Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1987-12-07
1991-09-10
Schain, Howard E.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 27, 564138, 564139, 564155, 530333, 530334, 530338, C07C20500, C07C26100, C07K 100
Patent
active
050475738
DESCRIPTION:
BRIEF SUMMARY
It is well known, that certain diacylamines-containing peptide elements-are suitable for peptide synthesis. For example the N-(N'-phthalyl-glycyl)-N-diphenylacetyl-4-methylaniline has been used for the synthesis of N-Phthalylglycyl-glycyl-glycin-ethyl ether (J. Am. Chem. Soc., 80, 1958, 4069).
To use the claimed diacylamines of formula IV has the advantage of reducing significantly the production expenses of synthesizing peptides. Furthermore in a reaction with amino-components of the formula V the claimed diacylamines give surprising high yield and a high purity of the peptides of formula I. It is surprising for experts, that using the claimed diacylamines of the general formula IV, peptides can be obtained, because these compounds if they contain unsubtituted phenyl grops (i.e. compounds of the general form IV with Y and Z as hydrogen atoms) were found unsuitable for peptide synthesis according to the literature (Biochemistry, 5, 1966, 2468) and the present inventors own experiments.
According to the claimed procedure for production of peptides of the general formula I, peptide and salt, are the same or different, a carboxyl acid of the general formula II carboxylic-acid-imidoylchloride of the general formula III, ##STR1## in which X--denotes a hydrogen or halogen atom, a nitro-- or an alkyl-group with maximal 4-C atoms, ##STR2## in which R.sub.1 CO, X, Y and Z denote the above mentioned meaning,
According to the claimed procedure, in the first reaction step a carboxylic acid of the general formula II reacts with a imidoylchloride of the general formula III. This reaction can be done preferably in a inert solvent containing bases. Suitable solvents are, for example, lower alcohols such as methanol, ethanol or isopropanol, lower carboxylic acid ester, such as ethyl acetate, polar ether such as dioxan, tetrahydrofuran, glycol monoethylether or dimethylether (diglyme), ketones such as acetone, methylacetone or methylisobutylketone and dipolar aprotic solvents, such as dimethylformamide, N-methylacetamide, tetramethylene sulfone (sulfolan) or hexamethylphosphoramide. Furthermore, suitable solvents include mixtures of the above mentioned with inert and nonpolar solvents such as chloronated hydrocarbons (dichloromethane, trichloromethane or tetrachloroethane etc.) or aromatic hydrocarbons (benzene, toluene etc.). Suitable bases are for example tertiary amines such as triethylamine, tributylamine, N-methylmorpholine or N-ethylpiperazine, inorganic bases such as caustic soda solution or potash, alkali metals carbonate such as natron sodium bicarbonate, potassium carbonate or potassium bicarbonate and alkali metals alcoholates such as natriummethylate or potassium ethylate. Usually this first reaction step is carried out under a temperature of -20.degree. C. to 100.degree. C., where a temperature between 0.degree. C. to 30.degree. C. is preferred for economical reasons. Diacylamines of the general formula IV ##STR3## in which R.sub.1 CO--denotes the acylating carboxy-component used in peptide synthesis; X denotes a hydrogen atom, a halogen atom, an acyl with 4C-atoms or a nitrogroup; Examples of such diacylamines include N-(2-chlorobenzoyl)-N-(N'-tert-butyloxycarbonyl-L-alanyl)-aniline and
In the second step of the claimed procedure, the diacylamine of formula IV obtained in the first step reacts with an amine of the general formula V. This reaction step is performed preferably in an inert solvent. The same solvents as in the first reaction step can be used. The temperature of the reaction is in the range from -20.degree. C. to 100.degree. C., where -10.degree. C. to 30.degree. C. is preferred.
The claimed procedure is useable for universal peptide synthesis like established procedures (Houben-Weyl "Methoden der organischen Chemie", Georg Thieme Verlag, Stuttgart BR-Deutschland, Band XV/1 "Synthese von Peptiden" Teil I, 1974 und Band XV/2 "Synthese von Peptiden" Teil II, 1974). As in the established procedures, in the claimed procedure it is useful to protect in known ways other amino groups-as well as if necessa
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Bradaczek Hans
Gruszecki Maria
Gruszecki Wojciech
Perkins Susan M.
Schain Howard E.
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