The Preparation of Colchicide¹ (Demethoxycolchicine)

Abstract

Dehydrobromination of 7-Keto-8-bromocholesteryl Acetate (IX).-A solution of 1 g. of IX and 30 cc. of pyridine was refluxed for 7 hours and the reaction mixture was treated in the usual manner; the reddish-brown oily product was chromatographed through a column of 50 g. of alumina (Brockmann Grade II) with a petroleum ether-benzene (1:1) solution (200 cc.). The eluate was fractionated into 40 cc. each.Fractions 3 and 4 afforded a solid which after crystallization from alcohol gave 80 mg. of colorless crystals, m.p. 119-120°, identical with V.Development of the column with a benzene-ether (1:1) mixture afforded 90 mg. of III, m.p. 152-153°. Preparation of 7-Keto-A3'6-8(9,-cholestatriene (V) from 7-Keto-A3'5-cholestadiene (XI).-To a solution of 4 g. of XI in 25 cc. of carbon tetrachloride, 2 g. of NBS and 150 mg. of dibenzoyl peroxide were added, and the mixture was refluxed on a water-bath, with protection from moisture, with irradiation of a 375-watt infrared lamp at a distance of 40 cm.Most of the NBS was converted to succinimide within 30 minutes, and the reaction was complete in about 50 minutes. The cooled reaction mixture was filtered, and the filtrate was evaporated to a brown, oily residue which could not be crystallized. Therefore, 2 g. of this bromide was dissolved in 30 cc. of pyridine, the mixture was refluxed for 6 hours, and the cooled mixture was poured into ice-cooled dilute hydrochloric acid. This was extracted with ether, the ether layer was washed consecutively with 10% hydrochloric acid and water, dried, and the solvent was removed under reduced pressure.The brown oily residue (1.2 g.) was dissolved in 200 cc. of petroleum ether-benzene (1:1) and passed through a column containing 40 g. of alumina (Brockmann Grade I/II). The column was eluted with 200 cc. of petroleum ether-benzene and the eluate was fractionated into 40 cc. each. The oily residue obtained from fractions 2 and 3 was recrystallized from ethanol; colorless needles (XV), m.p. 150-151°, X®'°H 294 µ (£ 10,700), yield 250 mg.

Synthesis and tubulin binding of novel C-10 analogs of colchicine

“…The product was purified by radial chromatography (95:5 CH2Cl2-MeOH) and was obtained as a yellow solid in a yield of 49%. Compound 14: mp 109-110 °C; [a]26D -179°(c 0.9); NMR 7.31 (d, 1 H, H-12, J = 9.9 Hz), 7.29 (s, 1 , H-8), 7.16 (d, 1 H, H-ll, J = 9.8 Hz), 6.90 (br, 1 , NH), 6.51 (s, 1 , H-4), 4.62 (p, 1 , H-7), 3.93 (s, 3 H, 3-OCH3), 3.90 (s, 3 H, 2-OCH3), 3.67 (s, 3 H, l-OCH3), 2.68 [m, 2 H, 10-CH2 (CH2)2CH3], 2.48 (m, 2 , H-5), 2.22 (m, 1 , H-6), 1.99 (s, 3 H, COCH3), 1.80 (m, 1 , H-6), 10-Isobutyl-l0-demethoxycolchicine (15). This compound was synthesized as described above using isobutylmagnesium bromide, and the reaction was monitored by TLC using 95:5 CH2Cl2-MeOH.…”

“…Attempts to hydrolyze 9demethoxy-9-tosylisocolchicine with 5% NaOH in water/ ethanol also resulted in ring contraction product as well as colchiceine. We have found that when the alkoxymagnesium compound is the nucleophile rather than the 7.9 13.2 (±1.7) 53.7 (±2.5) CH3 (10) 4.1 56.6 (±1.5) 96.7 (±9.9) CH2CH3 (11) 4.2 54.9 (±6.8) 96.5 (±9.4) CH2CH2CH3 (12) 3.5 41.7 (±1.5) 89.2 (±5.9) CH(CH3)2 (13) 4.2 44.9 (±5.4) 90.0 (±1.9) (CH2)3CH3 ( 14) 26 13.9 (±7.0) 24.7 (±5.8) CH2CH(CH3)2 (15) 8.5 13.4 (±1.9) 36.7 (±4.6) CH(CH2CH3)(CH3) (16) 10 19.6 (±5.7)…”

“…Table I. Synthesis of C-10 Analogues of Colchicine substrate, X = product, R = yield (%) OH (4) OTos ( 5) 89 (22) °O Tos Cl (6) 86 OTos Br (7) 73 Br K8) 70 OH F (9) 88 (66) F CH3 (10) 52 OH CH3 (10) 52 (39) F CH2CH3 (11) 48 OH CH2CH3 (11) 60 (45) F (CH2)2CH3 (12) 69 F CH(CH3)2 (13) 72 F (CH2)3CH3 (14) 49 F CH2CH(CH3)2 (15) 55 F CH(CH2CH3)(CH3) (16)…”

Colchicine Alkaloids and Synthetic Analogues: Current Progress and Perspectives

“…Another simple analogue of colchicine is colchicide ( 193 ), in which the C-10 methoxy group is replaced by a hydrogen atom. This compound ( 193 ) is accessible from thiocolchicine ( 6 ) by reaction with Raney nickel in acetone (Scheme ).…”

The Action of Raney Nickel on Organic Sulfur Compounds.

“…The more easily desulfurized 1,8-p-menthylene sulfone (XXXVIII) reacted in accordance with Bonner's findings (73) with complete inversion, which the author explains by assuming a Raney nickel desulfurization was also used in work on the chemistry of colchicine. Demethoxycolchicine (XLa) was obtained in 61% yield from thiocolchicine (XLb) by treatment with Raney nickel deactivated by boiling acetone (373), whereas hexahydrodemethoxycolchicine (XLI) was obtained in yields up to 40% when active nickel was used (373,452). The compound XLII was also desulfurized without hydrogenation of the aromatic ring (451).…”