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Process of synthesis of 3',4'-anhydrovinblastine, vinblastine and vincristine

a technology of vinblastine and vincristine, which is applied in the field of synthesis of dimer alkaloid compounds, can solve the problems that art methods also yield small quantities of target compounds

Inactive Publication Date: 2001-11-13
THE UNIV OF BRITISH COLUMBIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, these prior art methods also yielded small quantities of the target compounds.

Method used

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  • Process of synthesis of 3',4'-anhydrovinblastine, vinblastine and vincristine
  • Process of synthesis of 3',4'-anhydrovinblastine, vinblastine and vincristine
  • Process of synthesis of 3',4'-anhydrovinblastine, vinblastine and vincristine

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of the Iminium Intermediate (Formula VI) via Modified Polonovski Reaction

The reaction was performed under anhydrous conditions. All glassware was oven-dried at 120.degree. C. The solvent, methylene chloride, and coupling reagent, trifluoroacetic anhydride, were distilled from P.sub.2 O.sub.5 prior to use.

To a solution of catharanthine (Formula III, 200 mg, 0.6 mmol) in dry methylene chloride (2 ml) at -20.degree. C. under a positive atmosphere of argon was added m-chloroperbenzoic acid (132 mg, 0.8 mmol), and the mixture was stirred for 5 minutes. To the catharanthine N-oxide (IIIa; R.dbd.COOCH.sub.3 ; R.sub.1, R.sub.2, R.sub.3, and R.sub.4 =H), thus formed was added a solution of vindoline (IV, 270 mg, 0.6 mmol) in methylene chloride (1 ml) and the mixture was cooled to -60.degree. C. Trifluoroacetic anhydride (0.2 ml, 1.5 mmol) was added to the stirred reaction mixture maintained at -60.degree. C. for 2 hours. After this time, the solvent and excess reagents were remov...

example 2

Reduction of Iminium Intermediate (Formula VI) with 1-Benzyl-1,4-dihydronicotinamide [Formula IX, R.sub.1 =benzyl, R.sub.2, R.sub.4, R.sub.5, and R.sub.6 =H; R.sub.3 =CONH.sub.2 ; (Formula IX-A) Procedure A]

To a stirred solution of iminium intermediate (VI, 100 mg) in degassed acetonitrile (5 ml) was added 1-benzyl-1,4-dihydronicotamide (135 mg, 0.63 mmol, 6 equivalents) under a positive atmosphere of argon (greater than 760 mm Hg) at room temperature (20.degree. C.) over a period of 5 hours. After this time, the reaction mixture, as monitored by reverse phase HPLC (Waters Radial-Pak C.sub.18 or CN cartridge, methanol / H.sub.2 O / Dt.sub.3 N solvent system), indicated complete conversion of VI to a mixture of enamine VIII and 3',4'-dehydrovinblastine (VII) in a ratio of 1:1 (75% yield).

example 3

Reduction of Iminium Intermediate (Formula VI) with 1-Benzyl-1,4-dihydronicotinamide (Formula IX, R.sub.1 =benzyl, R.sub.2, R.sub.4, R.sub.5, and R.sub.6 =H; R.sub.3 =CONH.sub.2 (Formula IX-A) Procedure A]

To a stirred solution of iminium intermediate (VI, 100 mg) in methanol (5 ml) kept initially at 0.degree. C for 0.5 hours was added dropwise or in portions, a solution of 1-benzyl-1,4-dihydronicotinamide (56 mg, 0.26 mmol, 2.5 equivalents) in methanol (2ml) under a positive atmosphere of argon (greater than 760 mm Hg) over a period of 5 hours. During this time the solution was allowed to warn up to room temperature. HPLC monitoring, as in Example 1, indicated complete conversation of VI to a mixture of enamine VIII and 3',4'-dehydrovinblastine (VII) in a ratio of 1:1 (75% yield).

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Abstract

The present invention relates to the synthesis of dimer alkaloid compounds, particularly those of the Catharantus (Vinca) family, from an indole unit, such as cantharanthine, and a dihydroindole unit, such as vindoline. A multi-step process is disclosed including the steps of (1) of 1,4-reduction of a first dimeric iminium intermediate to an enamine compound by reaction with a 1,4-dihydropyridine compound; (2) oxidative transformation of the resulting enamine to a second iminium intermediate under controlled aeration; (3) reduction of the second iminium intermediate to form the target dimer alkaloid compounds. The entire process can be conducted in a one-pot operation to obtain the target compounds without isolation of the intermediates.

Description

BACKGROUND OF THE INVENTIONThe present invention relates to the synthesis of dimer alkaloid compounds, particularly those of the Catharantus (Vinca) family, such as vinblastine, vincristine and leurosidine, sometimes referred to hereinafter as the target compounds or the target dimer alkaloid compounds.The dimeric alkaloids of present interest have remarkable anti-viral, anti-tumor and anti-leukemic properties. In the past, these alkaloids were isolated from the Catharantus species, particularly C. roseus, in small quantities. More recently, progress has been made in the synthesis of these compounds (U.S. Pat. Nos. 4,144,237 and 4,279,817 to James P. Kutney, and parent application U.S. Ser. No. 07 / 011,810). Unfortunately, these prior art methods also yielded small quantities of the target compounds. The present invention overcomes the difficulties encountered in the prior art insofar as it yields dramatically increased quantities of the target dimer alkaloid compounds.SUMMARY OF THE...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D519/00C07D519/04C07D471/00C07D471/20
CPCC07D519/04
Inventor KUTNEY, JAMES P.CHOI, LEWIS S. L.NAKANO, JUNTSUKAMOTO, HIROKIBOULET, CAMILLE A.MCHUGH, MICHAEL
Owner THE UNIV OF BRITISH COLUMBIA
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