CN107445984B - A kind of preparation method of creatinol-o-phosphate - Google Patents
A kind of preparation method of creatinol-o-phosphate Download PDFInfo
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- CN107445984B CN107445984B CN201710619652.7A CN201710619652A CN107445984B CN 107445984 B CN107445984 B CN 107445984B CN 201710619652 A CN201710619652 A CN 201710619652A CN 107445984 B CN107445984 B CN 107445984B
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- creatinol
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- ethyl acetate
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- FOIPWTMKYXWFGC-UHFFFAOYSA-N creatinolfosfate Chemical compound NC(=N)N(C)CCOP(O)(O)=O FOIPWTMKYXWFGC-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 81
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229960002956 creatinolfosfate Drugs 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000010992 reflux Methods 0.000 claims abstract description 12
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000013078 crystal Substances 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 239000007787 solid Substances 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 9
- 230000006837 decompression Effects 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 210000003205 muscle Anatomy 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000007791 liquid phase Substances 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- -1 creatinol phosphoric acid salt Chemical class 0.000 claims description 3
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 150000001718 carbodiimides Chemical class 0.000 claims 3
- 235000013372 meat Nutrition 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 12
- ORTUDDOFSUHQKZ-UHFFFAOYSA-N 1-(2-hydroxyethyl)-1-methylguanidine Chemical compound NC(=N)N(C)CCO ORTUDDOFSUHQKZ-UHFFFAOYSA-N 0.000 abstract description 10
- 239000012024 dehydrating agents Substances 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 5
- 230000032050 esterification Effects 0.000 abstract description 5
- 238000005886 esterification reaction Methods 0.000 abstract description 5
- 150000002148 esters Chemical class 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000012452 mother liquor Substances 0.000 abstract description 2
- 238000001953 recrystallisation Methods 0.000 abstract description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 abstract 3
- 238000001914 filtration Methods 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 7
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 6
- 229940092714 benzenesulfonic acid Drugs 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- SADHVOSOZBAAGL-UHFFFAOYSA-N 3-(trifluoromethoxy)aniline Chemical compound NC1=CC=CC(OC(F)(F)F)=C1 SADHVOSOZBAAGL-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- DDFGTVSLZJLQEV-UHFFFAOYSA-N [C](C1CCCCC1)C1CCCCC1 Chemical compound [C](C1CCCCC1)C1CCCCC1 DDFGTVSLZJLQEV-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- XFDJMIHUAHSGKG-UHFFFAOYSA-N chlorethoxyfos Chemical compound CCOP(=S)(OCC)OC(Cl)C(Cl)(Cl)Cl XFDJMIHUAHSGKG-UHFFFAOYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229950007002 phosphocreatine Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of preparation methods of creatinol-o-phosphate, include the following steps: ethyl acetate, creatinol phosphate, p-methyl benzenesulfonic acid and dicyclohexylcarbodiimide after mixing, heating reflux reaction is to get creatinol-o-phosphate crystal.P-methyl benzenesulfonic acid plays the role of being catalyzed in creatinol phosphate creatinol and phosphoric acid into ester as catalyst.Dicyclohexylcarbodiimide (DCC) sloughs the water of esterification generation as dehydrating agent, so that entire reaction carries out thoroughly, improving reaction yield.Simultaneously, reaction dissolvent ethyl acetate can recycle, the byproduct and impurity generated during the reaction has been partially left in ethyl acetate mother liquor, remaining dicyclohexylcarbodiimide (DCC) water suction generates 1,3- dicyclohexylurea (DCU) (DCU), the substance is not soluble in water, easy to separate and purify in recrystallization process, and product purity has been effectively ensured.
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of preparation method of creatinol-o-phosphate.
