CN102584890A - Method for synthesizing creatinol-o-phosphate - Google Patents
Method for synthesizing creatinol-o-phosphate Download PDFInfo
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- CN102584890A CN102584890A CN2011104354904A CN201110435490A CN102584890A CN 102584890 A CN102584890 A CN 102584890A CN 2011104354904 A CN2011104354904 A CN 2011104354904A CN 201110435490 A CN201110435490 A CN 201110435490A CN 102584890 A CN102584890 A CN 102584890A
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Abstract
The invention discloses a method for synthesizing creatinol-o-phosphate, which comprises the steps as follows: (1) N-methyl-2-amino ethanol is taken as a raw material, and reacts with phosphoric acid so as to obtain N-methyl-2-amino ethanol phosphate ester; and (2) the N-methyl-2-amino ethanol phosphate ester obtained in the step (1) reacts with O-methyl isourea sulfate under an alkaline condition so as to obtain the creatinol-o-phosphate. The method is simple and feasible to operate, technological conditions are mild, the productivity and the purity of the obtained product are high, waste gas and waste acid are not generated during the whole process, the safety of equipment and operating staff are ensured, environment cannot be polluted, economical efficiency is achieved, and the requirements of clean production are satisfied.
Description
Technical field
The present invention relates to the preparation method of creatinol verivate, be specifically related to a kind of compound method of phosphoric acid creatinol, belong to the organic chemistry synthesis technical field.
Background technology
Phosphoric acid creatinol (Creatinol phosphate; Be called for short COP); Chemical name: 1-(2-hydroxyethyl)-1-methylguanidine dihydrogen phosphate, English name: 1-(2-Hydroxyethyl)-1-methylguanidine dihydrogen phosphate, another name: aplodan.
The phosphoric acid creatinol is a kind of important medicine intermediate, as medicine can be used for calmness, anticonvulsion, anti-heart disorder, treatment Cardiac Insufficiency, regulate osmotic pressure, bring high blood pressure down, treat arteriosclerosis, suppress nervus centralis, keep eyesight, cholagogic, protect the liver, detoxifcation, anti-inflammatory, analgesic etc.The phosphoric acid creatinol helps the intelligence growth of human brain, and adult cardiovascular systems is had the function of a series of uniquenesses, have build up health, preventing disease, relieving fatigue, the effect of improving work efficiency.The phosphoric acid creatinol has antioxygenation, can delay human aging.The phosphoric acid creatinol is a kind of novel sports type healthcare products, foodstuff additive, as athletic senior tonic.The phosphoric acid creatinol turns to creatinol and creatinine at transit cell, for body provides energy, improves muscular strength and explosive power, and the volume of building up muscle improves muscle flexibility, avoids muscle injury, delays muscle fatigue.Along with to its research extensively and profoundly, its purposes will be more and more wider also.
In the prior art, the compound method of phosphoric acid creatinol mainly is in THF, to obtain creatinol with sodium borohydride reduction through creatine monohydrate, then with the phosphoric acid salify; At high temperature be dehydrated into aplodan then, reductive creatinol less stable under alkaline condition in this method, it is careful to take every caution against error during operation; Simultaneously because used a large amount of tetrahydrofuran solutions and Peng Qinghuana; Seriously polluted, security is low, is unfavorable for suitability for industrialized production.Chinese patent publication number CN101671358A, the applying date is 2010 03 month No. 17, discloses a kind of preparation method of aplodan; Adopt every mole of creatinol sulphate and 2-2.5 mole protective group agent stirring reaction in the ketone reaction medium; Add 1-2.5 mole phosphorylating agent then several times, under normal pressure, in 2-100 ℃ of reaction 2-8h; Obtain the aplodan bullion, obtain the pure article of aplodan at the water recrystallization.This method produces a large amount of acid waste liquids in process of production, and environmental pollution is serious, simultaneously owing to having applied to the phosphorylating agent Vanadium Pentoxide in FLAKES, to reacting used equipment and operational requirement than higher.
Summary of the invention
The technical problem that the present invention mainly solves provide a kind of simple, yield is high, pollute the compound method of low benzenephosphonic acid creatinol.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: a kind of preparation method of phosphoric acid creatinol comprises the steps:
(1) methyl-the 2-monoethanolamine is a raw material to adopt N-, makes N-methyl-2-monoethanolamine SULPHOSUCCINIC ACID ESTER with phosphatase reaction;
(2) N-methyl-2-monoethanolamine SULPHOSUCCINIC ACID ESTER that step (1) is obtained and O-Methyl Isourea Sulfate are reacted under alkaline condition and are made the phosphoric acid creatinol.
In preferred embodiment of the present invention, in the step (1), described N-methyl-2-monoethanolamine is 1:1～1.1 with the mol ratio of phosphoric acid.
