US3739013A - Method of preparing alpha amides - Google Patents

Method of preparing alpha amides Download PDF

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Publication number
US3739013A
US3739013A US00074926A US3739013DA US3739013A US 3739013 A US3739013 A US 3739013A US 00074926 A US00074926 A US 00074926A US 3739013D A US3739013D A US 3739013DA US 3739013 A US3739013 A US 3739013A
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mol
ester
glutamic acid
dissolved
acid
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US00074926A
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G Picciola
L Rovati
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Rottapharm SpA
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Rotta Research Laboratorium SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups

Definitions

  • R is an alkyl group having from 1 to 6 carbon atoms.
  • the Formula I also indicates the nomenclature for identifying the various carbon atoms in the amino-acid chain.
  • the present invention arises from the following two considerations:
  • the purpose of the present invention is therefore to provide a high-yield process, with retention of configuration (that is to say without changing the configuration of the original glutamic acid, which may equally Well be L, DL or D) and selective for amidation in the alpha position, enabling amides having the Formula I to be obtained in commercially advantageous conditions.
  • the glutamic acid is esterified with benzyl alcohol in the presence of a strong mineral acid such as, for example, sulphuric, phosphoric, hydrochloric, hydrobromic, hydriodic or hydrofluoric acid; sulphuric acid should be used for preference, at a temperature of between 0 C. and 25 0., possibly but not necessarily in the presence of an inert organic solvent, such as ether or benzene.
  • a strong mineral acid such as, for example, sulphuric, phosphoric, hydrochloric, hydrobromic, hydriodic or hydrofluoric acid
  • sulphuric acid should be used for preference, at a temperature of between 0 C. and 25 0., possibly but not necessarily in the presence of an inert organic solvent, such as ether or benzene.
  • the ester so obtained is benzoylated with benzoyl chloride dissolved in a suitable water-miscible organic solvent such as dioxane or tetrahydrofuran in an aqueous medium and in the presence of a proton acceptor such as, for instance, sodium carbonate, at a temperature varying between -2 C. and +15 C.
  • a proton acceptor such as, for instance, sodium carbonate
  • the proton acceptor must be non-hydrolysing in relation to benzyl esters, so as not to restore the initial glutamic acid. It is thus necessary to avoid using strong bases such as caustic soda, but it is possible to use sodium carbonate, for example, or magnesium oxide.
  • the benzyl ester of N-benzoyl glutamic acid thus obtained is dissolved in an organic solvent such as tetrahydrofuran, dioxane or methylene chloride and amidated at the free carboxyl group with an amine R-H (R having the significance already explained), in the presence of dicyclohexylcarbodiimide or N,N'-carbonyldiimidazol as condensing agent, at a temperature between 10 C. and +25 c.
  • an organic solvent such as tetrahydrofuran, dioxane or methylene chloride
  • the amide is then debenzylated catalytically in the presence of a catalyst such as palladium on carbon or palladium chloride, in a solution of methanol, ethanol, propanol or isopropanolpreferably methanol-at room temperature, in a stream of hydrogen, until the evolution of carbon dioxide ends.
  • a catalyst such as palladium on carbon or palladium chloride
  • the reaction can be accelerated by the presence of acetic acid to the extent of 5% to 10% related to the solvent employed.
  • the reaction mixture is filtered and the solvent evaporated in vacuo.
  • the residue is dissolved in an organic solvent such as, for example, ethyl acetate; ethyl ether, benzene or chloroform and extracted with an alkali metal hydrate, carbonate or bicarbonate. Acidification produces the desired amide of N- benzoyl glutarnic acid.
  • EXAMPLE 1 Part 1 Preparation of the q-benzyl ester of L-glutamic acid (III) To 1,000 ml. of anhydrous ethyl ether is added 100 ml. of 98% sulphuric acid at C., agitation being applied, followed by 1,000 ml. of benzyl alcohol. The ether is distilled in vacuo and 147.13 g. (1 mol) (M.W. 147.13) of L-glutamic acid is added a little at a time.
  • the solution so obtained is left under agitation for 24 hours at 20 C.; then cooled to 0 C. and 2,000 ml. of 95% ethanol and 500 ml. of pyridine are added.
  • Part 2 Preparation of the acid of N-benzoyl-L-glutamic acid 'y-benzyl ester (IV) Of the ester obtained in part 1, 118.5 g. (0.5 mol) is suspended in 800 ml. of water. In this suspension, 53 g. (0.5 mol) of sodium carbonate is dissolved, this being followed by the addition, in 2 hours and at 0 C., of 58.2 ml. (0.5 mol) of benzoyl chloride dissolved in 300 ml. of anhydrous tetrahydrofuran.
  • Part 3 Preparation of the a-(di-n-propyDamide of N-benzoyl-L-glutamic acid y-benzyl ester
  • ester (IV) To a solution of 34.1 g. (0.1 mol) of ester (IV) in 500 ml. of tetrahydrofuran, maintained at 5 C., are added 10.12 g. (0.1 mol) of di-n-propylamine and 20.63 g. (0.1 mol) of dicyclohexyl carbodiimide. After agitation for 16 hours this is filtered and evaporated to dryness.
  • the substance is chromatographically pure.
