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Creatine is a nitrogenous organic acid that occurs naturally in vertebrates. It facilitates the recycling of adenosine triphosphate (ATP) primarily in muscle and brain tissue.
Synonyms: Methylguanidoacetic acid
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| CAS No. : | 57-00-1 |
| Formula : | C4H9N3O2 |
| M.W : | 131.13 |
| SMILES Code : | O=C(O)CN(C)C(N)=N |
| Synonyms : |
Methylguanidoacetic acid
|
| MDL No. : | MFCD00004282 |
| InChI Key : | CVSVTCORWBXHQV-UHFFFAOYSA-N |
| Pubchem ID : | 586 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H315-H319-H335 |
| Precautionary Statements: | P261-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 89% | With phosgene; dmap; at 10℃; for 0.5h;Sealed tube; | 1000 g of ethanol was sequentially added to a 2000 mL flask equipped with a stirring device.1.0 g 4-dimethylaminopyridine, 100 g creatine monohydrate, stir and cool to 10 C,Start to add 100g of phosgene (produced by the reaction of concentrated sulfuric acid and carbon tetrachloride, slowly added after low temperature condensation),After the completion of the dropwise addition, the reaction was carried out for 30 minutes. After filtration, it is dried in a hot air oven at 100 C.Obtained 117 g of a white solid (based on anhydrous creatine,The yield was 89%). |
| 73% | With chlorophosphonic acid; at 0 - 60℃; for 0.75h; | Example 12Ethyl[[[amino](imino)methyl](methyl)amino]acetate (24); Phosphorochloridic acid (2.0-2.5 equivalents to creatine) was added dropwise to a suspension of creatine in 10 mL of ethanol at 0 C. The reaction mixture was stirred for 15 min at 0 C. and the temperature then raised to 60 C. and stirred for 30 min. The reaction mixture was then cooled to provide 1.7 g of the hydrochloride salt of title compound (24) (73% yield) as a white solid. 1H NMR (CD3OD, 400 MHz): delta 4.20-4.30 (m, 4H), 3.16(s, 3H, creatinine NCH3), 3.08 (s, 3H, CBE NCH3), 1.31 (d, J=6.8 Hz), (CBE/creatinine=9:1). |
| 54% | at 37℃; for 20h;Acidic conditions;Product distribution / selectivity; | Optimization experiments were performed by varying certain parameters of the reaction scheme in Example 1, as described below. A 1.5 mole equivalent of acetyl chloride was added dropwise to anhydrous ethanol to generate the acidified ethanol. Creatine monohydrate was added to the acidified ethanol at a ratio of 1 g:6 ml of ethanol and the reaction medium was heated to 37 C. for 20 hours. The reaction medium was then allowed to cool to 30 C. prior to filtration and the product (filter cake) was washed with ethanol chilled to 0 C. The amount of ethanol used in the wash was on a 1:1 w/v (g/ml) basis with the quantity of creatine monohydrate employed as the starting material. This reaction scheme yielded an 83 to 86% conversion of creatine monohydrate to CEE HCl. [0044] A. Length of Reaction Time [0045] Shortening the reaction time from 20 hours to 10-12 hours resulted in a decrease in the conversion of creatine monohydrate to CEE HCl to about 76 to 83%. Increasing the reaction time to greater than 20 hours resulted in no significant increase in the conversion of creatine monohydrate to CEE HCl. Such longer reaction times, however, did result in the increased formation of the undesirable product creatinine HCl. [0046] B. Temperature at Filtration [0047] After heating the reaction medium to 37 C. for 20 hours, the reaction medium was cooled to various temperatures prior to filtration. The results of these experiments are summarized in Table 1. [TABLE-US-00001] TABLE 1 Temperature Product Product At Filtration Purity Yield 30 C. 99% 54% 25 C. 95% 66% 6 C. 94% 79% [0048] Cooling the filtrate to 6 C. resulted in significantly greater yields compared to either 25 C. or 30 C., but with a relatively slight loss of purity. In each of these experiments, the primary impurity found in the reaction product was creatine HCl. [0049] C. Ratio of Acetyl Chloride to Creatine Monohydrate [0050] The ratio of acetyl chloride to creatine monohydrate