IL26522A - Preparation of 4'-demethyl-epipodophyllotoxin - Google Patents
Preparation of 4'-demethyl-epipodophyllotoxinInfo
- Publication number
- IL26522A IL26522A IL2652266A IL2652266A IL26522A IL 26522 A IL26522 A IL 26522A IL 2652266 A IL2652266 A IL 2652266A IL 2652266 A IL2652266 A IL 2652266A IL 26522 A IL26522 A IL 26522A
- Authority
- IL
- Israel
- Prior art keywords
- epipodophyllotoxin
- bromide
- demethyl
- podophyllotoxin
- hydrogen
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
•flimi |Π3 ΤϊΙΠΙ"! 'ΊΊ PATENT ATTORNEYS · D'DIOS ' 3 Ί 1 U PATENTS AND DESIGNS ORDINANCE SPECIFICATION Preparation of 4,*deaethyl-epipo0ophyllotoxin SAIDOZ ( a Sviss Body Corporate of Basle, Switzerland do hereby declare the nature of this invention and in what manner the same is to "be performed, to he particularly described and ascertained in and by the following statement :- Case 2209 The present invention relates to the production of an-alAayolic oorope«a&r- 4 •-demethyl-epipodophyllotoxin.
The present invention provides a process for the production of V-demethyl-epipodophyllotoxin of formula I, characterized in that podophyllotoxin is reaoted with hydrogen bromide or hydrogen chloride, the resulting epipodophyllotoxin halide of general formula II, in which Hal signifies a chlorine or bromine atom, is treated with hydrogen bromide and the resulting 4'-demethyl-epipodophyliotoxin bromide of formula III is hydrolyzed.
It was hitherto not possible to effect a seleotive ether-splitting in the 4' -position of epipodophyllotoxin or podophyllotoxin. Surprisingly it has now been found that a selective ether-splitting in the '-position of epipodophyllotoxin halides of general formula II, which are extremely sensitive to the aotion of hydrogen halides, may be effected with hydrogen bromide. As a result it is possible to produoe 4,-demethyl-epipodophyllotoxin by a simple process from the readily obtainable podophyllotoxin.
One method of effecting the process of the invention consists in that podophyllotoxin is treated with hydrogen bromide gas or hydrogen chloride gas in an inert solvent, e.g. ethylene chloride, chloroform or methylene chloride, containing some ether1, at -20° to +40°C, preferably at 0°C. The resulting solution of epipodophyllotoxin halide is then again treated with hydrogen bromide gas under the con - 3 - 26522/2 After washing out the excess hydrogen bromide with water, drying the organic phase and evaporating in a vacuum, 4'-demethyl-epipodophyllotoxin bromide may be purified by crystallization from an inert solvent, e.g. acetone, a mixture of acetone and ether, a mixture of acetone and a hydrocarbon or a halogenated hydrocarbon. The pure 4*-demethyl-epipodophyllo-toxin bromide is subsequently dissolved in a mixture of water and a water miacible organic solvent which does not react with 41-demethyl-epipodophyllotoxin bromide, e.g. acetone, and hydrolyzed at a reaction temperature between 20° and 80°C in the presence of a proton acceptor. Proton acceptors which may be used are the salts of weak acids, the aqueous solutions of which give a neutral reaction or such a weak basic reaction that no epimerization of the lactone ring on the C atom in the 3-position occurs, and the anions of which do not participate in undesired exchange reactions with the bromine atom, e.g. barium carbonate and calcium carbonate. 4'-demethyl-epipodophyllotoxin may be isolated in manner known per se and subsequently purified, e.g. by crystallization or chromatography. 4»-demethyl-epipodophyllotoxin is a solid, crystalline compound at room temperature. It may be used as intermediate in the synthesis of cytostatics of the llgnan type having a high therapeutic activity* '-demethyl-epipodophyllotoxin Itself, however, also has a selective inhibiting effect on dividing phenomena in the cell nucleus and its use is therefore indicated in cases where, for medical reasons, the slowing down or prevention of cell division or cell multiplication is - 3a - 26522/2 desirable. The compound prepared by the process of the invention, as opposed to other podophyllin derivatives, is especially characterized in that it tends not to have a general cytotoxic effect and tends not to produce side effects, e.g. nausea and vomiting. - 4 - 2209 The W» compound may be used as a pharmaceutical on its own or in the form of appropriate medicinal preparations for administration, e.g. enterally or parenterally. In order to produce suitable medicinal preparations the compound is worked up with organic or lnorganio adjuvants which are inert and physiologically acceptable. Examples of such adjuvants aret for tablets and drage'es : lactose, starch, talc and steario acid; for syrups : solutions of cane sugar, invert sugar and glucose; for injectable solutions : water, alcohols, glycerin and vegetable oils; for suppositories : natural or hardened oils and waxes.