  • EXAMPLE 2 Part 1 Preparation of the benzyl ester of DL-glutamic acid T0 1,000 ml. of anhydrous ethyl ether are added, agitation being applied, first 100 ml. of 98% sulphuric aicd at 0 C. and then 1,000 ml. of benzyl alcohol. The ether is distilled in vacuo and 147.13 g. (1 mol) of DL-glutamic acid is added a little at a time.
  • the resultant solution is left under agitation for 24 hours at 22 C., after which it is cooled to 0 C. and 2,000 ml. of ethanol and 500 ml. of pyridine are added.
  • Part 2 Preparation of N-benzoyl-DL-glutamic acid 'y-benzyl ester
  • 118.5 g. (0.5 mol) is suspended in 800 ml. of water.
  • 53 g. (0.5 mol) of sodium carbonate is dissolved, this being followed by the addition, in 2 hours at 0 C., of 58.2 ml. (0.5 mol) of benzoyl chloride dissolved in 300 ml. of anhydrous tetrahydrofuran.
  • Part 3 Preparation of the a-(di-n-propyDamide of N-benzoyl-DL-glutamic acid 'y-benzyl ester
  • 34.1 g. (0.1 mol) of the ester obtained in part 2 in 5 00 ml. of tetrahydrofuran, maintained at 5 C. are added 10.12 g. (0.1 mol) of di-n-propylamine and 20.63 g. (0.1 mol) of dicyclohexyl carbodiimide. After agitation for 16 hours, this is filtered and evaporated to dryness.
  • Part 4 Preparation of the u-(di-n-propyDamide of N-benzoyl-DL-glutamic acid
  • 41 g. (0.0965 mol) is dissolved in 400 ml. of methanol, 2 g. of 10% palladiated carbon is added and hydrogenation is carried out at ambient temperature for 6 hours in a stream of hydrogen. Filtration follows and the methanol is distilled in vacuo. The residue is dissolved in ethyl acetate, extracted with aqueous sodium carbonate and precipitated with hydrochloric acid. Crystallisation takes place with chloroform. This produces 30.4 g. (M.W. 334.4); melting point 143 -144 C. Yield 94.2%. Overall yield 74.1%.
  • Example 3 Part 1 Preparation of the 'y-benzyl ester of D-glutamic acid To 1,000 ml. of anhydrous ethyl ether are added, agitation being applied, first 100 ml. of 98% sulphuric acid at C. and then 1,000 ml. of benzyl alcohol. The ether is distilled in vacuo and 147.13 g. (1 mol) of D-glutamic acid is added a little at a time.
  • the resultant solution is left agitation for 24 hours at 22 C., after which it is cooled to 0 C. and 2,000 ml. of 95 ethanol and 500 ml. of pyridine are added.
  • Part 2 Preparation of N-benzoyl-D- glutamic acid 'y-benzyl ester
  • 118.5 g. (0.5 mol) is suspended in 800 ml. of water.
  • 53 g. (0.5 mol) of sodium carbonate is dissolved, this being followed by the addition, in 2 hours at 0 C., of 58.2 ml. (0.5 mol) of benzoyl chloride dissolved in 300 ml. of anhydrous teerahydrofuran.
  • Part 3 Preparation of the a-(di-n-propyl) amide of N-benzoyl-D-glutamic acid 'y-benzyl ester
  • Part 4 Preparation of the ot-(di-n-propl) amide of N- benzoyl-D-glutamic acid
  • 39 g. (0.0924 mol) is dissolved in 400 ml. of methanol, 2 g. of palladiated carbon is added and hydrogenation is carried out at ambient temperature for 6 hours in a stream of hydrogen. Filtration follows and the methanol is distilled in vacuo from the filtrate. The residue is dissolved in ethyl acetate, extracted with aqueous sodium carbonate and precipitated with hydrochloric acid. Crystallisation takes place with chloroform. This produces 27 g. (M.W.
  • Part 3 Preparation of the a-(p-carbethoxy)-phenylamide of N-benzoyl-L-glutamic acid 'y-benzyl ester
  • Part 4 Preparation of the a-(p-carbethoxy)phenylamide of N-benzoyl-L-glutamic acid Of the substance obtained in Part 3 of this example, 45.3 g. (0.0927 mol) is dissolved in 400 ml. of methanol, 2 g. of 10% palladiated carbon is added and the hydrogenation is carried out at ambient temperature for 6 hours in a stream of hydrogen. The methanol is filtered from the catalyst and distilled from the filtrate in vacuo.
  • the product consists of chromotographically pure OL- amide; on unactivated DC plates-Fertigplatten Kieselgel F of Merck-the result is:
  • Part 3 Preparation of the a-(p-carbethoxy-phenylamide of N-benzoyl-DL-glutamic acid 'y-benzyl ester
  • Part 4 Preparation of the a- (p-carbethoxy)-phenylamide of N-benzoyl-DL-glutamic acid
  • 46.1 g. (0.0944 mol) is dissolved in 400 ml. of methanol, 1.5 g. of 10% palladiated carbon is added and hydrogenation is carried out at ambient temperature for 6 hours in a stream of hydrogen.
  • the methanol is filtered out of the catalyst and distilled in vacuo.
  • Example 1 Part 4 This substance too, when subjected to the tests referred to in Example 1, Part 4, is shown to be a chromatographically pure a-amide.
  • R is a member selected from the group consisting of a di-n-propylamino group and a (p-carboalkoxy)- phenylamino group NHC H COOR, wherein R represents an alkyl group of from 1 to 6 carbon atoms,
  • organic inert solvent is a member selected from the group consisting of dioxane, tetrahydrofuran and methylene chloride.
  • said condensing agent is a member selected from the group consisting of dicyclohexylcarbodiimide and N,N'-carbonyldiimidazole.
  • said proton acceptor is a member selected from the group consisting of sodium carbonate and magnesium oxide.
  • alcholic solvent is a member selected from the group consisting of methanol, ethanol, propanol, and isopropanol.
  • said catalyst is a member selected from the group consisting of palladium on a carbon support or palladium chloride.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US00074926A 1969-10-13 1970-09-23 Method of preparing alpha amides Expired - Lifetime US3739013A (en)