was varied to optimize the production of CEE HCl while minimizing the formation of the undesired product creatinine HCl. The amount of acetyl chloride employed was varied between 1.3 and 2.0 mole equivalents and the results of the experiments are summarized in Table 2. [TABLE-US-00002] TABLE 2 Mole equivalents of Product Product acetyl chloride Conversion Purity Yield 1.3 74% 99% 37% 1.4 84% 98% 48% 1.5 83-86% 99% 54% 1.6 86% 99% 57% 2.0 83% 93% 63% [0051] The only impurity present in the final solid reaction product was creatine HCl when 1.3 to 1.6 mole equivalents of acetyl chloride were employed. Creatinine HCl was the only impurity identified when 2.0 equivalents were employed. These results indicate that 1.5 to 1.6 equivalents of acetyl chloride may be optimal as these conditions produced the greatest conversion and yield of the desired product with a high degree of purity. Higher amounts of acetyl chloride, such as greater than 2.0 mole equivalents, are less desirable despite the higher yields because of the greater production of the undesired creatinine HCl reaction byproduct. [0052] D. Composition of Starting Ethanol [0053] The composition of the starting ethanol to which the acetyl chloride is added was varied between a 100:0 and 80:20 ratio (v/v) of ethanol (EtOH) to ethyl acetate (EtOAc). The results of these experiments are presented in Table 3. [TABLE-US-00003] TABLE 3 EtOH:EtOAc Product Product (v/v) Conversion Purity Yield 100:0 83-86% 99% 54% 95:5 88% 96% 65% 90:10 87% 93% 64% 80:20 84% 93% 64% [0054] These data indicate that the 95:5 EtOH:EtOAc ratio (v/v) may be preferred because the increase in yield likely outweighs the slight loss in purity. One notable disadvantage with using larger amounts of EtOAc is that the reaction impurities consisted of about a 3:1 molar ratio of creatinine HCl:creatine HCl. Filtering the reaction mixture at a slightly higher temperature would improve the purity of the isolated CEE HCl, but as noted hereinabove (see part B) such an increase in temperature may result in a concomitant decrease in yield. [0055] Notably, all of the acetyl chloride added to the ethanol is also converted to EtOAc. Therefore the actual ratio of EtOH:EtOAc at the time of creatine monohydrate addition is different than the starting material. [0056] A number of literature and patent references are cited in the foregoing application in order to more fully describe the state of the art to which this invention pertains. The entire disclosure of each of these citations is incorporated by reference herein. [0057] While certain embodiments of the present invention have been described and/or specifically exemplified above, various other embodiments will be apparent to those skilled in the art from the foregoing disclosure. The present invention is, therefore, not limited to such embodiments, but is capable of considerable variation and modification without departing from the scope of the following claims. |
| With acetyl chloride; In water; at 40℃; | A general procedure for the preparation of creatine ethyl ester hydrochloride will now be described. Two ml of anhydrous ethanol is diluted with 67 mul of a 9:1 mixture of ethanol and water and stirred under an Argon atmosphere. To the mixture is added acetyl chloride (164 mul, 2.30 mmol) and the solution stirred for 5 minutes. The solution is heated to 40 degrees C. and creatine (200 mg, 1.53 mmol) is added to the stirring mixture. The mixture is stirred overnight at 40 degrees C. The creatine ethyl ester hydrochloride is recovered by cooling the mixture to 0 degrees C., filtering the white precipitate and washing it with a minimum quantity of cold ethanol. The material can be stored under anhydrous conditions at -15 degrees C. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 48 - 63% | With hydrogenchloride; | Similar experiments performed with hydrogen chloride introduced directly from a gas cylinder led to yields of CEE HCl of only 48 to 63%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80 - 92% | Synthesis of Creatine Ethyl Ester Hydrochloride by Acid-Catalyzed Esterification of Creatine Monohyrdate [0039] A 1.5 molar equivalent of acetyl chloride was added dropwise to either anhydrous ethanol protected by a calcium chloride drying tube with constant stirring. The acetyl chloride was added at such a rate so as to prevent the temperature of the acidified solvent from exceeding 60 C. [0040] The temperature of the acidified ethanol was then allowed to decline to about 35 to 40 C. When the acidified ethanol reached the lower temperatures, creatine monohydrate was added in one portion in the ratio of 1 g of creatine monohydrate to 6 to 10 ml of acidified ethanol. The resultant reaction was stirred for 2 to 8 hours at about 40 to 50 C. [0041] The temperature of the reaction mixture was then allowed to cool to about room temperature with constant stirring. White crystalline creatine ethyl ester hydrochloride (CEE HCl) was collected by vacuum filtration and washed with approximately 1 ml of ice cold ethanol per 1 g of CEE HCl product. After the removal of most of the solvent by vacuum filtration, the CEE HCl was removed from the filter and then allowed to dry in a fume hood. [0042] The yield of CEE HCl from this method was 74%, but a total yield of about 80 to 92% (i.e. conversion) is obtainable when the CEE HCl remaining in the filtrate or mother liquor following the initial isolation of CEE HCl is considered. Additionally, the reaction product is 94 to 100% CEE HCl, with any impurities consisting of hydrochlorides of creatine and creatinine. | |
| 37 - 79% | Optimization experiments were performed by varying certain parameters of the reaction scheme in Example 1, as described below. A 1.5 mole equivalent of acetyl chloride was added dropwise to anhydrous ethanol to generate the acidified ethanol. Creatine monohydrate was added to the acidified ethanol at a ratio of 1 g:6 ml of ethanol and the reaction medium was heated to 37 C. for 20 hours. The reaction medium was then allowed to cool to 30 C. prior to filtration and the product (filter cake) was washed with ethanol chilled to 0 C. The amount of ethanol used in the wash was on a 1:1 w/v (g/ml) basis with the quantity of creatine monohydrate employed as the starting material. This reaction scheme yielded an 83 to 86% conversion of creatine monohydrate to CEE HCl. [0044] A. Length of Reaction Time [0045] Shortening the reaction time from 20 hours to 10-12 hours resulted in a decrease in the conversion of creatine monohydrate to CEE HCl to about 76 to 83%. Increasing the reaction time to greater than 20 hours resulted in no significant increase in the conversion of creatine monohydrate to CEE HCl. Such longer reaction times, however, did result in the increased formation of the undesirable product creatinine HCl. [0046] B. Temperature at Filtration [0047] After heating the reaction medium to 37 C. for 20 hours, the reaction medium was cooled to various temperatures prior to filtration. The results of these experiments are summarized in Table 1. [TABLE-US-00001] TABLE 1 Temperature Product Product At Filtration Purity Yield 30 C. 99% 54% 25 C. 95% 66% 6 C. 94% 79% [0048] Cooling the filtrate to 6 C. resulted in significantly greater yields compared to either 25 C. or 30 C., but with a relatively slight loss of purity. In each of these experiments, the primary impurity found in the reaction product was creatine HCl. [0049] C. Ratio of Acetyl Chloride to Creatine Monohydrate [0050] The ratio of acetyl chloride to creatine monohydrate was varied to optimize the production of CEE HCl while minimizing the formation of the undesired product creatinine HCl. The amount of acetyl chloride employed was varied between 1.3 and 2.0 mole equivalents and the results of the experiments are summarized in Table 2. [TABLE-US-00002] TABLE 2 Mole equivalents of Product Product acetyl chloride Conversion Purity Yield 1.3 74% 99% 37% 1.4 84% 98% 48% 1.5 83-86% 99% 54% 1.6 86% 99% 57% 2.0 83% 93% 63% [0051] The only impurity present