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[ CAS No. 15366-32-2 ]

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Chemical Structure| 15366-32-2
Chemical Structure| 15366-32-2
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CAS No. :15366-32-2 MDL No. :MFCD08704792
Formula : C6H14ClN3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :195.65 g/mol Pubchem ID :25114309
Synonyms :

Safety of [ 15366-32-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 15366-32-2 ]

  • Upstream synthesis route of [ 15366-32-2 ]
  • Downstream synthetic route of [ 15366-32-2 ]

[ 15366-32-2 ] Synthesis Path-Upstream   1~4

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YieldReaction ConditionsOperation in experiment
73% at 0 - 60℃; for 0.75 h; 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) (73percent yield) as a white solid. 1H NMR (CD3OD, 400 MHz): δ 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 20 h; Acidic conditions 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 86percent 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 83percent. 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. 99percent 54percent 25° C. 95percent 66percent 6° C. 94percent 79percent [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 74percent 99percent 37percent 1.4 84percent 98percent 48percent 1.5 83-86percent 99percent 54percent 1.6 86percent 99percent 57percent 2.0 83percent 93percent 63percent [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 83-86percent 99percent 54percent 95:5 88percent 96percent 65percent 90:10 87percent 93percent 64percent 80:20 84percent 93percent 64percent [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.
Reference: [1] Patent: US2007/281909, 2007, A1, . Location in patent: Page/Page column 53-54
[2] Patent: US2005/49428, 2005, A1, . Location in patent: Page/Page column 3-4
[3] Biochemische Zeitschrift, 1925, vol. 156, p. 186
[4] Journal of Biological Chemistry, 1922, vol. 54, p. 672
[5] Patent: US2006/67880, 2006, A1, . Location in patent: Page/Page column 1
[6] Patent: US9833427, 2017, B2, . Location in patent: Sheet 8/18
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Reference: [1] Patent: US2005/49428, 2005, A1, . Location in patent: Page/Page column 3
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YieldReaction ConditionsOperation in experiment
80%
Stage #1: at 35 - 60℃;
Stage #2: at 35 - 50℃; for 2 - 8 h;
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 74percent, but a total yield of about 80 to 92percent (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 100percent CEE HCl, with any impurities consisting of hydrochlorides of creatine and creatinine.
37%
Stage #2: at 37℃; for 10 - 20 h;
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 86percent 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 83percent. 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. 99percent 54percent 25° C. 95percent 66percent 6° C. 94percent 79percent [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 74percent 99percent 37percent 1.4 84percent 98percent 48percent 1.5 83-86percent 99percent 54percent 1.6 86percent 99percent 57percent 2.0 83percent 93percent 63percent [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 83-86percent 99percent 54percent 95:5 88percent 96percent 65percent 90:10 87percent 93percent 64percent 80:20 84percent 93percent 64percent [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.
Reference: [1] Patent: US2005/49428, 2005, A1, . Location in patent: Page/Page column 3
[2] Patent: US2005/49428, 2005, A1, . Location in patent: Page/Page column 3-4
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Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 12, p. 5173 - 5181
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