HU192276B - Process for preparing 4-deacetyl-3',4'-anhydro- vincristine - Google Patents

Abstract

4-desacetyl-3',4' anhydro-vincristine is obtd. from 3',4'-anhydro-vincristine by treatment with 1-2C alkali metal alcoholates in the presence of 1-2C alkanols and opt. a chlorinated hydrocarbon.

Description

The present invention relates to a novel process for the preparation of 4-desacetyl-3 ', 4'-anhydro-vincristine.

The effect of the compound was reported by Miller et al., J. Med. Chem. 20, 409 (1977)], the preparation of which is described in U.S. Patent 4,029,663. United States (= ⁵

No. 179,457 (Hungarian). The process of preparation consists in treating vincristine or its acid addition salt with cold concentrated sulfuric acid.

During the treatment with sulfuric acid is cleaved from the 4-position acetyl group, and the water outlet is formed during three different ^10-anhydro isomer. (3 ', 4'-anhydro, and 2 different 4', 20'-anhydro isomers). The three isomers formed are separated by chromatography and the effective 3 ', 4'-anhydro-4-deacetyl-vincristine is obtained in 15% yield. ¹⁵

It has been found in our experiments that the compound of interest can be obtained in better yields and by avoiding heavy chromatographic separation. No. 180,924 USA (= U.S. 4,199,505 c.) discloses described vé- ²⁰ an error process, in that the vinkrisztinszulfátból to the desired 3 ', 4'-anhydro-vincristine produced dimethylformamide thionyl chloride or phosphorus oxychloride reagent in 57% yield.

It was found that the thus obtained 3 ', ^{4'-anhydro-25} may be deacylated by vincristine 72%. The reaction is simple, no isomer formation occurs, and the total yield of vincristine is 41%, or nearly three times that of the Miller process.

Thus, a method of 4-desacetyl ³⁰ 3 ', 4'-anhydro-preparing vincristine, such that the 3', 4'-anhydro vincristine 1-2 alkanol optionally in the presence of a chlorinated hydrocarbon and an alkali metal (l The invention (C 2 -C 4) alcohol. 35

The process of the present invention is based on 3 ', 4'-anhydrovincristine, which is preferably prepared from vincristine sulfate with thionyl chloride or phosphorus oxychloride in the presence of dimethylformamide. 3 ', 4'-Anhydro-vincristine is converted to the corresponding 4-deacetyl compound by Zemplen desacetylation. The deacetylation is carried out in a mixture of C1-C2 alkanol and chlorinated hydrocarbon, preferably in a mixture of methanol and dichloromethane or chloroform, using alkali metal (C1-C2) alcohol. Sodium methylate is preferably used as the deacetylating agent. The reaction produces crystalline products.

The invention is illustrated by the following example, without being limited thereto.

Example

3 ', 4'-Anhydro-vincristine (300 mg, 0.337 mmol) was dissolved in a mixture of sodium methoxide in 0.5 N methanol (30 mL) and dichloromethane (0.15 mL) and allowed to stand at room temperature for 2 hours. The solution was then adjusted to pH 7 with glacial acetic acid and the solvent removed in vacuo. The residue was dissolved in water (15 ml) and the aqueous solution was concentrated to pH 3 with concentrated aqueous ammonium hydroxide.

After adjusting to 8.5, the basic solution was extracted with dichloromethane (3 x 15 mL). The combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo.

The residue was crystallized from methanol (2 mL). Yield: 200 mg (72%) of 4-desacetyl-3 ', 4'-anhydro-vincristine. Mp 223 ° C (dec.).

IR (KBr): 3400 (broad), 1735, 1690 ^cm-1

MS m / e (%): 778 (M + 14.2.0), 764 (M ⁺ , 49), 749 (3.5), 736 (8.7), 706 (3.9), 705 ( 4.9), 677 (1.8), 647 (1.4), 641 (5.3), 583 (1.8), 582 (1.7), 567 (1.5) 513 (2.4), 511 (1,8), 498 (1,3), 382 (6,0), 337 (2,9), 336 (4.5), 240 (2,8), 136 (100), 122 (48).

1 H-NMR (CDCl ₃ ): δ 8.55 (1Η, broad, OH), 8.00 (2H, indole NH, CHO), 7.60-6.85 (6H, m, aromatic),

5.82 (2H, C-6 and C-7H), 5.42 (1H, C-3'Η), 4.53 (1H, C-2H), 3.86, 3.78 and 3.63 (9H, s, OCH ₃ , CO ₂ CH ₃ ), 1.08-0.95 ppm (6H, t, 2 x CH ₂ Cl ₃ ).

Claims (3)

Claims A process for the preparation of 4-deacetyl-3 ', 4'-anhydro-vincristine comprising reacting the 3', 4'-anhydrovincristine with an alkali metal (C 1-2) alcohol in the presence of a C 1-2 alkanol and optionally a chlorinated hydrocarbon. . Process according to claim 1, characterized in that the reaction is carried out in a mixture of methanol and dichloromethane. 3. A process according to claim 1 wherein the alkali metal (C 1 -C 2) alcoholate is sodium methylate. Without drawing