in the final solid reaction product was creatine HCl when 1.3 to 1.6 mole equivalents of acetyl chloride were employed. Creatinine HCl was the only impurity identified when 2.0 equivalents were employed. These results indicate that 1.5 to 1.6 equivalents of acetyl chloride may be optimal as these conditions produced the greatest conversion and yield of the desired product with a high degree of purity. Higher amounts of acetyl chloride, such as greater than 2.0 mole equivalents, are less desirable despite the higher yields because of the greater production of the undesired creatinine HCl reaction byproduct. [0052] D. Composition of Starting Ethanol [0053] The composition of the starting ethanol to which the acetyl chloride is added was varied between a 100:0 and 80:20 ratio (v/v) of ethanol (EtOH) to ethyl acetate (EtOAc). The results of these experiments are presented in Table 3. [TABLE-US-00003] TABLE 3 EtOH:EtOAc Product Product (v/v) Conversion Purity Yield 100:0 83-86% 99% 54% 95:5 88% 96% 65% 90:10 87% 93% 64% 80:20 84% 93% 64% [0054] These data indicate that the 95:5 EtOH:EtOAc ratio (v/v) may be preferred because the increase in yield likely outweighs the slight loss in purity. One notable disadvantage with using larger amounts of EtOAc is that the reaction impurities consisted of about a 3:1 molar ratio of creatinine HCl:creatine HCl. Filtering the reaction mixture at a slightly higher temperature would improve the purity of the isolated CEE HCl, but as noted hereinabove (see part B) such an increase in temperature may result in a concomitant decrease in yield. [0055] Notably, all of the acetyl chloride added to the ethanol is also converted to EtOAc. Therefore the actual ratio of EtOH:EtOAc at the time of creatine monohydrate addition is different than the starting material. [0056] A number of literature and patent references are cited in the foregoing application in order to more fully describe the state of the art to which this invention pertains. The entire disclosure of each of these citations is incorporated by reference herein. [0057] While certain embodiments of the present invention have been described and/or specifically exemplified above, various other embodiments will be apparent to those skilled in the art from the foregoing disclosure. The present invention is, therefore, not limited to such embodiments, but is capable of considerable variation and modification without departing from the scope of the following claims. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With 4-methyl-morpholine; toluene-4-sulfonic acid; isobutyl chloroformate; In N,N-dimethyl-formamide; at -10 - 20℃; for 11.16h; | Example 1; Preparation of Creatinyl-Glycine Iso-Propyl Ester Acetate; Suspension of 5.67 g (38 mM) of Creatine monohydrate in 40 mL of N,N-Dimethylformamide was placed into a 250 mL 1-necked round bottom flask charged with a pressure equalization arm dropping funnel closed with calcium chloride tube then 7.23 g (38 mM) of p-Toluenesulfonic acid monohydrate was added at stirring on a magnetic stirrer. Creatine monohydrate is completely dissolved in 5 min. Then 6.71 g (40 mM) of Glycine iso-Propyl Ester Hydrochloride was added and reaction mixture was cooled down to (-)10 C. at ice-salted bath after its dissolution. Then 5.24 mL (38 mM) of iso-Butylchloroformate was added and 8.9 mL (81 mM) of N-Methylmorpholine was added via dropping funnel for 10 min. Reaction mixture was stirred at ice bath for 1 hour then a temperature was adjusted to room condition. N-Methylmorpholine hydrochloride precipitate formed was filtered off in 10 hours, a mother liquor was evaporated at 50 C. An oily residue was dissolved in 160 mL of chloroform and kept at (-)10 C. for 10 hours. Solution was filtered, extracted with H2O (3×100 mL). A combined aqueous phase containing a desired product was extracted with chloroform twice, an aqueous solution was evaporated in vacuo up to volume of 50 mL. Resulted solution was flowed through a column 30×250 mm filled with a Dowex 1×8 