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JP (1) JPS4825180B1 (enrdf_load_stackoverflow)
AT (1) AT293368B (enrdf_load_stackoverflow)
DE (1) DE2049332C3 (enrdf_load_stackoverflow)
GB (1) GB1304729A (enrdf_load_stackoverflow)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3979447A (en) * 1972-12-05 1976-09-07 Boehringer Mannheim G.M.B.H. γ-Glutamyl-4-nitroanilide compounds
US4049702A (en) * 1972-12-05 1977-09-20 Boehringer Mannheim G.M.B.H. γ-Glutamyl-4-nitroanilide compounds
US4425427A (en) 1980-03-13 1984-01-10 Vitafin N.V. Simultaneous, kinetic, spectrophotometric analysis of blood serum for multiple components
US4439448A (en) * 1980-11-12 1984-03-27 Mitsubishi Chemical Industries Ltd. Glutamine derivatives
US4769389A (en) * 1985-12-17 1988-09-06 Rotta Research Laboratories, S.P.A. Oxygenated-alkyl derivatives of glutamic and aspartic acids with antagonistic activity to bio-active polypeptides and a method for their preparation
US5105007A (en) * 1987-10-19 1992-04-14 Abbott Laboratories Phenylacetylglutamine (PAG) analytical test

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1217123B (it) * 1987-02-05 1990-03-14 Rotta Research Lab Derivati otticamente attivi dell acido 5 pentilammino 5 oxo pentanoico r ad attivita antagonista della colecistochinina e procedimento per la loro preparazione

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3979447A (en) * 1972-12-05 1976-09-07 Boehringer Mannheim G.M.B.H. γ-Glutamyl-4-nitroanilide compounds
US4049702A (en) * 1972-12-05 1977-09-20 Boehringer Mannheim G.M.B.H. γ-Glutamyl-4-nitroanilide compounds
US4425427A (en) 1980-03-13 1984-01-10 Vitafin N.V. Simultaneous, kinetic, spectrophotometric analysis of blood serum for multiple components
US4439448A (en) * 1980-11-12 1984-03-27 Mitsubishi Chemical Industries Ltd. Glutamine derivatives
US4769389A (en) * 1985-12-17 1988-09-06 Rotta Research Laboratories, S.P.A. Oxygenated-alkyl derivatives of glutamic and aspartic acids with antagonistic activity to bio-active polypeptides and a method for their preparation
US5105007A (en) * 1987-10-19 1992-04-14 Abbott Laboratories Phenylacetylglutamine (PAG) analytical test

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DE2049332C3 (de) 1979-09-20
GB1304729A (enrdf_load_stackoverflow) 1973-01-31
DE2049332B2 (de) 1979-01-25
AT293368B (de) 1971-10-11
JPS4825180B1 (enrdf_load_stackoverflow) 1973-07-26
DE2049332A1 (de) 1971-04-22

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