Title of Invention

"A PROCESS FOR THE PREPARATION OF 4ß-1"-2[(SUBSTITUTED 10 BENZOYL) ANILINO] -4-DESOXYPODOPHYLLOTOXIN USEFUL AS ANTICANCER AGENTS"

Abstract The present method employing Bu4N+I directs the substitution in an almost stereoselective manner which results in the formation of C-4ß-orientation as a main product. 2. This process has also improved the yields of these compounds, hence an efficient method.
Full Text This invention relates to a process for the preparation of 4ß-1"-[2-(substitutedl0benzoyl)anilino]-4-desoxypodophyllotoxin useful as anticancer agents. The said 4ß-1"-[2-(substituted benzoyl)anilino]-4-desoxypodophyllotoxin of formula (IV) of drawing accompanying this specification wherein R&R1=H,F CI, Br, I, alkyl, alkoxy, nitro, group R.2=H or alkyl group.
Etoposide and teniposide the semisynthetic derivatives of podophyllotoxin are being used as anticancer agents in the treatment of leukemia, testicular cancer and small cell lung cancer. These compounds exhibit their antitumour activity by inhibiting nuclear enzyme DNA topoisomerase-II. These podophyllum lignans block the catalytic activity of topoisomerase-II by stabilising a cleavable enzyme-DNA complex in which the DNA is cleaved and covalently linked to the enzyme. (MacDonald, T.L. ,Lewhnert, E.K., Loper, J.T., Chow, K.C., Ross, W.E.' On Mechanism of DNA Topoismerase-II with Chemotherapeutic Agents; In DNA Topoisomerases in Cancer, Potmesil, M., Kohn, K.W., Eds.; Oxford University Press, New York, 1991; pp 199-214). However, the clinical efficacy of etoposde is hindered by several limitations such as poor water solubility, development of drug resistance and metabolic inactivation.
Therefore, the objective of the present invention is to provide a process for the preparation of new podophyllotoxin useful as anticancer agents. The compounds of present invention has a difference with N-linked congeners by the replacement of C-4 sugar moiety of etoposide.
Accordingly, the present invention provides a process for the preparation of 40-l"-[2-(substituted benzoyl)anilino]-4-desoxypodophyllotoxin, of formula (IV) of drawing accompanying this specification wherein R and R1=H,F Cl, Br, I, alkyl, alkoxy, nitro, group R2=H or alkyl group, which comprises: reacting bromo podophyllotoxin derivative of formula II wherein R2=H or CH3 with amino benzophenone or its derivative of formula III wherein R and R1=H, halogens, nitro, alkyl, alkoxy in presence of a known base and a catalyst in aprotic solvent at a temperature in the range of 20 to 60°C for a period in the range of 3 to 8 hrs, removing solvent and purifying the residue by conventional column chromatography to afford the podophyllotoxin of general formula (IV) wherein R and R1=halogen, nitro, alkyl, alkoxy, and R2=H or alkyl group.
In an embodiment of the present invention bromopodophyllotoxin derivative used may be such as 4ß-bromo-4-desoxypodohyllotoxin, 4'-O-demethyl-4ß-bromo-4-desoxypodophyllotoxin. In another embodiment of the invention the base used may be such as triethyl amine (Et3N), pyridine.
In still another embodiment of the invention the catalyst used may be such as tetrabutyl ammonium iodide (Bu4N+I"), tetrabutyl ammonium bromide (BiulSTlBr").
In yet still another embodiment of the invention aprotic solvent used may be such as dichloromethane, tetrahydrofuran, ether, toluene.
The compounds of present invention are illustrated as 4ß-l"-[2-(substituted benzoyl)anilino]4-desoxypodophyllotoxin (IV) and 4'-O-demethyl-4ß-l"-[2-(substituted benzoyl) anilino]-4-desoxypodophyllotoxin (IV). The process for synthesis of new congeners of formulae (IV) comprises of following steps.
1) Synthesis of 4ß- bromo-4-desoxypodophyllotoxin (II) by known modified method (Kuhn, M.; Keller-juslen, C; Von wartburg, A. Helv. Chem. Acta. 1969, 52, 948).
2) Synthesis of 4-O-demethyl -4ß-bromo 4 -desoxypodophyllotoxin (II).