Background technique
Creatinol-o-phosphate is a kind of novel sports type products and health products additive agent, is a kind of efficiently movement tonic, nutritional agents
Main functional component, it is similar in the intracorporal function of people with phosphocreatine substance, in muscle phosphate group can participate in ADP to
The conversion of ATP provides energy for body, increases muscle power.Meanwhile creatinol-o-phosphate can increase muscle volume, improve
The flexibility and explosive force of muscle, delay muscular fatigue.Because creatinol-o-phosphate is highly soluble in water, can directly be absorbed by the body
It utilizes, and nonhazardous acts on, is pursued degree more than protein product.With the fast development of China's movement industry, correlation fortune
The demand of dynamic functional food will quickly increase, the wide market of creatinol-o-phosphate.Creatinol-o-phosphate can also be used simultaneously
In treating myocardial atrophy caused by Hypoxia and ischemia.Therefore a kind of synthesis technology is simple, safety, high yield, high-purity, " green "
Chemical synthesis process route will have great significance to the exploitation of muscle alcoholic product.
Creatinol-o-phosphate structural formula is as follows:
The synthetic method of the creatinol-o-phosphate being currently known mainly include the following types:
(1) it is original with creatinol phosphate that 1: 1977 year U.S. Patent Publication another kind of method, which is utilized using strong dehydrating agent,
Material, sloughs the method that a molecule moisture prepares creatinol creatinol-o-phosphate under the conditions of high-temperature low-pressure.Dehydrating agent therein has more
Polyphosphoric acid (US40124670).Creatinol phosphate and polyphosphoric acids reaction, reaction solution directly mix, and do not dilute or other
Solvent exists, and is heated to melt, moisture is removed under vacuum, is separated after reaction with organic solvent deposit, byproduct and original raw material
Equal impurity can be dissolved completely in solution, and filtering or suction filtration can completely remove impurity.Though the method process flow is easy to operate,
The raw material of reaction is rare, and industrialized requirement is not achieved (polyphosphoric acids is expensive, is not suitable for industrial production).
It is as follows to synthesize equation:
(2) N- is obtained with phosphatase reaction using N- (methylamino) ethyl alcohol as raw material in patent disclosed in method two: Wen Jianhua et al.
(methylamino) ethanol phosphate ester；N- methyl-2-amino ethanol phosphate ester is reacted under alkaline condition with O- Methyl Isourea Sulfate
It is made creatinol-o-phosphate (CN102584890).The first step esterification of this method is not easy to control, and there are phosphoric acid polyester
Mixture, separating-purifying are difficult.Practical synthesis yield and purity is not high, and reaction equation is as follows:
(3) method three: belgian patent report creatinol hydrobromate and phosphorus oxychloride carry out condensation reaction and prepare phosphoric acid
Creatinol (BE666891).This method is cumbersome, takes a long time, and hydrochloric acid and hydrobromic acid generate, and are not easy to be eliminated.Reaction side
Formula is as follows.
(4) method four: Zhang Guoji et al. discloses one kind using creatinol sulphate as raw material, utilizes phosphorus pentoxide, three
Chlorethoxyfos prepare the method (US2014256987) of creatinol-o-phosphate as dehydrating agent.This method uses dense sulphur in organic solvent
Acid, phosphorus pentoxide processing creatinol sulphate obtain creatinol-o-phosphate, and yield is higher, but last handling process is complex, produces
Raw a large amount of waste acid liquor.
In conclusion there are various problems, still shortage effective solution for the preparation method of creatinol-o-phosphate in the prior art
Scheme.
Summary of the invention
For above-mentioned the technical problems existing in the prior art, the object of the present invention is to provide a kind of systems of creatinol-o-phosphate
Preparation Method.The preparation method is easy to industrialized production, and purity and yield are higher, and the discharge amount of waste water is few.
In order to solve the above technical problems, the technical solution of the present invention is as follows:
A kind of preparation method of creatinol-o-phosphate, includes the following steps:
Ethyl acetate, creatinol phosphate, p-methyl benzenesulfonic acid and dicyclohexylcarbodiimide after mixing, are heated to reflux
Reaction is to get creatinol-o-phosphate crystal.
Reaction equation is as follows:
In this method, p-methyl benzenesulfonic acid plays in catalysis creatinol phosphate creatinol and phosphoric acid into ester as catalyst
Effect.Dicyclohexylcarbodiimide (DCC) sloughs the water of esterification generation as dehydrating agent, so that entire reaction progress is thorough
Bottom improves reaction yield.Meanwhile reaction dissolvent ethyl acetate can recycle, the byproduct generated during the reaction
It has been partially left in ethyl acetate mother liquor with impurity, remaining dicyclohexylcarbodiimide (DCC) water suction generates 1,3-, bis- hexamethylene
Base urea (DCU), the substance is not soluble in water, easy to separate and purify in recrystallization process, and product purity has been effectively ensured.