In preferred embodiment of the present invention, in the step (1), described reaction conditions is: 0～180 ℃ of temperature of reaction, reaction times 2～6h.
In preferred embodiment of the present invention, in the step (1), described reaction conditions is: 40～150 ℃ of temperature of reaction, reaction times 3～5h.
In preferred embodiment of the present invention, in the step (2), the mol ratio of described N-methyl-2-monoethanolamine SULPHOSUCCINIC ACID ESTER and 0-Methyl Isourea Sulfate is 1:1～1.1.
In preferred embodiment of the present invention, in the step (2), described reaction conditions is: 0～60 ℃ of temperature of reaction, reaction times 1～4h.
In preferred embodiment of the present invention, in the step (2), described reaction conditions is: 10～50 ℃ of temperature of reaction, reaction times 2～3h.
Operation is simple for technical scheme provided by the invention, and processing condition are gentle, and the product yield of gained and purity are high; Do not produce waste gas and spent acid in the whole process; Guaranteed equipment and operator's safety, environmentally safe has not only embodied economy but also met the requirement that cleans production.
Embodiment
A kind of compound method of phosphoric acid creatinol comprises the steps:
(1) methyl-the 2-monoethanolamine is a raw material to adopt N-, makes N-methyl-2-monoethanolamine SULPHOSUCCINIC ACID ESTER with phosphatase reaction;
(2) N-methyl-2-monoethanolamine SULPHOSUCCINIC ACID ESTER that step (1) is obtained and O-Methyl Isourea Sulfate are reacted under alkaline condition and are made the phosphoric acid creatinol.
Wherein, in step (1), described N-methyl-2-monoethanolamine is 1:1～1.1 with the mol ratio of phosphoric acid; Described reaction conditions is: 0～180 ℃ of temperature of reaction; Reaction times 2～6h, preferred reaction conditions is: 40～150 ℃ of temperature of reaction, reaction times 3～5h; In step (2); The mol ratio of described N-methyl-2-monoethanolamine SULPHOSUCCINIC ACID ESTER and 0-Methyl Isourea Sulfate is 1:1～1.1, and described reaction conditions is: 0～60 ℃ of temperature of reaction, reaction times 1～4h; Preferred reaction conditions is: 10～50 ℃ of temperature of reaction, reaction times 2～3h.
The chemical equation of this reaction is:
Embodiment 1
75.8g Mono Methyl Ethanol Amine and 100ml water are added in the 1000ml four-hole boiling flask, and temperature control drips 99.1g phosphoric acid for 30 ℃, is warming up to 160 ℃, is evaporated to driedly, is cooled to 90 ℃; Add 200ml water, temperature control to 30 ℃ drips 186g O-Methyl Isourea Sulfate, dropwises; Insulation reaction 3h, using liquid caustic soda regulator solution PH is 7.0, is cooled to 0 ℃, filters; Filter cake adds 100 milliliters of frozen water washings, obtains the 155.9g aplodan after the drying, and purity is 99.12%, and yield is 79.14%.
Embodiment 2
75.8g Mono Methyl Ethanol Amine and 100ml water are added in the 1000ml four-hole boiling flask, and temperature control drips 110g phosphoric acid for 72 ℃, is warming up to 180 ℃, is evaporated to driedly, is cooled to 90 ℃; Add 200ml water, temperature control to 20 ℃ drips the 176.5gO-Methyl Isourea Sulfate, dropwises; Insulation reaction 1h, using liquid caustic soda regulator solution PH is 7.0, is cooled to 0 ℃, filters; Filter cake adds 100 milliliters of frozen water washings, obtains the 130.2g aplodan after the drying, and purity is 99.34%, and yield is 66.09%.
Embodiment 3
75.8g Mono Methyl Ethanol Amine and 100ml water are added in the 1000ml four-hole boiling flask, and temperature control drips 102.1g phosphoric acid for 60 ℃, is warming up to 140 ℃, is evaporated to driedly, is cooled to 90 ℃; Add 200ml water, temperature control to 0 ℃ drips the 193.6gO-Methyl Isourea Sulfate, dropwises; Insulation reaction 4h, using liquid caustic soda regulator solution PH is 7.0, is cooled to 0 ℃, filters; Filter cake adds 100 milliliters of frozen water washings, obtains the 125.9g aplodan after the drying, and purity is 99.55%, and yield is 63.91%.
Embodiment 4
75.8g Mono Methyl Ethanol Amine and 100ml water are added in the 1000ml four-hole boiling flask, and temperature control drips 105.1g phosphoric acid for 40 ℃, is warming up to 120 ℃, is evaporated to driedly, is cooled to 90 ℃; Add 200ml water, temperature control to 60 ℃ drips 188.4g O-Methyl Isourea Sulfate, dropwises; Insulation reaction 1.5h, using liquid caustic soda to transfer the condition solution PH is 7.0, is cooled to 0 ℃, filters; Filter cake adds 100 milliliters of frozen water washings, obtains the 98.9g aplodan after the drying, and purity is 99.63%, and yield is 50.20%.
Embodiment 5
75.8g Mono Methyl Ethanol Amine and 100ml water are added in the 1000ml four-hole boiling flask, and temperature control drips 100g phosphoric acid for 10 ℃, is warming up to 126 ℃, is evaporated to driedly, is cooled to 90 ℃; Add 200ml water, temperature control to 40 ℃ drips the 190.2gO-Methyl Isourea Sulfate, dropwises; Insulation reaction 2h, using liquid caustic soda regulator solution PH is 7.0, is cooled to 0 ℃, filters; Filter cake adds 100 milliliters of frozen water washings, obtains the 62.0g aplodan after the drying, and purity is 99.04%, and yield is 31.47%.
Embodiment 6
75.8g Mono Methyl Ethanol Amine and 100ml water are added in the 1000ml four-hole boiling flask, and temperature control drips 109g phosphoric acid for 8 ℃, is warming up to 144 ℃, is evaporated to driedly, is cooled to 90 ℃; Add 200ml water, temperature control to 35 ℃ drips 179.9 g O-Methyl Isourea Sulfate, dropwises; Insulation reaction 1.6h, using liquid caustic soda regulator solution PH is 7.0, is cooled to 0 ℃, filters; Filter cake adds 100 milliliters of frozen water washings, obtains the 112.1g aplodan after the drying, and purity is 99.24%, and yield is 56.91%.
Embodiment 7
75.8g Mono Methyl Ethanol Amine and 100ml water are added in the 1000ml four-hole boiling flask, and temperature control drips 101.1g phosphoric acid for 12 ℃, is warming up to 167 ℃, is evaporated to driedly, is cooled to 90 ℃; Add 200ml water, temperature control to 42 ℃ drips 184.6 gO-Methyl Isourea Sulfate, dropwises; Insulation reaction 3.5h, using liquid caustic soda regulator solution PH is 7.0, is cooled to 0 ℃, filters; Filter cake adds 100 milliliters of frozen water washings, obtains the 99.6g aplodan after the drying, and purity is 99.50%, and yield is 50.27%.
Embodiment 8
75.8g Mono Methyl Ethanol Amine and 100ml water are added in the 1000ml four-hole boiling flask, and temperature control drips 104.1g phosphoric acid for 15 ℃, is warming up to 140 ℃, is evaporated to driedly, is cooled to 90 ℃; Add 200ml water, temperature control to 55 ℃ drips 178.8 gO-Methyl Isourea Sulfate, dropwises; Insulation reaction 2.5h, using liquid caustic soda regulator solution PH is 7.0, is cooled to 0 ℃, filters; Filter cake adds 100 milliliters of frozen water washings, obtains the 88.9g aplodan after the drying, and purity is 99.18%, and yield is 45.13%.
Embodiment 9
75.8g Mono Methyl Ethanol Amine and 100ml water are added in the 1000ml four-hole boiling flask, and temperature control drips 101.7g phosphoric acid for 10 ℃, is warming up to 149 ℃, is evaporated to driedly, is cooled to 90 ℃; Add 200ml water, temperature control to 27 ℃ drips the 176gO-Methyl Isourea Sulfate, dropwises; Insulation reaction 2.5h, using liquid caustic soda regulator solution PH is 7.0, is cooled to 0 ℃, filters; Filter cake adds 100 milliliters of frozen water washings, obtains the 78.9g aplodan after the drying, and purity is 99.67%, and yield is 40.05%.
Embodiment 10
75.8g Mono Methyl Ethanol Amine and 100ml water are added in the 1000ml four-hole boiling flask, and temperature control drips 99.1g phosphoric acid for 0 ℃, is warming up to 168 ℃, is evaporated to driedly, is cooled to 90 ℃; Add 200ml water, temperature control to 16 ℃ drips 192.2 g) the O-Methyl Isourea Sulfate, dropwise; Insulation reaction 2.2h, using liquid caustic soda regulator solution PH is 7.0, is cooled to 0 ℃, filters; Filter cake adds 100 milliliters of frozen water washings, obtains 148.9 g aplodans after the drying, and purity is 99.54%, and yield is 75.58%.
The above is merely embodiments of the invention; Be not so limit claim of the present invention; Every equivalent structure or equivalent flow process conversion that utilizes specification sheets of the present invention to do, or directly or indirectly be used in other relevant technical fields, all in like manner be included in the scope of patent protection of the present invention.