3) 4ß-bromo-4-desoxypodophyllotoxin (II) and 4'-O-demethyl-4ß-bromo-4-desoxypodo-phyllotoxin (II) have been coupled to amino benzophenones (III) having various substituents wherein, R may be alkyl, alkyloxy, halogens (F,CI,Br,I), nitro. R1 may be alkyl, alkyloxy, halogens (F,Br,I) nitro.
4) Using variety of solvents for the nucleophilic displacement of bromine such as dichloromethane, tetrahydrofuran, toluene etc.
5) Using catalytic amount of tetrabutyl ammonium iodide, tetrabutyl ammonium bromide.
6) Stirring the reaction mixture between 20 to 60°C for 3 to 8h.
7) Purification of (IV) by column chromatography. These new analogues of podophyllotoxins by replacement of C-4 sugar moiety of the etoposide with N-linked congeners have shown promising antitumour activity n various cell lines particularly in small cell lung, colon, CNS, ovarian, renal and breast cancers and leukemia. It is anticipated that these compounds may have better water solubility and improved drug resistance profile. The following examples are given by way of illustration and should not be construed to limit the scope of the invention.
EXAMPLE 1
Preparation of 4ß-bromo-4-desoxy podophyllotoxin (II):
Podophyllotoxin (I, l.lg) in 11 ml of 1,2-dichloromethane, 1 ml of ether was taken and molecular sieves powder 4A° was added to the above solution and kept at 0°C and then 2.75 g of HBr gas was passed for 45 minutes at 0°C. Later the solution was filtered to remove molecular sieves powder and the solvent was removed from the filtrate under the reduced pressure at 25°C, the compound of formula II was obtained in 70% yield.
Preparation of 4'-O-demethyl-4ß-bromo-4-desoxy podophyllotoxin (II)
Podophyllotoxin (I, l.lg) in 11ml of 1,3-dichloromethane, 1ml of ether was taken and molecular sieves powder 4A° was added to the above solution and kept at 0°C and the 2.75g of HBr gas was passed till saturation and the reaction vessel was kept closed for 48 h. After the completion of reaction the solvent was removed and the solution of acetone: water (1:1) and BaCO3 (eq) added to it and stirred at 40°C till the reaction was complete to obtain crude 4'-O-demethylepipodophyllotoxin. This was purified by column chromatography (chloroform : methanol, 9.8: 0.2 ml silicagel) to obtain pure product.
4'-O-Demethylepipodophyllotoxin (l.lg) as obtained above was, taken in 11ml of 1,2-dichloromethane, 1ml of ether was taken and molecular sieves powder 4A0 added to this solution and kept at 0°C and then 2.75 g of HBr gas passed for 45 minutes at 0°C. Later the solution was filtered to remove molecular sieve powder and the solvent was removed from the filtrate under reduced pressure at 25°C. The product obtained is 4'-O-demethyl-4ß-bromo-4-desoxypodophyllotoxin 30% yield.
EXAMPLE 2 4(3-l"-[2-(Benzoyl)anilino]-4-desoxypodophylotoxin (IV)
Method A:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, .0.21 mmol) was reacted with 2-aminobenzophenone (III, 0.045 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+F (0.015 g, 0.042 mmol) in dry tetrahydrofuran at room temperature. After the
completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 3
4ß-l"-[2"-(2-Chlorobenzoyl)-4"-chloroanilino]-4-desoxypodophylIotoxin(IV)
Method A:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-amino2'-5-dichloro benzophenone (III, 0.06 g, 0.23mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.015 g, 0.042 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-anino2',5-dichlorobenzophenone (III, 0.06 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.015 g, 0.042 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 4
4ß-l"-[2"-9benzoyl)4"-nitroanillino]-4desoxypodophylIotoxin (IV)
Method A:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-amino-5-nitrobenzophenone (III, 0.056 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I (0.015 g, 0.042 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4ß-l"-[2"-(benzoyl)4"-nitroanillino}-4-desoxypodophyIIotoxin (IV) Method B:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-amino-5-nitrobenzophenone (III, 0.056 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.015 g, 0.042 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 5