This method simple process is conducive to the purity and yield that improve product convenient for the control of technological parameter.This method
Raw material is simple and easy to get, is easy to carry out industrialized production.The discharge amount of waste water is few in preparation process simultaneously, and composite energy-saving environment protection is wanted
It asks.
Preferably, in the preparation method, the matter of ethyl acetate, creatinol phosphate and dicyclohexylcarbodiimide (DCC)
Measure ratio are as follows: 10-20:1-2:1-2, preferably 12-18:1-2:1-2, further preferably 15:1-2:1-2, still more preferably
For 15:2:1.
Preferably, in the preparation method, the dosage to benzene methanesulfonic acid is the 0.5-1% of creatinol phosphoric acid salt quality, into one
Step is preferably creatinol phosphatic 1%.
Preferably, the temperature of heating reflux reaction is 80-90 DEG C, and the time is 2-4 hours, and the preferred time is 3 hours.
Preferably, heating reflux reaction carries out under stirring.
Preferably, after reaction, decompression steams 75-85% ethyl acetate first, is separated by solid-liquid separation after cooling, obtains phosphoric acid
Creatinol crude product.
It is further preferred that the preparation method further includes the steps that purifying creatinol-o-phosphate crude product.
Still more preferably, the method purified to creatinol-o-phosphate crude product includes the following steps: phosphoric acid muscle
Alcohol crude product is dissolved in pure water, after being heated to 60-80 DEG C, is filtered while hot, filtered liquid phase crystallisation by cooling, after separation of solid and liquid
To creatinol-o-phosphate crystal after purification.
Preferably, the mass ratio of creatinol-o-phosphate crude product and pure water is 5-7:1, preferably 6:1.
Above-mentioned preparation method is preparing the application in creatinol-o-phosphate.
The beneficial effects of the present invention are:
1, using creatinol phosphate as raw material in the present invention, directly in organic solvent using p-methyl benzenesulfonic acid as catalysis
Agent is catalyzed creatinol and phosphoric acid into ester.The average yield (in terms of creatinol phosphate) for obtaining creatinol-o-phosphate is higher than 90%.
2, reaction efficiency is effectively raised using dicyclohexylcarbodiimide (DCC) as dehydrating agent in the present invention, dropped
Low reaction temperature, later period byproduct is easy to separate and purify, and the purity of the creatinol-o-phosphate of acquisition is greater than 98%.
3, entire technique can be recycled in synthesis process non-wastewater discharge, ethyl acetate.It is smaller to recrystallize water consumption,
Discharge amount is few, is easy to biochemical treatment.
Detailed description of the invention
The accompanying drawings constituting a part of this application is used to provide further understanding of the present application, and the application's shows
Meaning property embodiment and its explanation are not constituted an undue limitation on the present application for explaining the application.
Fig. 1 is the hot ellipsoid figure of mono-crystalline structures of 1 synthetic product of the embodiment of the present invention；
Fig. 2 is the FTIR spectrogram of 1 synthetic product of the embodiment of the present invention；
Fig. 3 is the high-efficient liquid phase chromatogram (chromatographic condition: Detection wavelength 207nm of 1 synthetic product of case study on implementation of the present invention；
Pure methanol/water=the 7:3 of mobile phase；C18 column；99%) test sample purity is higher than.
Specific embodiment
It is noted that following detailed description is all illustrative, it is intended to provide further instruction to the application.Unless another
It indicates, all technical and scientific terms used herein has usual with the application person of an ordinary skill in the technical field
The identical meanings of understanding.
It should be noted that term used herein above is merely to describe specific embodiment, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singular
Also it is intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet
Include " when, indicate existing characteristics, step, operation, device, component and/or their combination.
