| 摘要 |
<p>#CMT# #/CMT# Synthesis of amino acid N-carboxy anhydride compounds (I), comprises nitrosation and simultaneous cyclization of an amino acid N-carbamoyl compound (II), where the nitrosation reaction is carried out in single step under a pressure of =10 Pa, by contacting (II) in solid form or in a solution/dispersion form in an organic solvent, with a nitrosonium ion donor in solution in an organic solvent or in the gaseous state. #CMT# : #/CMT# Synthesis of amino acid N-carboxyanhydrides compound of formula (I), comprises nitrosation and simultaneous cyclization of an amino acid N-carbamoyl compound (II) of formula (H2N-C(O)-N(R1)-R-COOH), where the nitrosation reaction is carried out in single step under a pressure of =10 Pa, by contacting (II) in solid or a solution form or dispersion in an organic solvent, with a nitrosonium ion donor in solution in an organic solvent or in the gaseous state. Either R : primary amino acid radical such as glycine, alanine, valine, leucine, isoleucine, phenylalanine, serine, threonine, lysine, delta -hydroxylysine, arginine, ornithine, aspartic acid, asparagine, glutamic acid, glutamine, cysteine, cystine, methionine, tyrosine, thyroxine, tryptophan, histidine, proline and their derivatives, 1-40C alkylidene or cycloalkylidene, optionally substituted by aryl, alcohol, ether, thiol, amino acid or amide; and R1 : H or 1-9C alkyl, cycloalkyl, arylalkyl, alkyloxycarbonyl or arylalkyloxycarbonyl; or RR1 : 4-7 cyclic ring. #CMT#[Image]#/CMT# #CMT#USE : #/CMT# (I) is useful for the preparation of pharmaceutical compositions, food products such as nutritional supplements, and an intermediate compounds for peptide synthesis. #CMT#ADVANTAGE : #/CMT# The process is carried out in single step (claimed). The process avoids the use of hazardous reagents such as phosgene. The process provides non-polluting N-carboxyanhydrides products. The process provides the N-carboxy anhydride with a very good yield and purity. The process is simple. #CMT#ORGANIC CHEMISTRY : #/CMT# Preferred Process: The nitrosation/cyclization reaction is initiated by the presence and/or addition of a small amount of water in the reaction medium, when the nitrosonium ion donors are nitrogen oxychloride, nitrogen oxybromide, nitrosyl tetrafluoroborate. The nitrosation/cyclization reaction is: conducted entirely at a pressure of =5x105> Pa, preferably 5x104>-5x105> Pa; at a temperature of -10 to 120[deg]C, preferably 10-60[deg]C. The process, when the nitrosonium ions donors are nitrosonium compound (III) of formula (NxOy), comprises subsequent purification of expected product comprising sub-stages of filtration of the reaction mixture or raw product in solution in an organic solvent on a phase separator device, after optional addition of a small amount of water. Preferred Components: The amino acid comprising functional groups, and the process comprises a preliminary step for protecting the functional groups by a protector group. (II) is N-carbamoyl-alanine, N-carbamoyl-valine, N-carbamoyl-leucine, N-carbamoyl-phenylalanine, N-alpha -carbamoyl-N-epsilon-trifluoroacetyl-lysine, N-carbamoyl-gamma -benzyl-glutamate and N-carbamoyl-methionine. The nitrosonium ion donors are nitrogen oxychloride, nitrogen oxybromide, nitrosyl tetrafluoroborate, nitrosonium compound (III) and nitrite anion solution in acid medium. (III) are nitric oxide, nitrous anhydride, nitrogen dioxide, nitrogen peroxide, nitric anhydride and mixtures comprising of the given compounds optionally in mixture with oxygen and/or air e.g. nitric oxide (NO)/oxygen (O2) and NO/nitrogen dioxide (NO2)/nitrogen tetroxide (N2O4). The molar ratio of NO to O2 is 1-10. The reactive organic solvent, when present, is polar solvents and non-polar solvents of aliphatic or aromatic family, chlorinated and non-chlorinated hydrocarbons. The polar solvents are tetrahydrofuran, acetonitrile, dimethyl sulfoxide dioxane, dimethylformamide and aliphatic esters. The non-polar solvents are toluene and dichloromethane. The reactive organic solvent is toluene. (II) are used in the form of a solution or dispersion in toluene and the nitrosonium ions donor such as O2/NO and NO/NO2/N2O4 mixtures is used in the gaseous state. (II) are used in solid form and the nitrosonium ions donor such as O2/NO and NO/NO2/N2O4 mixtures is used in the gaseous state. x, y : 1-4. Provided that the ratio of y to x is 1-2.5 #CMT#EXAMPLE : #/CMT# N-Carbamoyl-alanine (1 g) and toluene (25 ml) were mixed. The mixture was stirring with nitrogen bubbles for 5-10 minutes. Nitric oxide (456 ml) and oxygen (115 ml) were added to the mixture and maintained under agitation. After 30 minutes, the gasses were evacuated under reduced pressure to obtain the crude product. Then the product was filtered to obtain alanine N-carboxyanhydride (ala-NCA) (85 wt.%). The crude product was recovered in isopropyle/heptane acetate mixture to 50[deg]C then crystallized for 12 hours to a temperature of -10[deg]C to obtain L-alanine- N-carboxyanhydride (60-70%).</p> |
