cyanic acid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%. in only low yields

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.23 g of Part A(6) cyano-alcohol (7.36 mmole) in 20 ml of dry methylene chloride was treated with 800 ml of dihydropyran (8.89 mmole) and catalytic amount of p-toluene sulfonic acid at 0°-5° C. After 4 hours, the reaction mixture was diluted with ether and washed with aqueous sodium bicarbonate solution. The aqueous layer was reextracted twice with ether. The combined organic extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude residue was chromatographed on a silica gel column and eluted with 20-25% ethyl acetate in hexane to obtain 1.61 g of title tetrahydropyranyl ether. washed with aqueous sodium bicarbonate solution The combined organic extract was dried over anhydrous magnesium sulfate concentrated under reduced pressure The crude residue was chromatographed on a silica gel column eluted with 20-25% ethyl acetate in hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By sequential reaction of diethyl 2-amino-2-methylnonanedioate with cyclohexyl vinyl ketone, sodium borohydride, and cyanic acid according to the general procedure described in Example 105, 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-5-methylhydantoin was obtained as a mixture of diastereomers. Separation by high performance liquid chromatography gave the individual racemic diastereomers as colourless gums, the less polar isomer having Rf. 0.52 relative to Rf. 0.48 for the more polar isomer on SiO2 in chloroform-methanol-acetic acid 90:5:5. The less polar isomer gave characteristic 'H n.m.r. signals at δ9.34 (1H, broad singlet, exch., NH), 5.83 (2H, broad singlet, exch., CO2H and OH), 3.6, 3.3 and 3.1 (3H, three multiplets, C-13 protons and C-15 methine), 2.31 (2H, triplet, CH2 adjacent to CO2H) and 1.39 (singlet, isolated CH3) in CDCl3. The more polar isomer gave characteristic 'H n.m.r. signals at δ9.23 (1H, broad singlet, exch., NH), 5.73 (2H, broad singlet, exch., CO2H and OH), 3.38 (3H, multiplet, C-15 methine and C-13 protons), 2.32 (2H, triplet, CH2 adjacent to CO2LH) and 1.40 (singlet, isolated CH3) in CDCl 3.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By sequential reaction of diethyl 2-amino-2-methylnonanedioate with cyclohexyl vinyl ketone, sodium borohydride, and cyanic acid according to the general procedure described in Example 105, 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-5-methylhydantoin was obtained as a mixture of diastereomers. Separation by high performance liquid chromatography gave the individual racemic diastereomers as colourless gums, the less polar isomer having Rf. 0.52 relative to Rf. 0.48 for the more polar isomer on SiO2 in chloroform-methanol-acetic acid 90:5:5. The less polar isomer gave characteristic 'H n.m.r. signals at δ9.34 (1H, broad singlet, exch., NH), 5.83 (2H, broad singlet, exch., CO2H and OH), 3.6, 3.3 and 3.1 (3H, three multiplets, C-13 protons and C-15 methine), 2.31 (2H, triplet, CH2 adjacent to CO2H) and 1.39 (singlet, isolated CH3) in CDCl3. The more polar isomer gave characteristic 'H n.m.r. signals at δ9.23 (1H, broad singlet, exch., NH), 5.73 (2H, broad singlet, exch., CO2H and OH), 3.38 (3H, multiplet, C-15 methine and C-13 protons), 2.32 (2H, triplet, CH2 adjacent to CO2LH) and 1.40 (singlet, isolated CH3) in CDCl 3.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Reaction of diethyl 2-((3-cyclohexyl-3-oxopropyl)amino)nonanedioate (20.8 g) with cyanic acid using the general procedure of Example 2d afforded 5-(6-ethoxycarbonylhexyl)-1-(3-cyclohexyl-3-oxopropyl)hydantoin which was converted to the corresponding acid which crystallised from ether, m.p. 77.5°-78.5° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.23 g of Part F cyano-alcohol (7.36 mmole) in 20 ml of dry methylene chloride was treated with 800 ml of dihydropyran (8.89 mmole) and catalytic amount of p-toluene sulfonic acid at 0°-5° C. After 4 hours, the reaction mixture was diluted with ether and washed with aqueous sodium bicarbonate solution. The