Embodiment 1:
150g ethyl acetate, 20g creatinol phosphate are sequentially added in the flask of the 500mL with reflux unit, to first
Benzene sulfonic acid 0.2g, dicyclohexylcarbodiimide (DCC) 10g, under stirring, reaction temperature is 90 DEG C, back flow reaction 3 hours
Decompression steams 120g ethyl acetate afterwards, obtains white solid after cold filtration.Solid is added in 100g distilled water, is heated to 60
It DEG C filters, is cooled to room temperature, filtration drying obtains white creatinol-o-phosphate 17g, with creatinol phosphate collecting rate 93% while hot.
Product prepared by the present invention is creatinol-o-phosphate it can be seen from Fig. 1 and Fig. 2.
Fig. 3 is the high-efficient liquid phase chromatogram of the synthetic product of embodiment 1, and table 1 is analysis result table.It can by Fig. 3 and table 1
Know, the purity of the creatinol-o-phosphate of preparation is higher than 99%.
Table 1
Embodiment 2:
150g ethyl acetate, 20g creatinol phosphate are sequentially added in the flask of the 500mL with reflux unit, to first
Benzene sulfonic acid 0.2g, dicyclohexylcarbodiimide (DCC) 20g, under stirring, reaction temperature is 87 DEG C, back flow reaction 3 hours
Decompression steams 122g ethyl acetate afterwards, and cold filtration obtains white solid.Solid is added in 100g distilled water, is heated to 60 DEG C
It filters, is cooled to room temperature while hot, filtration drying obtains white creatinol-o-phosphate 16.8g, is with creatinol phosphate collecting rate
92%；The purity of the creatinol-o-phosphate of preparation is higher than 99%.
Embodiment 3:
100g ethyl acetate, 20g creatinol phosphate are sequentially added in the flask of the 500mL with reflux unit, to first
Benzene sulfonic acid 0.1g, dicyclohexylcarbodiimide (DCC) 10g, under stirring, reaction temperature is 88 DEG C, back flow reaction 3 hours
Decompression steams 114g ethyl acetate afterwards, and cold filtration obtains white solid.Solid is added in 100g distilled water, is heated to 60 DEG C
It filters, is cooled to room temperature while hot, filtration drying obtains white creatinol-o-phosphate 15g, with creatinol phosphate collecting rate 82%；System
The purity of standby creatinol-o-phosphate is higher than 97%.
Embodiment 4:
200g ethyl acetate, 20g creatinol phosphate are sequentially added in the flask of the 500mL with reflux unit, to first
Benzene sulfonic acid 0.2g, dicyclohexylcarbodiimide (DCC) 10g, under stirring, reaction temperature is 86 DEG C, back flow reaction 2 hours
Decompression steams 125g ethyl acetate afterwards, and cold filtration obtains white solid.Solid is added in 100g distilled water, is heated to 60 DEG C
It filters, is cooled to room temperature while hot, filtration drying obtains white creatinol-o-phosphate 15g, with creatinol phosphate collecting rate 82%；System
The purity of standby creatinol-o-phosphate is higher than 97%.
Embodiment 5:
150g ethyl acetate, 20g creatinol phosphate are sequentially added in the flask of the 500mL with reflux unit, to first
Benzene sulfonic acid 0.2g, dicyclohexylcarbodiimide (DCC) 10g, under stirring, reaction temperature is 86 DEG C, back flow reaction 4 hours
Decompression steams 110g ethyl acetate afterwards, and cold filtration obtains white solid.Solid is added in 100g distilled water, is heated to 60 DEG C
It filters, is cooled to room temperature while hot, filtration drying obtains white creatinol-o-phosphate 16.5g, with creatinol phosphate collecting rate 90%；
The purity of the creatinol-o-phosphate of preparation is higher than 98%.
Embodiment 6:
200g ethyl acetate, 20g creatinol phosphate are sequentially added in the flask of the 500mL with reflux unit, to first
Benzene sulfonic acid 0.2g, dicyclohexylcarbodiimide (DCC) 10g, under stirring, reaction temperature is 86 DEG C, back flow reaction 3 hours
Decompression steams 160g ethyl acetate afterwards, and cold filtration obtains white solid.Solid is added in 100g distilled water, is heated to 60 DEG C
It filters, is cooled to room temperature while hot, filtration drying obtains white creatinol-o-phosphate 16g, with creatinol phosphate collecting rate 87%；System
The purity of standby creatinol-o-phosphate is higher than 96%.
