Preparative separation of tetrahydrofurfurylamine enantiomers

Article abstract of DOI:10.1134/S1070428007120123

Tetrahydrofurfurylamine enantiomers were separated on a preparative scale by fractional crystallization of diastereoisomeric salts with natural L-tartaric acid. (R)-Tetrahydrofurfurylamine was isolated in 68% yield with an optical purity of more than 98.5% according to the HPLC data.

Full text of DOI:10.1134/S1070428007120123

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 12, pp. 1813–1814. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © D.M. Musatov, V.S. Kublitskii, O.R. Malyshev, D.V. Kurilov, M.G. Vinogradov, 2007, published in Zhurnal Organicheskoi Khimii,
2007, Vol. 43, No. 12, pp. 1811–1812.
Preparative Separation of Tetrahydrofurfurylamine Enantiomers
D. M. Musatova, V. S. Kublitskiib, O. R. Malysheva, D. V. Kurilova, and M. G. Vinogradova
a Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Leninskii pr. 47, Moscow, 119991 Russia
e-mail: ving@ioc.ac.ru
b ChemBridgeCorp, Moscow, Russia
Received May 14, 2006; revised August 1, 2007
Abstract—Tetrahydrofurfurylamine enantiomers were separated on a preparative scale by fractional crystal-
lization of diastereoisomeric salts with natural L-tartaric acid. (R)-Tetrahydrofurfurylamine was isolated in
68% yield with an optical purity of more than 98.5% according to the HPLC data.
DOI: 10.1134/S1070428007120123
Tetrahydrofurfurylamine (I) is widely used in the
synthesis of various medical agents such as diuretics
[1–3], enzyme inhibitors [4–7], analgesics [8–10], and
neurotropic [11] and anticarcinogenic drugs [12].
Separation of tetrahydrofurfurylamine enantiomers by
crystallization of diastereoisomeric salts with natural
L-tartaric acid was reported in [13, 14]; however, no
experimental details were given, and enantiomeric
purity of the obtained compound was not specified.
perature 20ºC. The retention times of the (R)- and
(S)-enantiomers of N-tetrahydrofurfurylbenzamide are
26.91 and 27.80 min, respectively. The absolute con-
figurations were assigned using a commercial sample
of (R)-(–)-I from Acros Organics. The optical rotations
were measured on a Spectropol-1 spectropolarimeter.
Separation of the (R)- and (S)-enantiomers of
tetrahydrofurfurylamine (I). L-(+)-Tartaric acid,
386 g (2.57 mol), was dissolved in 1200 ml of water,
260 g (2.57 mol) of (RS)-I and 3 l of acetone were
added, the mixture was kept for 24 h at 4ºC, and the
colorless crystalline solid was filtered off and washed
with a mixture of 500 ml of acetone and 100 ml of
water. The salt was recrystallized from a mixture of 1 l
of acetone with 250 ml of water, dried in air, and
treated with a solution of 200 g of potassium hydrox-
ide in 500 ml of water. The oily material separated and
was extracted into THF (3×250 ml). The extracts were
combined, dried over solid alkali, and distilled under
atmospheric pressure. Yield of (R)-(–)-I 88.4 g (68%),
bp 152–153ºC; published data [14]: bp 154–157ºC; the
optical purity was higher than 98.5% ((HPLC), [α]D20 =
–12.15º (c = 5.05, CHCl3). From the mother liquor we
isolated 128 g of (S)-(+)-I, [α]D20 = + 9.73º (c = 5.05,
CHCl3), enantiomeric purity 79%.
Using L-tartaric acid as chiral resolving agent, we
have developed an effective preparative procedure for
the isolation of enantiomerically pure tetrahydrofur-
furylamine from commercially available racemate.
Enantiomer (R)-I with a purity of better than 98.5%
(according to the HPLC data) was isolated in 68%
yield. From the mother liquor we isolated (S)-I with
an enantiomeric purity of 79%.
EXPERIMENTAL
Racemic tetrahydrofurfurylamine (I) and L-tartaric
acid from Lancaster Synthesis were used. Chiral com-
pound I was analyzed for enantiomeric purity by
HPLC of the corresponding benzamide which was
prepared by treatment of I or its salt with tartaric acid
with benzoyl chloride in the two-phase system ethyl
acetate–aqueous potassium carbonate.
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Chem. Industries, Osaka, Japan); eluent hexane–pro-
pan-2-ol (95:5, by volume), flow rate 2 ml/min; tem-
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007