Diethyl Ether → Trifluoroacetate

When an organic compound containing both amino group and hydroxyl group in the molecule thereof is intended to be acetylated preferentially at the hydroxyl group, it has been proposed that the protection of the amino group is done by protonating such amino group with a strong organic acid such as trifluoroacetic acid so as to protect said amino group, and then the hydroxyl group may be acetylated preferentially using a usual acetylation reagent such as acetyl chloride or acetic anhydride or mixed anhydrides (see J. Bello & J. R. Vinograd; "Journal of American Chemical Society" Vol. 78, page 1369 (1956)). Using this known method of protonating the amino group with a strong organic acid such as trifluoroacetic acid for the purpose of protecting the amino groups of the initial 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin, the 6-O-((S)-α-hydroxy-ω-aminoacyl)-3', 4'-dideoxyneamine or -3',4'-dideoxyribostamycin of the formula (III) may also be prepared in the following way: The 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin (the free base form) is dissolved in trifluoroacetic acid under ice-cooling and the resulting solution is admixed with ethyl ether to precipitate such a trifluoroacetic acid salt of 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin in which the four amino groups of the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin molecule have each been protected with the trifluoroacetic acid molecule. This 3', 4' -dideoxyneamine or 3', 4'-dideoxyribostamycin trifluoroacetate so formed is then esterified or condensed with an (S)-α-hydroxy-ω-amino acid of the formula (V) in solution in an organic solvent such as dimethylformamide (DMF), acetone or tetrahydrofuran under ice-cooling and in the presence of a strong acid or a dehydrating agent such as dicyclohexylcarbodiimide. The acid of the formula (V) may conveniently be its functional derivative such as acid halide, azide derivative, active ester or mixed acid anhydride. In the reaction (esterification) of the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin trifluoroacetate with the acid of the formula (V), all the hydroxyl groups, including the 6-hydroxyl group, of the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin molecule are unblocked and are O-amino-acylated at random by the acid of the formula (V), so that there is formed a mixture of mono-O-aminoacylated and di-O-aminoacylated 3', 4'-dideoxyneamines (in the form of their trifluoroacetate) or a mixture of mono-O-aminoacylated to tetra-O-aminoacylated 3', 4'-dideoxyribostamycins (in the form of their trifluoroacetate). When this mixture of the O-aminoacylated 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin trifluoroacetates is neutralized with a base, there is given the mixed O-aminoacylated 3', 4'-dideoxyneamines or 3', 4'-dideoxyribostamycins which contain a 6-O-((S)-α-hydroxy-ω-aminoacyl)-3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin of the formula (III). From the above-mentioned mixed O-aminoacylated 3', 4'-dideoxyneamines or 3', 4'-dideoxyribostamycins may be isolated the 6-O-((S)-α-hydroxy-ω -aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin of the formula (III) by a chromatographic method using, for example, cellulose powder, silica gel or a molecular sieve consisting of a three dimensional dextran network (commercially available under a trade name "Sephadex G-15", a product of Pharmacia Co., Sweden). However, the above-mentioned mixed O-aminoacylated 3', 4'-dideoxyneamines or 3', 4'-dideoxyribostamycins containing the 6-O-((S)-α-hydroxy-ω-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycins as such may be immediately employed as the starting material for the process of this invention, before or after the trifluoroacetic acid is liberated therefrom by neutralizing with a base, as stated above. This is because the (S)-α-hydroxy-γ-aminoacyl substituent(s) on the other hydroxyl group(s) than the 6-hydroxyl group in these mixed O-aminoacylated product may be regarded as one of the hydroxyl-protecting group Y of the acyl type as stated before. When said mixed O-aminoacylated 3', 4'-dideoxyneamines or 3', 4'-dideoxyribostamycins are subjected to the action of the basic medium in the process of this invention, there is formed the desired 1-N-((S)-α-hydroxy-ω-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin of the formula (II) as the sole acyl-migration product, because the migration of the (S)-α-hydroxy-ω-aminoacyl substituent from the hydroxyl group to the amino group cannot take place except that from the 6-hydroxyl group to the 1-amino group as long as the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin (III) is concerned with as the starting compound in the present process. The N-aminoacylation product may be precipitated from the reaction mixture by concentration of the latter and filtered out and dissolved in water to prepare an aqueous solution of them at pH of about 8. This solution may then be subjected to a chromatographic separation in a column of CM-Sephadex C-25 (ammonium form) to isolate the desired 1-N-((S)-α-hydroxy-ω-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin of the formula (II). Active fractions of the eluate issued from the column and containing the 1-N-((S)-α-hydroxy-ω-aminoacyl)-3', 4'-dideoxyneamine or -3', 4'-dideoxyribostamycin can be detected by an oxidation test with periodic acid, as the presence of an 1-N-acyl substituent is detectable by said test (see "Tetrahedron Letters", Vol. 28, pages 2624-2628 (1971)).

1. additionWhen an organic compound containing both amino group and hydroxyl group in the molecule
2. custommay also be prepared in the following way
3. temperaturecooling
4. customto precipitate such a trifluoroacetic acid salt of 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin in which the four amino groups of the 3', 4'-dideoxyneamine or 3', 4'-dideoxyribostamycin molecule

ORD record

ord-86d1ef98b6ae4bfebfa3f22e37fc411d

Source dataset

uspto-grants-1976_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US03948882