The core of technical solution of the present invention is that directly using p-methyl benzenesulfonic acid as esterification catalyst, dicyclohexyl carbon two is sub-
Amine (DCC) is used as dehydrating agent, so that esterification progress is quickly thorough.And the by-product in reaction process is easily isolated, and is improved
The purity of creatinol-o-phosphate.It is substantially better than on yield and purity using technical solution of the present invention synthesis creatinol-o-phosphate existing
Some synthesis technologies.
The foregoing is merely preferred embodiment of the present application, are not intended to limit this application, for the skill of this field
For art personnel, various changes and changes are possible in this application.Within the spirit and principles of this application, made any to repair
Change, equivalent replacement, improvement etc., should be included within the scope of protection of this application.
Claims (8)
1. a kind of preparation method of creatinol-o-phosphate, characterized by the following steps:
Ethyl acetate, creatinol phosphate, p-methyl benzenesulfonic acid and dicyclohexylcarbodiimide after mixing, are heated to reflux anti-
It should be to get creatinol-o-phosphate crystal；The mass ratio of ethyl acetate, creatinol phosphate and dicyclohexylcarbodiimide are as follows: 10-
20:1-2:1-2；After reaction, decompression steams 75-85% ethyl acetate first, is separated by solid-liquid separation after cooling, obtains phosphoric acid muscle
Alcohol crude product；To the method that creatinol-o-phosphate crude product is purified, include the following steps: creatinol-o-phosphate crude product being dissolved in pure water
In, it after being heated to 60-80 DEG C, filters while hot, filtered liquid phase crystallisation by cooling, obtains phosphoric acid flesh after purification after separation of solid and liquid
Meat alcohol crystals.
2. preparation method according to claim 1, it is characterised in that: ethyl acetate, creatinol phosphate and dicyclohexyl
The mass ratio of carbodiimide is 12-18:1-2:1-2.
3. preparation method according to claim 2, it is characterised in that: ethyl acetate, creatinol phosphate and dicyclohexyl
The mass ratio of carbodiimide is 15:1-2:1-2.
4. preparation method according to claim 3, it is characterised in that: ethyl acetate, creatinol phosphate and dicyclohexyl
The mass ratio of carbodiimide is 15:2:1.
5. preparation method according to claim 1, it is characterised in that: in the preparation method, the dosage to benzene methanesulfonic acid is
The 0.5-1% of creatinol phosphoric acid salt quality.
6. preparation method according to claim 3, it is characterised in that: the dosage to benzene methanesulfonic acid is creatinol phosphate matter
The 1% of amount.
7. preparation method according to claim 1, it is characterised in that: heating reflux reaction is to carry out under stirring
's.
8. preparation method according to claim 7, it is characterised in that: the mass ratio of creatinol-o-phosphate crude product and pure water is 5-
7:1。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2006484C3 (en) * | 1969-11-18 | 1973-09-13 | Siphar S.A., Lugano (Schweiz) | Process for the production of creatinol-O-dihydrogen phosphate |
| CN102584890A (en) * | 2011-12-23 | 2012-07-18 | 江苏远洋药业股份有限公司 | Method for synthesizing creatinol-o-phosphate |
| CN106188131A (en) * | 2016-07-13 | 2016-12-07 | 启东瑞华药业有限公司 | A kind of preparation method of meat alcohol phosphate ester |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2006484C3 (en) * | 1969-11-18 | 1973-09-13 | Siphar S.A., Lugano (Schweiz) | Process for the production of creatinol-O-dihydrogen phosphate |
| CN102584890A (en) * | 2011-12-23 | 2012-07-18 | 江苏远洋药业股份有限公司 | Method for synthesizing creatinol-o-phosphate |
| CN106188131A (en) * | 2016-07-13 | 2016-12-07 | 启东瑞华药业有限公司 | A kind of preparation method of meat alcohol phosphate ester |
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