The preparations may furthermore contain suitable preserving, stabilizing and wetting agents, solubilizers, sweetening and colouring substances and flavourings.
The term "in manner known per sew as used herein designates methods in. use or described in the literature on the subject.
In the following non-limitative Example^ all temperatures are indicated in degrees Centigrade. The melting and decomposition points were determined on a Kofler block. - 5 2209 E amgle^ 41 -demethyl-epipodophyllotoxin. a) 4' -demethyl-epipodophyllotoxin bromide. g of podophyllotoxin are dissolved in 200 ml of ethylene chloride and the solution is saturated with hydrogen bromide gas at 0° . After 1 minutes, washing is effected once with 200 ml of water, the organic phase is dried over sodium sulphate, filtered and the sodium sulphate washed with 50 ∞1 of ethylene chloride. 5 ml of ether are added to the resulting solution of epipodophyllotoxin bromide and after cooling to 0° the solution is saturated with hydrogen bromide gas. The solution is allowed to react at 0° and after 3, 5, 20 and 25 hours saturation with hydrogen bromide gas is again effected. After 28 hours washing is effected thrice, each time with 400 ml of water and after drying the organic phase with sodium sulphate evaporation is effected in a vacuum. 40 ml of warm acetone are poured on the slightly reddish residue, whereby crystallization occurs. Further purification is effected by crystallizing once more from acetone, whereby 4' -demethyl-epipodophyllotoxin bromide, having a melting point of I8O-I900, [a]2^= +16.3° (c m 0.612 in chloroform) and +15 ,0° (c «= 0.632 in acetone) is obtained. The compound melts with decomposition. b) 4' -demethyl-epipodophyllotoxin bromide. 220 g of pure podophyllotoxin are suspended in a mixture of 2000 ml of ethylene chloride and 200 ml of ether. 550 to 570 g of hydrogen bromide gas are passed whereby a clear solution results. This solution is allowed to stand at -5° for 23 hours and is then evaporated in a vacuum at a bath temperature of 25-300. 100 ml of hot acetone are added to the residue and evaporation is again effected in a vacuum. 300 ml of a boiling mixture of acetone and ligroin (3 ·' 2) are then added, stirring is effected whilst heating on a steam bath until a fine powder results which is allowed to crystallize at 8°. After filtering the precipitate with suction, washing with $00 ml of acetone/pentane (2 : 1) and drying in a vacuum are effected. This crude product ¾till contains polar material in accordance with thin layer chromatography and is therefore suspended in 1200 ml of hot acetone (does not dissolve completely), the volume of the solution is reduced to about 00 to 00 ml in a vacuum and allowed to crystallize at 8°. "After filtering the precipitate by suction, washing with 150 ml of acetone/pentane (2 : 1) and drying in a vacuum at 500, 4' -demethyl-epipodophyllotoxin bromide, no longer containing.by-products in accordance with thin layer chromatography, is obtained. c) 4' -demethyl-epipodophyllotoxin. 2.3 g of ' -demethyl-epipodophyllotoxin bromide are added to a suspension of 2 g of barium carbonate in 50 ml of acetone/water (1 : 1 ) and stirring is effected at 40° for one hour. The excess barium carbonate is subsequently filtered off, washing is effected with acetone and the acetone is removed from the filtrate in a vacuum and the organic solvent evaporated in a vacuum after drying over sodium sulphate. Crystallization of the residue from chloroform and from methanol or ethanol yields pure 4' -demethyl-epipodophyllotoxin, having a melting point of 228-230°, [a]2°» -69.8° (c « O.630 in chloro orm) .
Claims (1)
1. characterized in that podophyllotoxin is reacted with hydrogen bromide or hydro general in which Hal signifies a chlorine or bromine is treated with hydrogen bromide and the resulting podophyllotoxin bromide of formula III 9 220 is A process according to Claim in which the epipodohyllotoxin bromide is produced in a single in that podophyllotoxin is reacted directl with hydrogen process acoording to Claim in which the hydrolysis is effected at a temperature between and in the presenoe of a proton A process according to Claim in which the reaction of podophyllotoxin with hydrogen bromide or hydrogen and the subsequent reaction of the epipodophyllotoxin halide of general formula II with hydrogen bromide are effected at a temperature between and A process according to Claim in which the reaction is effeoted at a temperature between and A process for the production of substantially as herein described with reference to the 10 whenever produced the process claimed in one of the preceding Pharmaceutical compositions in addition to a physiologically inert yHotoxin For the Applicants AND PARTNERS insufficientOCRQuality
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1301665A CH459255A (en) | 1965-09-21 | 1965-09-21 | Process for the preparation of new 4'-demethyl-epipodophyllotoxin halides |
| CH1301865A CH459257A (en) | 1965-09-21 | 1965-09-21 | Process for the preparation of 4'-demethyl-epipodophyllotoxin |
| CH747068A CH472403A (en) | 1965-09-21 | 1965-09-21 | Process for the preparation of a 4'-demethyl-epipodophyllotoxin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL26522A true IL26522A (en) | 1970-06-17 |
Family
ID=27175799
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL2652266A IL26522A (en) | 1965-09-21 | 1966-09-19 | Preparation of 4'-demethyl-epipodophyllotoxin |
Country Status (9)
| Country | Link |
|---|---|
| AT (1) | AT281300B (en) |
| BE (1) | BE687089A (en) |
| BR (1) | BR6683006D0 (en) |
| CH (3) | CH459257A (en) |
| FI (1) | FI44411B (en) |
| FR (2) | FR1502813A (en) |
| GB (1) | GB1145909A (en) |
| IL (1) | IL26522A (en) |
| SE (1) | SE327416B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5463040A (en) * | 1994-06-28 | 1995-10-31 | Teva Pharmaceutical Industries, Ltd. | Method of preparing etoposide |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8307614D0 (en) * | 1983-03-18 | 1983-04-27 | Pharma Medica As | Treatment of genital warts |
| EP0461141B1 (en) * | 1989-02-23 | 1999-11-03 | University Of North Carolina At Chapel Hill | Etoposide analogues |
-
1965
- 1965-09-21 CH CH1301865A patent/CH459257A/en unknown
- 1965-09-21 CH CH747068A patent/CH472403A/en not_active IP Right Cessation
- 1965-09-21 CH CH1301665A patent/CH459255A/en unknown
-
1966
- 1966-07-21 GB GB3289166A patent/GB1145909A/en not_active Expired
- 1966-09-19 IL IL2652266A patent/IL26522A/en unknown
- 1966-09-19 FI FI245566A patent/FI44411B/fi active
- 1966-09-19 FR FR76825A patent/FR1502813A/en not_active Expired
- 1966-09-19 BE BE687089D patent/BE687089A/xx unknown
- 1966-09-20 AT AT883566A patent/AT281300B/en not_active IP Right Cessation
- 1966-09-20 SE SE1261866A patent/SE327416B/xx unknown
- 1966-09-20 BR BR18300666A patent/BR6683006D0/en unknown
- 1966-12-16 FR FR87743A patent/FR6307M/fr not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5463040A (en) * | 1994-06-28 | 1995-10-31 | Teva Pharmaceutical Industries, Ltd. | Method of preparing etoposide |
Also Published As
| Publication number | Publication date |
|---|---|
| FI44411B (en) | 1971-08-02 |
| DE1543874A1 (en) | 1970-01-02 |
| AT281300B (en) | 1970-05-11 |
| CH472403A (en) | 1969-05-15 |
| SE327416B (en) | 1970-08-24 |
| BR6683006D0 (en) | 1973-12-27 |
| CH459257A (en) | 1968-07-15 |
| FR6307M (en) | 1968-09-16 |
| FR1502813A (en) | 1967-11-24 |
| GB1145909A (en) | 1969-03-19 |
| CH459255A (en) | 1968-07-15 |
| BE687089A (en) | 1967-03-20 |
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