4ß-l"-[2"-(benzoyl)4"-choroanilino]-4-desoxypodophylotoxin (IV)
Method A:
4ß-Bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-amino-5-chlorobenzophenone (III, 0.053g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4tN+ I- (0.015 g, 0.042mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4ß-l"-[2"-(benzoyl)4"-chloroanilino]-4-desoxypodophylIotoxin(IV)
Method B:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-amino-5-chlorobenzophenone (III, 0.053 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and BU4N+I" (0.015 g, 0.042 mmol) in dry dichlomethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products
EXAMPLE 6
4ß-l"-[2"-(4-fluorobenzoyl)anilino]-4-desoxypodophyllotoxin (IV)
Method A:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-amino-4'-fluorobenzophenone (III, 0.05 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+r (0.015 g, 0.042 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4ß-l"-[2-(4-fluorobanzoyl)anilino]-4-desoxypodophyIIotoxin (IV)
Method B:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.86 mmol) was reacted with 2-amino-4'-fluorobenzophenone (III, 0.05 g, 0.95 mmol), in presence of Et3N (0.3 g, 1.2 mmol) and Bu4N+I' (0.015 g, 0.17 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 7
4ß-l"-[2"-(2-fluorobenzoyl)4"-chloroanilino]-4-desoxypodophyllotoxin (IV)
Method A:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-amino-5-chloro-2-'-fluorobenzophenone (III, 0.057 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I (0.015 g, 0.042mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products
4ß-l"-[2"=(2-fluorobenzoyl)4"-chloroaniIino]-4-desoxypodophyIlotoxin (IV)
Method B:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-amino-5-chloro-2'-fluorobenzophenone (III, 0.057 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I (0.015 g, 0.042 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 8
4ß-l"-[2"-(4-bromobenzoyl)anilino]-4-desoxypodophyllotoxin (IV)
Method A:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-amino-4'-bromobenzophenone (III, 0.064 g, 0.23 mmol), in presence of Et3Nr (0.032 g, 0.32 mmol) and Bu4N+I (0.015 g, 0.042 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4ß-l"-[2-(4-bromobenzoyl)anilino]-4-desoxypodophyllotoxin (IV)
Method B:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 2-amino-4-'-bromobenzophenone (II, 0.064 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+ I" (0.015 G, 0.042 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 9
4ß-l"-[5"-(benzoyl)2"-aminoaniIino]-4-desoxypodophyllotoxin (IV)
Method A:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.2 mmol) was reacted with 3.4-diaminobenzophenone (III, 0.05 g, 0.23 mmol), in presence of Et3N (0.032 mmol) and Bu4N+F (0.015 g, 0.042 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4ß-l"-[5"-(benzoyl)2"-aminoaniIino]-4-desoxypodophyllotoxin(IV)
Method B:
4ß-Brino-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 3,4-diaminobenzpphenone (III, 0.05 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.015 G, 0.042mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 10
4ß-l"-[5"-(benzoyl)2"-nitroaniIino]-4-desoxypodophylIotoxin (IV)
Method A:
4ß-Bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 4-amino3-nitrobenzophenone (III, 0.056 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I (0.015 g, 0.042mmol) in dry tetrahydrofuran at room temperature After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4ß-l"-[5"-(benzoyl)2"-nitroanilino]-4-desoxypodophyllotoxin (IV) Method B:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with -4-amino3-nitrobenzophenone (III, 0.056 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and BmNTT (0.015 g, 0.042 mmol) in dry dichoromethane at room temperature After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 11
4ß-l"-[3"-(benzoyI)aniIIino]-4-despxypodophylIotoxin (IV)