in acetate form in H2O. Eluent-H2O, elution rate-2 mL/min. Column was eluted with H2O monitoring a pH of eluate. Fractions with a pH=7 were collected, analysed by Reverse Phase HPLC, combined, an acetic acid was added and fractions were evaporated. A residue was crystallized with 20 mL of acetonitrile at (-)10 C. for 20 hours. A precipitate of Creatinyl-Glycine iso-Propyl Ester Acetate was filtered off, washed with chilled acetonitrile, diethyl ether and dried. A resulted product was dissolved in 30 mL of ethanol, kept at (-)10 C. for 20 hours, a solution was filtered, ethanol was removed in vacuo, a residue was crystallized with diethyl ether. Yield of Creatinyl-Glycine iso-Propyl Ester Acetate C9H18N4O3*C2H4O2: 2.3 g (21%). Mass-spectra, found: m/z 290.29. Calculated: M 290.32. Assay of Creatinyl-Glycine iso-Propyl Ester Acetate by non-aqueous titration-97.7% mass, creatinine impurity content-1.5% mass. |
Tags: Creatine | Endogenous Metabolite | Dopamine Receptor | phosphocreatine | ATP regeneration | muscle energy | neuroprotection | ergogenic aid | metabolism | 57-00-1
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| H230 | May react explosively even in the absence of air |
| H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
| H240 | Heating may cause an explosion |
| H241 | Heating may cause a fire or explosion |
| H242 | Heating may cause a fire |
| H250 | Catches fire spontaneously if exposed to air |
| H251 | Self-heating; may catch fire |
| H252 | Self-heating in large quantities; may catch fire |
| H260 | In contact with water releases flammable gases which may ignite spontaneously |
| H261 | In contact with water releases flammable gas |
| H270 | May cause or intensify fire; oxidizer |
| H271 | May cause fire or explosion; strong oxidizer |
| H272 | May intensify fire; oxidizer |
| H280 | Contains gas under pressure; may explode if heated |
| H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
| H290 | May be corrosive to metals |
Health hazards | |
| Code | Phrase |
| H300 | Fatal if swallowed |
| H301 | Toxic if swallowed |
| H302 | Harmful if swallowed |
| H303 | May be harmful if swallowed |
| H304 | May be fatal if swallowed and enters airways |
| H305 | May be harmful if swallowed and enters airways |
| H310 | Fatal in contact with skin |
| H311 | Toxic in contact with skin |
| H312 | Harmful in contact with skin |
| H313 | May be harmful in contact with skin |
| H314 | Causes severe skin burns and eye damage |
| H315 | Causes skin irritation |
| H316 | Causes mild skin irritation |
| H317 | May cause an allergic skin reaction |
| H318 | Causes serious eye damage |
| H319 | Causes serious eye irritation |
| H320 | Causes eye irritation |
| H330 | Fatal if inhaled |
| H331 | Toxic if inhaled |
| H332 | Harmful if inhaled |
| H333 | May be harmful if inhaled |
| H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
| H335 | May cause respiratory irritation |
| H336 | May cause drowsiness or dizziness |
| H340 | May cause genetic defects |
| H341 | Suspected of causing genetic defects |
| H350 | May cause cancer |
| H351 | Suspected of causing cancer |
| H360 | May damage fertility or the unborn child |
| H361 | Suspected of damaging fertility or the unborn child |
| H361d | Suspected of damaging the unborn child |
| H362 | May cause harm to breast-fed children |
| H370 | Causes damage to organs |
| H371 | May cause damage to organs |
| H372 | Causes damage to organs through prolonged or repeated exposure |
| H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
| Code | Phrase |
| H400 | Very toxic to aquatic life |
| H401 | Toxic to aquatic life |
| H402 | Harmful to aquatic life |
| H410 | Very toxic to aquatic life with long-lasting effects |
| H411 | Toxic to aquatic life with long-lasting effects |
| H412 | Harmful to aquatic life with long-lasting effects |
| H413 | May cause long-lasting harmful effects to aquatic life |
| H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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