aqueous layer was reextracted twice with ether. The combined organic extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude residue was chromatographed on a silica gel column and eluted with 20-25% ethyl acetate in hexane to obtain 1.61 g of title tetrahydropyranyl ether. washed with aqueous sodium bicarbonate solution The combined organic extract was dried over anhydrous magnesium sulfate concentrated under reduced pressure The crude residue was chromatographed on a silica gel column eluted with 20-25% ethyl acetate in hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.23 g of Part F cyano-alcohol (7.36 mmole) in 20 ml of dry methylene chloride was treated with 800 ml of dihydropyran (8.89 mmole) and catalytic amount of p-toluene sulfonic acid at 0°-5° C. After 4 hours, the reaction mixture was diluted with ether and washed with aqueous sodium bicarbonate solution. The aqueous layer was reextracted twice with ether. The combined organic extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude residue was chromatographed on a silica gel column and eluted with 2 ethyl acetate in hexane to obtain 1.61 g of title tetrahydropyranyl ether. washed with aqueous sodium bicarbonate solution The combined organic extract was dried over anhydrous magnesium sulfate concentrated under reduced pressure The crude residue was chromatographed on a silica gel column eluted with 2 ethyl acetate in hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.23 g of Part F cyano-alcohol (7.36 mmole) in 20 ml of dry methylene chloride was treated with 800 ml of dihydropyran (8.89 mmole) and catalytic amount of p-toluene sulfonic acid at 0°-5° C. After 4 hours, the reaction mixture was diluted with ether and washed with aqueous sodium bicarbonate solution. The aqueous layer was reextracted twice with ether. The combined organic extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude residue was chromatographed on a silica gel column and eluted with 20-25% ethyl acetate in hexane to obtain 1.61 g of title tetrahydropyranyl ether. washed with aqueous sodium bicarbonate solution The combined organic extract was dried over anhydrous magnesium sulfate concentrated under reduced pressure The crude residue was chromatographed on a silica gel column eluted with 20-25% ethyl acetate in hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.23 g of Part F cyano-alcohol (7.36 mmole) in 20 ml of dry methylene chloride was treated with 800 ml of dihydropyran (8.89 mmole) and catalytic amount of p-toluene sulfonic acid at 0°-5° C. After 4 hours, the reaction mixture was diluted with ether and washed with aqueous sodium bicarbonate solution. The aqueous layer was reextracted twice with ether. The combined organic extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude residue was chromatographed on a silica gel column and eluted with 20-25% ethyl acetate in hexane to obtain 1.61 g of title tetrahydropyranyl ether. washed with aqueous sodium bicarbonate solution The combined organic extract was dried over anhydrous magnesium sulfate concentrated under reduced pressure The crude residue was chromatographed on a silica gel column eluted with 20-25% ethyl acetate in hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.23 g of Part F cyano-alcohol (7.36 mmole) in 20 ml of dry methylene chloride was treated with 800 ml of dihydropyran (8.89 mmole) and catalytic amount of p-toluene sulfonic acid at 0°-5° C. After 4 hours, the reaction mixture was diluted with ether and washed with aqueous sodium bicarbonate solution. The aqueous layer was reextracted twice with ether. The combined organic extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude residue was chromatographed on a silica gel column and eluted with 2 ethyl acetate in hexane to obtain 1.61 g of title tetrahydropyranyl ether. washed with aqueous sodium bicarbonate solution The combined organic extract was dried over anhydrous magnesium sulfate concentrated under reduced pressure The crude residue was chromatographed on a silica gel column eluted with 2 ethyl acetate in hexane