Method A:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 3-amiobenzophenone (III, 0.045 g, 0.23 mmol), in presence of Et3N (0.032 mmol) and Bu4N+I (0.015 g, 0.042 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4ß-l"-[3"-(benzoyl)anillino]-4-despxypodophyllotoxin (IV)
Method B:
4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.21 mmol) was reacted with 3-aminobenzophenone (III, 0.045 g, 0.23 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and BmN+I (0.015 g, 0.042 mmol) in dry dichlormethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 12
4'-O-demethyI-4ß-l"-[2"(benzoyl)anilino]-4-desoxypodophyIIotoxin(IV)
Method A:
4'-O-demethyl-4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-aminobenzophenone (III, 0.047g, 0.24 mmol), in presence of Et3N(0.032 g, 0.32 mmol) and Bu4N+I" (0.016 g, 0.043 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4'-O-demethyl-4ß-l"-[2"-(benzoyI)anillino]-4-desoxypodophyllotoxin(IV)
Method B:
4'-O-demethyl-4ß-Bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-aminobenzophenone (III, 0.047 g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.016 g, 0.043 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 13
4'-O-demethyl-4ß-l"-[2"-(benzoyl)4"-chloroaniIino]-4-desoxypodophylIotoxin(IV)
Method A:
4'-O-demethyl-4ß-bromo-4-desoxypodophyllotxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino-5-chlorobenzophenone (III, 0.055 g, 0.24 mmol), in presence of Et3N (0.032 mmol) and Bu4N+I (0.016 g, 0.043 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4'-O-demethyl-4ß-l"-[2"-(benzoyl)4"-chloroanilino]-4-desoxypodophyllotoxin (IV) Method B:
4'-O-demethyl-4ß-bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino5-chlorobenzophenone (III, 0.0555 g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.016 g, 0.043 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 14
4'-O-demthyl-4ß-l"-[2"-(2-chlorobenzoyl)4"-chloroanilIino]-4-desoxypodo-phyllotoxin (IV)
Method A:
4'-O-demethyl-4|3-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino-2,5-dichlorobenzophenone (III, 0.063 g, 0.24 mmol),in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+F (0.016 g, 0.043 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4ß-l"-[2"-(2-chlorobenzoyl)4"-chloroanillino]-4-desoxypodophyIlotoxin (IV)
Method B:
4'-O-demethyl-4ß-bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino2,5-dichlorobenzophenone (III, 0.063 g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.016 g, 0.043 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 15
4'-O-demethyl-4ß-l"-[2"-(benzoyI)4"-nitraniIIino]-4-desoxypodophyllotoxin (IV)
Method A:
4'-O-demethyl-4ß-Bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino-5-nitrobenzophenone (III, 0.058g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I (0.016 g, 0.043 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4'-O-demethyl-4ß-l"-[2"-(benzoyl)4"-nitranillino]-4-desoxypodophyllotoxin(IV)
Method B:
4'-O-demethyl-4ß-Bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino-5-'-nitrobenzophenone (III, 0.058 g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.016 g, 0.043 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE-16
4'-O-demethyl-4ß-l"-(2"-(4-fluorobenzoyl)anillino[-4-desoxypodophylIotoxin (IV)
Method A:
4'-O-demethyl-4ß-Bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino-4'-fiuoobenzophenone (III, 0.051 g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.016 g, 0.043 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4'-O-demethyl-4ß-1"-[2"-(4-fluorobenzoyl)anillino[-4-desoxypodophyllotoxin (IV) Method B:
4'-O-demethyl-4ß-Bromo-4-desoxy podophyllotoxin (II, O.lg, 0.22 mmol) was reacted with 2-amino-4'-fluorobenzophenone (III, 0.051 g, 0.24 mmol), in presence of Et3N (0.032g, 0.32 mmol) and B114NY (0.016 g, 0.043 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 17
4'-O-demethyl-4ß-l"-[2"-(2-fluorobenzoyl)4"chloroanillino]-4-desoxypodo-phyllotoxin (IV)
Method A:
