THEPREPARATION OF GLYCAMINES
July 5 , 1957
[CONTRIBUTION FROM
3541
RESEARCH LABORATORIES OF THE UPJOHNCo.]
THE
The Preparation of Glycaminesl BY FRED KAGAN, M. A. REBENSTORF AND RICHARD v. HEINZELMAN RECEIVED FEBRUARY 8, 1957 Large quantities of pure glycamines were conveniently prepared by the reductive alkylation of ammonia or by the hydrogenolysis of N-benzylglycamines. To ensure high quality products, purification of the glycamines from either process should be carried out through their Schiff bases.
Although 1-amino-1-deoxy sugars, the glycamines, have been known for over fifty years, a good preparative method which is practical for the synthesis of large quantities of high purity material is not available. The need for large quantities of galactamine of greater than %yopurity as a resolving agent in a synthesis of pantothenic acid2 prompted us to reinvestigate the preparation of this class of compounds. Glycamines previously have been prepared by the chemical reduction of sugar oxime^,^-^ by electrolytic, chemical and catalytic reduction of glycosylamines5and by the reductive alkylation of ammonia with a sugar.6-8 The chemical and electrolytic reduction methods were of little interest because they were not readily adaptable to large-scale operations. The Flint and Salzburg' method yielded impure sirups unsuitable for our purposes. Wayne and Adkins8 prepared glucamine in low yield by the reduction of glucose in methanolic ammonia. Holly and co-workerss synthesized glycamines of approximately SOYo purity by the reductive alkylation of liquid ammonia with sugars. None of these methods was suitable for the large-scale production of pure sugar amines. One route to glycamines which we investigated involved the hydrogenolysis of an N-benzylglycamine. For example, N-benzylgalactamine (111), prepared in 64y0 yield by the reductive alkylation
H--~-oH HO-C-H
H-C
I
CHZOH
I
CsHbCH2NHz
simplify the process by carrying out the two hydrogenations consecutively in the same vessel without isolating the intermediate N-benzylgalactamine yielded an impure product, a major constituent of which proved to be cyclohexylmethylgalactamine (V). Structure assignment was made on H C H ~ N H C H ~ CHz-NI H-C-OH I H-C-OH I HO-C-H I HO-C-H I HO-C-H I HO-C-H H-L-OH I H-C-OH I CHiOH 1 CHzOH
V
I
HO-C-H
I
I H-C-OH I Hz + HO-C-H Pt I
I
I
I I HC-C-H I
H-C-OH
HC-C-H
I
H-C-OH
I
CH20H
the basis of elementary analysis (6 more hydrogens than N-benzylgalactamine), the absence of characteristic phenyl absorption in the ultraviolet and by the neutral equivalent. One attempt to carry out the reductive alkylation and hydrogenolysis steps simultaneously in the presence of a mixed catalyst (platinum and palladium-on-charcoal) yielded another new sugar amine, didulcitylamine (VI). The structure VI has been assigned tentatively to the product on the basis of the elementary analyses of
HO-C-H
H-C-
CHz
VI
CHzNHCHzC6Hs
H-C-OH
I
K-C-OH
I
CHzNHz
I 1 HO-C-H 1
H-C-OH
Hz ___f
Pd/C
HO-C-H H-L-OH
1
CHzOH
CH,OH
CH2OH
I1
I11
Iv
of benzylamine with galactose, gave galactamine (IV) in 77y0 yield when hydrogenolyzed in the presence of palladium-on-charcoal. An attempt to (1) Presented in part before the 129th Meeting of The American Chemical Society, Dallas, Texas, April, 1956. (2) F. Kagan, R. V. Heinzelman, D. I. Weisblat and W. Greiner. T H I s JOURNAL, 1 9 , 3545 (1957). (3) L. Maquenne and E. Roux, Compl. vend., 132, 980 (1901). (4) E. Roux, ibid., 136, 691 (1902). (5) C. Neuberg and F. Marx. Biochem. Z.,3, 539 (1907). (6) A. R.Ling and D. R.Nanji, J. Chem. Soc., 1682 (1922). (7) R. B. Flint and P. L. Salzburg, U. S. Patent 2,016,982, Oct. 8, 1935; C. A., 29, 8007 (1935). (8) W. Wayne and H. Adkins, THISJOURNAL, 62, 3314 (1940). (9) F. W.Holly, E. W. Peel, R. Mozingo and K. Folkers, i b i d . , 72, 5416 (1950).
both the free base and the hydrochloride and on the basis of the neutral equivaient. In several experiments, the glycamines obtained by the hydrogenolysis procedure were dif ficult to purify. It seems likely that didulcitylamine and cyclohexylmethylgalactamine, were the main contaminants. T o ensure a high quality product, it is recommended that the crude hydrogenolysis mixture be purified through either the benzylidene or salicylidene derivative as described below. Although the hydrogenolysis of an N-benzylglycamine was a satisfactory low pressure laboratory procedure for the preparation of glycamines, cata-
FREDKAGAN, M. A. REBENESTDRP AND RICHARD V. HEINZELMAN
3542
Vol. 79
lyst costs and the multiplicity of steps made it una t tractive for large-scale preparative work. R o w 2 has reported the preparation of benzylideneglucamine and its hydrolysis by steam distillation. He suggested that this procedure could be used for the purification of glucamine; however, no experimental details were given. Wayne and Adkinss prepared benzylideneglucamine by heating glucamine with benzaldehyde a t 180-190° They obtained a dark reaction mixture from which the benzylidene derivative was isolated by fractional crystallization. The low over-all yield of glucamine in this case may have been due in part to the vigorous conditions used in the isolation of the product. These investigators stated that in their opinion the tlifliculty in obtaining glucamine was not in the hydroyenation stage but in the isolation of the compound. LVe found that crude glycamines could be converted to aromatic Schiff bases easily a t room temperature in aqueous solution. The Schiff bases separated in excellent yield leaving water-soluble sugar derivatives in solution. ,4 variety of aldehydes were used for Schiff base formation, the best
up to 12y0 yield by ion exchange treatment of crude reaction mixtures. It is of interest that even in the presence of a large excess of liquid ammonia a significant portion of the original sugar remained in the aldehyde form and was reduced to dulcitol during the hydrogenation. Didulcitylamine (VI) was also isolated; however, the yields were generally less than 10% when liquid ammonia was used as solvent during the hydrogenation. When concentrated aqueous ammonia was used as solvent, the yield of VI was variable, being as high as 20‘3, in one case. Compound VII, 1,2-dideoxydiaminodulcitol was not isolated as such; however, its presence in some of our products was inferred from potentiometric titration data. I n addition to the inflections for galactamine (PK,’ in water, 9.4) and didulcitylamine (pK,’ in water, 8.9), a basic group (in small amounts) with a pKa‘ of 5.9 was identified. The PKa’ of this group is typical of what one would expect from the neutralization of the second amino group in VIII; however, in addition to the titration behavior, we have further justification for assigning the vicinal diamine structure to VII. Careful purification of the salicylidenegalactamine 0 - C H O + HOCH2(CHOH)&H2NH2+ obtained from crude hydrogenation mixtures yielded a salicylidene derivative, rn.p. 12G12S0,iii X ‘ very low yield (