Claims (7)
1. the compound method of a phosphoric acid creatinol is characterized in that, comprises the steps:
(1) methyl-the 2-monoethanolamine is a raw material to adopt N-, makes N-methyl-2-monoethanolamine SULPHOSUCCINIC ACID ESTER with phosphatase reaction;
(2) N-methyl-2-monoethanolamine SULPHOSUCCINIC ACID ESTER that step (1) is obtained and O-Methyl Isourea Sulfate are reacted under alkaline condition and are made the phosphoric acid creatinol.
2. the compound method of phosphoric acid creatinol according to claim 1 is characterized in that, in the step (1), described N-methyl-2-monoethanolamine is 1:1～1.1 with the mol ratio of phosphoric acid.
3. the compound method of phosphoric acid creatinol according to claim 1 is characterized in that, in the step (1), described reaction conditions is: 0～180 ℃ of temperature of reaction, reaction times 2～6h.
4. the compound method of phosphoric acid creatinol according to claim 3 is characterized in that, in the step (1), described reaction conditions is: 40～150 ℃ of temperature of reaction, reaction times 3～5h.
5. the compound method of phosphoric acid creatinol according to claim 1 is characterized in that, in the step (2), the mol ratio of described N-methyl-2-monoethanolamine SULPHOSUCCINIC ACID ESTER and 0-Methyl Isourea Sulfate is 1:1～1.1.
6. the compound method of phosphoric acid creatinol according to claim 1 is characterized in that, in the step (2), described reaction conditions is: 0～60 ℃ of temperature of reaction, reaction times 1～4h.
7. the compound method of phosphoric acid creatinol according to claim 6 is characterized in that, in the step (2), described reaction conditions is: 10～50 ℃ of temperature of reaction, reaction times 2～3h.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117087A (en) * | 2016-07-13 | 2016-11-16 | 启东瑞华药业有限公司 | A kind of creatinol method for production of phosphate salt |
| CN107445984A (en) * | 2017-07-26 | 2017-12-08 | 泰山医学院 | A kind of preparation method of creatinol-o-phosphate |
| CN116115814A (en) * | 2023-03-10 | 2023-05-16 | 潍坊医学院附属医院 | Trauma hemostatic dressing based on chitin |
| CN116115814B (en) * | 2023-03-10 | 2024-11-08 | 潍坊医学院附属医院 | Trauma hemostatic dressing based on chitin |
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| JPH0821930B2 (en) * | 1987-08-17 | 1996-03-04 | 三洋電機株式会社 | Data transmission device |
| CN1140506C (en) * | 1998-12-23 | 2004-03-03 | Basf公司 | Method for preparing guanidine derivative |
| CN101671358A (en) * | 2009-10-16 | 2010-03-17 | 天津天成制药有限公司 | Preparation method for creatinol-O-organic phosphate |
| US20110105786A1 (en) * | 2009-11-02 | 2011-05-05 | Tianjin Tiancheng Pharmaceutical Co., Ltd. | Creatinol o-phosphate and synthesis method thereof |
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2011
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH0821930B2 (en) * | 1987-08-17 | 1996-03-04 | 三洋電機株式会社 | Data transmission device |
| CN1140506C (en) * | 1998-12-23 | 2004-03-03 | Basf公司 | Method for preparing guanidine derivative |
| CN101671358A (en) * | 2009-10-16 | 2010-03-17 | 天津天成制药有限公司 | Preparation method for creatinol-O-organic phosphate |
| US20110105786A1 (en) * | 2009-11-02 | 2011-05-05 | Tianjin Tiancheng Pharmaceutical Co., Ltd. | Creatinol o-phosphate and synthesis method thereof |
Non-Patent Citations (1)
| Title |
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| 谢斌等: "肌肉醇磷酸盐的合成研究", 《西北大学学报（自然科学版）》, vol. 40, no. 5, 31 October 2010 (2010-10-31) * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117087A (en) * | 2016-07-13 | 2016-11-16 | 启东瑞华药业有限公司 | A kind of creatinol method for production of phosphate salt |
| CN107445984A (en) * | 2017-07-26 | 2017-12-08 | 泰山医学院 | A kind of preparation method of creatinol-o-phosphate |
| CN107445984B (en) * | 2017-07-26 | 2019-07-19 | 泰山医学院 | A kind of preparation method of creatinol-o-phosphate |
| CN116115814A (en) * | 2023-03-10 | 2023-05-16 | 潍坊医学院附属医院 | Trauma hemostatic dressing based on chitin |
| CN116115814B (en) * | 2023-03-10 | 2024-11-08 | 潍坊医学院附属医院 | Trauma hemostatic dressing based on chitin |
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