4'-O-demethyl-4ß-Bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino-2'-fluoro-5-chlorobenzophenone (III, 0.059 g, 0.95 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.016 g, 0.043 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4'-O-demethyl-4ß-l"-[2"-(2-fluorobenzoyl)4"chloroaniIlino]-4-desoxypodo-phyllotoxin (IV)
Method B:
4'-O-demethyl-4ß-bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino-2'fluoro-5-chlorobenzophenone (III, 0.059 g, 0.24 mmol), in presence of Et3 N (0.032 g, 0.32 mmol) and Bu4N+I" (0.016 g, O.043 mmol) in dry dichlormethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 18
4'-O-demethyI-4ß-l"-[2"-(2-bromobenzoyl)-4-anillino]-4-desoxypodophyllotoxin
(IV)
Method A:
4'-O-demethyl-4ß-bromo-4-desoxypodophylotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino2'-bromobenzophenone (III, 0.066 g, 0.24 mmol), in presence of Et3N (0.032 mmol) and Bu4N+F (0.016 g, 0.043 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4'-O-demethyl-4ß-l"-[2"-(2-bromobenzoyl)-4-anilIino]-4-desoxypodophyllotoxin
(IV)
Method B:
4'-demethyl-4ß-bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-amino2'-benzophenone (III, 0.066 g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and BU4N4T (0.016 g, 0.043 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 19
4'-O-demethyl-4ß-l"-[5"-(benzoyl)2"aminoanillino]-4-desoxypodophyllotoxin (IV)
Method A:
4'-O-demethyl-4ß-bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-aminobenzophenone (III, 0.05 g, 0.24 mmol), in presence of Et3N (0.032g, 0.32 mmol) and Bu4N+I' (0.016 g, 0.043 mmol), in dry tetrahydrofuran at room
temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4'-O-demethyI-4|3-l"-[5"-(benzoyl)2"aminoanillino]-4-desoxypodophylIotoxin (IV)
Method B:
4'-O-demethyl-4ß-bromo-4-desoxypodophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 2-aminobenzophenone (III, 0.05g, 0.24 mmol), in presence of Et3N (0.032 mmol) and Bu4N+I" (0.016 g, 0.043 mmol) in dry dichlormethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 20
4'-O-demethyl-4ß-l"-[3"-(benzoyl)anillino]-4-desoxypodophylIotoxin (IV)
Method A:
4'-O-demethyl-4(3-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 3-aminobenzophenone (II, 0.047 g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I" (0.016 g, 0.043 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4'-O-demethyl-4ß-l"-[3"-(benzoyl)aniIlino]-4-desoxypodophyllotoxiii (IV)
Method B:
4'-O-demethyl-4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 3-aminobenzophenone (III, 0.047 g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I (0.016 g, 0.043 mmol) in dry dichloromethane at room
temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
EXAMPLE 21
4'-O-demethyl-4ß-l"-[4"-(benzoyl)2"-nitroanilIino]-4-desoxypodophyllatoxin (IV)
Method A:
4'-O-demethyl-4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 4-amino-3-nitrobenzophenone (III, 0.058 g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Du4N'I (0.016 g, 0.043 mmol) in dry tetrahydrofuran at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
4'-O-demethyl-4ß-l"-[4"-(benzoyl)2"-nitroaniIIino]-4-desoxypodophyllotoxin (IV)
Method B:
4'-O-demethyl-4ß-Bromo-4-desoxy podophyllotoxin (II, 0.1 g, 0.22 mmol) was reacted with 4-amino-3-nitorbenzophenone (III, 0.058 g, 0.24 mmol), in presence of Et3N (0.032 g, 0.32 mmol) and Bu4N+I (0.016 g, 0.043 mmol) in dry dichloromethane at room temperature. After the completion of reaction solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to afford the pure products.
Selected spectral data for IV 1HNMR (200 Mhz CDC13): 8.94 (d, J=6Hz, 1H), 7.65 (m, 8H), 6.8 (s, 1H), 6.68 (t, J=7Hz, 1H), 6.52 (s,lH), 6.35 (s, 1H), 5.95 (d, 2H04.98-4.90 (m, 1H), 4.62 (d, J=4HZ, 1H), 4.40 (t, J=6Hz, 1H), 3.95 (t, J=6HZ, 1H), 3.84-3.70 (m, 10H), 3.16-3.08 (m, 1H) and VIII. 1HNMR (200 Mhz CDC13): 8.94 (d, J=6Hz, 1H), 7.65 (m, 8H), 6.8 (s, 1H), 6.68 (t, J=4Hz, 1H), 6.52 (s, 1H), 6.35 (s, 1H), 5.95 (d, 2H), 4.94-4.88 (m, 1H), 4.62 (d, J=4Hz, 1H), 4.34 (t, J=6Hz, 1H), 3.90 (t, J=6Hz, 1H), 3.90-3.87 (m, 1H), 3.16-3.08 (m, 1H).





