolved in the 70mL trichloromethane, adds bromination tetrabutylammonium (2mmol), KHCO down successively in stirring
3(96.3mmol), K
2CO
3(96.3mmol), dibenzyl phosphite (48.1mmol) and CCl
4(51.2mmol), behind the room temperature reaction 24h, boil off solvent, get oily matter.This oily matter is dissolved in the ethyl acetate, respectively gives a baby a bath on the third day after its birth time through 5% citric acid and the saturated NaCl aqueous solution, with anhydrous sodium sulfate drying, the elimination siccative steams and desolventizes to such an extent that N-two benzyloxy phosphoryl creatine butyl esters are oily matter, yield 75.3%.
(3) N-two benzyloxy phosphoryl creatine butyl esters (20mmol) are stirred to raw material reaction and finish (TLC monitoring) in 10mL sodium carbonate solution (2mol/L) and 16mL alcoholic acid mixing solutions, and the gained reaction solution is directly used in next step reaction.
(4) add 5% palladium carbon catalyst, 1 gram in step (3) the gained reaction solution, stirring down, normal pressure suction H-H reaction stops to inhaling hydrogen, filtration catalizer, filter cake washs with 50% ethanol-water solution 10mL, merging filtrate, stir and slowly add 95% ethanol 250mL down, keep to stir 4-6 hour, and had the off-white color crystallization to separate out, next day suction filtration, it is white solid that vacuum-drying gets disodium creatine phosphate, two step yields 70.3%.Product is 98.9% through the HPLC purity assay.
Embodiment 3:
(1) gets creatine monohydrate (0.116mol) and be dissolved in the 10% TBAH aqueous solution (0.116mol), after evaporation is anhydrated, add dehydrated alcohol 50ml, drain dehydration again, get white solid, be the creatine tetrabutylammonium salt.
(2) creatine tetrabutylammonium salt (40.1mmol) is dissolved in the 100mL ethyl acetate, adds bromination tetrabutylammonium (2mmol), KHCO down successively in stirring
3(96.3mmol), K
2CO
3(96.3mmol), dibenzyl phosphite (48.1mmol) and CCl
4(51.2mmol), behind the room temperature reaction 24h, boil off solvent, get oily matter.This oily matter is dissolved in the ethyl acetate, respectively gives a baby a bath on the third day after its birth time through 5% citric acid and the saturated NaCl aqueous solution, with anhydrous sodium sulfate drying, the elimination siccative, steam desolventize N-two benzyloxy phosphoryl creatines, yield 62.3%.
(3) N-two benzyloxy phosphoryl creatines (20mmol) are dissolved in 10mL sodium hydroxide solution (4N) and the 16mL alcoholic acid mixing solutions, and gained solution is directly used in next step reaction.
(4) add 10% palladium carbon catalyst, 0.8 gram in step (3) the gained solution, stirring down, normal pressure suction H-H reaction stops to inhaling hydrogen, filtration catalizer, filter cake washs with 50% ethanol-water solution 10mL, merging filtrate, stir and slowly add 95% ethanol 250mL down, keep to stir 4-6 hour, and had the off-white color crystallization to separate out, next day suction filtration, it is white solid that vacuum-drying gets disodium creatine phosphate, two step yields 85.0%.Product is 98.5% through the HPLC purity assay.
Embodiment 4:
(1) gets creatine monohydrate (0.116mol) and be dissolved in 10% tetramethylammonium hydroxide aqueous solution (0.116mol), after evaporation is anhydrated, add dehydrated alcohol 50ml, drain dehydration again, get white solid, be creatine tetramethyl ammonium salt.
(2) creatine tetramethyl ammonium salt (40.1mmol) is dissolved in the 30mL ethylene dichloride, adds bromination tetrabutylammonium (4mmol), KHCO down successively in stirring
3(360mmol), K
2CO
3(360mmol), dibenzyl phosphite (180mmol) and CCl
4(190mmol), behind the room temperature reaction 24h, boil off solvent, get oily matter.This oily matter is dissolved in the ethyl acetate, respectively gives a baby a bath on the third day after its birth time through 5% citric acid and the saturated NaCl aqueous solution, with anhydrous sodium sulfate drying, the elimination siccative, steam desolventize N-two benzyloxy phosphoryl creatines, yield 53.9%.
(3), (4) two steps are identical with embodiment 3, two go on foot yields 81.3%.Product is 98.7% through the HPLC purity assay.
Embodiment 5:
(1) gets creatine monohydrate (0.116mol) and be dissolved in the 10% benzyl triethyl ammonium ammonium hydroxide aqueous solution (0.116mol), after evaporation is anhydrated, add dehydrated alcohol 50ml, drain dehydration again, get white solid, be creatine benzyl triethyl ammonium ammonium salt.
(2) creatine benzyl triethyl ammonium ammonium salt (40.1mmol) is dissolved in the 60mL ethylene dichloride, adds bromination tetrabutylammonium (3mmol), KHCO down successively in stirring
3(180mmol), K
2CO
3(180mmol), dibenzyl phosphite (90mmol) and CCl
4(92mmol), behind the room temperature reaction 24h, boil off solvent, get oily matter.This oily matter is dissolved in the ethyl acetate, respectively gives a baby a bath on the third day after its birth time through 5% citric acid and the saturated NaCl aqueous solution, with anhydrous sodium sulfate drying, the elimination siccative, steam desolventize N-two benzyloxy phosphoryl creatines, yield 72.3%.
(3), (4) two steps are identical with embodiment 3, two go on foot yields 78.9%.Product is 98.5% through the HPLC purity assay.
Claims (6)
1. the synthetic method of a disodium creatine phosphate is characterized in that, comprises following reactions steps:
(1) with creatine and C
1-4Alkyl alcohol reaction generate corresponding creatine ester, or with the level Four ammonium alkali reaction generation creatine quarternary ammonium salt of creatine and equimolar amount;
(2) the creatine ester that described (1) step is made or the dibenzyl phosphite and the carbon tetrachloride reaction of creatine quarternary ammonium salt and 1-5 times of molar weight generate N-(two benzyloxy phosphoryls) creatine ester or N-(two benzyloxy phosphoryls) creatine;
(3) with described (2) N-(two benzyloxy phosphoryls) the creatine ester that makes of step or N-(two benzyloxy phosphoryls) creatine with basic hydrolysis or neutralize N-(two benzyloxy phosphoryls) creatine sodium;
(4) described (3) (N-two benzyloxy phosphoryls) creatine sodium of making of step being carried out hydrogenolysis removes benzyl and gets disodium creatine phosphate.
2. according to the synthetic method of the described a kind of disodium creatine phosphate of claim 1, it is characterized in that step (1) is with creatine and C
1-4Alkyl alcohol condensation in the presence of acidic substance generate corresponding creatine ester, described acidic substance are Lewis acid, hydrochloric acid, sulfuric acid or tosic acid; Or the level Four ammonium alkali of creatine and equimolar amount reacted in water, boil off behind the water the creatine quarternary ammonium salt; Described Lewis acid is a sulfur oxychloride.
3. according to the synthetic method of the described a kind of disodium creatine phosphate of claim 1; it is characterized in that; to be creatine ester that step (1) is made or creatine quarternary ammonium salt make action solvent with methylene dichloride or trichloromethane, ethylene dichloride, ethyl acetate to step (2); in the presence of phase-transfer catalyst and alkaline matter, with dibenzyl phosphite and carbon tetrachloride reaction generation corresponding N-(two benzyloxy phosphoryls) the creatine ester or N-(the two benzyloxy phosphoryls) creatine of 1-5 times of molar weight.
4. according to the synthetic method of the described a kind of disodium creatine phosphate of claim 1; it is characterized in that, step (3) be N-(two benzyloxy phosphoryls) creatine ester that step (2) is made or N-(two benzyloxy phosphoryls) creatine with sodium hydroxide, yellow soda ash hydrolysis or neutralize N-(two benzyloxy phosphoryls) creatine sodium.
5. according to the synthetic method of the described a kind of disodium creatine phosphate of claim 1; it is characterized in that; step (4) is that N-(two benzyloxy phosphoryls) the creatine sodium that step (3) is made is catalyzer with palladium-carbon, carries out hydrogenolysis under the normal pressure and removes benzyl and get disodium creatine phosphate.
6. according to the synthetic method of the described a kind of disodium creatine phosphate of claim 1, it is characterized in that described level Four ammonium alkali is TBAH, Tetramethylammonium hydroxide or benzyl triethyl ammonium ammonium hydroxide.
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| CN103819502A (en) * | 2014-03-01 | 2014-05-28 | 张家港威胜生物医药有限公司 | Method for preparing creatine phosphate sodium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3036087A (en) * | 1958-09-26 | 1962-05-22 | Cfmc | Process for the preparation of phosphocreatine and/or phosphocreatinine |
| US3632603A (en) * | 1967-07-06 | 1972-01-04 | Ugine Kuhlmann | Process for the preparation of n2-di-chlorophosphoryl-creatinine |
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2007
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3036087A (en) * | 1958-09-26 | 1962-05-22 | Cfmc | Process for the preparation of phosphocreatine and/or phosphocreatinine |
| US3632603A (en) * | 1967-07-06 | 1972-01-04 | Ugine Kuhlmann | Process for the preparation of n2-di-chlorophosphoryl-creatinine |
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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