We claim :
1. A process for the preparation of 4ß-l"-[2-(substituted benzoyl)anilino]-4-desoxypodophyllotoxin, of formula (IV) of drawing accompanying this specification wherein R and R1=H,F Cl, Br, I, alkyl, alkoxy, nitro, group R2=H or alkyl group, which comprises: reacting bromo podophyllotoxin derivative of formula II wherein R2=H or CH3 with amino benzophenone or its derivative of formula III wherein R and Ri=H, halogens, nitro, alkyl, alkoxy in presence of a known base and a catalyst in aprotic solvent at a temperature in the range of 20 to 60°C for a period in the range of 3 to 8 hrs, removing solvent and purifying the residue by conventional column chromatography to afford the podophyllotoxin anlaoguoa of general formula (IV) wherein R and Ri=halogen, nitro, alkyl, alkoxy, and R2=H or alkyl group.
2. A process as claimed in claim 1 wherein the base used is triethylamine, pyridine.
3. A process as claimed in claim 1 and 2, wherein catalyst used is such as, tetrabutyl ammonium iodide, tetra butyl ammonium bromide.
4. A process as claimed in claims 1-3, wherein aprotic solvent used is such as dichloromethane, tetrahydrofuran, ether, toluene.
5. A process for the preparation of 4P-l"-[2-(substituted benzoyl)anilino]-4-desoxypodophyllotoxin, of formula (lv) of drawing accompanying this specification wherein r and r1=h,f cl, br, i, alkyl, alkoxy, nitro, group r2=h or alkyl group, substantially as herein described with reference to the examples.

Documents:

1712-del-1997-abstract.pdf

1712-del-1997-claims.pdf

1712-del-1997-complete specification (granted).pdf

1712-del-1997-correspondence-others.pdf

1712-del-1997-correspondence-po.pdf

1712-del-1997-description (complete).pdf

1712-del-1997-drawings.pdf

1712-del-1997-form-1.pdf

1712-del-1997-form-2.pdf

1712-del-1997-form-4.pdf


Patent Number 186131
Indian Patent Application Number 1712/DEL/1997
PG Journal Number 25/2001
Publication Date 23-Jun-2001
Grant Date 25-Jan-2002
Date of Filing 24-Jun-1997
Name of Patentee COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 AHMED KAMAL CHEMICAL TECHNOLOGY HYDERABAD ANDHRA PRADESH, INDIA.
2 NIMMA GADDA LAKSHMI GAYATRI CHEMICAL TECHNOLOGY HYDERABAD ANDHRA PRADESH, INDIA.
PCT International Classification Number A61K 31/12
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA